1197 lines (1196 with data), 1.8 MB

Patients previously untreated or treated with drug therapy for epithelioid hemangioendothelioma (EHE) are eligible; there is no limit on the number of prior regimens used to be eligible
Children with definitive confirmatory eligible histologic or cytological diagnosis of eligible CNS tumor within the brain or spinal cord, who have not previously received either irradiation or chemotherapy (except corticosteroids) will be eligible for study entry
Patients with >= grade 2 hypothyroidism due to history of autoimmunity are not eligible; note: hypothyroidism due to previous irradiation on thyroidectomy will not impact eligibility
Patients with known macular degeneration, uncontrolled glaucoma, or cataracts are not eligible
Patients with rheumatoid arthritis and other arthropathies, Sjogren’s syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
Patients with pathologic staging of ypN0(i+) or ypN0(mol+) are eligible
Patient who have undergone either a total mastectomy or a lumpectomy are eligible; (patients who have had a nipple-sparing mastectomy are eligible)
For patients with known molecular alterations, institution has been notified that patient is deemed eligible for Arm T per review of molecular testing reports
REGISTRATION STEP 2-RANDOMIZATION: Patients must be eligible for at least one of the currently active investigational treatment arms (S1612B or S1612C); if the patient does not meet eligibility criteria for at least one active investigational arm, then the patient is not eligible for S1612
Patients must have baseline troponin test performed for eligibility; however, no associated values must be met in order for the patient to be eligible
Patients with multifocal or multicentric invasive disease are eligible as long as all the lesions for which HER2 characterization is available are HER2 negative
Patients enrolled on AALL0932, with Down syndrome, meeting the following criteria will NOT be eligible to continue on AALL0932 but WILL BE eligible to enroll on the DS HR B-ALL stratum of this study at the end of Induction: \r\n* Day 29 MRD >= 0.01%\r\n* MLL rearrangement\r\n* Hypodiploidy (n < 45 chromosomes and/or DNA index < 0.81)
Patients must be newly diagnosed with histologically confirmed intracranial ependymoma; patients with classic ependymoma (WHO II) or anaplastic ependymoma (WHO III) are eligible, as are various subtypes described as clear cell, papillary, cellular or a combination of the above
Patients with disease limited to the skin are not eligible, regardless of how wide-spread
Pregnancy; lactating females must cease expression of milk prior to signing consent to be eligible
Patients with known active cutaneous squamous cell carcinoma (includes keratoacanthoma or mixed keratoacanthoma subtype) are not eligible; patients who have fully excised lesions with dermatologic confirmation of absence of disease are eligible
No late relapse with completely surgically resectable disease; patients with late relapses (defined as relapse >= 2 years from the date of completion of the last chemotherapy regimen) whose disease is completely surgically resectable are not eligible; patients with late relapses who have unresectable disease are eligible
Patients with subependymal giant cell astrocytomas (SEGAs) are not eligible
Patient must be eligible for treatment with nivolumab; patients previously treated with nivolumab, pembrolizumab or atezolizumab and who have progressed are eligible; patients with targetable with EGFR or ALK mutations are eligible after disease recurrence or progression after at least one targeted therapy for advanced or metastatic disease
HER2+ and HER2- patients are eligible
All patients must have diagnostic laparoscopy with diagnostic washings for cytology; both cytology positive and negative patients are eligible for enrollment, but only cytology negative patients will be included in the primary analyses; gross peritoneal disease is not eligible
Patients allergic to eggs are not eligible
Patients with uncontrolled hyperlipidemia (total cholesterol > 350 or triglycerides > 300) are NOT eligible for participation
Cystoscopically and radiographically confirmed cT2-4a cN0 cM0 disease. Patients with cT4a disease invading into the prostatic stroma with no cystoscopic confirmation of muscle invasion are eligible.
Patients with recurrent brainstem tumors with an atypical presentation who have undergone biopsy are eligible provided there is histologic confirmation of malignant glioma WHO II-IV; these patients must undergo Rb1 screening; these patients must have radiographic evidence of progression
Patients with secondary malignant gliomas will be eligible for this study but should conform to all other eligibility requirements; patients with low-grade gliomas are excluded
PHASE I (STRATUM 1): Patients with progressive DIPG, as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since last treatment, OR the appearance of a new tumor lesion since diagnosis \r\n* Please note:\r\n** Patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation\r\n** Patients with pontine lesions that do not meet these radiographic criteria will be eligible if there is histologic confirmation of malignant glioma WHO II-IV. These patients must have radiographic evidence of progression
Previous treatment with investigational agents that inhibit MDM2 or MDMX activity (some MDM2-treated patients may be eligible)
Patients being treated with any other experimental agents/clinical trials are not eligible for participation; if the patient is on any investigational agent, a wash-out period of minimum 2 weeks prior to registration is mandatory for the patient to be eligible for the study
Patients who have any prior chemoimmunotherapy are not eligible; NOTE: the use of steroids to control the disease is permitted and does not have a washout period
Unifocal primary disease NOTE: Patients with multifocal and/or multicentric in breast cancer, or evidence of EIC are NOT eligible. Patients with contralateral disease will remain eligible.
Patients who have had prior surgical intervention for lymphoma, unless performed for the sake of tissue diagnosis or on an urgent basis for disease-related threat to life, limb, or organ function, are not eligible
Patients with a prior malignancy will NOT be eligible for participation aside from the following exception:\r\n* Patients who have had any curatively treated invasive malignancy and have been disease free without treatment for 1 year prior to study entry ARE eligible for participation
Patients who have received prior treatment with oral or intravenous fenretinide as a single agent are eligible, provided they did not experience severe toxicity related to fenretinide
Patients who have received prior treatment with oral or intravenous fenretinide as a single agent are eligible, provided they did not experience severe toxicity related to fenretinide
Other \r\n* Lung cancer with pleural effusion (wet IIIB) are not eligible \r\n* Recurrent cancers are not eligible \r\n* Diffuse metastatic spread confined to one organ system is ineligible; examples of this include leptomeningeal spread in the CNS and peritoneal carcinomatosis
Patients with the following pure histologies of endometrial or ovarian cancer are not eligible for enrollment: germ cell, sex cord stroma, carcinosarcoma, or sarcoma.
Patients with active bacterial infections with systemic manifestations (malaise, fever, leukocytosis) are not eligible until completion of appropriate therapy. Patients taking low-dose antibiotics for biliary obstruction are exempted from this exclusion criterion.
A prior or concurrent metastatic second malignancy within 3 years, even if it does not require active therapy; for example, patients with concomitant indolent B-cell malignancies will not be eligible; patients with a prior resected in-situ or stage I malignancy felt to be cured will be eligible
Clinical American Joint Committee on Cancer (AJCC) (AJCC, 7th ed.) II, IIIA or IIIB (with non-operable disease; non-operable disease will be determined by a multi-disciplinary treatment team within 60 days prior to registration; note: for patients who are clearly nonresectable, the case can be determined by the treating radiation oncologist and/or a medical oncologist or pulmonologist \r\n* Patients who present with N2 or N3 disease and an undetectable NSCLC primary tumor are eligible\r\n* Patients who refuse surgery are eligible\r\n* Patients who develop local recurrence after surgery and rendered candidate for definitive concurrent chemoradiation are also eligible\r\n* Patients who have received systemic treatment (up to 4 cycles of induction chemotherapy, or up to 6 months of targeted therapy) are eligible
Patients with active lesions suspicious for keratoacanthomas/cutaneous squamous cell carcinoma (cSCC); patients who have excision of keratocanthomas/cSCC, with dermatologic confirmation of the absence of active disease may become eligible
Patients must have at least one of the following for a diagnosis/disease status:\r\n* Unresectable disease\r\n* Metastatic disease\r\n* Medically unfit for surgical resection but with an expected survival of > 3 months, Eastern Cooperative Oncology Group (ECOG) < 2 and New York Heart Association (NYHA) status =< II\r\n* Disease where no conventional therapy leads to a survival benefit > 6 months in the respective cohort and line of therapy for which the patient is otherwise eligible\r\n* Actionable alterations determined by FoundationOne
Follicular grades IIIA or IIIB are not eligible
Patients previously treated with anti-CD19 CAR or other adoptive cell therapies will be eligible if all other eligibility criteria are met but will be evaluated as a separate strata from CAR-naive patients in the expansion phase; circulating CAR T cells must be < 5% in peripheral blood
PHASE I: Patients with central nervous system (CNS) involvement are eligible provided that they are asymptomatic and in the opinion of the study principal investigator (PI) have a reasonable expectation that disease burden can be controlled in the interval between enrollment and T cell infusion; patients that have a significant neurologic deterioration will be not be eligible for T cell infusion until alternate therapies result in neurological stabilization
PHASE II: Patients with CNS involvement are eligible provided that they are asymptomatic and in the opinion of the study PI have a reasonable expectation that disease burden can be controlled in the interval between enrollment and T cell infusion; patients that have a significant neurologic deterioration will be not be eligible for T cell infusion until alternate therapies result in neurological stabilization AND
No prior genetically modified cell therapy that is still detectable or virotherapy allowed; patients who are otherwise eligible but have detectable circulating CAR T cells of < 5% will be eligible, but will be evaluated as a separate strata from CAR-naive patients in the phase 2 portion of the study
Phase I and expansion cohort: Up to two prior non-taxane chemotherapy regimens for metastatic disease are permitted for patients enrolled on the phase I portion of the trial; patients with HER2/neu positive breast cancer are not eligible; patients treated with prior anthracycline therapy as neoadjuvant, adjuvant, or metastatic therapy are not eligible unless the following conditions are met: (a) prior cumulative doxorubicin dose is =< 240 mg/m^2 (or epirubicin dose is =< 400 mg/m^2), and (b) left ventricular ejection fraction (LVEF) obtained at baseline is at least 50% (or >= 5% above lower institutional limits of normal whichever is higher); patients with estrogen receptor (ER)-positive disease are required to have relapse or progression on at least one line of endocrine therapy
Confirmation of HER2 positivity:\r\n* Phase I only: Patients with leptomeningeal disease from ependymomas, gliomas, and medulloblastoma will be eligible for phase I but are not required to have HER2 analysis; HER2 testing is only required for breast cancer patients with leptomeningeal metastases; HER2 positive (immunohistochemistry [IHC] 3+ and/or FISH positive; IHC 2+ HER2 patients are eligible with reflex FISH positive testing with the ratio >= 2.0) breast cancer patients with leptomeningeal metastases by magnetic resonance imaging (MRI) or CSF (if MRI is negative) are eligible\r\n* Phase II only: ALL patients with HER2+ cancers of other histology will be allowed to enroll in phase II if they have leptomeningeal disease\r\n* NOTE: review will be performed for cases not reviewed at the participation institution for confirmation, but will not preclude patients from entering the trial (pathology report showing HER2 positivity is sufficient for registration)
Patients with documented history of no response to cladribine, and without 50% improvement in platelets, hemoglobin or granulocytes; this exclusion does not apply to HCLv; these patients are eligible regardless of prior response to cladribine (CDA)
Patients with a known nonmalignant disease that is not clearly defined will need to be discussed with the protocol principal investigator (PI) (Dr. Lauri Burroughs) and potentially the nonmalignant board to determine if they are eligible for HCT on this study
Patients who have been treated with prior secondary hormonal manipulations with proposed investigational rationale for having efficacy against AR-V7 splice variants. This includes but is not limited to EPI-002 and AZD5312. (Note: patients previously treated with abiraterone, orteronel [TAK-700], apalutamide [ARN-509], galeterone, or VT-464 will be eligible for this study. Patients who have received prior chemotherapy will also be eligible for this study).
All stages of disease (IA through IVB) where radiation therapy is being considered for local control are eligible. Patients who are concomitantly undergoing systemic therapy for more advanced stage disease are eligible.
Inclusion Criteria:\n\n        Patients fulfilling the following criteria will be eligible to provide continued long-term\n        follow-up data as part of this study:\n\n          1. Enrolled and randomized on the BMT CTN 0702 protocol.\n\n          2. Alive at the completion of BMT CTN 0702 protocol specified follow-up defined as 4\n             years post-randomization.\n\n          3. Patients without evidence of disease progression at the completion of BMT CTN 0702\n             protocol specified follow up.\n\n          4. Signed Informed Consent Form.\n\n          5. Patients with the ability to speak English or Spanish are eligible to participate in\n             the HQL component of this trial.\n\n        Inclusion Criteria for Optional Long-term Lenalidomide Maintenance Therapy:\n\n        Patients fulfilling the following criteria will be eligible to provide continued long-term\n        follow-up data AND receive long-term lenalidomide maintenance therapy as part of this\n        study:\n\n          1. Enrolled and randomized to BMT CTN 0702.\n\n          2. Completion of 3 years of maintenance therapy on BMT CTN 0702.\n\n          3. Registered in the mandatory Revlimid REMS® program (formerly the RevAssist® for Study\n             Participants (RASP) program), and be willing and able to comply with the requirements\n             of the Revlimid REMS® program, including counseling, pregnancy testing, and phone\n             surveys.\n\n          4. Signed informed consent form.\n\n          5. Patients with the ability to speak English or Spanish are eligible to participate in\n             the HQL component of this trial.\n\n        Exclusion Criteria:\n\n        Patients who meet any of the following criteria will be ineligible to receive long-term\n        lenalidomide maintenance therapy as part of this study:\n\n          1. Patients who have evidence of disease progression prior to enrollment.\n\n          2. Patients who were discontinued from BMT CTN 0702 lenalidomide maintenance therapy, for\n             any reason, prior to the completion of the 3 years of 0702 maintenance.\n\n          3. Female patients who are pregnant (positive - Beta Human Chorionic Gonadotropin) or\n             breastfeeding.\n\n          4. Females of childbearing potential (FCBP) or men who have sexual contact with FCBP\n             unwilling to use contraceptive techniques during the length of lenalidomide\n             maintenance therapy.\n\n          5. Patients who experienced thromboembolic events while on full anticoagulation during\n             prior therapy with lenalidomide.\n\n          6. Patients unwilling to take Deep Vein Thrombosis (DVT) prophylaxis.\n\n          7. Patients who developed a second primary malignancy, excluding non-melanoma skin\n             cancers after initiation of lenalidomide maintenance therapy on BMT CTN 0702.
Diagnosis\r\n* Patients with CNS3 disease\r\n* Patients with isolated extra-medullary relapse involving only sanctuary sites (eg. testicular relapse) but patients with extramedullary disease involving nodal or other non-sanctuary sites are eligible\r\n* Patients with isolated testicular relapse \r\n* Patients with Philadelphia chromosome positive (Ph+) T-ALL/T-LLy\r\n* Patients with Down syndrome \r\n* Patients with pre-existing grade 2 (or higher) peripheral motor or sensory neurotoxicity per CTCAE 4.03 \r\n* Patients with a history of prior veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) or findings consistent with a diagnosis of VOD/SOS, defined as: conjugated serum bilirubin > 1.4 mg/dL AND unexplained weight gain greater than 10% of baseline weight or ascites AND hepatomegaly or right upper quadrant pain without another explanation, OR reversal of portal vein flow on ultrasound, OR pathological confirmation of VOD on liver biopsy
Patients with laboratory evidence of autoimmune disease (e.g. positive antinuclear antibody [ANA] or lupus anticoagulant) without associated symptoms; vitiligo, or mild autoimmunity not impacting the function of organs, such as Hashimoto or psoriasis may be eligible for study
Patients are eligible >= 6 weeks after therapeutic 131I-MIBG or stem cell infusion to support 131I-MIBG, whichever is later
Patients with extrahepatic disease are eligible
Patients with evidence of large B cell transformation (transformed disease) are not eligible; if in the opinion of the investigator there is high suspicion of transformed disease based on imaging (eg high standardized uptake value [SUV] uptake > 10 on the PET scan) and a biopsy of the suspected site is not feasible, then those patients are not eligible
PRE-CHEMORADIATION SAMPLE COLLECTION: Patients with muscularis propria invasion clinical stages 2 to 4 (T2-4a, N0 or N+, M0 or T1 with N+), who are not candidates for radical cystectomy\r\n* Patients may have undergone partial cystectomy for removal of bladder tumor prior to chemoradiation; patients who have down-staged from M1 disease to M0 with prior platinum-based chemotherapy will be eligible\r\n* Staging is determined prior to chemoradiation
STUDY TREATMENT: Patients with muscularis propria invasion clinical stages 2 to 4 (T2-4a, N0 or N+, M0 or T1 with N+), who are not candidates for radical cystectomy\r\n* Patients may have undergone partial cystectomy for removal of bladder tumor prior to chemoradiation; patients who have down-staged from M1 disease to M0 with prior platinum-based chemotherapy will be eligible\r\n* Staging is determined prior to chemoradiation
Have recurrent or refractory/unresectable disease for which there is no known curative therapy\r\n* Wild type-GIST: patients with recurrent or progressive disease will be eligible; newly diagnosed patients with resectable localized disease will not be eligible; newly diagnosed patients with metastatic disease and newly diagnosed patients with residual tumor following surgical debulking will be eligible\r\n* PHEO/PGL: patients with recurrent or progressive disease will be eligible; newly diagnosed patients with PHEO/PGL that is metastatic at diagnosis and/or unresectable will be eligible; patients with PHEO/PGL with localized (non-metastatic), resectable disease will not be eligible\r\n* Renal cell cancer associated with HLRCC: patients with localized, resectable HLRCC-associated renal cell cancer will not be eligible; patients with metastatic and/or unresectable HLRCC-associated renal cell cancer will be eligible
Patients may have received any prior therapy deemed necessary for them to be eligible to HDT/ASCT except for patients whom have progressed while on Zydelig. Patients who have responded to Zydelig previously are eligible for enrollment on the protocol
Patients will not be eligible if they have a history of color vision defects
Patients with resistant disease (initial or at relapse): those who fail to achieve an objective partial response to three cycles of combination non-cross resistant chemotherapy will not be eligible for transplant in this trial
Female patients who are pregnant or lactating are not eligible (because treatment involves unforeseeable risks to the embryo or fetus)
Patients with evidence of another malignancy or benign tumor requiring chemotherapy or radiation therapy are excluded; however, those patients with a plexiform neurofibroma requiring treatment will be eligible as selumetinib has documented activity in plexiform neurofibromas
Patients with bulky disease are eligible for study provided that the patient not undergo radiation therapy until 30 days after the end of blinatumomab administration
Patients may have received chemotherapy or radiation for a previous, curatively treated malignancy provided at least 2 years have elapsed and there is no current evidence of disease (patients with previous or concurrent additional skin cancers will be eligible); patients with chronic lymphoid or leukemic malignancies are eligible with or without active disease as long as they have not had treatment within the past three months
Patients should not be eligible for potentially curative surgical intervention in the case of oligometastatic disease at the time of enrollment or must have actively refused after explicit discussion of potential benefit of this intervention with multidisciplinary team
Per investigator's judgment, be eligible for treatment with valganciclovir.
Patients with multifocal or multi-centric disease are eligible if the treating clinician has determined the patient should be treated as ER+ and HER2- negative
Patients must have failed a prior >= 4-mponth course of either MMF/Myfortic or cyclophosphamide before being eligible for the study (determined at >= 1 week before start of mobilization); “failure” is defined as evidence of disease progression or absence of improvement; the response prior to MMF of cyclophosphamide will be assessed by the participating site study rheumatologist
Failure to one induction course of chemotherapy (these patients will be analyzed separately); patients who require steroids, ara-c or hydrea to manage disease symptoms prior to finalization of diagnosis and treatment plan are allowed and eligible
Eligible for LDAC therapy, based on Investigator assessment
Eligible for therapy for the lymphoid malignancy which has a high likelihood of a curative result in the opinion of the investigator
MPNST for which standard therapy is not curative, including patients with surgically unresectable lesions, progression (WHO criteria) or recurrence of an MPNST in a previously radiated field (if it has been at least 4 weeks prior to registration since the last dose of radiation); Note: patients with metastatic disease also are eligible for participation
Patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study
Has active hepatitis B or C. Patients with serologic evidence of prior exposure are eligible.
Patients with cytopenias below these thresholds deemed to be the result of disease will be considered eligible
Patients on EIADs are not eligible, unless the antiepileptic drug can be safely tapered and discontinued before C1D1.
FLT3-ITD and/or FLT3-D835 mutated patients with relapsed/refractory AML (any number of relapses) including patients who may have been previously exposed to one or more FLT3-inhibitor therapies will be eligible for the phase I portion of this study
Patients must be eligible for TACE
ADDITIONAL CRITERIA FOR STUDY CONTINUATION: Have a surgically resected (R0 or R1) American Joint Committee on Cancer (AJCC) pathologic stage I or stage II adenocarcinoma of the head, neck, or uncinate of the pancreas; (following study treatment #1, if the patient’s tumor is found intraoperatively to be limited to the distal portion (body or tail) of the pancreas and is resected by distal pancreatectomy, the patient may continue to receive study treatments but will be considered non-evaluable for the primary and efficacy endpoints and will be followed for additional endpoints;) the patients with an R2 resection will not be eligible for the continuation of the study; patients with intraoperative findings of metastatic disease will not be eligible for the continuation of the study
Patients with newly diagnosed or progressive DIPG as confirmed by gadolinium enhanced magnetic resonance imaging (MRI) are eligible; MRI must demonstrate that at least 2/3 of the tumor is situated in the pons and that the origin of the tumor is clearly in the pons; biopsy is not required; tumors with features not typical of diffuse intrinsic brainstem glioma are not eligible; these include dorsally exophytic brainstem gliomas, cervicomedullary junction tumors, and focal low grade gliomas of the midbrain or brainstem which should undergo resection and pathologic evaluation; patients, who have received re-irradiation for progression of the tumor, will be eligible if they show evidence of measurable progressive disease after the re-irradiation; patients at diagnosis with involvement of the spine will not be eligible, however if at progression features of spine involvement are present they will be eligible for stratum II
At least 2 weeks should have elapsed since the last dose of chemotherapy and must have recovered from the acute effects of prior therapy (grade 1 or better); however patients who have a > 50% rise in peripheral blast count (confirmed twice) or > 50% growth of lymph nodes are immediately eligible; patients who have relapsed following autologous or allogeneic bone marrow transplant (BMT) are eligible
Patients with neurofibromatosis are eligible
Patients with porphyria are not eligible
Patients with multiple viral infections including AdV are eligible if their AdV infection is persistent despite standard therapy as defined above. Patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll.
Patients must have high-risk neuroblastoma as defined by the Children's Oncology Group (COG) Risk Stratification Schema\r\n* Patients with International Agreement on Staging (INSS) stage 4 are eligible with the following:\r\n** MYCN amplification, regardless of age or additional biologic features OR\r\n** Age > 18 months, regardless of biologic features OR\r\n** Age 12-18 months, with any of the 3 following unfavorable biologic OR features: MYCN amplification, unfavorable pathology, and/or deoxyribonucleic acid (DNA) index = 1\r\n* Patients with INSS stage 3 are eligible with the following:\r\n** MYCN amplification, regardless of age or additional biologic features OR\r\n** Age > 18 months with unfavorable pathology, regardless of MYCN status\r\n* Patients with INSS stage 2a or 2b are eligible with the following:\r\n** MYCN amplification, regardless of age or additional biologic features\r\n* Patients with INSS stage 4s are eligible with the following:\r\n** MYCN amplification, regardless of additional biologic features
Patients with multiple CMV, EBV, adenovirus, HHV6 and BK virus infections are eligible given that each infection is persistent despite standard therapy; patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll
Only patients with mutated rat sarcoma (RAS) (KRAS and NRAS) mutations are eligible to participate (Phase II only)
An international normalized ratio (INR) =< 1.5 (patients who are therapeutically anticoagulated for unrelated medical conditions such as atrial fibrillation and whose antithrombotic treatment can be withheld for operation will be eligible)
Patients who have met the above criteria and who have undergone CRS and HIPEC in the past 18 months for the forementioned disease processes without evidence of recurrence will be eligible for participation in this study for analyzing ability to achieve complete cytoreduction, morbidity, progression and survival
F. Any one of the below complications\r\n* Vaso-occlusive crises; eligible for hydroxyurea*: at least 3 hospital admissions in the last year; eligible for hematopoietic stem cell transplantation (HSCT): more than 1 hospital admission per year while on maximal tolerated dose of hydroxyurea*\r\n* Acute chest syndrome (ACS); eligible for hydroxyurea*: 2 prior ACS while > 3 years of age and adequately treated for asthma; eligible for HSCT: any ACS while on hydroxyurea*\r\n* Osteonecrosis of 2 or more joints; eligible for hydroxyurea*: and significantly affecting their quality of life by Karnofsky score 50-60; eligible for HSCT: and on hydroxyurea* where total hemoglobin increase less than 1 g/dL or fetal hemoglobin increases < 2.5 times the baseline level\r\n* Red cell alloimmunization; eligible for hydroxyurea*: transfusion-dependent; eligible for HSCT: total hemoglobin increase < 1 g/dL while on hydroxyurea*\r\n* Note: hydroxyurea at maximum tolerated dose
Although rare, the only exception to this would be patients with Hashimoto’s thyroiditis who ARE eligible for participation
Patients who have had a positive SLNB but decline completion ALND are not eligible
Previous therapy:\r\n* It is expected that patients will have received upfront standard of care therapy for their respected disease\r\n* Patients who relapse after either single or tandem autologous BMT are eligible (> 6 months must have elapsed from start of last BMT)\r\n* Patients must be recovered from the acute toxicities of any prior chemo/radio/immunotherapy or BMT
For dose escalation study, patients must have histological confirmation of solid tumors that is metastatic or unresectable. For expansion cohorts, patients must have metastatic or unresectable GIST, melanoma, or uncategorized tumors with tumor biopsies that are positive for c-KIT mutations by polymerase chain reaction (PCR) or immunohistochemistry (IHC). For patients enrolled in the melanoma expansion cohort, only select KIT mutations will be eligible. Patients with mutations in exon 13 V654X, 14 T6701, 17 D816X and all exon 18 mutations will not be eligible for enrollment.
Patients with a radiosurgery boost or fractionated stereotactic boost as a part of their treatment plan are not eligible
Patients with major skull defects (such as missing bone without replacement) are not eligible
Patients in whom therapy for APL was initiated on an emergent basis are eligible (patients may have already started treatment with ATRA, ATO, and/or one dose of idarubicin due to the urgency to start therapy early)
Patients who require or likely to require corticosteroids or other immunosuppressives for intercurrent disease are NOT eligible
Patients with refractory-relapsed ALL of any age are eligible, provided they are not eligible for regimens of higher priority
Patients are eligible if, based on the postoperative CT scan, partial breast irradiation (PBI) is judged to be technically deliverable
Men are not eligible for this study
During phase II: all patients with relapsed disease will be eligible if they have received a minimum of 1 prior standard therapy and a maximum of 2 prior treatments (one of which must be a purine analog and/or an alkylating agent) for B-CLL and have developed relapse disease\r\n* Note: patients who have refractory disease (defined as – progressive disease on last treatment, or less than 6 months of clinical response to the last treatment) will not be eligible
Patients with cytogenetic abnormalities suggesting an improved prognosis [t(8:21), t(15;17) and inv(16)] will be eligible for transplantation in first remission
Patients can also be deemed not eligible for transplant because of specific organ toxicity; specifically, patients with pre-existing compromise to the heart, lungs, kidney, central nervous system (CNS) or liver may be excluded
Previous Therapies\r\n* Patients who are currently being treated with intrathecal (IT) IL-2 for LMD are eligible; no wash out period is required\r\n* Patients who have been previously treated with other IT therapies are eligible, as long as there is at least a 2 week wash out period\r\n* Patients who have previously received therapy with systemic TIL therapy are eligible\r\n* Patients with ventriculo-peritoneal (VP) shunts must have VP shunts with on/off valves and must be expected to tolerate VP shunt valve off for more than 6 hours; patients who have received CNS irradiation, including whole brain radiation or stereotactic radiosurgery, are eligible, if they are at least 1 weeks post CNS-irradiation (Cohort D); patients who are currently being treated with IT IL-2 for LMD are eligible; no wash out period is required. (Cohort D)
FGFR testing of patients will be performed at the investigators' discretion up to a max. of 90 days prior to start of screening. Investigators should ensure all patients will be eligible in terms of disease status and lines of treatment within this timeframe.
Patients are eligible unless their treatment is to be guided by a higher priority protocol
Prior history of standard dose focal RT to 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy fractions, or equivalent or lower doses; patients who have received prior treatment with non-standard RT dose and fractionation schemes are still eligible, provided they have only received a single course of RT; however, subjects treated with interstitial brachytherapy or single-fraction stereotactic radiosurgery are not eligible for this trial
Patients who test positive for infectious hepatitis types A, B, or C within 14 days of registration are NOT eligible for participation
Complex stenoses (Bismuth grade IV) will not be eligible for the trial
Patients who are unable to swallow the medication in its prescribed form are not eligible; the drug cannot be administered via gastric feeding (G)-tube; there will be no exceptions for this criteria
Patients with an active or uncontrolled infection; patients on prolonged antifungal therapy are still eligible if they are culture and biopsy negative in suspected radiographic lesions and meet other organ function criteria
Patients must have histologic or cytologic diagnosis of non-melanoma skin cancer (NMSC) or lymphomas other than B-cell lymphomas; as both of those terms are categories rather than specific diagnoses, specific guidance on eligible tumor types is provided below
Patients are not eligible who have had major surgery =< 14 days of registration; please contact principle investigator (PI) and quality assurance monitor (QAM) for questions about specific surgical procedures
Patients with feeding tubes are eligible for the study
Patients with hypothyroidism that is clinically stable and have normal TSH levels with hormone replacement, or patients with vitiligo or psoriasis not requiring treatment remain eligible for the study
Patients with feeding tubes are eligible for the study
Patients with mature teratoma or completely resected immature teratoma with normal tumor markers are not eligible
Newly diagnosed, previously untreated: (1) M0 medulloblastoma with > 1.5 cm^2 residual; (2) M+ medulloblastoma; patients with diffusely anaplastic medulloblastoma are eligible regardless of M-stage or residual tumor\r\n* As of amendment # 2, enrollment of patients with supratentorial PNET has been discontinued\r\n* All patients with M4 disease are not eligible
No prior chemotherapy or radiation therapy is allowed; patients should only have had a biopsy of the primary tumor without an attempt at complete or partial resection; patients will still be eligible if unplanned excision was attempted or accomplished as long as adequate imaging was obtained prior to surgery
Patients with anaplastic medulloblastoma are eligible regardless of M-stage or residual tumor
Patients requiring anticonvulsants known to activate the cytochrome p450 system, in particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are not eligible; benzodiazepines and gabapentin are acceptable
Patients must not be candidates for curative locoregional treatments; patients with recurrent locoregional disease following surgery and/or radiation for who a resection is unacceptably morbid and unlikely to be curative are eligible; patients must be reviewed at the Moffitt Cutaneous Tumor Board prior to enrolling on trial to verify unresectability
Patients with post-obstructive pneumonia are eligible provided they no longer require intravenous antibiotics at registration
Patients must not be eligible for full ablative regimens by the attending physician
Patients receiving nilotinib 200 mg PO BID or a lower dose are not eligible
Parts A and B: Patients who are able to swallow liquid or use a nasogastric or gastrostomy (G) tube are eligible
Patients with multiple, ipsilateral pulmonary nodules (T3 or T4) are eligible if a definitive course of daily fractionated radiation therapy (RT) is planned
History of hemoptysis within 30 days of registration; Note: patients who have minimal bleeding from the mouth, which is clearly not related to a source in the lungs, i.e., surgery such as a non-lung biopsy, are eligible only after good hemostasis has been documented
Newly diagnosed patients may need to be on steroids due to surgery or control of neurologic symptoms; patients on steroids postoperatively or for control of tumor-related edema are eligible, but attempts to keep patients on the lowest dose necessary to control symptoms should be made
Patients must have experienced at least one and at most two relapses prior to study enrollment; patients with primary refractory disease are eligible
Prior chemotherapy:\r\n* Ovarian cancer: patients with no prior PLD exposure are eligible after failure of platinum-containing chemotherapy; no more than 2 prior platinum containing regimens is permitted; dose escalating cohorts only: patients already on PLD are also eligible if they are receiving PLD beyond 3 cycles without prohibitive (i.e. no grade 3 or 4) skin or mucosal toxicities, and showing no progressive disease compared to a computed tomography (CT) scan obtained 2 or more months earlier; these patients are eligible in spite of any progression from baseline determined prematurely (i.e., applicable to those patients who are deemed in their best interest to continue to receive PLD after a CT obtained at 2 or 3 months has shown progression from baseline)\r\n** Breast cancer: patients may have received 0-2 prior chemotherapy regimens for metastatic disease; breast cancer patients may not have received prior PLD, and will not be eligible for the expanded cohort A \r\n** Interval between prior chemotherapy and registration for breast and ovarian cancer; there should be at least a 3 week interval between the last chemotherapy regimen and registration, and the patient should have recovered from acute toxicity related to prior therapy (6 weeks if the last regiment included BCNU or mitomycin C)\r\n** Dose escalating cohorts only: patients will be categorized in the following strata based upon prior PLD exposure: Stratum A –patients with ovarian cancer who have had prior PLD exposure and received at least 3 cycles of PLD without prohibitive (i.e. no grade 3 or 4 skin toxicity) and have not had progressive disease; Stratum B: patients with ovarian or breast cancer who have had no prior PLD exposure
* Phase 1 (Part A3) - COMPLETE: Patients with relapsed or refractory neuroblastoma, with or without bone marrow involvement, who are not eligible for Part A1 or A2 or cannot enroll on Part A1 because of stratum suspension or lack of available slots (these patients will be enrolled at one dose level below the dose level at which patients on Part A1 are actively enrolling)
Patients with a history of an invasive malignancy within the last 3 years are not eligible for the protocol; patients who are no evidence of disease (NED) from a prior invasive malignancy for at least 3 years or longer are eligible for the trial; patients with history of benign tumors such as a pituitary macroadenomas, meningiomas, or craniopharyngiomas are eligible as long as the benign tumor is under local control regardless of the time frame; patients with concurrent adequately treated basal cell or squamous cell carcinoma of the skin are also eligible for the protocol
Patients eligible for any higher priority transplant protocols
Patients with an active or uncontrolled infection. Patients on prolonged antifungal therapy are still eligible if they are culture and biopsy negative in suspected radiographic lesions and meet other organ function criteria.
Tumor Requirements: All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients asymptomatic by means of stable or decreasing doses of steroids within the last 2 weeks prior to study entry) will be eligible. Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) are eligible.
Previous treatment with investigational agents that inhibit MDM2 or MDMX activity (some MDM2-treated patients may be eligible)
Eligible for MRI [Form GCP-10131]
Patient must have progressed following 12 months of treatment with MEDI4736; patients who discontinue MEDI4736 prior to the completion of 12 months (for any reason) are not eligible; patients who have already completed two 12-month periods of treatment are not eligible
Patients with high-risk uterine leiomyosarcoma (LMS), Federation of Gynecology and Obstetrics (FIGO) stage I (confined to corpus +/- cervix); patients with known uterine serosa involvement are not eligible; patients should have had, at least, a complete hysterectomy (including removal of the cervix); bilateral salpingo-oophorectomy is not required \r\n* Institutional pathology review calls the uterine leiomyosarcoma “high grade”\r\n* Additionally, if the pathology report indicates a mitotic rate, the mitotic rate should be greater than or equal to 5 mitoses/10 high-power field\r\n* All patients must be no longer than 12 weeks (3 months) from surgical resection of cancer at the time of enrollment on study; if a patient requires a second operation to complete her surgery, i.e., trachelectomy to remove the cervix and/or bilateral salpingo-oophorectomy (BSO), the 12 weeks may be counted from the time of the second operation\r\n* Patients who had a “morcellation” hysterectomy procedure that involved morcellation within the peritoneal cavity are eligible IF a second operation is performed and biopsies from the second procedure show no evidence of leiomyosarcoma
Patients who have received any investigational products, antineoplastic therapies, or radiotherapy within 14 days prior to registration are not eligible; NOTE: patients actively receiving hydroxyurea are eligible and may continue to receive hydroxyurea through cycle 1 of protocol treatment; if the platelet count remains above 1 million after cycle 1, hydroxyurea can be used at the treating physician’s discretion, if the platelets are 1000 x 10^9/L, or more, or if there are symptoms from thrombocytosis
Patients with Gilbert's syndrome uncomplicated by other liver disease may be eligible if agreed upon by the investigator and medical monitor for the sponsor.
Patients who only present with localized disease
Patients whose insurance will not cover proton therapy will still be eligible for the study
Patients with tumors adjacent to a vertebral body are eligible as long as all gross disease can be encompassed in the radiation boost field; the boost volume must be limited to < 50% of the ipsilateral lung volume
B-ALL patients must be enrolled on AALL08B1 or APEC14B1 (if open for the classification of newly diagnosed ALL patients) prior to treatment and enrollment on AALL0932\r\n* Note: B-LLy patients are not eligible for AALL08B1, and can enroll directly onto AALL0932
Patients must have newly diagnosed National Cancer Institute (NCI) Standard Risk B-ALL or B-LLy Murphy stages I or II; patients with Down syndrome are also eligible\r\n* Note: for B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL; for tissue processed by other means (i.e. paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted
B-ALL patients with testicular leukemia are not eligible for AALL0932
Patients with porphyria are not eligible
Patients with primary spinal cord tumors are eligible. Patients with multi-focal disease within the cerebrum are eligible.
Patients with a diagnosis of oligodendroglioma or oligoastrocytoma are not eligible.
Eligible patients must have appropriate staging studies identifying them as specific subsets of the revised International Association for the Study of Lung Cancer (IASLC) stage IA based on the following combination of Tumor Node Metastasis (TNM) staging: T1a,N0,M0 or T1b,N0,M0
Eligible patients must have histopathologically confirmed myxoid liposarcoma with confirmation of DDIT3 rearrangement
Patients with T1, N0M0 disease are not eligible
Patients with ASM and MCL with or without an AHNMD are required to have at least one of the eligible organ damage findings as defined by the international consensus response criteria
Patients (with skin metastases only) who will be therapeutically anticoagulated with heparins or Coumadin at the time of the biopsy (they are eligible if anticoagulation can be held prior to biopsy as per investigator); patients on aspirin and other platelet agents are eligible
Magnetic resonance imaging (MRI) echocardiogram (ECHO) gradient sequences are required to evaluate for the presence or absence of central nervous system (CNS) hemorrhage; patients with intra-tumoral and/or CNS hemorrhage are not eligible for study entry except:\r\n* Patients with asymptomatic intra-tumoral hemorrhage of punctate size, at the time of diagnosis, after surgery, and/or any time during protocol therapy\r\n* Patients with asymptomatic post-operative hemorrhage in and/or around the surgical cavity are eligible for study entry; additional imaging studies are not required, but in the event a repeat MRI is performed for clinical reasons the post-operative hemorrhage must not have progressed
Patients must be considered unresectable or inoperable. Patients with nodal recurrence after surgery for early-stage NSCLC are eligible if the following criteria are met:
Eligible patient must show evidence of wild-type (WT) p53 as assessed by central DNA sequencing conducted at Dr. Jeffrey Sklar’s laboratory at Yale University Cancer Center; note, that since patients with AML have a rapidly proliferating disease, patient can be enrolled and begin treatment prior to obtaining the results of this test; patients who are found to the TP53 mutated will be removed from study and can continue on single agent decitabine; however patients will continue to be followed for toxicity
Is not eligible or has refused any protocols of higher priority
Patients receiving cyclosporine A, tacrolimus, or sirolimus are not eligible for this study.
Patients of childbearing potential, not practicing adequate contraception, patients who are pregnant, or patients who are breastfeeding are not eligible for this trial.
Patients receiving a haploidentical / T cell-depleted transplant are eligible to follow a modified treatment plan that does not include withdrawal of immunosuppression
Patients who have received Gliadel wafers or alternating electrical field therapy are not eligible for this study
Histologic evidence of angiolymphatic invasion (ALI); Note: Cases termed focally suspicious for ALI but where no definitive ALI is found are eligible
Patients with radiation-associated gliomas will not be eligible
Patients with a history of non-central line related thrombosis, more than one prior central-line related thrombosis, or known coagulopathy will not be eligible; patients with a first degree family member with a known coagulopathy will be excluded, and therefore, obtaining a family history is essential when possible; patients actively on anticoagulation therapy are not eligible
A survivor of prior cancer is eligible provided that ALL of the following criteria are met and documented:
Patients must not be eligible for a higher priority (e.g.; phase II/III), National Surgical Adjuvant Breast and Bowel Project, Radiation Therapy Oncology Group, and Gynecologic Oncology Group (NRG) protocol for the same population if one exists
Patients with nasopharyngeal carcinoma are not eligible
Patients with cancer are eligible provided they meet the specifications
Must be off prior systemic therapies for 2 weeks prior to enrollment; patients that have been previously treated with systemic therapy adjuvantly or for metastatic disease remain eligible as long as they continue to meet all other eligibility criteria (oligometastatic, no visceral metastasis > 5 cm, eligible for SABR)
Patients with second malignancies may be eligible at discretion of principal investigator (PI) given acute life threatening nature of untreated AML or higher risk MDS; patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are also eligible
Patients who have received yttrium-90 microspheres are not eligible
Due to risk of disease exacerbation patients with porphyria are not eligible
Patients with NF (neurofibromatosis) are eligible, and may have other stable central nervous system (CNS) tumors, such as schwannoma, acoustic neuroma, or ependymoma, but ONLY if these lesions have been stable in size for the preceding 6 months
All patients must be eligible to have either IMRT or IMPT as determined by the study radiation oncologist
Patients with multifocal or multicentric disease are eligible as long as each tumor individually meets eligibility criteria; central confirmation is needed for any site of disease that is tested to be HER2-positive by local testing (unless testing was done by Clarient)
Patients with any intercurrent organ damage or medical problems that would prohibit therapy are NOT eligible for participation
Prior therapy\r\n* Patients with prior exposure to brentuximab vedotin are not eligible; NOTE: prior exposure to gemcitabine is NOT an exclusion criterion\r\n* Patients who have undergone prior autologous or allogeneic SCT are not eligible\r\n* Patients with HL who were stage IA or IIA at initial diagnosis and treated with either radiation alone or < 4 cycles of chemotherapy are not eligible
Disease confined to the intraperitoneal and retroperitoneal cavity; Note: nodal disease below the diaphragm, implants adherent to the surface of the liver or intrahepatic lesions will not be exclusionary; patients remain eligible if all intrahepatic tumor is debulked or ablated by the time treatment is initiated
Patients who are receiving concomitant D2-antagonists (such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide) are NOT eligible for participation; patients must be off any such medications by the time of registration
Patients with second malignancies in remission may be eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible.
Patients who have received prior locoregional therapy for metastatic disease including surgical resection, microwave ablation, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, or radiation are eligible providing the measurable disease is clearly manifest and is outside of the radiation port or ablation field; patients who have received liver directed treatments such as yttrium-90 radioembolization or transarterial chemoembolization are eligible if their measurable disease is outside of the liver
Criteria that need to be met to participate in this study:\n\n          -  Patients must be > 12 months and < 30 years of age when registered on study.\n\n          -  Patients must have relapsed neuroblastoma, refractory neuroblastoma that had less than\n             a partial response to standard treatment or persistent neuroblastoma that had at least\n             a partial response to standard treatment. All patients must have at least ONE site of\n             evaluable disease.\n\n             o Patients who have at least a partial response to standard treatment who still have\n             neuroblastoma that can be seen on CT/MRI or MIBG scans must have a surgical biopsy\n             done of the tumor to confirm that it is neuroblastoma. Patients with relapsed or\n             refractory neuroblastoma do not need to have a biopsy done to enter on study.\n\n          -  Patients must have adequate heart, kidney, liver and bone marrow function. Patients\n             who have bone marrow disease must still have adequate bone marrow function to enter\n             the study.\n\n          -  MLN8237 must be swallowed as whole tablets. Therefore, patients must be able to\n             swallow pills to be eligible for study. One tablet is the size of small breath mint,\n             or baby aspirin. Due to the size of MLN8237 tablets, patients must have a body surface\n             area of at least 0.38 m2 to be eligible for study. A body surface area is a\n             combination of a patient's height and weight. An example of a child with a BSA of 0.45\n             is a child that is 25 inches tall and weighs 25 pounds.You can use the link below to\n             calculate your child's body surface area and determine if they are too small for this\n             trial.\n\n        Patients cannot participate in the study if:\n\n          -  Patients who have received prior MLN8237 are excluded from all phases of the study.\n             Patients previously treated with irinotecan and/or temozolomide will be eligible if\n             they have not had documented progressive disease during treatment with a regimen\n             containing these agents.\n\n          -  They have other medical problems that could get much worse if they had this treatment.\n\n          -  They are on dialysis for bad kidney function.\n\n          -  They are pregnant or breast feeding.\n\n          -  They have active infections such as hepatitis or fungal infections.\n\n          -  They have an allergy to treatment with cefixime and cefpodixime.\n\n          -  They have brain metastasis at study entry, or have received cranial spinal radiation.\n\n          -  They have had an allogeneic stem cell transplant (received stem cell from someone\n             else).\n\n          -  They can't cooperate with the special precautions that are needed for this trial.
Patients must discontinue antiandrogen therapy for at least 4 weeks (e.g. flutamide, bicalutamide, nilutamide) prior to registration with no evidence of a falling PSA after washout; patients on steroids are eligible as long as they will be switched to prednisone
Patients with a history of thromboembolism unrelated to a central line, or patients with a known predisposition syndrome for thromboembolism are not eligible
Both KRAS wild type and KRAS mutant patients are eligible
Patients scheduled to undergo laparotomy *Both optimal and suboptimal patients will be eligible for the study (Suboptimal patients, as well as those who undergo only exploratory laparotomy, are eligible.)
Individuals who do not meet criteria for cohort 1 (progressive disease) or cohort 2 (eligible for surgery) are not eligible for enrollment (i.e. patients with previously untreated disease that is not amenable/planned for surgical resection are not eligible)
Patients with a prior malignancy will NOT be eligible for participation aside from the following exception:\r\n* Patients who have had any curatively treated malignancy and have been disease free without treatment for 1 year prior to study entry ARE eligible for participation
Asymptomatic patients
Patients must not have any disease that will obscure toxicity or dangerously alter drug metabolism; patients with a history of psychosis/schizophrenia or cardiac disease requiring beta-blocker treatment (unable to change medication to non-beta blocker), anti-malarial drugs, or quinine or quinidine will not be eligible for enrollment to a mefloquine containing arm; patients who are on active treatment with one of the study drugs at the time of evaluation will not be eligible for enrollment to an arm containing that study drug
History of prior Lupron intolerance; Note: patients ARE eligible if prior or current Lupron exposure
Patients with uncontrolled diabetes mellitus or a fasting plasma glucose > 1.5 ULN; note: optimal glycemic control should be achieved before starting trial therapy; at the principal investigator’s discretion, non-eligible patients can be re-screened after adequate medical therapy has been instituted
Patients with psoriasis
Patients consuming >= 6 servings per day of fruits and vegetables (not including juices), as determined by the run-in dietary recalls, are not eligible
Patients with a history of central nervous system metastasis are allowed provided they have been treated (surgery, radiation, or radiosurgery) at least 4 weeks prior to initiating study drug and do not require medication(s) to control symptoms; patients with known leptomeningeal disease are not eligible
Patients must have progressed after at least one prior systemic therapy for GCT and meet one of the following criteria:\r\n* Patients with evidence of progressive or recurrent GCT after progression prior high dose chemotherapy (HDCT) treatment, defined as meeting at least one of the following criteria:\r\n** Tumor biopsy of new or growing or unresectable lesions demonstrating viable GCT; in the event of an incomplete gross resection where viable GCT is found, patients will be considered eligible for this study\r\n** Consecutive elevated serum tumor markers (HCG or AFP) that are increasing; increase of an elevated lactate dehydrogenase (LDH) alone does not constitute progressive disease\r\n** Development of new or enlarging lesions in the setting of persistently elevated HCG or AFP, even if the HCG and AFP are not continuing to rise\r\n* Patients deemed not to be a candidate for or benefit from potentially curative HDCT or other curative treatment options defined as follows:\r\n** Patients with inadequate renal function for HDCT\r\n** Patients who have had 3 or more lines of prior chemotherapy\r\n** Patients with late relapse (relapse > 2 years after last therapy)\r\n** Patient with inadequate stem cell collection to move forward with HDCT\r\n** Patients with significant medical or psychosocial comorbidities that are felt to be a contraindication to HDCT by the treating investigator\r\n* NOTE: There is no maximum number of prior treatments allowed\r\n* NOTE: Patients with clinically growing \teratoma\ (normal declining tumor markers and radiographic or clinical progression) should be considered for surgery; in patients with rising tumor markers as their only evidence of disease progression where AFP is < 30 or HCG is < 15, alternate causes of increased levels of these markers should be ruled out; (e.g., hypogonadism by testosterone suppression of luteinizing hormone [LH], hepatitis, use of marijuana)
Participants with splenic MZL who do not meet the radiographically measurable disease criteria described herein are eligible for participation provided that bone marrow infiltration of MZL is histologically confirmed.
Patients with contralateral mediastinal disease (N3) are eligible if all gross disease can be encompassed in the radiation boost field in accordance with the heterogeneity criteria; patients with superior sulcus tumors, or scalene, supraclavicular, or contralateral hilar node involvement, will be eligible if the RT treatment plan allows the dose to the critical structures to be within the tolerance limits (e.g. the dose per fraction can be changed to 1.8Gy for the lymph nodes and 2 Gy per fraction for the primary tumor) while keeping total dose to 60 Gy
Patients with a creatinine greater than 2.5 times the upper limit of normal are eligible, but will be told that they are at greater risk for kidney damage that could possibly result in temporary or even permanent dialysis
Patients may have had up to 2 prior relapses.
Patients must not have: a) active infection; b) disease that will obscure toxicity or dangerously alter drug metabolism, especially liver disease; c) serious intercurrent medical illness; d) prior treatment with HDAC inhibitors. However, patients who have received anticancer agents for non-therapeutic purposes (for eg., as part of a pharmacology study without therapeutic intent) will remain eligible for enrollment into the study.
Treatment with hydroxyurea, busulfan, cytoreductive agents other than frontline TKI, or an investigational agent within 28 days of registration; patients who are on alpha-interferon as primary therapy are not eligible
Patients with evidence of disease are only eligible if the disease is stable (or persistent) in comparison to the status prior to transplantation
Transplant eligible patients are eligible
Patient's ALT and AST must be < 5 x institutional upper limit of norm ULN. The hepatic requirements are waived for patients with known or suspected liver involvement who would otherwise be eligible after consultation with the Study Chair or Vice Chair.
Patients with psoriasis
Patients with cytogenetic breakpoint cluster region (BCR)-Abl variants and additional chromosomal abnormalities (‘clonal evolution’) will be eligible; cytogenetics to be performed, but results are not required to start therapy in patients with hematologic progression
Patients with any tumor (T) with node (N)2 or N3 are eligible; patients with T3, N1-N3 disease are eligible if deemed unresectable; patients with T4, any N are eligible
SCREENING: Patients with clinically evident or histologically proven sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to the lungs, mediastinum, or pleura who can be rendered no evidence of active disease (NED) following standard surgical therapy; note: patients with active disease outside the thorax may be eligible for the study once the extrathoracic disease is definitively treated by local modalities such as radiation, surgery, or radiofrequency ablation
SCREENING: Patients with no more than 3 intracranial metastases, which have been definitively treated by surgery or radiation therapy may be eligible for study provided there is no evidence of active disease for at least 2 months
RECURRENT/ PROGRESSIVE DIPG (STRATUM 1): Patients with progressive DIPG, as defined by progressive neurologic abnormalities or worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity wean, electrolyte disturbances, sepsis, hyperglycemia, etc.), OR an increase in the bi-dimensional measurement, taking as a reference the smallest disease measurement recorded since diagnosis, OR the appearance of a new tumor lesion since diagnosis\r\n* Please note: patients with a radiographically typical DIPG, defined as a tumor with a pontine epicenter and diffuse involvement of more than 2/3 of the pons, are eligible without histologic confirmation\r\n* Patients with pontine lesions that do not meet these radiographic criteria will be eligible if there is histologic confirmation of malignant glioma World Health Organization (WHO) II-IV
For Part 2 and 3, all patients must have an FGF19 IHC result available. Only FGF19 IHC+ HCC patients will be eligible for Part 3.
History of (within 24 months prior to enrollment) of kidney, ureter, or bladder stones with clinically significant sequelae (e.g. (painless gross hematuria; pain with or without infection; hydronephrosis, etc); patients with otherwise stable non-occluding kidney stones regardless of stone type incidentally found in computed tomography (CT) scans are eligible; patients with prior history of uric acid stones are eligible regardless of time of onset
Minimal residual disease (MRD) will be defined separately for each test (fluorescence-activated cell sorting [FACS], FISH or cytogenetics) using standard accepted definitions (that may change over the course of this study and are therefore not listed); thus, patients will be considered eligible only in cases where residual leukemia (i.e., MRD) can be detected above control values; in cases where MRD testing is not conclusive or when there is no control value for the test, the attending pathologist will be engaged and patients will only be eligible in cases where there is clear evidence of MRD
Patients who are immunologically compromised (excluding corticosteroids used for control of tumoral edema) are not eligible
Having chronic hepatitis B or C will not exclude patients from participating if they are otherwise eligible; however, requiring treatment with interferon is an exclusion; patients must be stable without having received interferon in at least 4 weeks
All stages of cancer are eligible
Patients who have an active or uncontrolled infection are not eligible; patients on prolonged antifungal therapy are still eligible if they are culture and biopsy negative in suspected radiographic lesions and meet other organ function criteria
Patients must be eligible for Alliance A031201 and must agree to proceed to enroll in A031201
For dose expansion cohorts: Dose expansion portion of study will include two separate cohorts\r\n* One cohort will incorporate patients with esophageal, gastroesophageal junction (GEJ) or gastric carcinomas (squamous cell carcinoma or adenocarcinoma if predominant histology); these patients must have received at least one prior systemic therapy for metastatic disease; patients who had prior neoadjuvant or adjuvant chemotherapy as part of curative intent primary therapy but recurred in less than 6 months would also be eligible; patients with HER2+ disease must have received trastuzumab with disease progression prior to enrollment; patients on this arm may have had prior treatment with drugs targeting the PD-1 pathway, but will be limited to a maximum of 5 patients\r\n* The second cohort will include patients who have progressed on prior PD-1 pathway inhibition (single agent or in combination) in solid tumor types where these drugs are standard of care; the reason for discontinuation of the prior PD-1 pathway drug must not have been for toxicity; eligible tumor types include melanoma, RCC, UC, NSCLC, and SCCHN, but subsequent tumor types wherein relevant agents become an approved standard of care would also become eligible
Patients with second malignancies in remission may be eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term non-chemotherapy treatment, e.g., hormonal therapy, are eligible.
Patients eligible for participation in Study CLTR0310-301 (Phase III study of CPX-351 NCT01696084) or who have already participated in that study are not eligible for this study.
Patients must have received crizotinib monotherapy at 250 mg BID on a continuous dosing schedule for at least 90 days; patients must be planning to start treatment at least three days, but no more than 30 days after discontinuing crizotinib monotherapy; patients who were not able to tolerate 250 mg BID of crizotinib are not eligible for this study
Patients taking the following medications may experience QT/QTc interval prolongation and are not eligible for the trial - most anti-arrhythmia drugs (incl. amiodarone), erythromycin, quinolone antibiotics, ketoconazole, Zithromax, and phenothiazine and will be denied enrollment in the study. The possible interactions of these drugs and DM-CHOC-PEN have not been established. Patients receiving these drug will only be eligible if they discontinue the drugs and have an acceptable ECG.
Patients with cutaneous disease only are not eligible
Patients presenting with untreated cord compression, visceral metastases or those in need of immediate treatment are not eligible (patients with prior treatment and stability will be eligible)
Only patients with a test result, using the 5-gene Hh signature assay, indicating Hhpathway activated MB are eligible for this study. All available tumor material obtained at any time during the course of the patient's disease should be submitted for these analyses
Patients who have an active or uncontrolled infection are excluded. Patients on prolonged antifungal therapy are still eligible if they are culture and biopsy negative in suspected radiographic lesions and meet other organ function criteria.
Patients with prior allogeneic transplant are not eligible.Patients with a documented history of cerebrovascular accidents and/or TIA within the past 6 months are not eligible.
Patients who have recurrent hepatocellular carcinoma following hepatic transplantation are excluded unless the following criteria are met: i. Transplantation was performed at least 6 months prior to the relapse of HCC. ii. Patients are on stable immune suppressive therapy with no clinical evidence of rejection. iii. Are receiving ? 2.5 mg everolimus daily. d. Patients with known HIV infection are excluded. e. Patients with Hepatitis B are eligible provided there is no active viral replication. Patients with Hepatitis C who are not on interferon are eligible.
Not eligible for or declined transplantation or any standard therapy known to be life prolonging or life saving
Cohort A: Stage IIA-IIIA (TanyN1M0 or T2b-4N0M0) (selected patients with single station N2 nodal involvement in close proximity to the primary tumor target may be considered eligible at the discretion of the principal investigator [PI] if all normal tissue guidelines can be met)
Patients with no prior therapy are eligible, provided they have metastatic disease that is not curable by surgery
Adult patients
Patients must not have had disease progression while receiving siltuximab. For those patients originally assigned to placebo in the CNTO328MCD2001 study, patients who have received less than 4 months of siltuximab following crossover will also be eligible
Patients who are eligible for HSCT but with non-optimal AML disease control (i.e., blasts > 5%) may be enrolled into this study as a bridge-to-transplant.
Eligible diagnoses:
Patients with a fasting plasma glucose > 1.5 ULN; Note: at the principle investigator’s discretion, non-eligible patients can be re-screened after adequate medical therapy has been instituted
Patients that are 12-18 months of age with INSS stage 4 and all 3 favorable biologic features (i.e., non-amplified MYCN, favorable pathology, and DNA index > 1) are not eligible
Patients with current diagnosis of primary cutaneous ALCL (patients who have transformed to systemic ALCL are eligible).
Patients that are not willing to adhere to the photosensitivity guidelines will not be eligible
Patient with suspected recurrence of osteosarcoma but who has not had surgery is eligible for enrollment but will not be randomized to receive study medication until deemed fully eligible following surgical removal of all lung nodules.
All patients must have CTCL diagnosed by morphologic, histochemical or cell surface marker criteria with stage never exceeding IB / IIB disease and mSWAT < 50%. CTCL patients with stage IA disease are not eligible for enrollment. CTCL patients with stage IB disease are eligible provided that they have failed a systemic treatment (this includes radiation). CTCL patients with bone marrow involvement but without lymph node involvement are eligible. Patients with a diagnosis of angioimmunoblastic T cell lymphoma are eligible, even with lymph node involvement. Age ? 18 years. Patients must have a performance status of < 2 on Eastern Cooperative Oncology Group scale (see Appendix). Patients must have fully recovered from toxicity of prior chemotherapy or radiation therapy.
Wilm's tumor and clear cell sarcoma\r\n * Patients with Wilm’s tumor or clear cell sarcoma will be eligible if relapse occurs following an autologous transplant or if the patient relapses following initial treatment, but is not eligible for an autologous transplant; patients who do not achieve a CR with initial therapy will also be eligible provided they can be rendered free of bulky disease as defined above
Neuroblastoma\r\n * Neuroblastoma patients will be eligible if relapse occurs following an autologous transplant or if the patient relapses following initial treatment, but is not eligible for an autologous transplant\r\n * Patients who do not achieve a CR with initial therapy will also be eligible provided they can be rendered free of bulky disease as defined above
Hodgkin disease (HD)\r\n * Patients with HD will be eligible if they fail to achieve a CR following conventional therapy\r\n * Patients who relapse following conventional therapy, but fail to achieve a second CR (or for any other reason cannot undergo autologous transplantation) will be eligible\r\n * Patients who relapse after an autologous transplant will be eligible
Patients with second malignancies in remission may be eligible if there is clinical evidence of disease stability for a period of greater than 6 months off cytotoxic chemotherapy, documented by imaging, tumor marker studies, etc., at screening. Patients maintained on long-term nonchemotherapy treatment, e.g., hormonal therapy, are eligible.
Patients with active disease outside the thorax may be eligible for study once the extrathoracic disease is definitively treated by local modalities such as radiation, surgery, or radiofrequency ablation
Patients with prior exposure to agents targeting interleukin 6 (IL -6) or the IL-6 receptor are not eligible
Patients with a motor, visual, or auditory handicap that prevents computer use (e.g., unresolved posterior fossa syndrome) are not eligible to participate in this trial
Patients with full-scale intelligence quotient (IQ) < 70 per previous testing OR existing diagnosis of/educational classification as a student with an intellectual disability are not eligible
People who are on long-term (> 1 year) chronic treatment are eligible
Patients on immunosuppression are also eligible
Patients with prior treatment with IFN-gamma will be eligible, if they previously tolerated IFN-gamma, however patients must be off of IFN-gamma for at least three weeks before initiation of therapy on this trial
Patients with a prior diagnosis of hand-foot skin reaction are not eligible.
All ethnicities eligible
Patients having no reconstruction are eligible for the study
Patients must be eligible for epidural placement
Treatable causes of fatigue have not been ruled out, at least by history and exam criteria, by the treating provider, such as uncontrolled pain, hypothyroidism, or insomnia; NOTE: if these are considered to be the primary cause for the patient’s fatigue then the patient is not eligible for this trial
Patients with paranasal sinus or nasopharyngeal carcinoma who are about to undergo radiation therapy; patients with paranasal sinus or nasopharyngeal carcinoma who have completed radiation therapy 3-6 months prior to enrollment who then show olfactory loss on a screening test (University of Pennsylvania Smell Identification Test [UPSIT] – score of 34 or 33 or lower out of 40, depending on female/male); both those patients undergoing chemotherapy and those who did not will be eligible, and this factor will be assessed as a possible confounder/contributor in a multi-regression analysis
Patients with a documented history of invasive fungal infection (IFI) within the previous 30 days are not eligible
Patients receiving treatment for an IFI are not eligible
Patients across all stages of disease
Patients must have a firm diagnosis of cGvHD, in accordance with National Institutes of Health (NIH) guidelines; patients with “overlap syndrome” are also eligible, but patients with recurrent, late onset and/or persistent acute GvHD (alone) are not eligible
Patients receiving treatment for an IFI are not eligible
Patients with history of liver transplantation may be eligible for the dose expansion cohorts (parts 2A and 2B) of this study provided all eligibility criteria are met and provided the subject has not had any episodes of acute rejection or serious opportunistic infection within 3 months from enrollment\r\n* Certain immunosuppressive agents such as tacrolimus and sirolimus are prohibited thus liver transplant patients who require these medications for immunosuppression are not eligible\r\n* Patients receiving everolimus at immunosuppressive dosages are eligible
Patients with fasting serum triglycerides > 300 and/or with hypertriglyceridemia requiring medication (but not patients with hypercholesterolemia: patients with hypercholesterolemia with or without medication are eligible).
An international normalized ratio (INR) =< 1.5 (patients who are therapeutically anticoagulated for unrelated medical conditions such as atrial fibrillation and whose antithrombotic treatment can be withheld for operation will be eligible)
Arm C1 and C2: SCNSL patients do not require one prior CNS directed treatment; newly diagnosed SCNSL patients are eligible as long as their systemic disease has been treated and does not require any active treatment
Patients must have histologically or cytologically confirmed solid tumor or heme malignancy; exceptions include patients with pancreatic cancer or colon cancer who are receiving oxaliplatin and are thus eligible for Comprehensive Cancer Center of Wake Forest University (CCCWFU) 98112; patients undergoing inpatient induction therapy for acute leukemia; and those hospitalized for marrow or peripheral blood stem cell transplantation
Patients for whom there is only one good surgical option or any other clinical/nonclinical reason for which the surgeon determines the patient is not eligible for the study
Patients who are not eligible to receive SCT with cyclophosphamide and total body irradiation (TBI) conditioning because they do not meet transplant criteria are also not eligible for this phenylephrine study
General exclusion criteria for transplant include:\r\n* Patients who have angina and/or congestive heart failure requiring treatment, or who have had a myocardial infarction within the past year\r\n* Patients who have had any complication that makes the risk of death during transplantation from non-malignant causes greater than the risk of relapse\r\n* Patients who have any active infection; if the infection is successfully treated, the patient may be reconsidered for transplantation at a later date\r\n* Patients with diabetes who are not controlled by medical management will be ineligible\r\n* Psychiatric illness requiring psychiatric counseling or medical intervention other than antidepressant medications may make an individual ineligible and will be considered on a case-by-case basis\r\n* Psychosocial assessment by the bone marrow transplant team may identify individuals for whom this form of therapy may be contraindicated; these decisions will be based upon estimated adequacy of patient support systems and prediction of patient’s compliance with medications, required diagnostic procedures, and/or follow-up care\r\n* Patients who have an ECOG performance status of greater than 2\r\n* Patients who have decreased pulmonary function due to any disorder as demonstrated by a diffusion capacity of less than 50% of predicted, a FEV1 of less than 60% of predicted, or a PO2 of less than 80mmHg on pulmonary function testing\r\n* Patients who have a resting ejection fraction of less than 50%\r\n* Patients who have renal disease as demonstrated by a serum creatinine clearance of greater than 2.0 mg/dL and/or a creatinine clearance of less than 50 mL/min\r\n* Patients who are pregnant or breast feeding at the time of admission for conditioning
Patients with tumors adjacent to a vertebral body are eligible as long as all gross disease can be encompassed in the radiation boost field; the boost volume must be limited to < 50% of the ipsilateral lung volume
Both heterosexual and same sex couples will be eligible
All diagnoses will be eligible
Patients who have had local genotyping are eligible, regardless of the local result
Individuals who are cognitively impaired are eligible for the study and consent for participation must be given by a legal authorized representative or parent; pregnant women are eligible for the study
Women who are regularly screened for cervical cancer are not eligible
Individuals with a history of natural or artificial sun exposure to the buttocks within 30 days of study participation are not eligible
Eligible for state quitline services
Women with an intact cervix (patients who have undergone previous loop electrosurgical excision procedure [LEEP], cone and/or cryotherapy are eligible)
Sexually active women of all ethnicities and races with an intact cervix are eligible for this trial
Drugs that interfere with mitochondrial function if they are unable to be discontinued 48 hours prior to 13MBT testing will be excluded for this test only but eligible for the rest of the protocol
Patients will have to undergo mutational testing for Isocitrate dehydrogenase 1 (IDH1) on a tumor specimen before entering study. Patients are eligible for Arm C regardless of their IDH1 mutational status.
Patient not eligible for sequential MRI evaluations are not eligible for this study.
Patients who have multicentric disease
Patients with solid tumors with diagnoses OTHER than neuroblastoma or those listed above will be eligible if they meet both of the following criteria:\r\n* Immunohistochemical demonstration of GD2 expression on cell surface (tumor assessment by immunohistochemistry is required for this group of patients)\r\n* Have refractory or relapsed disease or metastatic disease
250 consecutive consenting patients presenting to The Ohio State University College of Dentistry for routing dental care will be recruited; adult patients presenting to the screening clinic for initial oral evaluation will be eligible to participate
Patients will be eligible for this study regardless of prior treatment, as long as they meet other eligibility criteria; therefore, patients who are newly diagnosed, post-operative, post-radiation or post-chemotherapy are eligible
Patients who are excluded from 7T MR imaging because of titanium implants that are not yet established to be safe at 7T remain eligible for the imaging at 3T
Patients with cT2N1-3M0 or cT2-4NxM0 will be considered eligible for participation
Patients with thoracic disease to be treated using radiotherapy will be eligible for this study
ADULT PATIENTS:
Cannot eat normal table food by mouth; NOTE: patients with any form of feeding tube or a swallowing disorder are not eligible
Have taken fish oil, another dedicated n-3 supplement, or SH seed from another source within the last 28 days; patients on multivitamins that contain n-3 are eligible
Patients will be excluded if physicians/staff determine they will not be eligible for a trial during the study period (e.g., entering hospice; moving away)
All diseases that are indications for allogeneic BMT at Stanford University will be eligible for participation in this study
No limitations on prior therapy for eligibility; eligible patients must be receiving their first allogeneic BMT
Consent both to provide data themselves and to assist in identifying eligible patients for recruitment to the trial
While we are focusing on recruitment of clinicians who treat breast, prostate, or colorectal cancers, any eligible patients of the clinicians (e.g., a testicular cancer patient) will be approached for potential participation in the study
Patients are eligible if they have been in stable dasatinib induced CMR for a minimum of nine months, documented by at least three assessments, conducted 2 - 6.5 months apart, at a local lab.
Additional Criteria for Patients Eligible to Restart Dasatinib
Patients are eligible to be treated with RT or CRT and plan to start treatment
Patients with the following will be ineligible for registration onto this study:
Study entry PSA should not be obtained during the following time frames:             \r\n* 10-day period following prostate biopsy\r\n* Following initiation of hormonal therapy\r\n* Within 30 days after discontinuation of finasteride\r\n* Within 90 days after discontinuation of dutasteride
The following diagnoses are to be included:
PhaseII : Prior treatment with any of the following agents:
If sexually active female, patient must be/have one of the following:
Have at least one of the following:
Meets one of the sets of the following criteria:
Either of the following:
Any of the following:
For salivary duct carcinoma patients, the following are required:
Treatment with any of the following:
Patients must have available two UCB units fulfilling the following criteria:
One of the following:
Patients must fulfill one of the following:
Treatment with any of the following:
Any of the following cardiac criteria:
For subjects with TH-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT. At least 1 prior regimen with an anti-CD20 mAb in combination with chemotherapy is required following documented transformation
Treatment with any of the following:
Any of the following cardiac criteria:
Disease Status: Patients must have ONE of the following:
Tumor: patient must have one of the following diagnoses to be eligible:
All subjects must fulfill one of the following:
Any of the following cardiac criteria:
Dose Expansion Portion: Patients must satisfy one of the following criteria:
Treatment with chronic immunosuppressants (e.g., cyclosporine following transplantation)
Has received treatment with any of the following:
for subjects with TH-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT. At least 1 prior regimen with an anti-CD20 mAb in combination with chemotherapy is required following documented transformation
Any one of the following:
Use of the following:
Disease status must be 1 of the following:
Any of the following cardiac criteria:
Patients must have either of the following:
Treatment with any of the following:
Any of the following cardiac criteria:
Use or consumption of any of the following substances:
Each patient must satisfy at least one of the following criteria:
Patient must also satisfy at least one of the following criteria:
Patient must also satisfy at least one of the following criteria:
Study entry PSA should not be obtained during the following time frames: (1) 10-day period following prostate biopsy; (2) following initiation of hormonal therapy; (3) within 30 days after discontinuation of finasteride; (4) within 90 days after discontinuation of dutasteride
Combination of any two of the following (a+b or a+c, or b+c):
Have one of the following documented by a local test:
Have one of the following documented by a local test:
The combination of any 2 of the following methods when both are used simultaneously:
(Monotherapy - Parts A, B, C, D, G, H, J, and K) -- Relapsed, refractory, or progressive disease, specifically: (a) Solid tumors: Following at least 1 prior systemic therapy, and no further standard therapy is available for the patient's advanced solid tumor at the time of enrollment; or (b) Classical HL: Following at least 2 prior systemic therapies in patients who are not candidates for autologous stem cell transplant (SCT), or following failure of autologous SCT; or (c) DLBCL: Following at least 1 prior systemic therapy; patients must have also received intensive salvage therapy unless they refused or were deemed ineligible; or (d) Indolent lymphoma: Following at least 1 prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody and for which no other more appropriate treatment option exists
Study entry PSA and serum testosterone must not be obtained during the following time frames: (1) 10-day period following prostate biopsy; (2) following initiation of oral androgen manipulation; (3) within 30 days after discontinuation of finasteride or dutasteride
Has either of the following:
Any of the following cardiac criteria:
Subjects must satisfy the following criteria to be enrolled in the study:
Use of a combination of any two of the following (a+b or a+c, or b+c):
Patients with either of the following diagnoses:
Patients must satisfy 1 of the following criteria for prior therapy:
At least one of the following indications for treatment:
Subjects must satisfy the following criteria to be enrolled in the study:
The following medications are excluded:
The following medications are excluded:
Treatment with any of the following:
Subjects must satisfy the following criteria to be enrolled into the study:
one or more of the following Myeloma-related organ dysfunction (at least one of the following);
one or more of the following biomarkers of malignancy:
The following medications are excluded:
Indication for treatment consistent with IWCLL criteria, i.e. at least one of the following criteria should be met
Prior treatment with the following:
Subjects must satisfy the following criteria to be enrolled in the study:
Have any history of the following:
Must have significant residual invasive disease at the time of definitive surgery following preoperative chemotherapy. Significant residual disease is defined at least one of the following:
History of prior therapy that satisfies one of the following criteria:
Treatment with any of the following:
Any of the following cardiac criteria:
One of the following acceptable forms of contraception is required:
Treatment with any of the following:
Any of the following cardiac criteria:
Must have significant residual invasive disease at the time of definitive surgery following preoperative chemotherapy. Significant residual disease is defined as at least one of the following:
Patient must have one of the following:
Depending upon patient prior treatment the following apply:
Resistant to or intolerant of hydroxyurea, that is, fulfilling at least 1 of the following criteria:
Diagnosed with one of the following diseases:
One of the following is required:
One of the following is required:
Satisfy at least one of the following criteria
Have either of the following diagnoses:
Patients must have one of the following:
Treatment with chronic immunosuppressants (e.g., cyclosporine following transplantation)
Patients with Ph+ B-precursor ALL, with any of the following:
Treatment with chronic immunosuppressants (e.g., cyclosporine following transplantation)
Recipient must have one of the following diagnoses:
Recipient must not have had (the following therapies within the following timeframe):
Vital signs criteria defined as 3 or more of the following at Baseline:
One or more of the following indications for treatment:
presence of at least one of the following B-symptoms:
All patients must have completed therapy including intensive induction followed by ASCT and radiotherapy to be eligible for ANBL0032; radiotherapy may be waived for patients who either have small adrenal masses which are completely resected up front, or who never have an identifiable primary tumor; examples of such therapies include:              \r\n* Following treatment per A3973 protocol\r\n* Following treatment per Pediatric Oncology Group (POG)-9341/9342 protocol\r\n* Following treatment per CCG3891\r\n* Following treatment on New Approaches to Neuroblastoma Therapy (NANT) 2001-02\r\n* Enrollment on or following treatment per ANBL02P1\r\n* Enrollment on or following treatment per ANBL07P1\r\n* Tandem transplant patients are eligible:                     \r\n** Following treatment on or per ANBL0532\r\n** Following treatment per POG 9640\r\n** Following treatment per COG ANBL00P1\r\n** Following treatment per CHP 594/Dana-Farber Cancer Institute (DFCI) 34-DAT
Subject has received or plans to receive the following therapy/treatment within the following periods prior to leukapheresis or lymphodepleting chemotherapy:
Has all of the following:
Patients with any of the following are not eligible:
Use of the following:
Exposure to any of the following:
hospitalized with one of the following
At least one of the following:
Treatment with any of the following:
Patients are to be excluded from the study if they have any of the following:
Use of a combination of any two of the following:
TKI treatment failure will be defined as 1 of the following:
Intolerance to TKI therapy will be defined as 1 of the following:
Use or consumption of any of the following substances:
Use or consumption of any of the following substances:
CERITINIB INCLUSION CRITERIA: ECOG performance status 0-1
CERITINIB INCLUSION CRITERIA: Life expectancy >= 12 weeks
CERITINIB INCLUSION CRITERIA: Histologically or cytologically confirmed invasive melanoma
CERITINIB INCLUSION CRITERIA: Measurable disease by RECIST v1.1
CERITINIB INCLUSION CRITERIA: Documentation of absence of activating and targetable BRAF or NRAS point mutations
CERITINIB INCLUSION CRITERIA: Presence of an oncogenic kinase fusion involving ALK, confirmed by assay by a CLIA-approved laboratory
CERITINIB INCLUSION CRITERIA: Absolute neutrophil count >= 1.5 x 10^9/L
CERITINIB INCLUSION CRITERIA: Platelets >= 75 x 10^9/L
CERITINIB INCLUSION CRITERIA: Serum amylase =< 2 x ULN
CERITINIB INCLUSION CRITERIA: Serum lipase =< ULN
CERITINIB EXCLUSION CRITERIA: Uveal melanoma
CERITINIB EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to components of ceritinib formulation
CERITINIB EXCLUSION CRITERIA: Prior treatment with the following antineoplastic therapies within the following time frame:\r\n* Any prior treatment with ceritinib\r\n* Radiotherapy to lung fields =< 4 weeks prior to starting ceritinib; for all other anatomic sites (including radiotherapy to thoracic vertebrae and ribs), radiotherapy =< 2 weeks prior to starting ceritinib; palliative radiotherapy for bone lesions =< 2 weeks prior to starting ceritinib is allowed\r\n* Receipt of any cytotoxic chemotherapy, biologic agent, or investigational agent within 4 weeks prior to the first dose of study drug (within 6 weeks for nitrosoureas, mitomycin C or liposomal doxorubicin)
Prior therapy with ceritinib
Impaired gastrointestinal (GI) function or GI disease that may alter absorption of ceritinib or inability to swallow up to five ceritinib capsules daily; although, patients unable to swallow capsules will be allowed to participate in this study, by following the specific instructions on making a slurry of the medication
Patients who have received prior everolimus or ceritinib
Potassium before the first dose of ceritinib
Magnesium before the first dose of ceritinib
Phosphorus before the first dose of ceritinib
Prior therapy with ceritinib
Impaired gastrointestinal (GI) function or GI disease that may alter absorption of ceritinib or inability to swallow up to five ceritinib capsules daily
Patient has been permanently and prematurely discontinued from ceritinib study treatment in the parent study due to any reason.
Patient currently has unresolved toxicities for which ceritinib dosing has been interrupted in the parent study.
Prior cancer therapy is allowed, including crizotinib, ceritinib, and investigational drugs.
Group B: progression following any ALK inhibitor(s) other than ceritinib is required and the last dose of the ALK inhibitor must be no more than 60 days prior to the first dose of study drug. Prior ceritinib is not permitted.
Group C: progression following ceritinib is required and the last dose of ceritinib must be no more than 60 days prior to the first dose of study drug.
Patients who have previously been unable to tolerate ceritinib, in the opinion of the investigator. Exceptions to this exclusion include nausea, vomiting and diarrhea in patients taking ceritinib under fasted conditions.
Prior therapy with ceritinib or other ALK or ROS1 inhibitor agents
Known inability to swallow up to five ceritinib (LDK378) capsules daily
Patient has received prior treatment with ceritinib.
Impaired gastrointestinal (GI) function such as from significant small bowel resection or gastric bypass surgery or inability to swallow up to five ceritinib capsules daily
Inclusion criteria:\n\n        Subjects must satisfy all the following inclusion criteria to be enrolled in the study:\n\n          1. Signed, written Institutional Review Board/Ethics Committee-approved Informed Consent\n             Form(s).\n\n          2. Stage IV pancreatic ductal adenocarcinoma (PDA) with histological or cytological\n             confirmation of PDA.\n\n          3. Subjects must be determined to be HA-high based on archived or fresh tumor core biopsy\n             or sample obtained after the subject has documented metastatic disease.\n             Biopsies/samples must meet the following requirements:\n\n               1. Pancreas tumor biopsies/samples obtained on or after the date that metastatic\n                  disease is documented or tumor biopsies/samples from a metastatic lesion are\n                  acceptable.\n\n               2. Tumor biopsies or samples must meet the requirements provided in the Study\n                  Laboratory Manual with regard to tumor tissue architecture. Note: cytology\n                  samples from fine needle aspirates without maintained tissue architecture or\n                  brushing biopsies are not acceptable.\n\n               3. Tumor tissue (formalin-fixed paraffin-embedded [FFPE] block preferred) must\n                  include enough tumor to make a minimum of 5-10 unstained, consecutive FFPE slides\n                  (10 slides are preferred) of 1 archival block that meet specific tissue sample\n                  requirements (see Study Laboratory Manual).\n\n          4. Radiographic confirmation of Stage IV PDA with at least 1 tumor metastasis measurable\n             on computed tomography (CT) scan and/or magnetic resonance imaging (MRI) per Response\n             Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, excluding the\n             primary pancreatic lesion.\n\n          5. If a subject has had adjuvant/neoadjuvant therapy and/or therapy for locally advanced\n             disease (chemotherapy for non-metastatic pancreatic cancer in combination with or\n             without radiation therapy), tumor recurrence or disease progression must have occurred\n             no sooner than 6 months after completing the last dose of the aforementioned\n             therapies, provided all toxicities have returned to baseline or ? Grade 1.\n\n          6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.\n\n          7. Life expectancy ?3 months.\n\n          8. Age ?18 years.\n\n          9. A negative urine or serum pregnancy test within 7 days before Cycle 1, Day 1 (C1D1;\n             first dose of study medication) if female subject is of childbearing potential.\n\n         10. Screening clinical laboratory values as follows:\n\n               1. Total bilirubin ?1.5 times upper limit of normal (ULN) (subjects with Gilbert\n                  syndrome are eligible independent of bilirubin levels).\n\n               2. Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) and alanine\n                  aminotransferase (serum glutamic pyruvate transaminase) ?2.5 times ULN, (if liver\n                  metastases are present, then ?5 times ULN is allowed).\n\n               3. Serum creatinine ?2.0 mg/dL or calculated creatinine clearance ?40 mL/min.\n\n               4. Serum albumin ?2.5 g/dL.\n\n               5. Prothrombin time or international normalized ratio (INR) within normal limits\n                  (±15%), unless subject takes warfarin, in which case prothrombin time or INR\n                  result must be within therapeutic range.\n\n               6. Partial thromboplastin time (PTT) within normal limits (±15%).\n\n               7. Hemoglobin ?9 g/dL (transfusion and erythropoietic agents allowed).\n\n               8. Absolute neutrophil count ?1,500 cells/mm3.\n\n               9. Platelet count ?100,000/mm3.\n\n         11. For women of childbearing potential (WOCBP) and for men, agreement to use a highly\n             effective contraceptive method from the time of screening throughout the study until 1\n             month (WOCBP) or 6 months (men) after administration of the last dose of any study\n             medication. Highly effective contraceptive methods consist of prior sterilization,\n             intrauterine device (IUD), intrauterine hormone-releasing system (IUS), oral or\n             injectable contraceptives, barrier methods, and/or true sexual abstinence.\n\n        Exclusion criteria:\n\n        Subjects are ineligible for enrollment if they meet any of the following exclusion\n        criteria:\n\n          1. Clinical evidence of deep vein thrombosis (DVT), pulmonary embolism (PE) or other\n             known TE event present during the screening period.\n\n               1. Subjects with superficial vein thrombosis are eligible.\n\n               2. Subjects with visceral/splanchnic vein thrombosis are still eligible if, in the\n                  opinion of the Investigator, the visceral/splanchnic vein thrombosis is primarily\n                  associated with the anatomic location of the underlying disease of metastatic\n                  pancreatic cancer.\n\n          2. Previous radiotherapy, surgery, chemotherapy, or investigational therapy for the\n             treatment of metastatic disease.\n\n             a. Palliative radiotherapy for pain control of metastatic bone lesions is allowed.\n\n          3. Known central nervous system involvement or brain metastases.\n\n          4. New York Heart Association Class III or IV cardiac disease (Appendix C) or myocardial\n             infarction within the past 12 months.\n\n          5. History of cerebrovascular accident or transient ischemic attack.\n\n          6. Clinically significant pre-existing carotid artery disease.\n\n          7. Known infection with human immunodeficiency virus, or active infection with hepatitis\n             B or hepatitis C within the past 12 months.\n\n          8. Known allergy to hyaluronidase.\n\n          9. Current use of megestrol acetate or megestrol acetate-containing drugs (use within 10\n             days of Day 1).\n\n         10. Contraindication to heparin as per institutional guidelines.\n\n         11. Women currently pregnant or breastfeeding.\n\n         12. Intolerance to dexamethasone.\n\n         13. History of another primary cancer within the last 3 years with the exception of\n             non-melanoma skin cancer, early-stage prostate cancer, or curatively treated cervical\n             carcinoma in-situ.\n\n         14. Any other disease, active, uncontrolled bacterial, viral or fungal infection requiring\n             systemic therapy, metabolic dysfunction, physical examination finding or clinical\n             laboratory finding that leads to reasonable suspicion of a disease or condition that\n             contraindicates the use of an investigational drug, or that may affect the\n             interpretation of the results, or that may render the subject at high risk for\n             treatment complications.\n\n         15. Immunization with a live vaccine up to 2 weeks prior to Day 1.\n\n         16. Hypersensitivity to the active substance or ingredients of PEGPH20, gemcitabine, and\n             nab-paclitaxel.\n\n         17. Inability to comply with study and follow-up procedures as judged by the Investigator.
INCLUSION CRITERIA\n\n          -  Histological diagnosis of squamous cell carcinoma of the oral cavity, oropharynx,\n             hypopharynx, or larynx\n\n          -  HPV negative disease, Stage III, IVa, IVb; non-oropharyngeal HPV positive disease\n             Stage III, IVa, IVb, HPV positive oropharyngeal disease T4 or N2c or N3\n\n          -  No prior therapy for advanced stage SCCHN; eligible for definitive CRT with curative\n             intent.\n\n          -  Available tumor samples for submission or willing to undergo further tumor biopsies:\n\n          -  Age ?18 years (?19 in Korea;20 years in Japan and Taiwan).\n\n          -  ECOG Performance Status 0 or 1\n\n          -  Adequate bone marrow function\n\n          -  Adequate renal function\n\n          -  Adequate liver function\n\n          -  Pregnancy test (for patients of childbearing potential) negative at screening\n\n        EXCLUSION CRITERIA\n\n          -  Prior immunotherapy with an anti PD 1, anti PD L1, anti PD L2, anti CD137, or anti\n             CTLA 4 antibody (including ipilimumab), or any other antibody or drug specifically\n             targeting T cell co stimulation or immune checkpoint pathways.\n\n          -  Major surgery 4 weeks prior to randomization.\n\n          -  Prior malignancy requiring tumor-directed therapy within the last 2 years prior to\n             enrollment, or concurrent malignancy associated with clinical instability. Exceptions\n             for disease within the 2 years are superficial esophageal cancer (TIS or T1a) fully\n             resected by endoscopy, prostate cancer (Gleason score 6) either curatively treated or\n             deemed to not require treatment, ductal IS carcinoma of the breast that has completed\n             curative treatment, adequately treated basal cell or squamous cell skin cancer.\n\n          -  Active autoimmune disease\n\n          -  Any of the following in the 6 months prior to randomization: myocardial infarction,\n             severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic\n             congestive heart failure, cerebrovascular accident, transient ischemic attack, or\n             symptomatic pulmonary embolism.\n\n          -  Active infection requiring systemic therapy.\n\n          -  Use of immunosuppressive medication at time of randomization\n\n          -  Prior organ transplantation including allogenic stem-cell transplantation.\n\n          -  Diagnosis of prior immunodeficiency or known human immunodeficiency virus (HIV) or\n             acquired immunodeficiency syndrome (AIDS) related illness.\n\n          -  Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection\n\n          -  Vaccination within 4 weeks prior to randomization.\n\n          -  Current use of or anticipated need for treatment with other anti-cancer drugs.\n\n          -  Pregnant female patients, breastfeeding female patients, and male patients able to\n             father children and female patients of childbearing potential who are unwilling or\n             unable to use 2 highly effective methods of contraception as outlined in the protocol\n             for the duration of the study and for at least 6 months after the last dose of\n             cisplatin and 60 days after the last dose of avelumab/placebo (whichever is later).
INCLUSION CRITERIA:\n\n          1. ECOG performance status ? 2.\n\n          2. Histopathologically or cytologically confirmed NSCLC.\n\n          3. Disease progression during or after treatment with one or two treatment regimen(s)\n             Treatment regimens can be chemotherapy, targeted therapy, biological therapy, or\n             immunotherapy for advanced (Stage IIIB) or metastatic disease (Stage IV). Modification\n             of a regimen to manage toxicity with a different drug does not constitute a new\n             regimen. Maintenance therapy following platinum-based chemotherapy is not considered\n             as a separate regimen. Adjuvant or neoadjuvant chemotherapy and/or chemo-radiation for\n             early stage disease do not count as prior systemic therapy. Prior radiation therapy is\n             not exclusionary. Prior immunotherapy with a PD-1/PD-L1 inhibitor is not exclusionary.\n             Prior treatment for advanced or metastatic disease must have included a platinum-based\n             regimen. (Treatment of early stage disease [Stage IIIA or earlier] with a\n             platinum-containing therapy does not count).\n\n          4. At least 1 lesion ?10 mm in longest diameter in lung parenchyma.\n\n          5. patients with nonsquamous NSCLC must have been tested for EGFR exon 19 deletion and\n             Exon 21 L858R substitution mutation. Only patients without EGFR sensitizing mutations\n             are eligible, and they must have progressed on platinum-based chemotherapy. Patients\n             with known ALK-rearrangements should be treated with an appropriate tyrosine kinase\n             inhibitor (TKI) before entering the study. The TKI regimen would count as a line of\n             treatment\n\n          6. Patients with active brain metastasis or leptomeningeal involvement with brain\n             metastases who are asymptomatic, and whose lesions by imaging are at least stable and\n             without interim development of new lesions for at least 4 weeks may be enrolled.\n\n          7. All AE's of prior systemic therapy, surgery, or radiotherapy, must have resolved to\n             CTCAE v 4.03 Grade ?2, except for neurological AE's that must have resolved to Grade\n             ?1.\n\n          8. The following laboratory results ?14 days prior to study drug admin:\n\n             Hgb ?9 g/dL independent of transfusion or growth factor support; absolute neutrophil\n             count 1.5x10^9/L independent of growth factor support; platelet count ?100x10^9/L\n             independent of transfusion or growth factor support; Serum total bilirubin ? ULN,\n             unless the patient has a diagnosis of Gilbert's disease then serum bilirubin 3.0 times\n             ULN;\n\n          9. AST & ALT ?2.5 x ULN(?1.5 x ULN if alkaline phosphatase is > 2.5 x ULN), and serum\n             creatinine ?1.5 x ULN.\n\n         10. Life expectancy >12 weeks.\n\n         11. Female patients of childbearing potential have a negative pregnancy test at baseline.\n\n         12. Signed informed consent.\n\n        EXCLUSION CRITERIA: Patients with any of the following:\n\n          1. Administration of chemo, biological, immunotherapy, radiotherapy or investigational\n             agent (therapeutic or diagnostic) ?3 weeks prior to receipt of study medication. Major\n             surgery, other than diagnostic surgery, ?4 weeks before first study drug admin.\n\n          2. Significant cardiac history:\n\n             History of myocardial infarction or ischemic heart disease ?1 year before 1st study\n             drug administration; uncontrolled arrhythmia; history of congenital QT prolongation;\n             ECG findings consistent with acute ischemic heart disease; NYHA Class III-IV cardiac\n             disease; & uncontrolled hypertension: BP consistently >150 mm Hg systolic & 100 mm Hg\n             diastolic in spite of antihypertensive medication\n\n          3. Patients who have received prior treatment with docetaxel.\n\n          4. Prior transient ischemic attack or cerebrovascular accident with in the past year.\n             Neurologic toxicities ?Grade 2 within 3 weeks of randomization.\n\n          5. History of hemorrhagic diarrhea, inflammatory bowel disease or active uncontrolled\n             peptic ulcer disease. (Concomitant therapy with ranitidine or its equivalent and/or\n             omeprazole or its equivalent is acceptable.) History of ileus or other significant\n             gastrointestinal disorder known to predispose to ileus or chronic bowel hypomotility.\n\n          6. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.\n\n          7. Known infection with human immunodeficiency virus (HIV) or active hepatitis A, B, or\n             C.\n\n          8. Known prior hypersensitivity reaction to any product containing polysorbate 80,\n             Polyoxyethylene 15 hydroxystearate/Macrogol 15 Hydroxystearate (Solutol HS 15).\n\n          9. Female subject who is pregnant or lactating\n\n         10. Second malignancy unless in remission for >5 years. (Non-melanoma skin cancer or\n             carcinoma in situ of the cervix treated with curative intent is not exclusionary.)\n\n         11. Medical conditions that would impose excessive patient risk. Examples: uncontrolled\n             diabetes, infection requiring parenteral anti infective treatment, liver failure,\n             altered mental status or psychiatric condition that would interfere with the\n             understanding of the informed consent.\n\n         12. Unwilling or unable to comply with protocol.
The study is open to all males and females who meet the following inclusion criteria at\n        screening and baseline to participate in the study.\n\n        To be included to participate in this study each patient must:\n\n          -  be ? 18 years of age;\n\n          -  have an Eastern Cooperative Oncology Group performance status of 0-1 (not declining\n             within past 2 weeks, see Appendix 1);\n\n          -  have confirmed HER2 gene amplified tumor fluorescence in-situ hybridization (FISH,\n             HER2/cep17 ratio > 2) or HER2 overexpression (IHC 3+) or documented HER2 gene\n             mutation. Documentation of HER2 status using FDA approved test(s) for HER2 testing\n             specific for HER2 breast and gastric cancer is required prior to screening;\n\n          -  for part 1:\n\n               1. Patients with HER2 positive (defined as documented overexpression or\n                  amplification or mutation) metastatic breast cancer who have experienced disease\n                  progression following at least 2 prior anti-HER2 therapies for metastatic disease\n                  that contain trastuzumab with or without pertuzumab, prior T-DM1, or lapatinib\n                  therapy is required;\n\n               2. Patients with HER2 positive metastatic gastric cancer who have disease\n                  progression on prior trastuzumab therapy;\n\n               3. other HER2-positive solid tumors (defined as documented overexpression or\n                  amplification or mutation) that have no approved targeted agent as standard of\n                  care\n\n          -  for part 2:\n\n               1. Patients with HER2 positive metastatic breast cancer who have experienced disease\n                  progression after at least 2 prior anti-HER2 therapies for metastatic disease\n                  that contain trastuzumab with or without pertuzumab, prior T-DM1, or lapatinib\n                  therapy is required;\n\n               2. Patients with documented HER2 mutated NSCLC whose disease progressed on prior\n                  therapy;\n\n               3. Patients in Part 2 extension must have at least one measurable lesion as defined\n                  by modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria;\n\n          -  Left ventricular ejection fraction within institutional limits of normal (by multi\n             gated acquisition scan or echocardiography;\n\n          -  have the required screening laboratory values including the following parameters:\n\n               1. Absolute neutrophil count ? 1.5×109/L (1,500/mm3);\n\n               2. Platelets ? 75×109/L (75,000/mm3);\n\n               3. Hemoglobin ? 9.0 g/dL (90 g/L);\n\n               4. Total bilirubin ? 1.5× upper limit of normal (ULN);\n\n               5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 2.5×ULN;\n                  for patients with liver metastases, ALT and AST ? 5×ULN;\n\n               6. Serum creatinine ? 1.5×ULN;\n\n          -  have a life expectancy of > 12 weeks;\n\n          -  for female patients who are of child bearing potential, a negative serum pregnancy\n             test result before study entry. A female patient of childbearing potential is one who\n             is biologically capable of becoming pregnant. This includes women who are using\n             contraceptives or other means of birth control or whose sexual partners are either\n             sterile or using contraceptives;\n\n          -  and who have provided informed consent by signing the informed consent form.\n\n        Main Exclusion Criteria:\n\n        Patients who meet any of the criteria listed below will not be eligible for participation\n        in this study. A patient will not be eligible for study participation if:\n\n          -  is unable or unwilling to swallow pyrotinib;\n\n          -  has been < 2 weeks since the last radiotherapy, chemotherapy, hormone therapy, surgery\n             or molecule-target therapy (< 6 weeks if chemotherapy included nitrosoureas or\n             mitomycin);\n\n          -  the bone or skin is the only site of disease (for Part 2 extension only);\n\n          -  has pleural or peritoneal only disease;\n\n          -  has uncontrolled ? grade 2 hypokalemia and hypomagnesemia;\n\n          -  has had other cancer(s) within 5 years prior to screening with the exception of\n             contralateral breast carcinoma, adequately treated cervical carcinoma in situ, or\n             adequately treated basal or squamous cell carcinoma of the skin;\n\n          -  has active central nervous system (CNS) metastases, as indicated by clinical symptoms,\n             cerebral edema, and/or progressive growth (patients with a history of CNS metastases\n             or cord compression are allowable if they have been definitively treated and have been\n             clinically stable for at least 4 weeks, and off steroids and anticonvulsants, before\n             first dose of study drug);\n\n          -  has either QTcF prolongation (> 470 ms for female and > 450 ms for male), a known\n             history of QTcF prolongation or Torsade de Pointes; or is on drugs that are required\n             for existing medical conditions and that may result in QT prolongation (e.g.,\n             anti-arrhythmic drugs); patients who use medications that have a minimal impact on the\n             QTcF interval in the Arizona-CERT criteria are allowed to participate in this study at\n             Investigator's discretion based on his/her clinical assessment);\n\n          -  has a significant chronic or recent acute gastrointestinal disorder with diarrhea as a\n             major symptom (e.g., Crohn's disease, malabsorption, or ? grade 2 diarrhea of any\n             etiology at baseline);\n\n          -  has participated in any other investigational drug clinical studies within the last 4\n             weeks;\n\n          -  is concurrently receiving other anti-tumor therapies at time of study screening visit;\n\n          -  has an active infection (per Investigator judgment);\n\n          -  has a history of immunodeficiency including seropositive for human immunodeficiency\n             virus, or has other acquired or congenital immunodeficient disease;\n\n          -  has evidence of uncontrolled heart disease, including (1) congestive heart failure\n             (New York Heart Association functional classification) of ? 2), (2) angina requiring\n             treatment (3) myocardial infarction within the past 12 months, or (4) any clinically\n             significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment\n             or intervention;\n\n          -  has allergies or a known history of hypersensitivity to any components of the\n             pyrotinib;\n\n          -  is female and of childbearing potential (WOCBP) who is unwilling or unable to use an\n             acceptable method (barrier methods only) to avoid pregnancy for the entire study\n             period and for up to 28 days post last dose;\n\n          -  is female and pregnant (or found to be pregnant at screening) or breastfeeding;\n\n          -  evidence of significant medical illness or an abnormal laboratory finding, which\n             according to the Investigator's judgment, will substantially increase the risk of\n             participation in and completion of the study. Including, but not limited to, serious\n             ongoing infection (ie, requiring intravenous antibiotic or antiviral agent),\n             uncontrolled major seizure disorder, or significant pulmonary disorder (e.g.\n             interstitial pneumonitis, pulmonary hypertension); hypertension (> grade 3), severe\n             diabetes (uncontrolled > grade 3 hyperglycemia), serious ongoing infection or thyroid\n             disease;\n\n          -  has a known history of neurological psychiatric disease including epilepsy or dementia\n             that would interfere with patient's ability to participate in the study or to provide\n             consent;\n\n          -  has had prior exposure to any other investigational HER2 targeted agents within 4\n             weeks of screening visit.\n\n          -  is currently taking strong CYP3A4 inhibitor or concomitant meds.
Inclusion Criteria\n\n        All Subjects:\n\n          1. Phase 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.\n\n             Phase 2: ECOG performance status of 0 to 2.\n\n          2. Life expectancy ? 3 months before starting tazemetostat.\n\n          3. Subjects with Hepatitis B or C are eligible on the condition that subjects have\n             adequate liver function as defined by Inclusion Criterion #6 and are hepatitis B\n             surface antigen negative and/or have undetectable hepatitis C virus (HCV) RNA.\n\n          4. Adequate renal function defined as calculated creatinine clearance greater than or\n             equal to 40 mL/min per the Cockcroft and Gault formula or the local institutional\n             standard formula.\n\n          5. Adequate bone marrow function:\n\n               1. Absolute neutrophil count (ANC) ?750/mm3 (?0.75 x 10^9/L) - Without growth factor\n                  support (filgrastim or pegfilgrastim) for at least 14 days\n\n               2. Platelets greater ? 75,000/mm3 (?75 x 10^9/L) - Evaluated after at least 7 days\n                  since last platelet transfusion\n\n               3. Hemoglobin greater than or equal to 9.0 g/dL - May receive transfusion\n\n          6. Adequate liver function:\n\n               1. Total bilirubin less than or equal to 1.5 x the upper limit of normal (ULN)\n                  except for unconjugated hyperbilirubinemia of Gilbert's syndrome\n\n               2. Alkaline phosphatase (ALP) (in the absence of bone disease), alanine\n                  aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal\n                  to 3 x ULN (less than or equal to 5 x ULN if subject has liver metastases)\n\n          7. Time between prior anticancer therapy and first dose of tazemetostat as below:\n\n               1. Cytotoxic chemotherapy - At least 21 days\n\n               2. Non-cytotoxic chemotherapy (eg. Small molecule inhibitor) - At least 14 days\n\n               3. Nitrosoureas - At least 6 weeks\n\n               4. Monoclonal antibody (ies) - At least 28 days\n\n               5. Radiotherapy- At least 14 days from local site radiation therapy/At least 6 weeks\n                  from prior radioisotope therapy/At least 12 weeks from 50% pelvic or total body\n                  irradiation\n\n               6. High dose therapy with autologous hematopoietic cell infusion - At least 60 days\n\n               7. High dose therapy with allogeneic transplant - At least 90 days (if graft versus\n                  host disease [GVHD] is present, must be < Grade 2) and no prohibited medications\n                  per Exclusion Criteria #3)\n\n             Note: Starting at Cycle 1 Day 1, subjects may receive no more than 10 mg of prednisone\n             daily (or equivalent corticosteroid, excluding protocol-defined prednisolone dosing\n             for subjects enrolled in Cohort 6) when used for treatment of lymphoma related\n             symptoms, with the intent to taper by the end of Cycle 1.\n\n          8. Males or females aged ? 18 years at the time of informed consent (Phase 2). Males and\n             females aged ? 16 years at time of informed consent (Phase 1).\n\n          9. Females must not be lactating or pregnant at screening or baseline (as documented by a\n             negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity\n             of 25 IU/L or equivalent units of beta-hCG). A separate baseline assessment is\n             required if a negative screening pregnancy test was obtained more than 72 hours before\n             the first dose of study drug. All females will be considered to be of childbearing\n             potential unless they are postmenopausal (at least 12 months consecutive amenorrheic,\n             in the appropriate age group, and without other known or suspected cause) or have been\n             sterilized surgically (ie, bilateral tubal ligation, total hysterectomy or bilateral\n             oophorectomy, all with surgery at least 1 month before dose). Females of childbearing\n             potential must not have had unprotected sexual intercourse within 30 days prior to\n             study entry and must agree to use a highly effective method of contraception, from the\n             last menstrual period prior to randomization, during Treatment Cycles, and for 30 days\n             after the last final dose of study treatment, and have a male partner who uses a\n             condom. Highly effective contraception includes:\n\n               1. Double barrier methods of contraception such as condom plus diaphragm or\n                  cervical/vault cap with spermicide.\n\n               2. Placement of an intrauterine device.\n\n               3. Established hormonal contraceptive methods: oral, injectable, or implant. Females\n                  who are using hormonal contraceptives must have been on a stable dose of the same\n                  hormonal contraceptive product for at least 4 weeks prior to dosing and must\n                  continue to use the same contraceptive during the study and for 30 days after\n                  study drug discontinuation.\n\n             Female subjects exempt from this requirement are subjects who practice total\n             abstinence or have a male partner who is vasectomized. If currently abstinent, the\n             subject must agree to use a highly effective method of contraception as described\n             above if they become sexually active during the Treatment Cycles, and for 30 days\n             after study drug discontinuation.\n\n         10. Male subjects must have had a successful vasectomy or they and their female partner\n             must meet the criteria above (ie, not of childbearing potential or practicing highly\n             effective contraception and use a condom throughout the study period and for 30 days\n             after study drug discontinuation).\n\n         11. Voluntary agreement to provide written informed consent and the willingness and\n             ability to comply with all aspects of the protocol.\n\n             Phase 1 only:\n\n         12. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or\n             B-cell lymphomas that have progressed after treatment with approved therapies or for\n             which there are no standard therapies available.\n\n             Phase 2 only:\n\n         13. Subjects must satisfy all of the following criteria:\n\n               1. Have histologically confirmed DLBCL (including primary mediastinal B-cell\n                  lymphoma), with relapsed or refractory disease following at least 2 lines of\n                  prior standard therapy, including alkylator/anthracycline (unless\n                  anthracycline-based chemotherapy is contraindicated)/anti-CD20-based therapy\n                  (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone\n                  [R-CHOP] or equivalent) AND must be considered unable to benefit from\n                  intensification treatment with autologous hematopoietic stem cell transplantation\n                  (ASCT) as defined by meeting at least 1 of the following criteria:\n\n                    -  Relapsed following, or refractory to, previous ASCT\n\n                    -  Did not achieve at least a partial response to a standard salvage regimen\n                       (eg, rituximab, ifosfamide, carboplatin, and etoposide phosphate [R-ICE] or\n                       rituximab, dexamethasone, cytarabine, and cisplatin [R-DHAP])\n\n                    -  Ineligible for intensification treatment due to age or significant\n                       comorbidity\n\n                    -  Ineligible for intensification treatment due to failure to mobilize an\n                       acceptable number of hematopoietic stem cells\n\n                    -  Refused intensification treatment and/or ASCT\n\n                  OR have histologically confirmed FL. Subjects may have relapsed/refractory\n                  disease following at least 2 standard prior treatment regimens, including at\n                  least 1 anti-CD20-based regimen, as well as alkylating agents (eg,\n                  cyclophosphamide or bendamustine), and have no curative option with other\n                  available therapies OR have a contra-indication to their use. Subjects with prior\n                  ASCT may be included.\n\n               2. Have provided sufficient archival tumor tissue that has been successfully tested\n                  for EZH2 mutation status and cell of origin (DLBCL only) at study specific\n                  laboratories allowing for allocation into an open cohort.\n\n               3. Have measurable disease as defined by International Working Group-Non-Hodgkin's\n                  Lymphoma (IWG-NHL [Cheson, 2007]).\n\n        Exclusion Criteria\n\n        All Subjects:\n\n          1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2.\n\n          2. Subjects with leptomeningeal metastases or brain metastases or history of previously\n             treated brain metastases.\n\n          3. Subjects taking medications that are known potent CYP3A4 inducers/inhibitors\n             (including St. Johns Wort) (see\n             http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti\n             onsLabeling/ucm080499.htm; http://medicine.iupui.edu/clinpharm/ddis/)\n\n          4. Subjects unwilling to remove Seville oranges, grapefruit juice and grapefruit from\n             their diet.\n\n          5. Any prior treatment-related (i.e. chemotherapy, immunotherapy, radiotherapy)\n             clinically significant toxicities have not resolved to ? Grade 1 per CTCAE version\n             4.03 or prior treatment-related toxicities are clinically unstable and clinically\n             significant at time of enrollment.\n\n          6. Major surgery within 4 weeks before the first dose of study drug.\n\n             Note: Minor surgery (eg. minor biopsy of extracranial site, central venous catheter\n             placement, shunt revision) is permitted within 3 weeks prior to enrollment.\n\n          7. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled\n             gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the\n             bioavailability of tazemetostat.\n\n          8. Significant cardiovascular impairment: history of congestive heart failure greater\n             than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension,\n             unstable angina, myocardial infarction, or stroke within 6 months of the first dose of\n             study drug; or cardiac ventricular arrhythmia.\n\n          9. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 480 msec.\n\n         10. Venous thrombosis or pulmonary embolism within the last 3 months before starting\n             tazemetostat.\n\n         11. Active infection requiring systemic therapy.\n\n         12. Known hypersensitivity to any component of tazemetostat, prednisolone/prednisone\n             (combination cohort only), or inability to be treated with a Pneumocystis prophylaxis\n             medication (combination cohort only).\n\n         13. Immunocompromised patients, including patients known to be infected with human\n             immunodeficiency virus (HIV).\n\n         14. Any other major illness that, in the investigator's judgment, will substantially\n             increase the risk associated with the subject's participation in this study.\n\n         15. Females who are pregnant or breastfeeding.\n\n         16. Subjects who have undergone an organ transplant.\n\n             Phase 2 only:\n\n         17. Subjects with noncutaneous malignancies other than B-cell lymphomas. Exception:\n             Subjects with another malignancy who have been disease-free for 5 years, or subjects\n             with a history of a completely resected non-melanoma skin cancer or successfully\n             treated in situ carcinoma are eligible.
Inclusion criteria:\n\n        Phase 1:\n\n          -  For dose escalation cohorts, patients with confirmed selected CD38+ hematological\n             malignancies as specified below who have progressed on after standard therapy or for\n             whom there is no effective standard therapy (refractory/relapsed patients). B-cell\n             Non-Hodgkin-lymphoma/leukemia (NHL) patients having at least 1 measurable lesion.\n             Multiple myeloma (MM) patients with measurable M-protein serum and/or 24-hour urine.\n             Acute myeloid leukemia (AML) patients, all types except M3 based on\n             French-American-British (FAB) classification. Acute Lymphoblastic Leukemia (B-cell\n             ALL) patients. Chronic lymphocytic leukemia (CLL) patients.\n\n          -  For expansion cohorts, patients with relapsed/refractory MM with measurable M-protein\n             (serum M-protein of >0.5 g/dL and/or urine M-protein of >200 mg (24-hr urine)) or\n             elevated serum free light chains (FLC) >10 mg/dL with abnormal FLC ratio) who have\n             progressed on or after standard therapy that includes an iMiD and a proteasome\n             inhibitor and who meet the protocol defined criteria for standard risk or high risk.\n\n        Phase 2:\n\n          -  Patients must have a known diagnosis of multiple myeloma with evidence of measurable\n             disease, and have evidence of disease progression based on International Myeloma\n             Working Group (IMWG) criteria: Serum M-protein ?1 g/dL, or urine M-protein ?200 mg/24\n             hours or in the absence of measurable m-protein, serum FLC ?10 mg/dL, and abnormal\n             serum immunoglobulin kappa lambda FLC ratio (<0.26 or >1.65).\n\n          -  Patients must have received at least three prior lines of therapy for MM and must\n             include treatment with an Immunomodulatory drug (IMiD) (for ?2 cycles or ?2 months of\n             treatment) and a proteasome inhibitor (PI) (for ?2 cycles or ?2 months of treatment)\n             OR patients whose disease is double refractory to an IMiD and a PI. For patients who\n             have received more than 1 type of IMiD and PI, their disease must be refractory to the\n             most recent one.\n\n          -  Patients must have achieved a minimal response or better to at least one prior line of\n             therapy.\n\n          -  Patients must have received an alkylating agent (?2 cycles or ?2 months) either alone\n             or in combination with other MM treatments.\n\n          -  Stage 2 only: Patients must have evidence of disease progression on or after the most\n             recent prior regimen based on IMWG criteria.\n\n        Exclusion criteria:\n\n        Phase 1:\n\n          -  Karnofsky performance status <60\n\n          -  Poor bone marrow reserve\n\n          -  Poor organ function\n\n          -  Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or\n             known hypersensitivity to any of the components of the study therapy that is not\n             amenable to pre-medication with steroids and H2 blockers\n\n          -  Any serious active disease (including clinically significant infection that is\n             chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the\n             investigator, could interfere with the safety, the compliance with the study or with\n             the interpretation of the results\n\n          -  Any severe underlying medical conditions including presence of laboratory\n             abnormalities, which could impair the ability to participate in the study or the\n             interpretation of its results\n\n        Phase 2:\n\n          -  Patients with multiple myeloma immunoglobulin M (IgM) subtype\n\n          -  Previous treatment with any anti-CD38 therapy\n\n          -  Patients with concurrent plasma cell leukemia\n\n          -  Patients with known or suspected amyloidosis\n\n          -  Karnofsky performance status <60 (stage 1)/ECOG Performance status >2 (stage 2).\n\n          -  Poor bone marrow reserve\n\n          -  Poor organ function\n\n          -  Known intolerance to infused protein products, sucrose, histidine, polysorbate 80 or\n             known hypersensitivity to any of the components of the study therapy that is not\n             amenable to pre-medication with steroids and H2 blockers\n\n          -  Any serious active disease (including clinically significant infection that is\n             chronic, recurrent, or active) or co-morbid condition, which, in the opinion of the\n             investigator, could interfere with the safety, the compliance with the study or with\n             the interpretation of the results\n\n          -  Any severe underlying medical conditions including presence of laboratory\n             abnormalities, which could impair the ability to participate in the study or the\n             interpretation of its results\n\n        The above information is not intended to contain all considerations relevant to a patient's\n        potential participation in a clinical trial.
-  Relapsed or refractory, pathologically proven mantle cell lymphoma. Must have a\n             current or prior tissue sample that is IHC positive for cyclin D 1 or that is positive\n             by FISH or cytogenetics for t(11;14).\n\n          -  Must have been refractory to and/or relapsed/progressed after at least 1 prior\n             therapy.\n\n          -  Prior autologous or allogeneic transplant are allowed. Patients may not have active\n             grade II-IV acute graft-versus-host disease (GVHD) or moderate/severe chronic GVHD by\n             NIH criteria and may not require immunosuppressive medications and/or corticosteroids\n             for the management of acute or chronic GVHD.\n\n          -  Phase I: Prior proteasome inhibitor and/or Bruton's tyrosine kinase (BTK) inhibitors\n             are allowed but patients may not have been exposed to the combination of proteasome\n             inhibitor and BTK inhibitor. Patients who have progressed on ibrutinib that are felt\n             to be at high risk for rapid progression on this study shall not be eligible for the\n             phase I portion of the study. NOTE: Ibrutinib pre-treated patients must meet all\n             eligibility criteria AND must have discontinued prior ibrutinib at least 3 months\n             prior to starting study therapy.\n\n          -  Phase II: Prior proteasome inhibitor and/or Bruton's tyrosine kinase inhibitors are\n             allowed but patients may not have been exposed to the combination of proteasome\n             inhibitor and BTK inhibitor. NOTE: Patients must have tolerated prior ibrutinib (i.e.,\n             not discontinued therapy due to toxicity).\n\n          -  Age ? 18 years.\n\n          -  Eastern Oncology Oncology Group (ECOG) performance status of 0-2.\n\n          -  Ability to understand and willingness to sign Institutional Review Board\n             (IRB)-approved informed consent.\n\n          -  Willing to provide archived tumor tissue and blood samples for research.\n\n          -  Adequate organ function as measured by the following criteria\n\n               -  Absolute Neutrophil Count (ANC) ? 750/mm³\n\n               -  Platelets ?50,000/mm³\n\n               -  Serum Creatinine ? 2x Upper Limit Normal (ULN)\n\n               -  ALT and AST ? 3x ULN\n\n               -  Total Bilirubin ? 1.5x ULN\n\n          -  Patients must not have received systemic treatment for MCL for at least 14 days prior\n             to enrollment, except for steroids which may be used to manage acute symptoms related\n             to disease up to 48 hours prior to starting study therapy. Radiation therapy must be\n             concluded at least 14 days prior to enrollment.\n\n          -  Women must not be pregnant or breastfeeding since we do not know the effects of\n             ixazomib and ibrutinib on the fetus or breastfeeding child. All sexually active\n             females of childbearing potential must have a blood test to rule out pregnancy within\n             2 weeks prior to registration.\n\n          -  Sexually active women of child-bearing potential with a non-sterilized male partner\n             and sexually active men must agree to use 2 methods of adequate contraception\n             (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the\n             duration of study participation, and for 3 months following last dose of study drugs.\n\n          -  Patients must have resolved all prior non-hematologic toxicities assessed as related\n             to prior therapy to ? grade 1.\n\n          -  Patients must have measurable disease (i.e., ? 1.5 cm in largest diameter) by\n             conventional imaging modalities. Patients with spleen or extranodal involvement as the\n             only measurable site of disease must have a discrete splenic lesion ? 1.5 cm in\n             largest diameter.\n\n          -  Patients may not have current/active Central Nervous System (CNS) involvement with\n             mantle cell lymphoma (patients with prior CNS involvement are eligible as long as they\n             have had no evidence of active CNS disease for at least 6 months).\n\n          -  Patients may not have another malignancy that could interfere with the evaluation of\n             safety or efficacy of this combination. Patients with a prior malignancy will be\n             allowed without study chair approval in the following circumstances:\n\n               -  Not currently active and diagnosed at least 3 years prior to the date of\n                  enrollment.\n\n               -  Non-invasive diseases such as low risk cervical cancer or any cancer in situ\n\n               -  Localized disease in which chemotherapy would not be indicated (such as Stage I\n                  colon, lung, prostate or breast cancer). Patients with other malignancies not\n                  meeting these criteria must be discussed with PrECOG prior to enrollment.\n\n          -  Patients requiring long-term anticoagulation must be managed on an anticoagulant\n             besides warfarin. Patients who require warfarin are not eligible.\n\n          -  Patients with a clinically significant bleeding episode as judged by the investigator\n             within 3 months of registration are not eligible, except patients who suffer bleeding\n             due to trauma.\n\n          -  Patients may not have had major surgery within 14 days, or minor surgery within 3\n             days, before registration.\n\n          -  Patients may not have any active infection requiring oral or intravenous antimicrobial\n             therapy at the time of therapy initiation. Patients with a recent self-limited\n             infection that has clinically resolved may complete a prescribed course of\n             antimicrobial therapy after study initiation as long as they are asymptomatic with no\n             clinical evidence of infection for at least 7 days prior to treatment. Patients with a\n             recent serious (grade ? 3) infection requiring hospitalization must have completed all\n             antimicrobial therapy within 14 days of therapy initiation.\n\n          -  Patients may not have evidence of uncontrolled cardiovascular conditions, including\n             uncontrolled hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive\n             heart failure (New York Heart Association (NYHA) class III or higher, unstable angina,\n             or myocardial infarction within the past 6 months. Patients with a history of any\n             significant cardiovascular disease that has been controlled for at least 14 days\n             before registration are allowed (except for patients who have had a myocardial\n             infarction within 6 months).\n\n          -  No systemic treatment, within 14 days before the first dose of ibrutinib with moderate\n             or strong inhibitors of CYP3A (Strong Inhibitors: ketoconazole, itraconazole,\n             voriconazole, posaconazole, clarithromycin, and telithromycin; Moderate Inhibitors:\n             fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir,\n             fosamprenavir, crizotinib, imatinib, verapamil, ciprofloxacin, grapefruit juice\n             products, and Seville oranges) or strong CYP3A inducers for ibrutinib and ixazomib\n             (carbamazepine, rifampin, phenytoin, St. John's wort).\n\n          -  Patients with ongoing or active systemic infection, active hepatitis B or C virus\n             infection, or known Human Immunodeficiency Virus (HIV) positive are not eligible.\n             Testing is not required in absence of clinical suspicion.\n\n          -  Patients with a history of hepatitis B or C must have a negative peripheral blood\n             Polymerase Chain Reaction (PCR) and may not be positive for Hepatitis B surface\n             antigen. Patients with cirrhosis or other evidence of liver damage due to Hepatitis B\n             or C are not eligible.\n\n          -  Patients with any serious medical or psychiatric illness that could, in the\n             investigator's opinion, potentially interfere with the completion of the treatment\n             according to the protocol are not eligible.\n\n          -  Patients with a known allergy to any of the study medications, their analogues, or\n             excipients in the various formulations of any agent are not eligible.\n\n          -  Patients with known gastrointestinal (GI) disease or prior GI procedure that could\n             interfere with the oral absorption or tolerance of ixazomib or ibrutinib including\n             difficulty swallowing are not eligible.\n\n          -  Patients with ? Grade 2 peripheral neuropathy, or Grade 1 peripheral neuropathy with\n             pain on clinical examination during the screening period are not eligible.\n\n          -  Patients may not participate in any other therapeutic clinical trials, including those\n             with other investigational agents not included in this trial throughout the duration\n             of this study.\n\n          -  As ibrutinib will not be provided by the study, the patient must be able to obtain\n             ibrutinib through other means (i.e., commercially or through patient assistance\n             programs). This must be confirmed prior to registration.
Inclusion criteria:\n\n        Parts A, B, C and D:\n\n          -  Patients must be postmenopausal women\n\n          -  Histological diagnosis of breast adenocarcinoma\n\n          -  Locally advanced or metastatic disease\n\n          -  Measurable disease\n\n          -  Previously treated for advanced disease\n\n          -  Either primary tumor or any metastatic site to be positive for Estrogen Receptors\n             (ER+) and negative for human epidermal growth factor receptor 2 (HER2-) by\n             immunohistochemistry (IHC)\n\n        Exclusion criteria:\n\n          -  Medical history or ongoing gastrointestinal disorders that could affect absorption of\n             SAR439859 and/or palbociclib (including difficulties with swallowing capsules)\n\n          -  Patient with any other cancer (except for adequately treated basal cell or squamous\n             cell skin cancer, in situ cervical cancer or any other cancer from which the patient\n             has been disease free for >3 years)\n\n          -  Patients with known brain metastases and endometrial disorders\n\n          -  Treatment with anticancer agents (including investigational drugs) less than 2 weeks\n             before first study treatment starts (less than 4 weeks if the anticancer agents were\n             antibodies)\n\n          -  Prior treatment with another selective ER down-regulator (SERD) (except fulvestrant)\n\n          -  Inadequate hematological and biochemical lab tests\n\n          -  Patients with Gilbert disease\n\n          -  Treatment with human immunodeficiency virus (HIV)-antiviral, antifungal and\n             antioxidant agents less than 2 weeks before study treatment starts\n\n          -  Treatment with strong and moderate CYP3A inducers/inhibitors within 2 weeks before\n             first study treatment\n\n        Part A only:\n\n        Patients with liver metastases only\n\n        Parts C and D only:\n\n          -  Prior therapy with any selective cyclin-dependent kinase (CDK) 4/6 inhibitor\n\n          -  Treatment with strong and moderate CYP3A inducers or strong CYP3A inhibitors within 2\n             weeks before first study treatment starts\n\n          -  Medical conditions requiring concomitant medications with that are metabolized by\n             CYP3A\n\n        The above information is not intended to contain all considerations relevant to a patient's\n        potential participation in a clinical trial.
Key Inclusion Criteria Part 1:\n\n          -  Patients with advanced (unresectable) or metastatic solid tumor and have disease\n             progression after treatment with available therapies that are known to confer clinical\n             benefit or who are intolerant to treatment.\n\n          -  Patients must have tumor tissue available.\n\n          -  Female patients must have a negative serum or urine pregnancy test or be of\n             non-childbearing potential.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to\n             1 and adequate organ function.\n\n        Key Inclusion Criteria Part 2:\n\n        - Patients must have not been previously treated with an anti - LAG - 3, anti - PD - 1,\n        anti - PD - L1, or anti - PD - L2 antibody.\n\n        Key Exclusion Criteria for all:\n\n          -  Known uncontrolled central nervous system metastases and - or carcinomatous\n             meningitis.\n\n          -  History of human immunodeficiency virus (HIV), active Hepatitis B or Hepatitis C.\n\n          -  Participated in another investigational study (drug or device) within 4 weeks of first\n             dose.\n\n          -  Received prior anticancer therapy within 21 days of first dose.\n\n          -  Not recovered from Adverse Events (AEs) and - or complications from major surgery\n             prior to first dose.\n\n          -  Vaccine within 7 days of planned start of study treatment.
Inclusion Criteria:\n\n        Male or female patients ?18 years of age. For Japan only: written consent is necessary both\n        from the patient and his/her legal representative if he/she is under the age of 20 years.\n\n        Histologically documented advanced or metastatic solid tumors or lymphomas\n\n          -  Part 1: histologically confirmed renal cell carcinoma (RCC), pancreatic cancer,\n             urothelial cancer, head and neck cancer, diffuse large B-cell lymphoma (DLBCL),\n             microsatellite stable (MSS) colon cancer, triple negative breast cancer (TNBC) or\n             melanoma\n\n          -  Part 2: histologically confirmed diagnosis of advanced/metastatic NSCLC. For those\n             with mixed histology, there must be a predominant histology\n\n          -  Part 3: histologically confirmed diagnosis of advanced/metastatic NSCLC and one\n             additional tumor type based on emerging data from part 1 of the study.\n\n        Patient (except for those participating in Japanese safety run-in) must have a site of\n        disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating\n        institution's guidelines. Patient must be willing to undergo a new tumor biopsy at\n        screening, and again during therapy on this study.\n\n        o Part 4: Safety run-in part in Japanese patients can enroll any tumor type included in\n        part 1 and 2.\n\n        The collection of recent sample is permitted under the following conditions (both must be\n        met):\n\n          -  Biopsy was collected ? 3 months before 1st dose of study treatment and available at\n             the site.\n\n          -  No immunotherapy was given to the patient since collection of biopsy.\n\n        Part 1 - 3 only: Patients (other than those with DLBCL) must previously have received at\n        least 1 and no more than 3 prior lines of therapy for their disease, specifically including\n        the following, unless considered inappropriate for the patient (e.g. safety concern, label\n        contraindication):\n\n          -  Patients with NSCLC must have received a prior platinum-based combination.\n\n          -  Patients with EGFR positive NSCLC with a T790M mutation must have progressed on\n             osimertinib or discontinued due to toxicity.\n\n          -  Patients with head and neck cancer must have received a prior platinum-containing\n             regimen.\n\n          -  Patients with bladder cancer must have received a prior platinum-containing regimen or\n             be ineligible for cisplatin.\n\n          -  Patients with renal cell carcinoma must have received a prior VEGF tyrosine kinase\n             inhibitor (TKI).\n\n          -  Patients with MSS colorectal cancer must have received (or be intolerant to) prior\n             therapy with fluoropyrimidine-oxaliplatin- and irinotecan- based regimens.\n\n          -  Patients with triple negative breast cancer must have received a prior\n             taxane-containing regimen.\n\n        Patients with DLBCL should be limited to those with no available therapies of proven\n        clinical benefit\n\n        o Patients should have had prior autologous hematopoietic stem cell transplantation\n        (auto-HSCT) or determined to be ineligible for auto-HSCT.\n\n        Patients must not have received prior immunotherapy (previous immune checkpoint inhibitors;\n        single agent and/or combination therapy with anti-CTLA-4, anti-PD-1, anti-PD-L1), except\n        for NSCLC patients enrolled in part 3 and Japanese safety run-in part.\n\n        Patients must have measurable disease, defined as at least one lesion that can be\n        accurately measured in at least one dimension (longest diameter to be recorded for\n        non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional techniques\n        or as >10 mm with spiral computer tomography (CT) scan, Magnetic Resonance Imaging (MRI),\n        or calipers by clinical exam.\n\n        Other protocol-defined inclusion criteria may apply.\n\n        Exclusion Criteria:\n\n        Ongoing or prior treatment with A2aR inhibitors. Patients previously treated with A2aR\n        inhibitors for non-oncologic indications (e.g. Parkinson's disease) may be considered for\n        enrollment on a case by case basis.\n\n        Current or prior use of immunosuppressive medication within 28 days before the first dose\n        of PDR001, with the exception of intranasal/inhaled corticosteroids or systemic\n        corticosteroids at physiological doses (not exceeding equivalent of 10 mg/day of\n        prednisone) History of another primary malignancy except for:\n\n          -  Malignancy treated with curative intent and with no known active disease ?2 years\n             before the first dose of study drug and of low potential risk for recurrence\n\n          -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of\n             disease\n\n          -  Adequately treated carcinoma in situ without evidence of disease Active or prior\n             documented autoimmune disease within the past 2 years. Patients with vitiligo, Grave's\n             disease, or psoriasis not requiring systemic treatment (within the past 2 years) are\n             not excluded.\n\n        More than 3 prior lines of therapy except for Japanese safety run-in part. History of\n        interstitial lung disease or non-infectious pneumonitis Participation in another clinical\n        study with an investigational product during the last 21 days prior to starting on\n        treatment.\n\n        Other protocol-defined exclusion criteria may apply.
Inclusion criteria:\n\n        Dose escalation (Part 1A and Part 1B)\n\n          -  Patients with histologically confirmed, advanced unresectable or metastatic solid\n             tumor whom in the opinion of the Investigator does not have a suitable alternative\n             therapy.\n\n        Dose expansion (Part 2A)\n\n          -  Patients with histologically confirmed, advanced unresectable or metastatic melanoma\n             whom in the opinion of the Investigator does not have a suitable alternative therapy.\n\n          -  Patients must have failed a prior therapy based on anti-PD-1 or anti-PD-L1 as defined\n             by disease progression confirmed radiologically within 12 weeks of commencing\n             treatment without any evidence of a response.\n\n          -  Patients must have a site of disease amenable to biopsy and be a candidate for tumor\n             biopsy. Patients must be able to provide mandatory tumor biopsies prior to and during\n             study treatment.\n\n        Dose expansion (Part 2B)\n\n          -  Patients with histologically confirmed advanced unresectable or metastatic melanoma\n             who have failed a prior therapy based on anti-PD-1 or anti-PD-L1 or patients with a\n             specific type of colorectal adenocarcinoma who have progressed after last line of\n             therapy and have no other alternative approved standard therapy or refuse approved\n             standard therapy.\n\n        All cohorts\n\n          -  At least 1 measurable lesion by RECIST v1.1.\n\n          -  Patient understands and has signed Informed Consent form and is willing and able to\n             comply with the requirements of the trial.\n\n        Exclusion criteria:\n\n          -  Age <18 years.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status >1.\n\n          -  Concurrent treatment with any other anticancer therapy (including radiotherapy or\n             investigational agents) or participation in another clinical study.\n\n          -  Washout period of less than 3 weeks to prior anticancer therapy.\n\n          -  Women of reproductive potential and male subjects with female partners of childbearing\n             potential who are not willing to avoid pregnancy by using effective contraceptive.\n\n          -  Pregnant or breast-feeding women.\n\n          -  Unwillingness and inability to comply with scheduled visits, drug administration plan,\n             laboratory tests, other study procedures, and study restrictions.\n\n          -  Significant and uncontrolled concomitant illness, including any psychiatric condition.\n\n          -  Active infections, including unexplained fever (temperature >38.1ºC), or antibiotic\n             therapy within 1 week prior to enrollment.\n\n          -  Any prior organ transplant including allogeneic bone marrow transplant.\n\n          -  History within the last 5 years of an invasive malignancy other than the one treated\n             in this study.\n\n          -  History of known human immunodeficiency virus (HIV), unresolved viral hepatitis.\n\n          -  Any major surgery within the last 28 days.\n\n          -  Patients with primary central nervous system (CNS) tumors and/or metastases.\n\n          -  History of severe, acute or chronic heart diseases.\n\n          -  History of severe, acute or chronic renal diseases or inadequate renal function.\n\n          -  Any of the following within 6 months prior to study enrollment: pulmonary embolism,\n             infectious or inflammatory bowel disease, diverticulitis, intestinal obstruction or\n             perforation and gastrointestinal hemorrhage.\n\n          -  Inadequate hematological or liver function.\n\n          -  Non-resolution of any prior treatment related toxicity to Grade <2.\n\n          -  Prior treatment with any anti-transforming growth factor ? (anti-TGF?) inhibitors.\n\n          -  Known allergies to any component of SAR439459 and/or REGN2810.\n\n          -  Patients who received prior immunotherapy who developed toxicity leading to a\n             permanent discontinuation of immunotherapy.\n\n          -  Ongoing or recent (within 2 years) evidence of significant autoimmune disease that\n             required treatment with systemic immunosuppressive treatments.\n\n          -  Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within\n             4 weeks prior to the first dose of SAR439459 and/or REGN2810 (occasional use of\n             inhaled, intraocular, nasal or topical steroids for symptomatic relief allowed).\n\n          -  History of pneumonitis or bowel perforation.\n\n          -  Patients with underlying cancer predisposition syndromes.\n\n        The above information is not intended to contain all considerations relevant to a patient's\n        potential participation in a clinical trial.
Inclusion Criteria:\n\n          -  ? 18 years of age at the time of signing informed consent\n\n          -  Diagnosis of AML according to the World Health Organization (WHO) 2008 criteria\n\n          -  Relapsed or refractory disease meeting the following criteria: (a) Primary refractory,\n             ie, refractory to induction with a standard anthracycline-based regimen or a\n             hypomethylating agent (e.g. decitabine or azacitidine) for patients ineligible for\n             anthracycline-based therapy; (b) First relapse after a first complete remission (CR)\n             lasting less than 12 months; or (c) Second or later relapse. Relapse is defined as the\n             reappearance of leukemic blasts in the peripheral blood or ? 5% leukemic blasts in the\n             bone marrow after prior achievement of a CR or CRi.\n\n          -  Blasts at least 5% in bone marrow\n\n          -  Peripheral white blood cell (WBC) count: no upper limit at Screening, but must be < 10\n             x 109/L on Day 1 prior to treatment; patients with excessive blasts may be treated\n             with hydroxyurea to bring counts down.\n\n          -  Chemistry laboratory parameters within the following range:\n\n               1. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2x the\n                  upper limit of normal (ULN)\n\n               2. Total bilirubin ? 1.5x the ULN; patients with Gilbert's syndrome can enroll if\n                  conjugated bilirubin is within normal limits.\n\n               3. Creatinine clearance > 50 mL/min (measured or calculated by Cockcroft-Gault\n                  method)\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with\n             ECOG score of 2 may be included, after discussion with the Sponsor Medical Monitor, if\n             score is influenced by symptoms attributable to underlying AML disease.\n\n          -  Able to read, understand and provide written informed consent\n\n        Exclusion Criteria:\n\n        Patients who meet any of the following criteria will be excluded from the study.\n\n          -  History of, or known, central nervous system (CNS) disease involvement, or prior\n             history of National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events\n             (CTCAE) Grade ? 3 drug-related CNS toxicity\n\n          -  Prior allogeneic transplant is excluded during Dose Escalation Stage;\n\n          -  Prior solid organ transplantation\n\n          -  Treatment with anti-thymocyte globulin (ATG) within 14 days prior to start date\n\n          -  Treatment with any local or systemic antineoplastic therapy or radiation within 14\n             days prior to the initiation of AMV564 administration (hydroxyurea is exempted if used\n             to reduce total WBC counts)\n\n          -  Clinically significant cardiac disease,\n\n          -  Pulmonary, renal, hepatic, gastrointestinal, neurological or psychiatric disease that\n             would limit compliance with study requirements\n\n          -  Evidence of active, uncontrolled, viral, bacterial, or systemic fungal infection.\n             Prophylactic therapy according to institutional protocols is acceptable.\n\n          -  Known positive test result for human immunodeficiency virus (HIV) or acquired immune\n             deficiency syndrome (AIDS)\n\n          -  Active hepatitis C virus (HCV) or hepatitis B virus (HBV).\n\n          -  Second primary malignancy that has not been in remission for greater than 3 years.\n             Exceptions that do not require a 3-year remission include: non-melanoma skin cancer;\n             cervical carcinoma in situ on biopsy or squamous intraepithelial lesion on\n             Papanicolaou (PAP) smear; localized prostate cancer (Gleason score < 6); or resected\n             melanoma in situ.\n\n          -  Any serious underlying medical or psychiatric condition (e.g. alcohol or drug abuse),\n             dementia or altered mental status or any issue that would impair the ability of the\n             patient to understand informed consent or that in the opinion of the investigator\n             would contraindicate the patient's participation in the study or confound the results\n             of the study.\n\n          -  Ability to become pregnant. However, female patients who have a negative serum or\n             urine pregnancy test before enrollment and agree to use two highly effective forms of\n             contraception (oral, injected or implanted hormonal contraception and condom;\n             intrauterine device and condom; diaphragm with spermicidal gel and condom) during the\n             trial and for 90 days afterward (90 days after the end of AMV564 treatment) are\n             considered eligible.\n\n          -  Male patients with partners of childbearing potential.\n\n          -  Pregnant or breastfeeding women
Inclusion Criteria:\n\n        Phase Ib subjects must meet the following inclusion criteria:\n\n          -  Locally advanced urothelial cancer of bladder with any of the following:\n\n               1. T3-4, N0-2 M0, OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR\n                  medically unfit for surgery, OR cisplatin ineligible. T3 N0 M0 patients can be\n                  included if they are cisplatin ineligible.\n\n               2. Patients who have T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 post-neoadjuvant\n                  chemotherapy who become unresectable OR medically unfit for surgery.\n\n                  Phase II subjects must meet the following inclusion criteria:\n\n          -  Locally advanced urothelial cancer of bladder with any of the following:\n\n               1. T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR\n                  medically unfit for surgery OR cisplatin ineligible. T3 N0 M0 patients can be\n                  included if they are cisplatin ineligible.\n\n               2. T3-4, N0-1 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 patients post-neoadjuvant chemotherapy\n                  who become unresectable OR medically unfit for surgery.\n\n          -  T2, N0, M0 who are ineligible to get cisplatin based chemotherapy.\n\n        All subjects:\n\n          -  Written informed consent and HIPAA authorization for personal health information,\n             obtained from the subject prior to performing any protocol-related procedures,\n             including screening evaluations.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.\n\n          -  Life expectancy of >6 months per treating physician.\n\n          -  Subjects must have archival tissue available from previous TURBT (preferred) or lymph\n             node core biopsy within 8 weeks of treatment or be assessed by the treating urologist\n             to undergo maximal TURBT. The extent of TURBT may vary for each patient and will be\n             determined by the treating urologist. Further, the treating urologist will decide if\n             performing the TURBT is clinically appropriate. If the potential subject does not have\n             tumor amenable to biopsy, there is insufficient tissue for PD-L1 testing or is not\n             clinically appropriate for TURBT, enrollment must be discussed with the\n             sponsor-investigator on a case by case basis.\n\n          -  Histologically proven urothelial carcinoma of bladder with predominant transitional\n             cell component. Adenocarcinoma, squamous cell differentiation, or other atypical\n             histology (such as plasmacytoid or sarcomotoid) of the bladder will be allowed on the\n             study, provided they form <50% of the histology.\n\n          -  Females of childbearing potential must have a negative urine and serum pregnancy test\n             within 3 days of study registration.\n\n        NOTE: Female subjects are considered of child bearing potential unless they are surgically\n        sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral\n        oophorectomy) or they are ?60 years old and naturally postmenopausal for at least 12\n        consecutive months.\n\n          -  Subject is willing and able to comply with the protocol for the duration of the study\n             including undergoing treatment and scheduled visits and examinations including follow\n             up.\n\n        Exclusion Criteria:\n\n          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca\n             staff and/or staff at the study site).\n\n          -  Participation in another clinical study with an investigational product within 2 weeks\n             prior to registration.\n\n          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.\n\n          -  Previous systemic immunotherapy. Previous use of intravesical BCG is acceptable.\n\n          -  History of another primary malignancy except for:\n\n               1. Malignancy treated with curative intent and with no known active disease ?5 years\n                  before the first dose of study drug and of low potential risk for recurrence.\n                  However adequately treated prostate cancer >3 years ago with no significant\n                  change in PSA for past 6 months can be included. Patients with a history of\n                  prostate cancer must not have any definitive radiation therapy to prostate area.\n\n               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence\n                  of disease.\n\n               3. Adequately treated carcinoma in situ without evidence of disease e.g., cervical\n                  cancer in situ.\n\n          -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,\n             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal\n             antibodies, other investigational agent) within14 days prior to the first dose of\n             study drug (14 days prior to the first dose of study drug for subjects who have\n             received prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for\n             nitrosourea or mitomycin C).\n\n          -  Mean QT interval corrected for heart rate (QTc) ?470 ms on electrocardiogram (ECG)\n             using Frediricia's Correction.\n\n          -  Current or prior use of immunosuppressive medication within 28 days before the first\n             dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or\n             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of\n             prednisone, or an equivalent corticosteroid.\n\n          -  Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. (Subjects\n             with irreversible toxicity that is not reasonably expected to be exacerbated by the\n             investigational product may be included (e.g., hearing loss, peripheral neuropathy).\n\n          -  Any prior Grade ?3 Immune-mediated adverse event (imAE) while receiving any previous\n             immunotherapy agent, or any unresolved imAE >Grade 1.\n\n          -  Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects\n             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within\n             the past 2 years) are not excluded. Patients with h/o completely resolved childhood\n             asthma or atopy will not be excluded. Patients with well-controlled hypothyroidism on\n             thyroxine replacement will be eligible as well.\n\n          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,\n             ulcerative colitis).\n\n          -  History of and/or confirmed pneumonitis.\n\n          -  History of primary immunodeficiency.\n\n          -  History of allogeneic organ transplant.\n\n          -  History of hypersensitivity to durvalumab or any excipient.\n\n          -  History of hypersensitivity to the combination or radiation therapy.\n\n          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable\n             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active\n             bleeding diatheses including any subject known to have evidence of acute or chronic\n             hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric\n             illness/social situations that would limit compliance with study requirements or\n             compromise the ability of the subject to give written informed consent.\n\n          -  Known history of previous clinical diagnosis of tuberculosis.\n\n          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within\n             30 days of starting treatment with durvalumab.\n\n        Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and\n        are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated\n        vaccines, and are not allowed.\n\n          -  Female subjects who are pregnant, breast-feeding or male or female patients of\n             reproductive potential who are not employing an effective method of birth control. For\n             this study male or female patients of reproductive potential need to employ two highly\n             effective and acceptable forms of contraception throughout their participation in the\n             study and for 90 days after last dose of study drug\n\n          -  Any condition that, in the opinion of the investigator, would interfere with\n             evaluation of study treatment or interpretation of patient safety or study results.\n\n          -  Brain metastases or history of leptomeningeal carcinomatosis.\n\n          -  Subjects with uncontrolled seizures.\n\n          -  Previous definitive radiation to pelvic area.
Inclusion Criteria:\n\n        To be eligible for participation in the study, patients must meet all of the following\n        inclusion criteria:\n\n          1. Patients enrolled in the Phase 1a study must:\n\n               1. Have a histologically confirmed diagnosis of advanced metastatic or progressive\n                  solid tumor\n\n               2. Be refractory to, or intolerant of, established therapy known to provide clinical\n                  benefit for their condition\n\n          2. Patients enrolled in the Phase 1b study must meet criteria for one of the following\n             tumor types:\n\n               1. Have tumors that have progressed despite immunotherapy and are felt to be\n                  appropriate for this type of treatment*\n\n               2. Have EGFR+ NSCLC and have progressed on ?2 lines of oral TKIs and are felt to be\n                  appropriate for this type of treatment*\n\n                  *Patients with immunotherapy-resistant tumors or EGFR+ NSCLC who are enrolled in\n                  these expansion cohorts will continue treatment with their previous immunotherapy\n                  or TKI regimens, respectively, and add TP-0903. The rationale is based on\n                  preclinical data that has shown that the combination is superior in patients who\n                  have progressed on prior immunotherapy or a TKI.\n\n               3. Have BRAF-, KRAS-, or NRAS-mutated CRC for whom there is no standard therapy\n                  remaining\n\n               4. Have persistent/recurrent ovarian cancer who would be platinum refractory/\n                  resistant and have had any number of lines of prior therapy\n\n               5. Have BRAF-mutated melanoma that has not responded to immunotherapy or a\n                  combination BRAF/MEK inhibitor\n\n          3. Have one or more tumors measurable or evaluable as outlined by modified RECIST v1.1\n\n          4. Have an Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO])\n             performance of ?1\n\n          5. Have a life expectancy ?3 months\n\n          6. Be ?18 years of age\n\n          7. Have a negative pregnancy test (if female of childbearing potential)\n\n          8. Have acceptable liver function:\n\n               1. Bilirubin ?1.5x upper limit of normal (ULN)\n\n                  *Patients receiving immunotherapy should have a bilirubin level <3.0x ULN.\n\n               2. Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) and\n                  alkaline phosphatase ?2.5x upper limit of normal (ULN)\n\n                    -  If liver metastases are present, then ?5x ULN is allowed.\n\n                    -  Patients receiving immunotherapy should have AST and ALT levels <5.0x ULN.\n\n          9. Have acceptable renal function:\n\n             a. Calculated creatinine clearance ?30 mL/min\n\n         10. Have acceptable hematologic status:\n\n               1. Granulocyte ?1500 cells/mm3\n\n               2. Platelet count ?100,000 (plt/mm3)\n\n               3. Hemoglobin ?9 g/dL\n\n         11. Have no clinically significant abnormalities on urinalysis\n\n         12. Have acceptable coagulation status:\n\n               1. Prothrombin time (PT) within 1.5x normal limits\n\n               2. Activated partial thromboplastin time (aPTT) within 1.5x normal limits\n\n         13. Be nonfertile or agree to use an adequate method of contraception. Sexually active\n             patients and their partners must use an effective method of contraception (hormonal or\n             barrier method of birth control; or abstinence) prior to study entry and for the\n             duration of study participation and for at least 30 days after the last study drug\n             dose (see Section 4.6.3). Should a woman become pregnant or suspect she is pregnant\n             while participating in this study, she should inform her treating physician\n             immediately.\n\n         14. Have read and signed the IRB-approved informed consent form prior to any study related\n             procedure. (In the event that the patient is re-screened for study participation or a\n             protocol amendment alters the care of an ongoing patient, a new informed consent form\n             must be signed.)\n\n         15. Patients enrolled in each of the five Expansion Cohorts must be willing to consider\n             pre-study and on-study biopsies, if safe and medically feasible, as determined by\n             local interventional radiology (3 to 5 core samples requested at each biopsy\n             timepoint)\n\n        Patients meeting any one of these exclusion criteria will be prohibited from participating\n        in this study:\n\n          1. Have New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial\n             infarction within the past 6 months prior to Day 1, unstable arrhythmia, or evidence\n             of ischemia on electrocardiogram (ECG) or during Cardiac Stress Testing within 14 days\n             prior to Day 1 (Appendix C)\n\n          2. Have a corrected QT interval (QTcF, Fridericia's method) of >450 msec in men and 470\n             msec in women\n\n          3. Have a seizure disorders requiring anticonvulsant therapy\n\n          4. Presence of symptomatic central nervous system metastatic disease or disease that\n             requires local therapy such as radiotherapy, surgery, or increasing dose of steroids\n             within the prior 2 weeks\n\n          5. Have severe chronic obstructive pulmonary disease with hypoxemia (defined as resting\n             O2 saturation of ?88% breathing room air)\n\n          6. Have undergone major surgery, other than diagnostic surgery, within 2 weeks prior to\n             Day 1\n\n          7. Have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic\n             therapy\n\n          8. Are pregnant or nursing\n\n          9. Received treatment with radiation therapy, surgery, chemotherapy, or investigational\n             therapy within 28 days or 5 half lives, whichever occurs first, prior to study entry\n             (6 weeks for nitrosoureas or Mitomycin C)\n\n             a. This exclusion criterion is not applicable for patients with EGFR+ NSCLC or\n             immunotherapy-resistant tumors who are enrolled in expansion cohorts at the MTD.\n\n         10. Are unwilling or unable to comply with procedures required in this protocol\n\n         11. Have known infection with human immunodeficiency virus (HIV), hepatitis B, or\n             hepatitis C. Patients with history of chronic hepatitis that is currently not active\n             are eligible\n\n         12. Have a serious nonmalignant disease (eg, hydronephrosis, liver failure, or other\n             conditions) that could compromise protocol objectives in the opinion of the\n             investigator and/or the sponsor\n\n         13. Are currently receiving any other investigational agent\n\n         14. Have exhibited allergic reactions to a similar structural compound, biological agent,\n             or formulation\n\n         15. Have undergone significant surgery to the gastrointestinal tract that could impair\n             absorption or that could result in short bowel syndrome with diarrhea due to\n             malabsorption\n\n         16. Have a history of severe adverse reaction (eg, hypersensitivity reaction, anaphylaxis)\n             to sulfonamides
Inclusion criteria. Patients may be entered in the study only if they meet all of the\n        following criteria:\n\n        1. Adults at least 18 years of age. 2. Eastern Cooperative Oncology Group (ECOG)\n        performance status ?1. 3.\n\n          1. Subjects with histopathologically or cytologically confirmed diagnosis of cutaneous\n             Melanoma, RCC or NSCLC, for whom the use of nivolumab is indicated. NSCLC subjects\n             with EGFR or ALK genomic aberrations in tumor should have disease progression on\n             FDA-approved therapy for these aberrations prior to receiving nivolumab (Phase 1b).\n\n          2. Subjects with histopathologically or cytologically confirmed diagnosis of cutaneous\n             Melanoma, or NSCLC, for whom the use of nivolumab is indicated. NCSLC subjects with\n             EGFR or ALK genomic aberrations in tumor should have disease progression on\n             FDA-approved therapy for these aberrations prior to receiving nivolumab (Phase 2\n             expansion).\n\n          3. Cutaneous melanoma and NSCLC patients whose disease has progressed after achieving PR\n             or CR on previous treatment with antagonists to PD1-PD-L1 axis, or patients whose\n             disease remains stable on previous treatment with antagonists to PD1-PD-L1 axis and\n             modification to treatment is being considered. NSCLC patients with EGFR or ALK genomic\n             aberrations in tumor should have disease progression on FDA-approved therapy for these\n             aberrations prior to receiving nivolumab (Phase 2 expansion).\n\n             4. Subject must have at least one measurable target lesion as defined by Response\n             Evaluation Criteria in Solid Tumors (RECIST) v.1.1.\n\n             5. All prior systemic therapy (chemotherapy, mutation targeting therapy, immune\n             checkpoint therapy), surgical or radiation treatment must have been completed at least\n             4 weeks before study drug administration (2 weeks for palliative radiotherapy, 1 week\n             for minor surgery) pending full recovery from therapy.\n\n             6. The following laboratory results within 7 days prior to study drug administration:\n             Adequate hematopoietic, electrolyte, hepatic, and renal laboratory findings as defined\n             below: WBC ?3000/?L, Neutrophils ?1500/?L, Platelets ?100x103/?L, Hemoglobin ?9.0g/dL\n             independent of transfusion, Creatinine ?1.5mg/dL, AST and ALT ?3x ULN, Alkaline\n             phosphatase ?2.5x ULN unless bone metastases present, Bilirubin ?1.5x ULN (unless\n             known Gilbert's disease where it must be ?3x ULN) and serum albumin ?3.0g/dL.\n\n             7. Life expectancy ?12 weeks. 8. A negative serum pregnancy test at baseline for women\n             of childbearing potential.\n\n             9. Are willing to abstain from heterosexual activity or practice physical barrier\n             contraception prior to time of study entry to at least 5 months after the last day of\n             treatment.\n\n             10. Have the ability to understand and the willingness to sign a written informed\n             consent document.\n\n             Exclusion criteria. Subjects who fulfill any of the following criteria at screening\n             will not be eligible for admission into the study:\n\n               1. History of Grade 3 or above hypersensitivity reactions to other monoclonal\n                  antibodies.\n\n               2. Subjects with a history of a cardiovascular illness including: QTcF >450ms in\n                  male, and >470ms in female, congenital long QT syndrome, congestive heart failure\n                  (New York Heart Association Grade III or IV); unstable angina or myocardial\n                  infarction within the previous 6 months; or symptomatic cardiac arrhythmia\n                  despite medical management.\n\n               3. Uncontrolled hypertension, SBP >160 or DBP >100.\n\n               4. Subjects with untreated, or treated brain metastasis, unless stable for 4 weeks\n                  or more and not requiring steroids.\n\n               5. Presence of leptomeningeal disease.\n\n               6. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled\n                  peptic ulcer disease or recurrent pleural effusion requiring repetitive\n                  palliative thoracentesis within 3 months prior to study entry, except for\n                  subjects with a pleurex port. and immune-mediated toxicity leading to treatment\n                  discontinuation\n\n               7. Active, known, or suspected autoimmune disease, except for type I diabetes\n                  mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such\n                  as vitiligo, psoriasis, or alopecia).\n\n               8. Active uncontrolled bacterial, viral, or fungal infection requiring systemic\n                  therapy.\n\n               9. Known history of testing positive for human immunodeficiency virus (HIV), known\n                  acquired immunodeficiency syndrome (AIDS).\n\n              10. Active hepatitis B (serum hepatitis B surface antigen [HBV sAg] positive), or\n                  hepatitis C (HCV antibody test or serum hepatitis C RNA positive) indicating\n                  acute or chronic infection.\n\n              11. Subjects with a condition requiring systemic treatment with either\n                  corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive\n                  medications within 14 days of study drug administration. Inhaled or topical\n                  steroids are permitted.\n\n              12. Use of other investigational agent (drug not marketed for any indication) within\n                  28 days or at least 5 half-lives (whichever is longer) before study drug\n                  administration.\n\n              13. Pregnant or breast-feeding women.\n\n              14. Second malignancy unless in remission for 2 years, except for non-melanomatous\n                  skin cancer, carcinoma in situ of the cervix treated with curative intent.\n\n              15. Underlying medical conditions that, in the Investigator's opinion, will make the\n                  administration of study drug hazardous or obscure the interpretation of toxicity\n                  determination or adverse events.\n\n              16. Unwilling or unable to comply with procedures required in this protocol.
Inclusion Criteria:\n\n        Subjects must meet all of the following criteria:\n\n          1. Written and signed informed consent.\n\n          2. Age ? 18 years at the time of study entry.\n\n          3. Subjects must have received and have progressed, are refractory, or are intolerant to\n             standard therapy appropriate for the specific tumor type. Subjects should not have\n             received more than 3 prior lines of systemic therapy for recurrent or metastatic.\n\n          4. Subjects in the dose-escalation phase, must have histologic documentation of advanced\n             solid tumors, excluding primary CNS tumors and hematologic malignancies.\n\n          5. Subjects in the dose-expansion phase, must have recurrent or metastatic disease solid\n             tumors according to treatment arm as specified in the protocol.\n\n          6. Subjects who have received prior therapy with regimens containing CTLA 4, PD L1, or PD\n             1 antagonists are permitted to enroll if additional protocol criteria are met.\n\n          7. Subjects must have at least 1 lesion that is measurable using RECIST guidelines.\n\n          8. Subjects must consent to provide archived tumor specimens for correlative biomarker\n             studies. In the setting where archival material is unavailable or unsuitable for use,\n             subjects must consent and undergo fresh tumor biopsy.\n\n          9. All subjects are encouraged to consent to and provide both pretreatment and on\n             treatment tumor biopsies.\n\n         10. ECOG Performance score of 0 or 1, unless protocol exceptions are met.\n\n         11. In the opinion of the investigator likely to complete ? 8 weeks of treatment.\n\n         12. Adequate hematologic, renal and hepatic function as determined by blood laboratory\n             values.\n\n         13. At the time of Day 1 of the study, subjects with CNS metastases must have been treated\n             and must be asymptomatic and meet the following:\n\n               1. No concurrent treatment, inclusive of, but not limited to surgery, radiation,\n                  and/or corticosteroids\n\n               2. At least 42 days without progression of CNS metastases as evidenced by magnetic\n                  resonance imaging (MRI) or computed tomography (CT) after last day of treatment\n\n               3. At least 14 days since last dose of corticosteroids Note: Subjects with\n                  leptomeningeal disease or cord compression are excluded from the study.\n\n         14. Female subjects of childbearing potential who are sexually active with a\n             non-sterilized male partner must use at least 1 highly effective method of\n             contraception from screening, and must agree to continue using such precautions for\n             180 days after the final dose of investigational product.\n\n         15. Non-sterilized male subjects who are sexually active with a female partner of\n             childbearing potential must use male condom plus, if locally available, spermicide\n             from Day 1 and for 180 days after receipt of the final dose of investigational\n             product.\n\n        Exclusion Criteria:\n\n        Any of the following would exclude the subject from participation in the study:\n\n          1. Prior treatment with TNFRSF agonists\n\n          2. Prior treatment with IMT for certain disease types may be restricted per protocol.\n\n          3. History of severe allergic reactions to any unknown allergens or any components of the\n             study drug formulations\n\n          4. Active or prior documented autoimmune disease within the past 2 years.\n\n          5. Concurrent enrollment in another clinical study, unless it is an observational\n             clinical study or the follow up period of an interventional study\n\n          6. Receipt of any conventional or investigational anticancer therapy not otherwise\n             specified above within 28 days prior to the first dose\n\n          7. Any concurrent chemotherapy, IMT, or biologic or hormonal therapy for cancer\n             treatment.\n\n          8. Unresolved toxicities from prior anticancer therapy.\n\n          9. Systemic therapeutic anticoagulation or daily aspirin dose exceeding 325 mg/per day.\n\n         10. Current or prior use of immunosuppressive medication within 14 days prior to the first\n             dose of MEDI0562 with exceptions as per protocol.\n\n         11. History of primary immunodeficiency, solid organ transplantation, or tuberculosis\n\n         12. Test results indicating active infection with human immunodeficiency virus (HIV) or\n             hepatitis B or C defined by positive serologic testing and confirmatory viral nucleic\n             acid testing\n\n         13. Pregnant or breastfeeding women\n\n         14. Major surgery within 4 weeks prior to first dose of MEDI0562 or still recovering from\n             prior surgery.\n\n         15. Other invasive malignancy within 2 years with the exception of protocol specified\n             criteria\n\n         16. Any uncontrolled intercurent illness or condition that, in the opinion of the\n             investigator, would interfere with evaluation of the investigational product or\n             interpretation of subject safety or study results.
INCLUSION CRITERIA: -Pathologically documented, multiple myeloma relapsed or refractory\n        disease after at least 2 lines of therapy, -Must be willing and able to undergo bone marrow\n        biopsy at screening, -Measurable disease per the IMWG response criteria, -Eastern\n        Cooperative Oncology Group (ECOG) performance status of ? 2, -Satisfactory hematological\n        function without transfusion or growth factor support, -Subjects should not have received\n        platelet transfusions for at least 1 week prior to screening, -Hemoglobin > 8 g/dL,\n        -Subjects may receive RBC transfusions or receive supportive care), -Other Inclusion\n        Criteria May Apply.\n\n        EXCLUSION CRITERIA: -Previously received an allogeneic stem cell transplant within 6 months\n        OR having received immunosuppressive therapy within the last three months OR having signs\n        or symptoms of acute or chronic graft-versus-host disease, -Autologous stem cell transplant\n        less than 90 days prior to study day 1, -Multiple myeloma with IgM subtype, -POEMS\n        syndrome, -Existing plasma cell leukemia, -Waldenstrom's macroglobulinemia, -Amyloidosis,\n        -Glucocorticoid therapy (prednisone > 30 mg/day or equivalent) within 7 days prior to\n        starting treatment, -Topical or inhaled corticosteroids are permitted, -Infection requiring\n        intravenous anti-infective treatments within 1 week of study enrollment (day 1), -Other\n        exclusion Criteria May Apply.
Inclusion Criteria:\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          -  Histologically or cytologically confirmed, Stage IV non-squamous NSCLC. Participants\n             with tumors of mixed non-small cell histology (i.e., squamous and non-squamous) are\n             eligible if the major histological component appears to be non-squamous\n\n          -  No prior treatment for Stage IV non-squamous NSCLC. Participants with a sensitizing\n             mutation in the epidermal growth factor receptor (EGFR) gene or with an anaplastic\n             lymphoma kinase (ALK) fusion oncogene are excluded. Participants with unknown EGFR and\n             ALK status require test results at screening from a local or central laboratory\n\n          -  Participants who have received prior neo-adjuvant, radiotherapy, adjuvant\n             chemotherapy, or chemoradiotherapy with curative intent for non-metastatic disease\n             must have experienced a treatment-free interval of at least 6 months from\n             randomization since the last dose of chemotherapy and/or radiotherapy\n\n          -  Participants should submit a pre-treatment tumor tissue sample if available before or\n             within 4 weeks after enrollment. If tumor tissue is not available, participants are\n             still eligible\n\n          -  For participants enrolled in the extended China enrollment phase: current resident of\n             mainland China, Hong Kong, or Taiwan and of Chinese ancestry\n\n          -  Measurable disease, as defined by RECIST v1.1\n\n          -  Adequate hematologic and end organ function\n\n          -  For women of childbearing potential: agreement to remain abstinent or use\n             contraceptive methods that result in a failure rate of less than (<) 1 percent (%) per\n             year during the treatment period and for at least 5 months after the last dose of\n             atezolizumab or 6 months after the last dose of cisplatin\n\n          -  For men: agreement to remain abstinent or use contraceptive measures and agreement to\n             refrain from donating sperm\n\n        Exclusion Criteria:\n\n        Cancer-Specific Exclusions\n\n          -  Participants with a sensitizing mutation in the EGFR gene or an ALK fusion oncogene\n\n          -  Active or untreated central nervous system (CNS) metastases as determined by computed\n             tomography (CT) or magnetic resonance imaging (MRI) evaluation during screening and\n             prior radiographic assessments\n\n          -  Spinal cord compression not definitively treated with surgery and/or radiation or\n             previously diagnosed and treated spinal cord compression without evidence that disease\n             has been clinically stable for greater than or equal to (>= 2) weeks prior to\n             randomization\n\n          -  Leptomeningeal disease\n\n          -  Uncontrolled tumor-related pain\n\n          -  Uncontrolled or symptomatic hypercalcemia (greater than [>] 1.5 millimole/Liter\n             ionized calcium or calcium >12 milligrams/deciliter or corrected serum calcium >upper\n             limit of normal)\n\n          -  Malignancies other than NSCLC within 5 years prior to randomization\n\n          -  Known tumor programmed death-ligand 1 (PD-L1) expression status from other clinical\n             studies (e.g., participants whose PD-L1 expression status was determined during\n             screening for entry into a study with anti-PD-1 or anti-PD L1 antibodies but were not\n             eligible are excluded)\n\n        General Medical Exclusions:\n\n          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to\n             chimeric or humanized antibodies or fusion proteins\n\n          -  History of certain autoimmune disease\n\n          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced\n             pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis\n\n          -  All participants will be tested for human immunodeficiency virus (HIV) prior to the\n             inclusion into the study and HIV-positive participants will be excluded from the\n             clinical study\n\n          -  Severe infections within 4 weeks prior to randomization\n\n          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease\n             (Class II or greater), myocardial infarction or cerebrovascular accident within 3\n             months prior to randomization, unstable arrhythmias, or unstable angina\n\n          -  Illness or condition that may interfere with a participant's capacity to understand,\n             follow, and/or comply with study procedures\n\n        Exclusion Criteria Related to Medications and Chemotherapy:\n\n          -  Prior treatment with EGFR inhibitors or ALK inhibitors\n\n          -  Any approved anti-cancer therapy, including hormonal therapy within 21 days prior to\n             initiation of study treatment\n\n          -  Prior treatment with cluster of differentiation 137 (CD137) agonists or immune\n             checkpoint blockade therapies, anti-PD-1, and anti-PD-L1 therapeutic antibodies\n\n          -  Treatment with systemic immunostimulatory agents within 4 weeks prior to randomization\n\n          -  Treatment with systemic immunosuppressive medications\n\n        Exclusion Criteria Related to Chemotherapy:\n\n          -  History of allergic reactions to cisplatin, carboplatin, or other platinum-containing\n             compounds\n\n          -  Participants with hearing impairment (cisplatin)\n\n          -  Grade >=2 peripheral neuropathy as defined by National Cancer Institute Common\n             Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 criteria (cisplatin)\n\n          -  Creatinine clearance (CRCL) <60 milliliters/minute (mL/min) for cisplatin or <45\n             mL/min for carboplatin
Inclusion Criteria (Part 2 Only):\n\n          -  Histological or cytological diagnosis of locally advanced or metastatic NSCLC or\n             urothelial carcinoma who have progressed on or were intolerant to standard of care\n             systemic therapy, or for whom standard of care systemic therapy was refused (refusal\n             must be documented) or unavailable.\n\n          -  No prior treatment with anti-PD-1 or anti-PD-L1 therapy.\n\n          -  NSCLC patients whose tumor is not known to have ALK or EGFR mutations must have\n             progressed on or after no more than 1 prior line of platinum-containing systemic\n             therapy or were intolerant or refused standard of care systemic therapy.\n\n          -  NSCLC patients whose tumor is known to have ALK or EGFR mutation must have received\n             prior systemic therapies that only include 1 or more lines of ALK or EGFR targeting\n             drugs and chemotherapy limited to 1 line of a platinum-based regimen and they must\n             have progressed on or after both types of therapies.\n\n          -  Urothelial carcinoma patients must have received up to 2 lines of prior systemic\n             therapy and progressed on or after, experienced disease recurrence within 12 months of\n             neoadjuvant or adjuvant treatment, were intolerant to, ineligible or refused\n             platinum-containing systemic therapy.\n\n          -  Provide archived tumor tissue sample taken within the past 2 years or provide a fresh\n             tumor biopsy sample.\n\n          -  At least one measurable lesion as defined by RECIST version 1.1.\n\n          -  Adequate renal, liver, thyroid and bone marrow function.\n\n          -  Performance status 0 or 1.\n\n          -  Patient is capable of receiving study treatment for at least 8 weeks.\n\n        Exclusion Criteria (Part 2 Only)\n\n          -  Active brain or leptomeningeal metastases.\n\n          -  Active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes\n             mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone\n             replacement, psoriasis not requiring systemic treatment, or conditions not expected to\n             recur in the absence of an external trigger are permitted to enroll. Diagnosis of\n             prior immunodeficiency or organ transplant requiring immunosuppressive therapy or\n             prior allogeneic bone marrow or hematopoietic stem cell transplant.\n\n          -  Patients with a condition requiring systemic treatment with either corticosteroids\n             (>10mg daily prednisone equivalents) or other immunosuppressive medications within 14\n             days of study drug administration. Inhaled or topical steroids, and adrenal\n             replacement doses >10 mg daily prednisone equivalents are permitted in the absence of\n             active autoimmune disease.\n\n          -  Patients with a history of interstitial lung disease, non-infectious pneumonitis, or\n             active pulmonary tuberculosis. Those with active lung infections requiring treatment\n             are also excluded.\n\n          -  History of Grade ?3 immune mediated AE (including AST/ALT elevations that where\n             considered drug related and cytokine release syndrome) that was considered related to\n             prior immune modulatory therapy (eg, immune checkpoint inhibitors, co-stimulatory\n             agents, etc.) and required immunosuppressive therapy.\n\n          -  Active hepatitis B or C, HIV/AIDS.\n\n          -  Other potentially metastatic malignancy within past 5 years.
Inclusion Criteria:\n\n          1. Male and female subjects at least 18 years at the time of screening\n\n          2. Adequate organ function within 14 days of enrollment confirmed by laboratory results\n\n          3. Off immunosuppressive medications including, but not limited to, systemic\n             corticosteroids at doses exceeding 10 mg/day prednisone or equivalent\n\n        Additional Inclusion Criteria for Part 1:\n\n          1. Metastatic/locally advanced solid tumor malignancy that has progressed on, is\n             refractory to, or for which there is no standard of care therapy\n\n          2. At least one lesion that is easily accessible for injection (subjects enrolled prior\n             to Amendment 3 only)\n\n          3. At least one deep-seated lesion suitable for intervention (subjects enrolled in the\n             deep-seated lesion expansion portion only)\n\n          4. At least 2 lesions (for subjects enrolled to evaluate addition of concurrent\n             palliative radiation to MEDI9197 therapy)\n\n        Additional Inclusion Criteria for Subjects in Part 2\n\n          1. Clinical diagnosis of CTCL, including documentation of a skin biopsy with histological\n             findings consistent with CTCL\n\n          2. Stage IB, IIA or IIB disease: T1, T2 or T3 (patches, plaques or tumors) with\n             measurable lesions\n\n          3. Previous treatment with at least one standard therapy used to treat the stage of\n             disease at study entry\n\n          4. At least 2 lesions amenable to response assessment\n\n        Additional Inclusion Criteria for Subjects in Part 3A and 3B\n\n        1. Metastatic/locally advanced solid tumor malignancy that has progressed on, is refractory\n        to, or for which there is no standard of care therapy\n\n        Exclusion Criteria:\n\n        Any of the following would exclude the subject from participation in the study:\n\n          1. Subjects who have received prior immunotherapy are NOT permitted to enroll unless all\n             of the following apply:\n\n               1. Prior anti-CTLA 4 inhibitor last dose administered at least 100 days ago. Other\n                  prior immunotherapies, the last dose administered at least 28 days prior to\n                  planned first dose of MEDI9197\n\n               2. Must not have experienced a toxicity that led to permanent discontinuation of\n                  prior immunotherapy\n\n               3. All AEs while receiving prior immunotherapy must have resolved to ? Grade 1 or\n                  baseline prior to screening for this study. Must not have experienced a ? Grade 3\n                  AE or neurologic, pneumonitis or ocular AE of any grade while receiving prior\n                  immunotherapy\n\n               4. Must not have required the use of additional immunosuppression other than\n                  corticosteroids for the management of an AE, not have experienced recurrence of\n                  an AE if re-challenged, and not currently require maintenance doses of > 10 mg\n                  prednisone or equivalent per day\n\n          2. Pregnant or lactating\n\n          3. Active bacterial, fungal, or viral infections\n\n          4. Active autoimmune disease, chronic inflammatory condition, conditions requiring\n             concurrent use of any systemic immunosuppressants or steroids\n\n          5. Immune-deficiency states - myelodysplastic disorders, marrow failures, human\n             immunodeficiency virus (HIV) infection, history of solid organ transplant or bone\n             marrow allograft, or recent pregnancy\n\n          6. Requires continuous anticoagulation or antiplatelet therapy.\n\n          7. History of coagulopathy resulting in uncontrolled bleeding.\n\n          8. Rapidly progressing disease\n\n          9. Untreated or uncontrolled central nervous system (CNS) involvement.\n\n         10. Any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer\n             treatment\n\n         11. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to\n             NCI CTCAE v4.03 Grade 0 or 1, with exception of alopecia, vitiligo and laboratory\n             values listed per inclusion criteria\n\n         12. Chronic active hepatitis B or C\n\n         13. Known allergy to sesame oil and/or nuts\n\n         14. Cardiac exclusions: New York Heart Association Class 3 or 4 congestive heart failure,\n             uncontrolled hypertension, unstable angina pectoris, clinical important cardiac\n             arrhythmia, mean QTC interval corrected for heart rate >500ms\n\n         15. Major surgery within 4 weeks prior to study entry or still recovering from prior\n             surgery\n\n         16. Receipt of live, attenuated vaccine within 28 days prior to study entry.\n\n         17. Receipt of any systemic anticancer therapy not mentioned above within the last 2 weeks\n             or 5 half-lives\n\n         18. Subjects with CTCL, must not have had prior therapy with Imiquimod, total body\n             electron beam radiation, investigational drugs or treatments within 8 weeks. They must\n             not have had prior therapy with local radiation, UBV therapy, PUVA, any topical\n             chemotherapy, photopheresis, systemic retinoids, corticosteroids, immune response\n             modifiers, IFN inducers, chemotherapeutic agents or biological agents or any topical\n             treatment within 4 weeks. They must not have a known history or positive test for\n             infection with HTLV-1.\n\n         19. Cognitive disorder such that informed consent cannot be obtained directly from the\n             subject\n\n         20. Subjects who have previously participated in this study and received MEDI9197.\n\n         21. Subjects who have received prior TLR agonists, both systemic and topical.\n\n         22. Patients who have received prior therapeutic radiation within 28 days of dosing. All\n             toxicities from prior radiotherapy must have resolved to ? Grade 1 or baseline prior\n             to dosing.
Inclusion Criteria:\n\n          1. Written informed consent in accordance with federal, local, and institutional\n             guidelines.\n\n          2. Age ? 18 years at the time of informed consent\n\n          3. Histologically confirmed diagnosis, measurable disease and evidence of disease\n             progression of MM, as described below.\n\n          4. Symptomatic MM, based on IMWG guidelines. Patients must have measurable disease as\n             defined by at least one of the following:\n\n               1. Serum M-protein ? 0.5 g/dL by serum protein electrophoresis (SPEP) or, for IgA\n                  myeloma, by quantitative IgA\n\n               2. Urinary M-protein excretion at least 200 mg/24 hours\n\n               3. Serum FLC ? 100 mg/L, provided that FLC ratio is abnormal\n\n               4. If serum protein electrophoresis is felt to be unreliable for routine M-protein\n                  measurement (e.g., for IgA MM), then quantitative Ig levels by nephelometry or\n                  turbidometry are acceptable.\n\n          5. Any non-hematological toxicities (except for peripheral neuropathy as described in\n             exclusion criterion #24) that patients experienced from treatments in previous\n             clinical studies must have resolved to ? Grade 2 by Cycle 1 Day 1.\n\n          6. Eastern Cooperative Oncology Group (ECOG) Performance Status of ? 2.\n\n          7. Adequate hepatic function within 21 days prior to C1 D1:\n\n               -  For SPd and SRd: Total bilirubin < 2x ULN (except patients with Gilbert's\n                  syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin\n                  of ? 3x ULN) and both AST and ALT < 2.5x ULN)\n\n               -  For SVd, SPVd and SDd): Total bilirubin of ? 1.5x ULN (except patients with\n                  Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total\n                  bilirubin of ? 3x ULN) and both AST and ALT < 2.0x ULN)\n\n          8. Adequate renal function within 21 days prior to C1 D1:\n\n               -  Estimated creatinine clearance of (calculated using the formula of Cockroft and\n                  Gault):\n\n               -  ? 20 mL/min for SVd, SPVd, and SDd Arms\n\n               -  ? 45 mL/min for SPd Arm (as requested by the manufacturer)\n\n               -  > 50 mL/min for SRd Arm\n\n          9. Adequate hematopoietic function within 21 days prior to C1 D1: total white blood cell\n             (WBC) count ? 1,500/mm3, ANC ? 1000/mm3, hemoglobin (Hb) ? 8.0 g/dL, and platelet\n             count ? 75,000/mm3. For expansion cohorts only, platelet counts > 50,000/mm3; for\n             patients in whom ? 50% of bone marrow nucleated cells are plasma cells, platelets or ?\n             30,000/mm3 are acceptable for expansion cohorts. Patients receiving hematopoietic\n             growth factor support, including erythropoietin (EPO), darbepoetin, granulocyte-colony\n             stimulating factor (G-CSF), granulocyte macrophagecolony stimulating factor (GM-CSF),\n             and platelet stimulators (e.g., eltrombopag or romiplostim) may continue to do so.\n             However, patients in the escalation cohorts must be platelet transfusion independent\n             for > 1 week in order to be enrolled in the study.\n\n         10. Female patients of child-bearing potential must agree to use dual methods of\n             contraception and have a negative serum pregnancy test at Screening. Male patients\n             must use an effective barrier method of contraception if sexually active with a female\n             of child-bearing potential. Acceptable methods of contraception are condoms with\n             contraceptive foam, oral, implantable or injectable contraceptives, contraceptive\n             patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is\n             surgically sterilized or post-menopausal. For both male and female patients, effective\n             methods of contraception must be used throughout the study and for three months\n             following the last dose.\n\n             SPd (Arm 1) Only:\n\n         11. Relapsed and refractory MM with:\n\n               1. Documented evidence of PD after achieving at least SD for ? 1 cycle during a\n                  previous MM regimen (i.e., relapsed MM)\n\n               2. ? 25% response (i.e., patients never achieved ? MR) or PD during or within 60\n                  days from the end of the most recent MM regimen (i.e., refractory MM)\n\n               3. Previously undergone ? 2 cycles of lenalidomide and a proteasome inhibitor (in\n                  separate therapeutic regimens [not for maintenance] or in combination)\n\n               4. In the expansion arm at RP2D, patients must not be pomalidomide refractory\n\n             SVd (Arm 2) Only:\n\n         12. Relapsed or refractory MM with\n\n               1. Documented evidence of relapse after ? 1 previous line of therapy\n\n               2. Not refractory to bortezomib in their most recent line of therapy\n\n             SRd in RRMM (Arm 3) Only:\n\n         13. Patients who received ? 1 prior therapeutic regimen (prior lenalidomide is allowed as\n             long as patient's MM was not refractory to prior lenalidomide; patients whose MM was\n             refractory to lenalidomide maintenance regimens will be allowed in this cohort).\n\n             SPVd (Arm 4) Only:\n\n         14. Patients whose MM is relapsing after ? 1 prior therapy with progression on their last\n             therapy.\n\n             SDd (Arm 5) Only:\n\n         15. Patients who received ? 3 prior lines of therapy, including a PI and an IMiD, or\n             patients with MM refractory to both a PI and an IMiD.\n\n         16. Patients must not have received prior daratumumab therapy (Cohort 5.3 ONLY - dose\n             expansion at RP2D).\n\n             SKd (Arm 6) Only:\n\n         17. Patients may have received prior bortezomib or carfilzomib therapy, however their MM\n             must NOT be refractory to carfilzomib.\n\n             SRd in NDMM (Arm 7) Only:\n\n         18. Patients must have symptomatic myeloma per IMWG guidelines with either CRAB criteria\n             or Myeloma Defining Events and need systemic therapy.\n\n         19. No prior systemic therapy for NDMM is permitted other than pulse dose dexamethasone\n             (maximum dose of 160 mg).\n\n        Exclusion Criteria:\n\n        Patients meeting any of the following exclusion criteria are not eligible to enroll in this\n        study:\n\n          1. Smoldering MM\n\n          2. MM that does not express M-protein or FLC (i.e., non-secretory MM is excluded), and\n             quantitative immunoglobulin levels cannot be used instead\n\n          3. Documented active systemic amyloid light chain amyloidosis\n\n          4. Active plasma cell leukemia\n\n          5. Blood (or blood product) transfusions and blood growth factors within 7 days of C1D1\n             (only for patients enrolling into the Expansion Phase)\n\n          6. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ? 2 weeks\n             prior to C1D1, and radio-immunotherapy within 6 weeks prior to C1D1. Patients on\n             long-term glucocorticoids during Screening do not require a washout period. Prior\n             radiation is permitted for treatment of fractures or to prevent fractures as well as\n             for pain management\n\n          7. Patients with history of SCC with residual paraplegia (Dose Escalation Phase only).\n\n          8. Treatment with an investigational anti-cancer therapy within 3 weeks prior to C1D1\n\n          9. Prior autologous stem cell transplantation < 1 month, or allogeneic stem cell\n             transplantation < 3 months prior to C1D1\n\n         10. Active graft versus host disease after allogeneic stem cell transplantation\n\n         11. Life expectancy < 3 months\n\n         12. Major surgery within 4 weeks prior to C1D1\n\n         13. Active, unstable cardiovascular function:\n\n               1. Symptomatic ischemia, or\n\n               2. Uncontrolled clinically-significant conduction abnormalities (e.g., patients with\n                  ventricular tachycardia on antiarrhythmics are excluded; patients with 1st degree\n                  atrioventricular (AV) block or asymptomatic left anterior fascicular block/right\n                  bundle branch block (LAFB/RBBB) will not be excluded), or\n\n               3. Congestive heart failure (CHF) of New York Heart Association (NYHA) Class ? 3, or\n\n               4. Myocardial infarction (MI) within 3 months prior to C1D1\n\n               5. Ejection fraction (EF) < 50% at Screening\n\n         14. Uncontrolled active hypertension\n\n         15. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or\n             antifungals within one week prior to first dose\n\n         16. Known active hepatitis A, B or C\n\n         17. Known HIV infection or HIV seropositivity\n\n         18. Any active gastrointestinal dysfunction that prevents the patient from swallowing\n             tablets or interferes with absorption of study treatment\n\n         19. Currently pregnant or breastfeeding\n\n         20. A serious psychiatric or medical condition which, in the opinion of the Investigator,\n             could interfere with treatment\n\n         21. Hypersensitivity to any of the treatments for the Arm in which the patient is enrolled\n\n         22. In the SVd (Arm 2) only: Prior history of neuropathy Grade > 2, or Grade 2 neuropathy\n             with pain at screening (within 21 days prior to C1D1)\n\n         23. Prior exposure to a SINE compound, including selinexor
Inlcusion criteria:\n\n        - Adult patients with histologically or cytologically confirmed cholangiocarcinoma at the\n        time of diagnosis.\n\n        Patients with cancers of the gallbladder or ampulla of Vater are not eligible.\n\n        - Patients must have received at least one prior regimen containing gemcitabine with or\n        without cisplatin for advanced/ metastatic disease. Patient should have evidence of\n        progressive disease following prior regimen, or if prior treatment discontinued due to\n        toxicity must have continued evidence of measurable or evaluable disease.\n\n        Exclusion criteria:\n\n          -  Prior or current treatment with a MEK or selective FGFR inhibitor\n\n          -  insufficient organ function\n\n               -  ANC < 1,000/mm3 [1.0 x 109/L]\n\n               -  Platelets < 75,000/mm3 [75 x 109/L]\n\n               -  Hemoglobin < 109.0 g/dL\n\n               -  Total bilirubin > 1.5x ULN\n\n               -  AST/SGOT and ALT/SGPT > 2.5x ULN (AST and ALT > 5x ULN in the presence of liver\n                  metastases)\n\n               -  Serum creatinine > 1.5x ULN and a calculated or measured creatinine clearance <\n                  45 mL/min\n\n               -  Inorganic phosphorus outside of normal limits\n\n               -  Total and ionized serum calcium outside of normal limits\n\n        Other protocol-defined inclusion/exclusion criteria may apply.
Inclusion Criteria:\n\n        For Advanced GI Malignancies (Dose Escalation and MTD Cohorts):\n\n          1. Advanced histologically proven GI cancer.\n\n          2. First line or progressive disease if already treated with any form of therapy,\n             including but not limited to chemotherapy, radiotherapy, local therapy, surgery or\n             immuno-therapy. Patients with HCC who failed sorafenib, with documented PD or AEs that\n             resulted in discontinuance of that agent. Patients with pancreatic cancer (dose\n             escalation only) who have progressed following a gemcitabine based regimen. Subjects\n             failing prior platinum containing regimens are eligible. Gastric cancer subjects that\n             express tumor HER-2 amplification must be treated with trastuzumab prior to\n             enrollment, unless trastuzumab is not available for those indications in a particular\n             country.\n\n          3. Measurable disease using RECIST 1.1 criteria (Appendix A). At least 1 measurable\n             lesion must be present. Subjects who have received local-regional therapy such as (but\n             not limited to) chemoembolization, embolization, cryoablation, hepatic artery therapy,\n             percutaneous ethanol injection, radiation therapy, radiofrequency ablation or surgery\n             are eligible, provided that they have either a target lesion which has not been\n             treated with local therapy and/or the target lesion(s) within the field of the local\n             regional therapy has shown an increase of ? 20% in size. Local-regional therapy must\n             be completed at least 4 weeks prior to the baseline CT scan.\n\n          4. ECOG performance status of 0 - 1.\n\n          5. Expected survival of at least 3 months.\n\n        For HCC (Dose Escalation and MTD Expansion):\n\n        19. Prior treatment with sorafenib, with documented PD or AEs that resulted in\n        discontinuance of that agent. Patient may have been treated with other lines off therapy as\n        well excluding ADI-PEG 20.\n\n        20. Cirrhotic status of Child-Pugh grade A. Child-Pugh status should be determined based on\n        clinical findings and laboratory data during the screening period (Appendix C). Subjects on\n        Coumadin anti-coagulants are to receive only 1 point for their INR status.\n\n        21. Serum albumin level ? 2.8 g/dl. 22. Prothrombin time (PT)-international normalized\n        ratio (INR): PT <6 seconds above control or INR <1.7. Subjects on Coumadin anti-coagulants\n        are to receive only 1 point for their INR status.\n\n        23. Subjects with active hepatitis B or C on anti-viremic compounds may remain on such\n        treatment, except for interferon.\n\n        Exclusion Criteria:\n\n          1. Serious infection requiring treatment with systemically administered antibiotics at\n             the time of study entrance, or an infection requiring systemic antibiotic therapy\n             within 7 days prior to the first dose of study treatment.\n\n          2. Pregnancy or lactation.\n\n          3. Expected non-compliance.\n\n          4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure (New York Heart Association Class III\n             or IV), cardiac arrhythmia, or psychiatric illness, social situations that would limit\n             compliance with study requirements.\n\n          5. Subjects who have had any anticancer treatment prior to entering the study and have\n             not recovered to baseline (except alopecia) or ? Grade 1 AEs, or deemed irreversible\n             from the effects of prior cancer therapy. AEs > Grade 1 that are not considered a\n             safety risk by the Sponsor and investigator may be allowed upon agreement with both.
Inclusion Criteria\n\n        Each patient must meet all of the following inclusion criteria to be enrolled in the study:\n\n        Phase 1b and Phase 2\n\n          1. Advanced or metastatic breast cancer.\n\n          2. Histological or cytological confirmation of ER+ status (defined as > 1% positive tumor\n             cells), and histological or cytological confirmation of HER2-negative (HER2-) status\n             by local laboratory testing using criteria in the American Society of Oncology\n             (ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.[44]\n\n          3. Female patients 18 years of age or older who:Are postmenopausal for at least 1 year\n             before the Screening visit, where menopause is defined by: Age ? 55 years and 1 year\n             or more of amenorrhea\n\n             Age < 55 years and 1 year or more of amenorrhea, with an estradiol assay < 20 pg/mL\n             oSurgical menopause with bilateral oophorectomy\n\n             Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone\n             agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of\n             ovarian suppression.\n\n          4. Patients who have a history of brain metastasis are eligible for the study provided\n             that all the following criteria are met:\n\n               -  Brain metastases which have been treated\n\n               -  No evidence of disease progression for ? 3 months or hemorrhage after treatment\n\n               -  Off-treatment with dexamethasone for 4 weeks before administration of the first\n                  dose of MLN0128\n\n               -  No ongoing requirement for dexamethasone or anti-epileptic drugs\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.\n\n          6. Clinical laboratory values as specified below within 4 weeks before the first dose of\n             MLN0128:\n\n               -  Bone marrow reserve consistent with absolute neutrophil count (ANC) ? 1.5 x\n                  10^9/L; platelet count ? 100 x 10^9/L; hemoglobin ? 9 g/dL\n\n               -  Total bilirubin ? 1.5 x the upper limit of the normal range (ULN), aspartate\n                  aminotransferase (AST) and alanine aminotransferase (ALT) ? 2.5 x ULN (? 5 x ULN\n                  if liver metastases are present)\n\n               -  Creatinine clearance ? 50 mL/min based either on Cockcroft-Gault estimate or\n                  based on a 12- or 24-hour urine collection\n\n               -  Fasting serum glucose ? 130 mg/dL and fasting triglycerides ? 300 mg/dL\n\n          7. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of\n             institutional standard of normal as measured by echocardiogram (ECHO) or multiple\n             gated acquisition scan (MUGA) within 4 weeks before the first dose of MLN0128 (ie, if\n             the institutional standard of normal is 50%, LVEF may be as low as 45% to be eligible\n             for the study).\n\n          8. Able to provide paraffin blocks or a minimum of 10 unstained slides of available\n             archival tumor tissues (paraffin blocks are preferred). If archival tumor tissue is\n             not available, a tumor biopsy may be performed before the patient begins treatment\n             with MLN0128. If fewer than 10 slides are available or the tumor content/area\n             requirements are not met, study eligibility will be determined upon discussion with\n             the sponsor.\n\n          9. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and\n             suitable venous access for the study-required blood sampling.\n\n         10. Voluntary written consent must be given before the performance of any study related\n             procedure not part of standard medical care, with the understanding that consent may\n             be withdrawn by the patient at any time without prejudice to future medical care.\n\n             Phase 1b Only: In addition to the previously mentioned inclusion criteria, each\n             patient must meet the following inclusion criterion to be enrolled in the phase 1b\n             portion of the study:\n\n         11. Patients may have SD or disease progression during their most recent treatment with\n             exemestane or fulvestrant, or everolimus in combination with either exemestane (any\n             country) or fulvestrant (US only). Exemestane or fulvestrant in combination with\n             MLN0128 can also be initiated as a new line of therapy.\n\n             Phase 2 Only: In addition to the previously mentioned inclusion criteria, each patient\n             must meet all of the following inclusion criteria to be enrolled in the phase 2\n             portion of the study:\n\n         12. Measureable disease defined as follows:\n\n               -  At least 1 extra-osseous lesion that can be accurately measured in at least 1\n                  dimension. The lesion must measure ? 20 mm with conventional imaging techniques\n                  or ? 10 mm with spiral CT or MRI, or\n\n               -  Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable\n                  disease as defined above\n\n         13. Patients must have had disease progression during treatment with everolimus in\n             combination with either exemestane (any country) or fulvestrant (US only) (duration of\n             treatment ? 4 weeks) and must have tolerated everolimus treatment in combination with\n             exemestane (any country) or fulvestrant (US only) adequately according to the treating\n             physician's judgment. Everolimus in combination with exemestane or fulvestrant is not\n             required to be the most recent treatment before enrollment, but progression on the\n             most recent anticancer therapy is required for enrollment.\n\n        Exclusion Criteria\n\n        Patients meeting any of the following exclusion criteria are not to be enrolled in the\n        study:\n\n        Phase 1b and Phase 2\n\n          1. Prior anticancer therapy or other investigational therapy within 2 weeks before\n             administration of the first dose of MLN0128 (except for exemestane or fulvestrant,\n             which should be continued). Treatment with everolimus must be discontinued 2 weeks\n             before administration of the first dose of MLN0128.\n\n          2. Chronic concomitant therapy with bisphosphonates or denosumab for the prevention of\n             bone metastases. Concomitant treatment with bisphosphonates or denosumab is permitted\n             for treatment of osteoporosis or management of existing bone metastases if initiated\n             at least 4 weeks before administration of the first dose of MLN0128.\n\n          3. Initiation of treatment with hematopoietic growth factors, transfusions of blood and\n             blood products, or systemic corticosteroids (either IV or oral steroids, excluding\n             inhalers) within 1 week before administration of the first dose of MLN0128 (patients\n             already receiving erythropoietin on a chronic basis for ? 4 weeks are eligible).\n\n          4. Previous treatment with dual PI3K/mTOR inhibitors or TORC1/2 inhibitors.\n\n          5. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI\n             disease, or for an unknown reason that may alter the absorption of MLN0128.\n\n          6. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%;\n             patients with a history of transient glucose intolerance due to corticosteroid\n             administration may be enrolled in this study if all other inclusion/exclusion criteria\n             are met.\n\n          7. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,\n             active central nervous system disease, active infection, or any other condition that\n             could compromise participation of the patient in the study.\n\n          8. Known human immunodeficiency virus infection.\n\n          9. History of any of the following within the last 6 months before administration of the\n             first dose of MLN0128:\n\n               -  Ischemic myocardial event, including angina requiring therapy and artery\n                  revascularization procedures\n\n               -  Ischemic cerebrovascular event, including transient ischemic attack and artery\n                  revascularization procedures\n\n               -  Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)\n                  cardiac arrhythmia (including atrial flutter/fibrillation, ventricular\n                  fibrillation, or ventricular tachycardia)\n\n               -  Placement of a pacemaker for control of rhythm\n\n               -  New York Heart Association Class III or IV heart failure\n\n               -  Pulmonary embolism\n\n         10. Significant active cardiovascular or pulmonary disease before administration of the\n             first dose of MLN0128, including:\n\n               -  Uncontrolled hypertension (ie, systolic blood pressure > 180 mm Hg; diastolic\n                  blood pressure > 95 mm Hg)\n\n               -  Pulmonary hypertension\n\n               -  Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis or\n                  pulse oximetry on room air\n\n               -  Significant valvular disease; severe regurgitation or stenosis by imaging\n                  independent of symptom control with medical intervention; or history of valve\n                  replacement\n\n               -  Medically significant (symptomatic) bradycardia\n\n               -  History of arrhythmia requiring an implantable cardiac defibrillator\n\n               -  Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated\n                  demonstration of QTc interval > 480 ms, or history of congenital long QT\n                  syndrome, or torsades de pointes)\n\n         11. Diagnosed or treated for another malignancy within 2 years before administration of\n             the first dose of MLN0128 or previously diagnosed with another malignancy and have any\n             evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in\n             situ of any type are not excluded if they have undergone complete resection.\n\n             Phase 1b Only: In addition to the previously mentioned exclusion criteria, patients\n             meeting the following exclusion criterion are not to be enrolled in the phase 1b\n             portion of the study:\n\n         12. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease.\n\n             Phase 2 Only: In addition to the previously mentioned exclusion criteria, patients\n             meeting the following exclusion criterion are not to be enrolled in the phase 2\n             portion of the study:\n\n         13. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease.
Inclusion Criteria:\n\n        Key Inclusion Criteria:\n\n        Subjects must meet all of the following criteria to be included:\n\n          1. Male aged between 50 and 80 years (inclusive) with histologically documented\n             clinically localized, adenocarcinoma of the prostate.\n\n          2. Subject with clinical stage T1 or T2 with Gleason score of 6 or 7 (3+4 or 4+3).\n\n          3. At least one (1) MRI evaluable tumor with volume of 400 mm3 or greater.\n\n          4. At least total of 10 mm of cancer tissue based on an MRI guided 12-core biopsy.\n\n          5. Recent (? 6 months prior to study entry) negative bone scan and computerized\n             tomography (CT) scan of abdomen/pelvis.\n\n          6. Life expectancy of at least 5 years.\n\n          7. Subjects should have adequate bone marrow function defined as an absolute peripheral\n             granulocyte count ? 1,500 and platelet count of ? 100,000, adequate hepatic function\n             with a bilirubin ? 1.5 mg/dl and serum glutamic-pyruvic transaminase (SGPT) < 4x the\n             upper limits of normal, adequate renal function defined as serum creatinine ? 2.0\n             mg/dl\n\n          8. Subjects must have a coagulation profile (prothrombin time [PT], partial\n             thromboplastin time [PTT]) not more than 2-times the upper limit of normal and no\n             history of substantial non-iatrogenic bleeding diatheses. Use of anticoagulants within\n             5-days of the Ad5-SGE-REIC/Dkk-3 injections is limited to local use only (for control\n             of central line patency).\n\n          9. Subject is willing to refrain from sexual activity or agrees to use a barrier\n             contraceptive device (e.g. condom) for 8-weeks after treatment with\n             Ad5-SGE-REIC/Dkk-3.\n\n         10. Subjects must sign an informed consent indicating that they are aware of the\n             investigational nature of the study.\n\n        Key Exclusion Criteria\n\n        Subjects meeting any of the following criteria will be excluded:\n\n          1. Prior primary radiation treatment to the prostate.\n\n          2. Severe bladder outlet obstructive disorder (AUA >25) or urinary track retention.\n\n          3. Chemotherapy, immunotherapy or other investigational study drug within the past 4\n             weeks.\n\n          4. Unable to tolerate TRUS.\n\n          5. Subjects with uncontrolled cardiac, hepatic, renal or neurologic/psychiatric\n             disorders, that in the opinion of the investigator put the subject at significant\n             risk, are not eligible.\n\n          6. Subjects who are HIV positive or have active hepatitis B or C infections are not\n             eligible.\n\n          7. Subjects with a clinical history of primary or secondary immunodeficiency, autoimmune\n             disease or subjects taking immunosuppressive drugs such as corticosteroids\n             continuously for > 4 months [> 5 mg hydrocortisone/day] are ineligible.\n\n          8. As a result of medical review, physical examination, the Principal Investigator (or\n             medically qualified nominee) considers the subject unfit for the study.
Inclusion Criteria:\n\n        Arms 1 and 2 Participants:\n\n          -  Has any histologically or cytologically confirmed advanced/metastatic solid tumor by\n             pathology report and has received, or have been intolerant to all treatment known to\n             confer clinical benefit. Solid tumors and lymphomas of any type are eligible for\n             enrollment. For cutaneous T-cell lymphoma (CTCL), histopathological diagnosis should\n             be confirmed in a skin biopsy representative of disease.\n\n          -  Have Stage III or Stage IV disease that is not surgically resectable. Stage IIB\n             (T3N0M0B0-1) CTCL participants are eligible.\n\n        Arm 3 Participants:\n\n        -Has metastatic liver and/or liver lesion involvement that does not exceed one third of the\n        total liver volume in participants to be treated by liver IT injection. Hepatocellular\n        carcinoma participants are excluded from eligibility of IT liver injection.\n\n        All Participants:\n\n          -  Stage III or Stage IV disease that is not surgically resectable.\n\n          -  Has ?1 injectable lesion that is amenable to injection and biopsy via visual\n             inspection for a cutaneous lesion, or via ultrasound guidance for a subcutaneous\n             lesion.\n\n          -  Has ?1 discrete, distant noninjected lesion that is amenable to biopsy via visual\n             inspection or amenable to biopsy via image guidance.\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.\n\n          -  Demonstrates adequate organ function.\n\n          -  If of childbearing potential, must agree to use adequate contraception during the\n             treatment period and for at least 120 days after the last dose of study treatment.\n\n        Exclusion Criteria:\n\n          -  History of a second malignancy, unless potentially curative treatment has been\n             completed, with no evidence of malignancy for 2 years (except for successful\n             definitive resection of basal cell carcinoma of the skin, superficial bladder cancer,\n             or in situ cervical cancer).\n\n          -  Clinically active central nervous system metastases and/or carcinomatous meningitis.\n\n          -  Severe hypersensitivity reaction to treatment with a monoclonal antibody (mAb).\n\n          -  Active autoimmune disease that has required systemic treatment in the past 2 years.\n\n          -  History of vasculitis.\n\n          -  Active infection requiring therapy.\n\n          -  History of (noninfectious) pneumonitis that required steroids or current pneumonitis.\n\n          -  Undergone prior allogeneic hematopoietic stem cell transplantation within the last 5\n             years.\n\n          -  Known human immunodeficiency virus (HIV) and/or Hepatitis B or C infection.\n\n          -  Pregnant or breastfeeding, or expecting to conceive or father children within the\n             projected duration of the study.\n\n          -  Not fully recovered from any effects of major surgery, and is free of significant\n             detectable infection.\n\n          -  Had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2\n             weeks for palliative radiation) prior to the first dose of study treatment, or has not\n             recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) Grade\n             1 from the AEs due to cancer therapeutics administered >4 weeks earlier.\n\n          -  Been treated within 2 weeks of Cycle 1 Day1 with any of the following: strong/moderate\n             Cytochrome P450 2C9 (CYP2C9) inhibitors, such as: amiodarone, felbamate, fluconazole,\n             miconazole, piperine, oxandrolone, fluorouracil and its derivatives (combination drug\n             tegafur/gimeracil/oteracil [TS-1], Uftoral [UFT], tegafur, carmofur, doxifluridine,\n             capecitabine), sulfaphenazole, cyclosporine, bucurol, tienilic acid; UGT1A3 inhibitors\n             (including ritonavir, quinidine, probenecid, and valproic acid); or strong carbonyl\n             reductase (CBR) inhibitors (including quercetin, menadione, glycyrrhetinic acid, and\n             flufenamic acid).\n\n          -  Currently participating and receiving study therapy or has participated in a study of\n             an investigational agent and has received study therapy or has used an investigational\n             device within 28 days of administration of MK 2118.\n\n          -  Expected to require any other form of antineoplastic therapy while on study.\n\n          -  On chronic systemic steroid therapy in excess of replacement doses (prednisone ?10\n             mg/day is acceptable), or on any other form of immunosuppressive medication. For CTCL,\n             continued use of either prednisone ?10 mg/day or continued use of topical steroids is\n             acceptable.\n\n          -  Received a live vaccine within 28 days prior to first dose.\n\n          -  Been treated with a stimulator of interferon genes (STING) agonist (eg, MK-1454,\n             ADU-S100 [synthetic cyclic dinucleotide (CDN)]).\n\n          -  Has a history of re-irradiation for SCCHN at the projected injection site.\n\n          -  Has a tumor(s) in direct contact or encases a major blood vessel and has ulceration\n             and/or fungation onto the skin surface at the projected injection site.
Inclusion Criteria:\n\n          -  Disease Related\n\n               -  Patients must have documented history of histologically confirmed solid tumors\n                  (as defined by ASCO/CAP guidelines) originating in breast, pancreas, prostate,\n                  lung, colon, esophagus, liver, or ovary, and lymphomas, which are locally\n                  advanced or metastatic and who are refractory or intolerant beyond primary\n                  treatment for their malignancy, or for lymphoma patients who are not eligible for\n                  or who have refused autologous or allogenic hematopoietic stem cell transplant\n\n               -  Measurable or evaluable disease documented within one month of the planned\n                  protocol treatment (Treatment Period Cycle 1, Day 1)first dose of study drug (PK\n                  Period Day 1)\n\n               -  ECOG performance score of 0 and 1\n\n               -  Able to swallow capsules/tablets\n\n        Demographic • Male and females who are 18 years or older\n\n        Laboratory Values\n\n          -  Hemoglobin ? 9.0 g/dL\n\n          -  Absolute neutrophil count ? 1500/uL\n\n          -  Platelet count ? 100,000/uL\n\n          -  Serum creatinine ? 1.5 mg/dL or a 24-hour calculated estimated creatinine clearance of\n             ? 60 mL/min\n\n          -  Serum bilirubin ? 1.5 mg/dL\n\n          -  Serum albumin ? 3g/dL\n\n          -  AST (SGOT), ALP and ALT (SGPT) ? 2.5 times upper limit of normal (OR ? 5 times ULN in\n             the presence of known liver metastases)\n\n          -  Prothrombin time (PT)/International Normalized Ratio (INR) and partial thromboplastin\n             time (PPT) ? 1.5 times the upper limit of normal\n\n          -  Serum sodium, potassium, magnesium, calcium and phosphorous levels within\n             institutional normal limits; supplements required to maintain normal electrolyte\n             levels will be permitted\n\n        Ethical\n\n        • Before any study-specific procedure, the appropriate written informed consent must be\n        obtained\n\n        Exclusion Criteria:\n\n        Disease Related\n\n          -  Clinical or radiographical evidence of active brain metastasis\n\n          -  Patients who have not recovered to ? grade 1 toxicities except grade 2 alopecia or\n             neuropathy associated with previous chemotherapy, radiotherapy, biologic, hormone or\n             prior investigational therapies.\n\n        Medications:\n\n          -  Chemotherapy or other cancer, radiation or surgical treatments within 2 weeks or five\n             half-lives (whichever is shorter) of the first dose of study drug (PK Period Day 1)\n             planned first protocol treatment (i.e., cycle 1 day 1) or not yet recovered from\n             respective treatments\n\n          -  Patients who have had allogenic hematopoietic stem cell transplant or allogenic bone\n             marrow transplant\n\n          -  Patients who have had prior solid organ transplant\n\n          -  Patients who are on immune suppression drugs or anti-transplant rejection drugs\n\n        General:\n\n          -  History of any medical or psychiatric condition or addictive disorder, or laboratory\n             abnormality that in the opinion of the investigator, may increase the risks associated\n             with study participation or treatments that may interfere with the conduct of the\n             study or the interpretation of study results\n\n          -  Prior history of clinically significant gastrointestinal bleeding, intestinal\n             obstruction or gastrointestinal perforation within 6 months before planned initiation\n             of study treatment\n\n          -  Uncontrolled diabetes\n\n          -  History of long QT syndrome or clinically significant cardiac arrhythmia, other than\n             stable atrial fibrillation\n\n          -  Mean QTcF > 450 msec in men and mean QTcF > 470 msec in women at screening\n\n          -  Myocardial infarction within the previous 6 months before planned initiation of study\n             treatment\n\n          -  Active infection requiring intravenous antibiotics within 2 weeks of the first dose of\n             study drug (PK Period Day 1) before planned initiation of study treatment\n\n          -  Prior history or current positive tests for hepatitis B, hepatitis C or human\n             immunodeficiency virus\n\n          -  Currently enrolled in or has not yet completed at least 30 days since ending other\n             investigational device or drug study before planned date of first dose, or the patient\n             is currently receiving other investigational agent(s)\n\n          -  Pregnant, planning a pregnancy or breast feeding during the study\n\n          -  Male or female not willing to use adequate contraceptive precautions during the study\n             period\n\n          -  Unwilling or unable to comply with study requirements or not available for follow-up\n             assessments\n\n          -  Any disorder that compromises the ability of the patient to give written informed\n             consent and/or to comply with study procedures.
Inclusion Criteria: All subjects\n\n          1. Age ?18 years old.\n\n          2. Confirmed malignancy at advanced or metastatic stage.\n\n          3. ECOG status ? 1.\n\n          4. Adequate bone marrow function.\n\n          5. Adequate renal and hepatic function.\n\n          6. Females of childbearing potential and non-sterile males must agree to use highly\n             effective methods of birth control throughout the course of study and at least up to\n             90 days after last dosing.\n\n          7. Must have measurable or evaluable disease per RECIST [Dose escalation phase only]\n\n             Additional inclusion criteria 8 - 12 are specific to tumor types in dose expansion\n             phase:\n\n          8. Ovarian cancer\n\n               1. Previously received at least 1 line of platinum containing chemotherapy.\n\n               2. No progression or recurrent disease in 6 months from last platinum containing\n                  regimen.\n\n          9. Triple-Negative Breast Cancer\n\n             a. 0 - 1 prior platinum-containing regimen (any treatment setting) and received ? 3\n             prior regimens (advanced or metastatic setting).\n\n         10. Prostate cancer\n\n               1. Documented progressive disease.\n\n               2. Chemotherapy-naïve or previously received ?2 taxane-based regimens.\n\n               3. May be pre-or post-treatment with a novel androgen receptor targeted agent.\n\n               4. Completed in ? 2 weeks radiation or treatment with anti-androgen agents.\n\n         11. Ovarian, breast and prostate cancer: If homologous recombinant deficiency (HRD) or\n             BRCA status unknown, need pre-screening for eligibility.\n\n         12. Small cell lung and gastric cancer: previously received ? 2 prior lines of therapy.\n\n        Exclusion Criteria: All subjects\n\n          1. Prior exposure to a PARP inhibitor.\n\n          2. Prior chemotherapy, biologic therapy, immunotherapy or investigational agents within 3\n             weeks prior to start of study treatment.\n\n          3. Refractory to platinum-based therapy.\n\n          4. Toxicity of ? Grade 2 from prior therapy.\n\n          5. Major surgery or significant injury ? 4 weeks prior to start of study treatment.\n\n          6. History of other active malignancies within 2 years with exception of (i) adequately\n             treated in situ carcinoma of the cervix, (ii) non-melanoma skin cancer, or (iii)\n             localized adequately treated cancer with curative intent or malignancy diagnosed > 2\n             years ago with no evidence of disease and no treatment ? 2 years prior to study\n             treatment.\n\n          7. Untreated leptomeningeal or brain metastasis.\n\n          8. Active infection requiring systemic treatment.\n\n          9. Known human immunodeficiency virus (HIV) or active viral hepatitis.\n\n         10. Active, clinically significant cardiac disease or any Class 3 or 4 cardiac disease,\n             ventricular arrhythmia or CVA ? 6 months prior to start of treatment.\n\n         11. Active, clinically significant gastrointestinal disease.\n\n         12. Use of any medications or food known to be strong or moderate cytochrome P450, family\n             3, subfamily A (CYP3A) inhibitors or strong inducers.\n\n         13. Pregnant or nursing females.
Inclusion Criteria (Solid Tumor Patients):\n\n          1. Patients ?18 years of age,\n\n          2. Must have progressed on all available therapies known to confer benefit for disease\n\n          3. Must have tissue source of tumor cells\n\n          4. Must have 1 measurable lesion according to RECIST Version 1.1\n\n          5. Must have objective evidence of progression of lesions that have been previously\n             irradiated\n\n          6. Must have ECOG performance status of 0-1\n\n          7. Bone Marrow Function: absolute neutrophil count (ANC) ?1500/µL; hemoglobin ?9 g/dL;\n             platelet count ?75,000/µL\n\n          8. Hepatic Function: Total serum bilirubin ?1.5 times the upper limit of normal (ULN;\n             except for patients with known Gilbert syndrome);); serum aspartate aminotransferase\n             (AST)/alanine aminotransferase (ALT), ?32.5×ULN (?5×ULN in the presence of hepatic\n             metastases)\n\n          9. Renal Function: Serum creatinine ?1.5×ULN or creatinine clearance ?50 mL/min based\n             either on urine collection or Cockcroft-Gault estimation\n\n         10. Coagulation Profile: Prothrombin time (PT) - international normalized ratio\n             (INR)/partial thromboplastin time (PTT) ?1.5xULN5×ULN.\n\n        Inclusion Criteria (Hematologic Malignancies):\n\n          1. Patients ?18 years of age, except for patients with ALL who can be ?16 years of age\n\n          2. Morphologically documented relapsed/refractory myelodysplastic syndrome (MDS), acute\n             myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic lymphocytic\n             leukemia (CLL) as defined by World Health Organization (WHO) criteria\n\n          3. Patients with relapsed/refractory MDS, AML, ALL must have progressed on least 1 prior\n             therapy and cannot be a candidate for any available therapies in patients with a\n             rationale for known to confer clinical benefit\n\n          4. For patients with MDS, AML, ALL, or CLL, must have cells obtained either by bone\n             marrow biopsy or blood collection to use for biomarkers that may enrich for DCC-3014\n             response or provide PD information\n\n          5. For CLL, must have measurable disease per International Workshop on Chronic\n             Lymphocytic Leukemia (IWCLL) criteria (Hallek criteria) to allow evaluation of\n             response\n\n          6. May have primary phagocytic malignancies including histocytoses, including Erdheim\n             Chester Disease (as diagnosed in Diamond et al 2014) and Langerhans histiocytoses are\n             eligible if refractory to or unsuitable for other therapies.\n\n          7. ECOG PS of 0-2\n\n          8. Bone Marrow Function: ANC ?1000/µL; hemoglobin ?8 g/dL; platelet count ?75,000/?L.\n\n          9. Hepatic Function: Total serum bilirubin <1.5×ULN; serum AST and ALT <2.5×ULN (?5×ULN\n             in the presence of hepatic metastases).\n\n         10. Renal Function: Serum creatinine <2xULN1.5×ULN, or glomerular filtration rate >2050\n             mL/hr as calculated by CockgroftCockroft-Gault formula.\n\n         11. Serum potassium, magnesium and calcium (corrected for albumin) that are within\n             institutional normal limits or can be corrected with supplementation.\n\n         12. Total serum bilirubin <2xULN (except for patients with known Gilbert syndrome).\n\n         13. Serum AST and ALT <5xULN.\n\n         14. Coagulation Profile: Prothrombin time (PT) - international normalized ratio\n             (INR)/partial thromboplastin time (PTT) ?1.5×ULN.\n\n        Exclusion Criteria (Solid Tumors):\n\n          1. Treatment with anticancer therapy, including investigational therapy, within 2 weeks\n             prior to the administration of study drug. For immediately prior therapies with a\n             half-life longer than 3 days, or if the half-life is not available, the interval must\n             be ?28 days prior to the first administration of study drug.\n\n          2. Unresolved toxicity according to National Cancer Institute Common Terminology Criteria\n             for Adverse Events (NCI-CTCAE), Version 4.03 (ie, >Grade 1 or baseline) from previous\n             anticancer therapy, excluding alopecia.\n\n          3. The patient has known active CNS metastases. Patients with previously treated brain\n             metastases may participate provided that:\n\n               -  They are stable (ie, without evidence of progression by magnetic resonance\n                  imaging [MRI]) for ?4 weeks prior to the first dose of study drug),\n\n               -  All neurologic symptoms have returned to baseline, and\n\n               -  Patients do not require continued steroid therapy or use of enzyme-inducing\n                  antiepileptic drugs. Patients can be switched to a non-enzyme inducing\n                  antiepileptic drug. If signs or symptoms suggest CNS metastases, a brain MRI must\n                  be performed to confirm absence of detectable CNS disease within 2 weeks prior to\n                  receiving study drug.\n\n          4. New York Heart Association class III or IV heart disease, active ischemia or any other\n             uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac\n             arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.\n\n          5. Systemic arterial thrombotic or embolic events, such as cerebrovascular accident\n             (including ischemic attacks) or hemoptysis within 6 months prior to the start of study\n             drug.\n\n          6. Systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial\n             events (eg, pulmonary embolism) within the 1 month prior to the start of study drug.\n             Patients with venous thrombotic events before the start of study drug on stable\n             anticoagulation therapy are eligible.\n\n          7. Baseline prolongation of the rate-corrected QT interval based on repeated\n             demonstration of QT interval corrected (QTc) >450 ms or history of long QTc syndrome.\n\n          8. Left ventricular ejection fraction (LVEF) <50%.\n\n          9. Concurrent treatment with proton-pump inhibitor. Other medications that increase\n             gastric pH, ie, histamine H2 receptor antagonists and antacids may be taken provided\n             they are not administered within 2 hours before or after administration of study drug.\n\n         10. Major surgery within 2 weeks of the first dose of study drug; following major\n             surgeries >2 weeks prior to the first dose of study drug, all surgical wounds must be\n             healed and free of infection or dehiscence.\n\n         11. Any other clinically significant comorbidities, such as uncontrolled pulmonary\n             disease, active infection, or any other condition, which in the judgment of the\n             Investigator, could compromise compliance with the protocol, interfere with the\n             interpretation of study results, or predispose the patient to safety risks.\n\n         12. Malabsorption syndrome or other illness that could affect oral absorption.\n\n         13. Known human immunodeficiency virus, active hepatitis B, active hepatitis C, or active\n             mycobacterium tuberculosis infection.\n\n         14. If female, the patient is pregnant or lactating.\n\n         15. Known allergy or hypersensitivity to any component of the study drug.\n\n         16. Patients with known Gilbert's disease.\n\n        Exclusion Criteria (Hematologic Malignancies):\n\n          1. Concurrent active malignancy with expected survival of less than 1 year.\n\n          2. Graft versus host disease (GVHD) that is not well-controlled on a stable treatment\n             regimen for at least 3 weeks prior to initial dose of study drug.\n\n          3. Cancer-directed therapy within 2 weeks prior to starting treatment, with the exception\n             of hydroxyurea, which is allowed to control white blood cell count.\n\n          4. History of, or current, central nervous system involvement with MDS, AML, or CLL.\n\n          5. Systemic arterial thrombotic or embolic events, such as cerebrovascular accident\n             (including ischemic attacks) or hemoptysis within 2 months prior to the start of study\n             drug.\n\n          6. Systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial\n             events (eg, pulmonary embolism) within the 1 month prior to the start of study drug.\n             Patients with venous thrombotic events before the start of study drug on stable\n             anticoagulation therapy are eligible.\n\n          7. Clinically significant coagulation disorder, such as disseminated intravascular\n             coagulation.\n\n          8. New York Heart Association class III or IV heart disease, active ischemia or any other\n             uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac\n             arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.\n\n          9. Baseline prolongation of the rate-corrected QT interval based on repeated\n             demonstration of QTc >450 ms or history of long QTc syndrome.\n\n         10. LVEF <50%.\n\n         11. Concurrent treatment with proton-pump inhibitor.\n\n         12. Major surgery within 2 weeks of the first dose of study drug; following major\n             surgeries >2 weeks prior to the first dose of study drug, all surgical wounds must be\n             healed and free of infection or dehiscence.\n\n         13. Any other clinically significant comorbidities, such as uncontrolled pulmonary\n             disease, active infection, or any other condition, which in the judgment of the\n             Investigator, could compromise compliance with the protocol, interfere with the\n             interpretation of study results, or predispose the patient to safety risks.\n\n         14. Malabsorption syndrome or other illness that could affect oral absorption.\n\n         15. Known human immunodeficiency virus, active hepatitis B, active hepatitis C, active\n             cytomegalovirus (CMV), or active mycobacterium tuberculosis infection.\n\n         16. Active infection that is not well-controlled by antibacterial or antiviral therapy.\n\n         17. If female, the patient is pregnant or lactating.\n\n         18. Known allergy or hypersensitivity to any component of the study drug.\n\n         19. Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype).\n\n         20. Unwillingness to receive infusion of blood products.\n\n         21. Patients with known Gilbert's disease.
Inclusion Criteria (Preliminary Screening)\n\n          1. Signed Preliminary Screening Informed Consent Form obtained prior to any study\n             specific assessments and procedures\n\n          2. Age ?18 years (or per national guidelines)\n\n          3. Participants must have histologically confirmed invasive breast cancer that is\n             metastatic or not amenable for resection or radiation therapy with curative intent.\n             Histological documentation of metastatic/recurrent breast cancer is not required if\n             there is unequivocal evidence for recurrence of the breast cancer.\n\n          4. Patients must have histologically confirmed HER2+ and hormone receptor positive (ER+\n             and/or PR+), metastatic breast cancer. ER, PR and HER2 measurements should be\n             performed according to institutional guidelines, in a CLIA-approved setting in the US\n             or certified laboratories for Non-US regions. Cut-off values for positive/negative\n             staining should be in accordance with current ASCO/CAP (American Society of Clinical\n             Oncology/College of American Pathologists) guidelines.\n\n          5. Patients must agree to provide a representative formalin-fixed paraffin-embedded\n             (FFPE) tumor tissue block (preferred) from primary breast or metastatic site\n             (archival) OR at least 15 freshly cut unstained slides from such a block, along with a\n             pathology report documenting HER2 positivity and hormone receptor positivity.\n\n          6. Patients should be willing to provide a representative tumor specimen obtained from\n             metastatic disease if clinically feasible. This is a recommended but optional research\n             biopsy.\n\n             Inclusion Criteria (Randomization Screening)\n\n          7. Signed Main Informed Consent Form obtained prior to any study specific assessments and\n             procedures\n\n          8. Age ? 18 years (or per national guidelines)\n\n          9. ECOG performance status 0-1\n\n         10. Patients must be able and willing to swallow and retain oral medication without a\n             condition that would interfere with enteric absorption.\n\n         11. Serum or urine pregnancy test must be negative within 7 days of randomization in women\n             of childbearing potential. Pregnancy testing does not need to be pursued in patients\n             who are judged as postmenopausal before randomization, as determined by local\n             practice, or who have undergone bilateral oophorectomy, total hysterectomy, or\n             bilateral tubal ligation. Women of childbearing potential and male patients randomized\n             into the study must use adequate contraception for the duration of protocol treatment\n             and for 6 months after the last treatment with palbociclib if they are in Arm A and\n             for 7 months after last treatment with trastuzumab if in either Arm A or Arm B\n             Adequate contraception is defined as one highly effective form (i.e. abstinence,\n             (fe)male sterilization OR two effective forms (e.g. non-hormonal IUD and condom /\n             occlusive cap with spermicidal foam / gel / film / cream / suppository).\n\n         12. Resolution of all acute toxic effects of prior induction anti-HER2-based chemotherapy\n             regimen to NCI CTCAE version 4.0 Grade ?1 (except alopecia or other toxicities not\n             considered a safety risk for the patient at investigator's discretion) 12 weeks\n             between last dose of chemotherapy-anti-HER2therapy and randomization are allowed.\n             Endocrine therapy could start before study randomization.\n\n         13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory\n             tests, and other study procedures\n\n             Prior Treatment Specifics\n\n         14. Patients may or may not have received neo/adjuvant therapy, but must have a\n             disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ?6\n             months.\n\n         15. Patients must have received an acceptable, standard, chemotherapy containing anti-HER2\n             based induction therapy for the treatment of metastatic breast cancer prior to study\n             enrollment. For this study, chemotherapy is limited to a taxane or vinorelbine (only\n             for trastuzumab-based regimen). Eligible patients are expected to have completed 6\n             cycles of chemotherapy containing anti-HER2-therapy treatment. A minimum of 4 cycles\n             of treatment is acceptable for patients experiencing significant toxicity associated\n             with treatment as long as they are without evidence of disease progression (i.e. CR,\n             PR or SD). The maximum number of cycles is 8. Patients can randomize immediately\n             following completion of their induction therapy, or for those who have already\n             completed induction, a gap of 12 weeks between their last infusion/dose of induction\n             therapy and the C1D1 visit is permitted. Patients are eligible provided they are\n             without evidence of disease progression by local assessment (i.e. CR, PR or SD).\n\n         16. Participants with a history of treated CNS metastases are eligible, provided they meet\n             all of the following criteria:\n\n               -  Disease outside the CNS is present.\n\n               -  No evidence of interim progression between the completion of CNS-directed therapy\n                  and the screening radiographic study\n\n               -  No history of intracranial hemorrhage or spinal cord hemorrhage\n\n               -  Not requiring anti-convulsants for symptomatic control\n\n               -  Minimum of 3 weeks between completion of CNS radiotherapy and Cycle 1 Day 1 and\n                  recovery from significant (Grade ? 3) acute toxicity with no ongoing requirement\n                  for corticosteroid\n\n             Baseline Body Function Specifics\n\n         17. Absolute neutrophil count ? 1,000/mm3\n\n         18. Platelets ? 100,000/mm3\n\n         19. Hemoglobin ? 10g/dL\n\n         20. Total serum bilirubin ? ULN; or total bilirubin ? 3.0 × ULN with direct bilirubin\n             within normal range in patients with documented Gilbert's Syndrome.\n\n         21. Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ?\n             3 × institutional ULN (?5 x ULN if liver metastases are present).\n\n         22. Serum creatinine within normal institutional limits or creatinine clearance ? 60\n             mL/min/1.73 m2 for patients with serum creatinine levels above institutional ULN.\n\n         23. Left ventricular ejection fraction (LVEF) ? 50% at baseline as determined by either\n             ECHO or MUGA\n\n        Exclusion Criteria (Randomization)\n\n          1. Concurrent therapy with other Investigational Products.\n\n          2. Prior therapy with any CDK 4/6 inhibitor.\n\n          3. History of allergic reactions attributed to compounds of chemical or biologic\n             composition similar to palbociclib.\n\n          4. Patients receiving any medications or substances that are strong inhibitors or\n             inducers of CYP3A isoenzymes within 7 days of randomization (see Section 8.6.3 for\n             list of strong inhibitors or inducers of CYP3A isoenzymes).\n\n          5. Uncontrolled current illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac\n             arrhythmia, diabetes, or psychiatric illness/social situations that would limit\n             compliance with study requirements. Ability to comply with study requirements is to be\n             assessed by each investigator at the time of screening for study participation.\n\n          6. Pregnant women, or women of childbearing potential without a negative pregnancy test\n             (serum or urine) within 7 days prior to randomization, irrespective of the method of\n             contraception used, are excluded from this study because the effect of palbociclib on\n             a developing fetus is unknown. Breastfeeding must be discontinued prior to study\n             entry.\n\n          7. Patients on combination antiretroviral therapy, i.e. those who are HIV-positive, are\n             ineligible because of the potential for pharmacokinetic interactions or increased\n             immunosuppression with palbociclib.\n\n          8. QTc interval >480 msec, Brugada syndrome or known history of QTc prolongation or\n             Torsade de Pointes.\n\n          9. Patients with clinically significant history of liver disease, including viral or\n             other known hepatitis, current alcohol abuse, or cirrhosis
Inclusion Criteria:\n\n        Part A:\n\n          -  Subjects must have signed written informed consent.\n\n          -  Male or female subjects age greater than equals to (>=)18 years.\n\n          -  Subjects must have histologically or cytologically proven metastatic or locally\n             advanced solid tumors for which no standard therapy exists, standard therapy has\n             failed, subject is intolerant of established therapy known to provide clinical benefit\n             for their condition, or standard therapy is not acceptable to the subject.\n\n          -  Subjects who have been treated previously with a checkpoint inhibitor may enroll\n             (except as outlined below for expansion cohorts).\n\n          -  At least 1 unidimensional radiographically measurable lesion based on Response\n             Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (v1.1), except for subjects\n             with metastatic castration-resistant prostate cancer (CRPC) or metastatic breast\n             cancer who may be enrolled with objective evidence of disease without a measureable\n             lesion.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at Screening\n\n          -  Estimated life expectancy of more than 12 weeks\n\n          -  Adequate hematological function as defined below:\n\n               -  White blood cells (WBC) count >= 3.0 × 10^9 per liter (/L)\n\n               -  Absolute neutrophil count >= 1.5 × 10^9/L\n\n               -  Lymphocyte count >= 0.5 × 10^9/L\n\n               -  Platelet count >= 100 × 10^9/L\n\n               -  Hemoglobin >= 9 gram per deciliter (g/dL) (may have been transfused)\n\n          -  Adequate hepatic function as defined below:\n\n               -  A total bilirubin level lass than equals to (<=) 1.5 × the upper limit of normal\n                  (ULN) range • Aspartate aminotransferase (AST) levels <= 2.5 × ULN (? 3 × ULN for\n                  expansion cohorts)\n\n               -  Alanine aminotransferase (ALT) levels <= 2.5 × ULN (? 3 × ULN for expansion\n                  cohorts)\n\n               -  Subjects with documented Gilbert disease are allowed if total bilirubin > 1.5 but\n                  less than 3 × ULN\n\n          -  Adequate renal function as defined by an estimated creatinine clearance >= 50\n             milliliter per minute (mL/min) according to the Cockcroft-Gault formula\n\n          -  Negative blood pregnancy test at Screening for women of childbearing potential. For\n             the purposes of this trial, women of childbearing potential are defined as all female\n             subjects after puberty unless they are postmenopausal for at least 1 year, are\n             surgically sterile or are sexually inactive.\n\n          -  Highly effective contraception (ie, methods with a failure rate of less than 1% per\n             year) must be used before the start of treatment, for the duration of the trial\n             treatment, and for at least 50 days after stopping study treatment for both men and\n             women if the risk of conception exists. The effects of avelumab and NHS-IL12 on the\n             developing human fetus are unknown; thus, women of childbearing potential and men must\n             agree to use highly effective contraception.\n\n        Part B:\n\n          -  Urothelial carcinoma (UC) post-platinum: Histologically or cytologically confirmed\n             locally advanced or metastatic transitional cell carcinoma of the urothelium\n             (including renal pelvis, ureters, urinary bladder, and urethra). Subjects must have\n             progressed after treatment with at least 1 platinum containing regimen for inoperable\n             locally advanced or metastatic UC or disease recurrence. Availability of either tumor\n             archival material (< 6 months old)or fresh biopsies (obtained within 28 days) is\n             acceptable with one of these being mandatory. For formalin-fixed paraffin-embedded\n             samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor\n             archival material must be suitable for biomarker assessment.\n\n          -  Non-small cell lung cancer (NSCLC), first-line metastatic: Stage IV (per seventh\n             International Association for the Study of Lung Cancer classification) histologically\n             confirmed NSCLC. Subjects must not have received treatment for their metastatic\n             disease. Subjects could have received adjuvant chemotherapy or loco-regional treatment\n             that included chemotherapy for locally advanced disease, as long as disease recurrence\n             occurred at least 6 months after the completion of the last administration of\n             chemotherapy. Only epidermal growth factor receptor (EGFR) and anaplastic lymphoma\n             kinase (ALK) wild-type are allowed (ie, EGFR mutation and ALK translocation / re\n             arrangement excluded). Non squamous cell histologies and never / former light smoker\n             (< 15 pack years) squamous cell carcinoma subjects (per local standard of care)\n             require testing if status is unknown. Subjects must have low tumor PD-L1 expression\n             defined as < 50% tumor proportion score determined using PD-L1 IHC 22C3 pharmDx test\n             or an equivalent Food and Drug Administration (FDA)- approved PD-L1 test. Availability\n             of either tumor archival material or fresh biopsies within 28 days is acceptable with\n             one of these being mandatory. For FFPE samples, either block or sections (> 15) may be\n             provided. Tumor biopsies and tumor archival material must be suitable for biomarker\n             assessment. This cohort will not be opened for enrollment in Belgium, Czech Republic,\n             Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom.\n\n          -  Colorectal cancer (CRC): Histologically or cytologically confirmed recurrent or\n             refractory metastatic CRC (according to American Joint Committee on Cancer /\n             International Union Against Cancer Tumor Node Metastasis [TNM] Staging System seventh\n             edition) after failure of prior therapy containing oxaliplatin / fluoropyrimidine and\n             / or irinotecan / fluoropyrimidine and, if eligible, cetuximab (Erbitux®) and\n             bevacizumab (Avastin®). Only subjects with microsatellite instability (MSI)-low or\n             microsatellite stable (MSS) metastatic CRC are eligible. Subjects without existing MSI\n             test results will have MSI status performed locally by a Clinical Laboratory\n             Improvement Amendments (CLIA)-certified IHC or polymerase chain reaction (PCR)-based\n             test (PCR based MSI test is preferred). Subjects must be willing to undergo an\n             on-treatment biopsy procedure. Availability of either tumor archival material or fresh\n             biopsies within 28 days is acceptable with one of these being mandatory. For FFPE\n             samples, either block or sections (> 15) may be provided. Tumor biopsies and tumor\n             archival material must be suitable for biomarker assessment. For Belgium, Czech\n             Republic, Germany, Hungary, Italy, Netherlands, Spain, and United Kingdom, subjects in\n             the second-line setting should have exhausted or be considered ineligible or\n             intolerant (in the opinion of the Investigator) of available second-line chemotherapy\n             options.\n\n          -  Renal cell carcinoma (RCC), primary immune checkpoint inhibitor failure:\n             Histologically or cytologically documented metastatic RCC with a component of clear\n             cell subtype. Subjects must have had progressive disease (PD) within 6 months or best\n             overall response of stable disease (SD) for ? 6 months following start of therapy with\n             any antibody / drug targeting T cell co-regulatory proteins (immune checkpoints) such\n             as anti-PD-1, anti-PD-L1, or anticytotoxic T lymphocyte antigen-4 (CTLA-4) for\n             advanced or metastatic disease (either as monotherapy or combination therapy, in any\n             line). Availability of a fresh tumor biopsy is mandatory for eligibility in the RCC\n             cohort. The biopsy or surgical specimen should be collected within 28 days prior to\n             the first IMP administration. Subjects must also be willing to undergo an on-treatment\n             biopsy procedure.\n\n        Exclusion Criteria:\n\n          -  Concurrent treatment with a non-permitted drug/intervention (listed below)\n\n               -  Anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy,\n                  cytokine therapy, monoclonal antibody, targeted small molecule therapy) or any\n                  investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior\n                  to start of trial treatment, or not recovered from adverse event (AE) related to\n                  such therapies, with the following exceptions: Palliative radiotherapy delivered\n                  in a normal organ-sparing technique is permitted; Erythropoietin and\n                  darbepoetin-? are permitted; Hormonal therapies acting on the\n                  hypothalamic-pituitary-gonadal axis are permitted (i.e. luteinizing\n                  hormone-releasing hormone agonist/antagonists). No other hormonal anticancer\n                  therapy is permitted.\n\n               -  Major surgery (as deemed by Investigator) for any reason, except diagnostic\n                  biopsy, within 4 weeks prior to start of trial treatment, or not fully recovered\n                  from surgery within 4 weeks prior to start of trial treatment\n\n               -  Subjects receiving immunosuppressive agents (such as steroids) for any reason\n                  should be tapered off these drugs before start of trial treatment, with the\n                  following exceptions: Subjects with adrenal insufficiency, may continue\n                  corticosteroids at physiologic replacement dose, equivalent to ? 10 mg prednisone\n                  daily; Administration of steroids through a route known to result in a minimal\n                  systemic exposure (topical, intranasal, intra-ocular, or inhalation) is\n                  permitted; Previous or ongoing administration of systemic steroids for the\n                  management of an acute allergic phenomenon is acceptable as long as it is\n                  anticipated that the administration of steroids will be completed in 14 days, or\n                  that the dose after 14 days will be equivalent to <= 10 mg prednisone daily.\n\n          -  Any prior treatment with any form of interlukin-12 (IL-12)\n\n          -  For the NSCLC, CRC, and UC expansion cohorts, prior therapy with any antibody / drug\n             targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1,\n             anti-PD-L1, or anticytotoxic T lymphocyte antigen-4 (CTLA-4) antibody is prohibited.\n\n          -  Intolerance to checkpoint inhibitor therapy, as defined by the occurrence of an AE\n             requiring drug discontinuation.\n\n          -  Active or history of primary or metastatic central nervous system tumors\n\n          -  Prior organ transplantation, including allogeneic stem-cell transplantation\n\n          -  Previous malignant disease (other than the indication for this trial) within the last\n             5 years (except adequately treated non-melanoma skin cancers, carcinoma in situ of\n             skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission\n             without further recurrence was achieved at least 2 years prior to trial entry and the\n             subject was deemed to have been cured with no additional therapy required or\n             anticipated to be required.\n\n          -  Significant acute or chronic infections requiring systemic therapy including, among\n             others:\n\n               -  History of testing positive test for human immunodeficiency virus (HIV) or known\n                  acquired immunodeficiency syndrome\n\n               -  Hepatitis B or C infection (HBV surface antigen positive and HBV core antibody\n                  positive with reflex to positive HBV deoxy ribonucleic acid (DNA) or HBV core\n                  antibody positive alone with reflex to positive HBV DNA or positive hepatitis C\n                  virus [HCV] antibody with reflex to positive HCV ribonucleic acid [RNA]).\n                  Subjects with history of infection must have polymerase chain reaction\n                  documentation that infection is cleared.\n\n          -  Active or history of autoimmune disease that might deteriorate when receiving an\n             immuno-stimulatory agent. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or\n             hyperthyroid disease not requiring immunosuppressive treatment are eligible if they\n             are stable on other medical treatment and do not fulfill exclusion criterion including\n             Uncontrolled intercurrent illness\n\n          -  Known severe hypersensitivity reactions to monoclonal antibodies (Grade>= 3 National\n             Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03, or\n             uncontrolled asthma (ie, 3 or more features of partially controlled asthma)\n\n          -  History of allergic reaction to methotrexate (trace methotrexate may be present in\n             NHS-IL12 as a part of the manufacturing process) or history of severe hypersensitivity\n             reaction to any other ingredient of the study drug(s) and / or their excipients. Since\n             NHS-IL12 contains sucrose as an excipient, subjects suffering from hereditary fructose\n             intolerance are also excluded\n\n          -  Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v4.03 with the\n             following exceptions:\n\n               -  Neuropathy Grade <= 2 is acceptable.\n\n               -  All grades of alopecia are acceptable.\n\n               -  Endocrine dysfunction on replacement therapy is acceptable.\n\n          -  Pregnancy or lactation\n\n          -  Known alcohol or drug abuse as deemed by the Investigator\n\n          -  Uncontrolled intercurrent illness including, but not limited to:\n\n               -  Hypertension uncontrolled by standard therapies (not stabilized to 150/90\n                  millimeter of mercury (mm Hg) or lower)\n\n               -  Uncontrolled active infection\n\n               -  Uncontrolled diabetes (eg, glycosylated hemoglobin [HgbA1c] >= 8%)\n\n          -  Clinically significant (or active) cardiovascular disease: cerebral vascular\n             accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months\n             prior to enrollment), unstable angina, congestive heart failure (New York He
Inclusion Criteria:\n\n        To be eligible for this study, a patient must meet all of the following inclusion criteria:\n\n          1. Be at least 18 years of age.\n\n          2. Has signed the current approved informed consent form.\n\n          3. Has a histologically confirmed diagnosis of malignant melanoma.\n\n          4. Has at least two separate cutaneous lesions suitable for punch biopsies (at least 3 mm\n             diameter).\n\n          5. For women of childbearing potential and men, agree to use a highly effective method of\n             contraceptive from screening, through the study, and for at least 4 weeks after the\n             last dose of study drug.\n\n          6. For women of childbearing potential, must have a negative pregnancy test (serum or\n             urine) on Day 1 prior to initiating study treatment, and are not nursing.\n\n          7. Be willing and able to comply with the schedule, treatment, and biopsies specified by\n             this protocol.\n\n        Exclusion Criteria:\n\n        Patients with any of the following will be excluded from participation in the study:\n\n          1. Has performance status Grade 2 or higher (Eastern Cooperative Oncology Group [ECOG]\n             criteria).\n\n          2. Has ongoing acute clinical adverse events NCI CTCAE Grade 2 or greater resulting from\n             prior cancer therapies (except alopecia).\n\n          3. Has had within the past 6 months the occurrence or persistence of one or more of the\n             following medical conditions that could not be controlled with usual medical care\n             (e.g., required emergency care or hospitalization): angina, congestive heart failure,\n             diabetes, seizure disorder.\n\n          4. Has had within the past 6 months the occurrence of one or more of the following\n             events: myocardial infarction, cerebrovascular accident, hemorrhage (CTC Grade 3 or\n             4), chronic liver disease (meeting criteria for Child-Pugh Class B or C), a second\n             active malignancy requiring ongoing treatment during the trial, organ transplantation.\n\n          5. Has had within the 4 weeks prior to initiation of study drug, or is expected to have\n             during the study period, surgery requiring general anesthesia\n\n          6. Has, at screening, serologic laboratory tests meeting one or more of the following\n             criteria:\n\n               -  An indeterminate or positive test for antibody to human immunodeficiency virus\n                  (HIV-1 or -2).\n\n               -  An indeterminate or positive test for antibody to hepatitis C virus (HCV), unless\n                  documented to have no detectable viral load on two independent samples.\n\n               -  A positive test for hepatitis B surface antigen (HBsAg).\n\n          7. Has, at screening, safety laboratory tests meeting one or more of the following\n             criteria:\n\n               -  Hemoglobin <9.0 g/dL\n\n               -  Absolute neutrophil count (ANC) <1,500/?L\n\n               -  Platelets <100,000/?L\n\n               -  Creatinine >2.0x ULN\n\n               -  Serum aspartate transaminase (AST) >3x ULN\n\n               -  Serum alanine transaminase (ALT) >3x ULN\n\n               -  Total bilirubin >1.5x ULN (unless due to Gilbert's Syndrome)\n\n               -  International normalized ratio (INR) >1.5x ULN (unless on therapeutic\n                  anti-coagulation).\n\n          8. Has been previously treated with approved or investigational immunotherapy including\n             oncolytic viruses, or agents directed at CTLA-4, PD-1, or PD-L1 (\checkpoint\n             inhibitors\).\n\n          9. Has previously received other anti-cancer therapy within 2 weeks prior to Day 1,\n             including radiation therapy or chemotherapy. For investigational anti-cancer\n             therapies, the interval will be determined in consultation with the Medical Monitor.\n\n         10. Has, within 2 weeks prior to Day 1, been regularly taking a medication prohibited\n             based on CYP3A4 interaction.\n\n         11. Has, at the planned initiation of study drug, an uncontrolled infection.\n\n         12. Has any other medical or personal condition that, in the opinion of the Investigator,\n             may potentially compromise the safety or compliance of the patient, or may preclude\n             the patient's successful completion of the clinical trial.
Inclusion Criteria:\n\n        Subjects must meet all of the following applicable inclusion criteria to participate in\n        this study:\n\n          -  Male or female ? 18 years of age at time of consent. NOTE: Both pre- and\n             post-menopausal women are eligible. Pre-menopausal status is defined as either:\n\n               -  Last menstrual period within the last 12 months.\n\n               -  In case of therapy-induced amenorrhea, plasma estradiol and /or FSH is in the\n                  premenopausal range per local normal range.\n\n          -  Locally advanced, locoregionally recurrent, or metastatic disease, not amenable to\n             curative therapy. NOTE: Although not required as a protocol procedure, a patient with\n             a new metastatic lesion should be considered for biopsy whenever possible to reassess\n             ER/PR/HER2 status if clinically indicated. If a biopsy is prospectively done as part\n             of standard of care, the study would like to store samples for correlative research.\n\n          -  Histologically and/or cytologically confirmed diagnosis of ER positive and/or PR\n             positive (ER >1%, PR >1%), HER2 negative breast cancer. NOTE: Subject has\n             HER2-negative breast cancer (based on most recently analyzed biopsy) is defined as a\n             negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a\n             negative in situ hybridization (e.g. FISH, CISH, SISH, DISH, etc.) test is required by\n             local laboratory testing.\n\n          -  Metastatic disease evaluable on imaging studies. Subjects may have measurable disease\n             as per RECIST 1.1 or bone-only disease. NOTE: Bone-only subjects are eligible if their\n             disease can be documented/ evaluated by bone scans, CT or MRI. Their disease will be\n             assessed using MDA criteria. NOTE: Previously irradiated lesions are eligible as a\n             target lesion only if there is documented progression of the lesion after irradiation.\n\n          -  No prior systemic anti-cancer therapy for advanced HR+ disease. NOTE: Subjects\n             receiving adjuvant treatment with aromatase inhibitors at time of recurrence are\n             allowed to participate. There is no AI washout period required.\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2\n\n          -  Provided written informed consent and Health Insurance Portability and Accountability\n             Act of 1996 (HIPAA) authorization for release of personal health information, approved\n             by an Institutional Review Board/Independent Ethics Committee (IRB/IEC). NOTE: HIPAA\n             authorization may be included in the informed consent or obtained separately.\n\n          -  Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A\n             negative serum or urine pregnancy test is required within 72 hours of study\n             registration from women of childbearing potential. If the urine test cannot be\n             confirmed as negative, a serum pregnancy test will be required.\n\n          -  Women of childbearing potential (WOCP) must be willing to use two effective methods of\n             birth control such as use of a double barrier method (condoms, sponge, diaphragm, or\n             vaginal ring with spermicidal jellies or cream), or total abstinence for the course of\n             the study until 120 days after the last dose of study drug. The use of hormonal\n             contraceptives is discouraged. NOTE: Women are considered to be of childbearing\n             potential unless they are postmenopausal for at least 12 consecutive months or\n             surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or\n             hysterectomy).\n\n          -  Willingness and ability to comply with scheduled visits, treatment plans, laboratory\n             tests, and other study procedures.\n\n          -  Male subjects capable of fathering a child must agree to use adequate contraception or\n             total abstinence for the course of the study until 120 days after the last dose of the\n             study drug.\n\n        NOTE: Male subjects will be considered as capable of fathering a child unless they have\n        azoospermia (whether due to having had a vasectomy or due to an underlying medical\n        condition).\n\n          -  Co-enrollment in an imaging biomarker study or other non-therapeutic study is allowed.\n\n        Exclusion Criteria:\n\n        Subjects meeting any of the criteria below may not participate in the study:\n\n          -  Prior treatment with any CDK 4/6 inhibitor.\n\n          -  Confirmed diagnosis of HER2 positive disease.\n\n          -  Known uncontrolled or symptomatic CNS metastases. Subjects with known brain metastasis\n             will only be eligible after their tumors have been treated with definitive resection\n             and /or radiotherapy and they are neurologically stable for at least 1 month off\n             steroids.\n\n          -  Advanced, symptomatic, visceral spread with a life expectancy less than 4 months.\n\n          -  Prior (neo)adjuvant treatment with tamoxifen within the 12 months before study entry.\n\n          -  Prior history of blood clots, pulmonary embolism or deep vein thrombosis.\n\n          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly\n             alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled\n             nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).\n\n          -  Concurrent malignancy or malignancy within 3 years of randomization, with the\n             exception of adequately treated basal cell carcinoma, squamous cell skin carcinoma,\n             non-melanomatous skin cancer or curatively resected cervical cancer.\n\n          -  Any other concurrent severe and/or uncontrolled medical condition that would, in the\n             investigator's judgment, contraindicate subject participation in the clinical study.\n\n          -  Currently receiving any of the following substances and cannot be discontinued 7 days\n             prior to study registration:\n\n               -  Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit\n                  hybrids, pomelos, star-fruit, and Seville oranges.\n\n               -  Medications that have a narrow therapeutic window and are predominantly\n                  metabolized through CYP3A4/5.\n\n               -  Known strong inducers or inhibitors of CYP2D6.\n\n          -  Major surgery within 14 days prior to study registration or has not recovered from\n             major side effects of surgery.\n\n          -  Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies].\n\n          -  Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA\n             [qualitative] is detected) (testing not mandatory)\n\n          -  Any clinically significant infection defined as any acute viral, bacterial, or fungal\n             infection that requires specific treatment. NOTE: Anti-infective treatment must be\n             completed ? 7 days prior to study registration.\n\n          -  Known allergy to palbociclib or any of its excipients\n\n          -  Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study\n             registration. NOTE: if fracture is at a metastatic site, is chronic, and no surgical\n             treatment is planned, the subject can be enrolled.\n\n          -  Any condition that, in the opinion of the investigator, might jeopardize the safety of\n             the subject or interfere with protocol compliance.\n\n          -  Any mental or medical condition that prevents the subject from giving informed consent\n             or participating in the trial.\n\n          -  Treatment with any therapeutic investigational agent within 28 days prior to\n             registration for protocol therapy. The subject must have recovered from the acute\n             toxic effects of the regimen.
Inclusion criteria for all parts of the study\n\n          -  Confirmation of locally advanced/metastatic cancer. Refractory or resistant to\n             standard therapy, or have no effective standard\n\n          -  Aged at least 18 yrs\n\n          -  Reasonable health (performance status 0 or 1), stable over the previous 2 weeks\n\n          -  Females who can have children must use contraception; have a negative pregnancy test,\n             & not be breast feeding\n\n          -  Sexually active male patients must use contraception for duration of study and for 3\n             months afterwards Inclusion criteria for Part B only\n\n          -  Tumour(s) that can be measured by CT or MRI, at least 1cm in size Inclusion Part B\n\n          -  Confirmation of metastatic/locally advanced cancer of specific tumour type which\n             failed to respond to standard treatments Exclusion criteria for all parts of the study\n\n          -  Prior treatment with an ATM inhibitor\n\n          -  Past medical history of an inflammatory type(interstitial) lung disease or current\n             inflammatory lung disease\n\n          -  Radiotherapy within the last 4 weeks, except palliative radiotherapy for bone pain\n             relief\n\n          -  Prior treatment with drugs that may cause lung damage\n\n          -  Poor of lung function\n\n          -  History/presence of muscle weakness or abnormal blood tests relating to muscle\n             function\n\n          -  Cancer affecting the spinal cord and/or brain unless asymptomatic and stable\n\n          -  Any evidence of severe or uncontrolled diseases, active bleeding,kidney transplant, or\n             active infection including liver infections (hepatitis B, hepatitis C) and human\n             immunodeficiency virus (HIV).\n\n          -  Evidence of severe lung infections\n\n          -  Receiving, or having received during the four weeks prior to starting study treatment\n             other chemotherapy treatment for your cancer\n\n          -  Treatment with certain doses of steroids during the two weeks prior to starting study\n             treatment\n\n          -  A known sensitivity to AZD0156 or any of its components\n\n          -  Treatment with any unapproved medicine within 28 days prior to starting study\n             treatment\n\n          -  Receiving, or having received medications, herbal supplements and/or foods that\n             significantly affect how your liver works\n\n          -  Low numbers of certain blood cells\n\n          -  If your liver and kidney aren't working normally\n\n          -  If your heart isn't working normally or you have a strong family history of certain\n             heart diseases\n\n          -  Other cancers within the past 3 years, except for certain types of cervical and skin\n             cancers\n\n          -  Sickness and vomiting, digestive diseases or previous significant bowel removal\n\n          -  Patients with uncontrolled fitting\n\n          -  Infections requiring treatment\n\n          -  Other severe and/or uncontrolled medical conditions in addition to your cancer\n\n          -  A blockage in your digestive system or severe bleeding from the stomach within 4 weeks\n             before your take medication on the stuy\n\n          -  Patients with acute leukaemia or certain bone marrow diseases\n\n          -  Patients with a known sensitivity to olaparib or its components (Module 1), or\n             components of FOLFIRI (Module 2)\n\n          -  Any previous treatment with drugs that work like olaparib. (Module 1 Only)
Principal Inclusion Criteria for All Patients\n\n          1. Male and female patients ? 18 years of age.\n\n          2. Any prior palliative radiation therapy must have been completed at least 7 days prior\n             to the start of study drugs, and patients must have recovered from any acute adverse\n             effects prior to the start of study treatment.\n\n          3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1.\n\n          4. Baseline laboratory values within 7 days of study drug(s) initiation:\n\n             ANC ? 1500/?L Haemoglobin (Hgb) ?10 g/dL without transfusion in the past 28 days\n             Platelets ? 100,000/?L Alanine aminotransferase (ALT) and aspartate aminotransferase\n             (AST) ? 3 x ULN or ? 5 x ULN if known liver metastases.\n\n             Serum bilirubin within normal limits (WNL) or ?1.5 x ULN in patients with liver\n             metastases, or total bilirubin ?3.0 x ULN with direct bilirubin WNL in patients with\n             well-documented Gilbert's Syndrome.\n\n             Serum creatinine ?1.5 x ULN and creatinine clearance (CrCl) ? 51 mL/min\n\n          5. Female patients who are not of child-bearing potential, and fertile females of\n             childbearing potential who agree to use two highly effective forms of contraception in\n             combination from 2 weeks prior to study treatment and until 1 month after study\n             treatment discontinuation, are not breastfeeding, and must have a negative serum or\n             urine pregnancy test within 28 days of study treatment and confirmed prior to the\n             start of study treatment on first day of dosing.\n\n          6. Male patients should be willing to abstain or use barrier contraception (i.e., condoms\n             with a spermicide) for the duration of the study drug exposure and for 3 months after\n             study treatment discontinuation. Female partners of male patients should also use a\n             highly effective form of contraception if they are of childbearing potential, unless\n             the male patient is abstaining from sexual intercourse.\n\n          7. Predicted life expectancy ? 12 weeks. For patients in Part C the timing of this\n             assessment is applied from the beginning of Stage 2\n\n             Inclusion criteria specific to Part A\n\n          8. Histologically confirmed refractory solid tumour for which there is no known or\n             established treatment available with curative intent, after at least one course of\n             systemic therapy for locally advanced or metastatic disease including chemotherapy,\n             targeted therapy or hormonal therapy.\n\n          9. Measurable or non-measurable disease according to RECIST v1.1\n\n             Inclusion criteria specific to Part B\n\n         10. Relapsed small-cell lung cancer (SCLC) (defined as a histologically confirmed\n             diagnosis of SCLC) with advanced disease (recurrent or metastatic).\n\n         11. Patients must have a confirmed response (either PR or CR) to first-line platinum\n             therapy and then relapsed after completing that treatment. Patients who progressed\n             whilst on platinum-containing treatment (platinum refractory) are not permitted to\n             enter the study. Prior treatment with immunotherapy is permitted..\n\n         12. Has agreed to the collection of archival tumour tissue or recent tumor biopsy sample,\n             if taken for routine clinical purposes at baseline if archival tissue is not available\n             for molecular biomarker analyses.\n\n         13. Measurable disease according to RECIST v1.1 criteria.\n\n        Principal Exclusion Criteria\n\n          1. Prior treatment with a PARP inhibitor.\n\n          2. Use of an investigational drug during the past 30 days or 5 half-lives (whichever is\n             longer) prior to 1st dose of study treatment.\n\n          3. Use of anti-cancer treatment drug ? 21 days or 5 half-lives (whichever is shorter)\n             prior to 1st dose of study treatment. For drugs for which 5 half-lives is ? 21 days, a\n             minimum of 10 days between termination of the prior treatment and administration of\n             study treatment is required.\n\n          4. Radiotherapy (except for palliative reasons) within ? 21 days prior to study\n             treatment.\n\n          5. No other anti-cancer therapy (except for palliative local radiotherapy), biological\n             therapy, or other novel agent is permitted while the patient is receiving study\n             medication.\n\n          6. Major surgical procedures ? 28 days of beginning study treatment, or minor surgical\n             procedures ? 7 days. Patients must have recovered from any of the effects of any major\n             surgery. No waiting period required following port-a-cath placement.\n\n          7. Persistent Grade >1 toxicity from prior cancer therapy (except alopecia or anorexia).\n\n          8. Patient has an inability to swallow oral medications.\n\n          9. Known malignant central nervous system (CNS) disease other than neurologically stable,\n             treated brain metastases, defined as metastasis having no evidence of progression or\n             haemorrhage for at least 2 weeks after treatment. Must be off any systemic\n             corticosteroids for the treatment of brain metastases for at least 14 days prior to\n             enrolment.\n\n         10. Patient has had prescription or non-prescription drugs or other products known to be\n             sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index,\n             or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued\n             2 weeks prior to the olaparib PK sub-study dosing and withheld throughout the study\n             until 2 weeks after the last dose of study drug.\n\n         11. The use of sensitive substrates of CYP3A4, such as atorvastatin, simvastatin and\n             lovastatin are prohibited in this study. Co-administration of aprepitant or\n             fosaprepitant during this study is prohibited.\n\n         12. Herbal preparations are not allowed throughout the study, including but not limited\n             to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone\n             (DHEA), yohimbe, saw palmetto and ginseng. Patients should stop using these herbal\n             medications 7 days prior to first dose of study treatment.\n\n         13. Any known hypersensitivity or contraindication to the components of the study drug\n             AZD1775 or olaparib.\n\n         14. Patients with either previous or current myelodysplastic syndrome/acute myeloid\n             leukaemia or features suggestive of MDS/AML.\n\n         15. Any of the following cardiac diseases currently or within the last 6 months as defined\n             by New York Heart Association (NYHA) ? Class 2.\n\n             Unstable angina pectoris Congestive heart failure Acute myocardial infarction\n             Conduction abnormality not controlled with pacemaker or medication Significant\n             ventricular or supraventricular arrhythmias (patients with chronic rate controlled\n             atrial fibrillation in the absence of other cardiac abnormalities are eligible)\n\n         16. AZD1775 should not be given to patients who have a history of Torsades des pointes\n             (TdP) unless all risk factors that contributed to TdP have been corrected.\n\n         17. Mean resting corrected QTc interval using the Fridericia formula [QTcF]) ? 470 msec\n             for female patients and ? 450 msec for male patients from 3 electrocardiograms (ECGs)\n             performed 2-5 minutes apart at study entry or congenital long QT syndrome. .\n\n         18. Pregnant or breastfeeding.\n\n         19. Serious known active infection at the time of enrolment, or another serious underlying\n             medical condition that would impair the ability of the patient to receive study\n             treatment.\n\n         20. Presence of other known active invasive cancers.\n\n         21. Psychological, familial, sociological, or geographical conditions that do not permit\n             compliance with protocol.\n\n         22. Patients considered a poor medical risk due to a serious, uncontrolled medical\n             disorder, non-malignant systemic disease or active, uncontrolled infection. Examples\n             include, but are not limited to, uncontrolled ventricular arrhythmia, recent (< 3\n             months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal\n             cord compression, superior vena cava syndrome, extensive interstitial bilateral lung\n             disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder\n             that prohibits obtaining informed consent.\n\n         23. Immunocompromised patients, e.g., patients who are known to be serologically positive\n             for human immunodeficiency virus (HIV).\n\n         24. Previous allogeneic bone marrow transplant or non-leukocyte depleted whole blood\n             transfusion within 120 days of genetic sample collection will exclude patients from\n             the pharmacogenetic portion of the study. If a patient declines to participate in the\n             optional exploratory pharmacogenetic research, there will be no penalty or loss of\n             benefit to the patient. The patient will not be excluded from other aspects of the\n             study.
Inclusion Criteria:\n\n        Adult participants (greater than or equal to 18 years old):\n\n          -  Histologically confirmed de novo (primary) Glioblastoma Multiforme with unequivocal\n             tumor progression or recurrence.\n\n          -  In case of testing at the time of first progression: either at least 3 months after\n             the end of radiotherapy or have tumor progression that is clearly outside the\n             radiation field or have tumor progression unequivocally proven by surgery/biopsy\n\n          -  Absence of any psychological, familial, sociological or geographical factors\n             potentially hampering compliance with the study protocol and follow-up schedule; such\n             conditions should be assessed with the patient before registration in the trial.\n\n          -  Availability of adequate biological material (formalin-fixed paraffin embedded [FFPE]\n             tumor) for central testing of Epithelial Growth Factor Receptor (EGFR) amplification\n\n          -  Presence of EGFR amplification confirmed by central assessment; participants with\n             undetermined EGFR status are excluded\n\n          -  World Health Organization (WHO) Performance status 0 - 2\n\n          -  No more than one line of chemotherapy (concurrent and adjuvant Temozolomide based\n             chemotherapy including in combination with another investigational agent is considered\n             one line of chemotherapy). Chemotherapy must have been completed at least 4 weeks\n             prior to randomization.\n\n          -  Post surgery MRI within 48 hours following surgery, however an MRI scan has to be done\n             within 2 weeks prior to randomization.\n\n          -  Surgery completed at least 2 weeks before randomization and patients should have fully\n             recovered as assessed by investigators.\n\n        Pediatric sub-study participants (less than 18 years old):\n\n          -  The study will only include patients under 3 years of age when results of a juvenile\n             repeated mouse toxicity study become available and are favorable to support use in\n             patients aged under 3 years.\n\n          -  Histologically proven high grade glioma (HGG: WHO grade III glioma [e.g anaplastic\n             astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma], grade IV\n             glioma [e.g glioblastoma, gliosarcoma] or diffuse intrinsic pontine glioma [DIPG]).\n\n          -  Must either have recurrent/progressive tumor or, if newly diagnosed, have completed\n             any planned radiation therapy at least 4 weeks prior to first dose of ABT-414.\n\n          -  The tumor tissue must have been determined to have EGFR amplification, (by local or\n             other testing service).\n\n          -  Availability of adequate biological material for retrospective confirmatory central\n             testing of EGFR amplification\n\n          -  Participant has sufficiently recovered from previous therapy. The investigator\n             believes that benefit of treating the pediatric subject with ABT-414 outweighs the\n             expected risks and that this treatment is in the best interests of the pediatric\n             subject.\n\n        Exclusion Criteria:\n\n        Adult population (greater than or equal to 18 years old):\n\n          -  Prior treatment with nitrosoureas\n\n          -  Prior treatment with bevacizumab\n\n          -  Previous exposure to Epithelial Growth Factor Receptor (EGFR) targeted agents,\n             including EGFRvIII targeting agents\n\n          -  Prior discontinuation of temozolomide chemotherapy for toxicity reasons\n\n          -  Prior Radiation Therapy (RT) with a dose over 65 Gy, stereotactic radiosurgery or\n             brachytherapy unless the recurrence is histologically proven\n\n          -  Previous other malignancies, except for any previous malignancy which was treated with\n             curative intent more than 5 years prior to randomization, and except for adequately\n             controlled limited basal cell carcinoma of the skin, squamous carcinoma of the skin or\n             carcinoma in situ of the cervix\n\n          -  Women of childbearing potential must have a negative serum or urine pregnancy test\n             (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to\n             randomization.\n\n          -  No history of wheat allergies and Coeliac disease.\n\n          -  No EIAED, patients who require anti-convulsant therapy must be taking non-enzyme\n             inducing antiepileptic drugs (non-EIAED). Patients previously on EIAED must be fully\n             switched to non-EIAED at least 2 weeks prior to randomization.\n\n        Pediatric sub-study (less than 18 years old):\n\n          -  (For recurrent disease) No prior RT with a dose over 65Gy to the brain, stereotactic\n             radiosurgery or brachytherapy unless the recurrence is histologically proven\n\n          -  No current or recent (within 4 weeks or 5 half-lives (whichever is shorter) before\n             enrollment) treatment with another investigational drug\n\n          -  Female participants of childbearing potential must have a negative serum or urine\n             pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72\n             hours prior to randomization.
Other serious illnesses or medical conditions including but not limited to:\r\n* Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry\r\n* History of significant neurologic or psychiatric disorders including dementia or seizures \r\n* Active clinically significant uncontrolled infection \r\n* Active peptic ulcer disease defined as unhealed or clinically active \r\n* Active drug addiction including alcohol, cocaine or intravenous drug use defined as occurring within the 6 months preceding diagnosis \r\n* Chronic obstructive pulmonary disease, defined as being associated with a hospitalization for pneumonia or respiratory decompensation within 12 months of diagnosis; this does not include obstruction from tumor \r\n* Autoimmune disease requiring therapy, prior organ transplant, or known human immunodeficiency virus (HIV) infection\r\n* Interstitial lung disease\r\n* Hepatitis C by history \r\n* Concurrent treatment with any other anticancer therapy\r\n* Participation in an investigational therapeutic drug trial within 30 days of study entry
Inclusion Criteria:\n\n        Patients must meet all of the following criteria in order to be included in the study:\n\n          1. Male or female patients, 18 years of age or older at the time of consent.\n\n          2. Provide written informed consent prior to performing any study-related procedure.\n\n          3. Histologically or cytologically confirmed patients with advanced or metastatic solid\n             tumors for both Dose Escalation and Expansion cohort.\n\n          4. Patients for whom no available treatment options are known to confer clinical benefit.\n\n          5. Measurable disease (i.e., at least one measurable lesion per Response Evaluation\n             Criteria in Solid Tumors (RECIST), version 1.1.\n\n          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          7. At least 21 days since the last chemotherapy, immunotherapy, biological or radiation,\n             or approved tyrosine kinase inhibitor (TKI) therapy.\n\n          8. Adequate organ function defined as:\n\n               -  Hepatic:\n\n                    -  Serum alanine aminotransferase (ALT) ?3 × upper limit of normal (ULN), ?5 ×\n                       ULN in the presence of liver metastases\n\n                    -  Serum aspartate aminotransferase (AST) ?3 × ULN, ?5 × ULN in presence of\n                       liver metastases\n\n                    -  Serum bilirubin ?1.5 × ULN\n\n               -  Renal:\n\n                  - Creatinine clearance >60 mL/minute using Cockcroft Gault equation\n\n               -  Hematologic:\n\n                    -  White Blood Count (WBC) ?3,500/µL\n\n                    -  Absolute neutrophil count ?1000/µL\n\n                    -  Absolute lymphocytes ? 0.5 ×10 9/l\n\n                    -  Platelets ?75,000/µL\n\n                    -  Hemoglobin ?9 g/dL\n\n          9. Normal coagulation profile except:\n\n               -  International Normalized Ratio (INR) within 1.5 × ULN\n\n               -  Activated partial thromboplastin time (aPTT) within 1.5 × ULN\n\n         10. Patient is willing and able to comply with all protocol required assessments, visits,\n             and procedures, including pretreatment tumor biopsy. Archival tumor biopsies are\n             acceptable at baseline.\n\n         11. Females of childbearing potential must have negative serum pregnancy test prior to\n             starting study therapy, and agree to use a reliable form of contraceptive during the\n             study treatment period and for at least 120 days following the last dose of study\n             drug.\n\n             Subject not of childbearing potential (i.e., permanently sterilized, postmenopausal)\n             can be included in study. Postmenopausal is defined as 12 months with no menses\n             without an alternative medical cause.\n\n             Male patients must agree to use an adequate method of contraception during the study\n             treatment period and for at least 120 days following the last dose of study drug.\n\n         12. Cannot be breast feeding.\n\n        Exclusion Criteria:\n\n        Patients meeting any of the following criteria are ineligible to participate in this study:\n\n          1. Patients currently participating in or has participated in a study of an\n             investigational anticancer therapy received within 28 days prior to the first dose of\n             OBI-888.\n\n          2. Has undergone a major surgical procedure (as defined by the investigator) or\n             significant traumatic injury within 28 days prior to the first dose of OBI-888.\n\n          3. Presence of an active autoimmune or inflammatory disease requiring systemic treatment\n             within the past 2 months or a documented history of clinically severe autoimmune\n             disease that requires systemic steroids or other immunosuppressive medications. Local\n             steroid injections, intermittent use of topical, inhaled, ophthalmologic,\n             intra-articular, topical, or intranasal corticosteroids, or systemic corticosteroids\n             at physiologic doses not to exceed 10 mg/day of prednisone or equivalent would not be\n             excluded from the study.\n\n          4. Presence of primary immunodeficiency or receiving systemic steroids of >10 mg/day of\n             prednisone or equivalent or other immunosuppressive agents within 7 days prior to the\n             first dose of OBI 888.\n\n          5. Has active bacterial, viral, fungal, or mycobacterial infection requiring systemic\n             therapy, including known infection with human immunodeficiency virus (HIV) or active\n             infection with hepatitis B virus or hepatitis C virus.\n\n          6. Patients with a history of solid organ transplant.\n\n          7. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to\n             Grade 0 or 1 (using National Cancer Institute Common Terminology Criteria for Adverse\n             Events [NCI CTCAE] version 4.03), except for alopecia and laboratory values listed in\n             the inclusion criteria.\n\n          8. Receipt of any prior therapy targeting Globo H.\n\n          9. Prior anti cancer mAb within 3 weeks or 5 half lives prior to the first dose of OBI\n             888.\n\n         10. Known hypersensitivity to OBI 888 or its excipients.\n\n         11. Has known central nervous system metastases and/or leptomeningeal metastases.\n\n         12. Any medical co morbidity or psychiatric illness that is life threatening or, in the\n             opinion of the Investigator, renders the patient unsuitable for participation in a\n             clinical trial due to possible noncompliance, would place the patient at an\n             unacceptable risk and/or potential to affect interpretation of results of the study.\n\n         13. Unable or unwilling to complete any study procedures or discontinue any prohibited or\n             restricted medications for the duration of the study.\n\n         14. Positive serum pregnancy test.\n\n         15. Is receiving any concurrent prohibited medication
Part-1 Escalation Phase [Key Inclusion]:\n\n          -  Histologically or cytologically confirmed diagnosis of solid tumor malignancy or\n             lymphoma that is not responsive to standard therapies, are unfit for standard\n             chemotherapy or for which there is no approved or curative therapy.\n\n          -  ECOG score of 0 or 1.\n\n          -  Able to swallow and retain oral medication.\n\n          -  Adequate organ system function.\n\n        Part-2 Expansion Phase [Key Inclusion]:\n\n          -  Part-1 Escalation Phase inclusion criteria.\n\n          -  (a) Thymic carcinoma, thymoma, pancreatic cancer, or breast cancer (TNBC); or (b) any\n             other cancer with histologically or cytologically or genomically confirmed diagnosis\n             of NTRK1 (TrkA) mutation, or fusion, or overexpression, translocation, amplification\n             or other alterations that may interfere with TrkA (NTRK1) signaling, as previously\n             identified with prior testing as routinely performed at Clinical Laboratory\n             Improvement Amendments (CLIA)-certified or other similarly-certified laboratories.\n\n        Part-3 Pharmacodynamic Activity (Eligible subjects in Part-2 may enroll in Part-3):\n\n          -  Part-2 Expansion Phase inclusion criteria.\n\n          -  Tumor with readily accessible lesion that is amenable to biopsy and consent to pre-and\n             post-dose biopsy.\n\n        Key Exclusion Criteria (Part-1, -2 and -3):\n\n          1. Received chemotherapy having delayed toxicity within the last 21 days (six weeks for\n             prior nitrosourea or mitomycin C).\n\n          2. Received anticancer therapy with radiation, immunotherapy, a biologic, surgery and/or\n             tumor embolization within the past 2 weeks.\n\n          3. Received an investigational anti-cancer drug within 21 days or 5 half-lives of the\n             investigational agent prior, whichever is shorter, to the first dose of VMD-928.\n\n          4. Unresolved toxicity from previous anti-cancer therapy ? CTCAE Grade 1 (except alopecia\n             or anemia) unless agreed to by both the Investigator and Sponsor.\n\n          5. Known active infections including HIV disease.\n\n          6. Currently pregnant, nursing, or planning to become pregnant during the course of the\n             study.\n\n          7. QTcF interval ? 480 msec.\n\n          8. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA)\n             functional classification system.\n\n          9. Acute coronary syndromes (including unstable angina), coronary angioplasty, or\n             stenting within the past 24 weeks.\n\n         10. Unstable or uncompensated respiratory, hepatic, renal, or cardiac disease that would\n             compromise the patient's safety or interfere with assessment of the drug.\n\n         11. Psychological, familial, sociological, geographical or other concurrent conditions\n             that would interfere with safety evaluation, limit the subject's ability to follow the\n             procedures in the protocol or otherwise jeopardize compliance with the protocol.\n             Subjects with uncontrolled major depression, bipolar disorder, or severe anxiety\n             disorder are excluded.\n\n             Key Exclusion Criteria (For Part-1 Escalation Phase only):\n\n         12. Any current medical condition that would alter the absorption, distribution,\n             metabolism or excretion of VMD-928 including but not limited to:\n\n               -  Severe uncontrolled nausea or vomiting\n\n               -  Severe uncontrolled diarrhea The intended population for VMD-928 are expected to\n                  have had bowel resections and these subjects will be eligible for Part-1 Dose\n                  Escalation phase.
Inclusion criteria:\n\n          -  Existence of archival or fresh tumor biopsy specimen for FGFR1/3 mRNA expression\n             testing\n\n          -  High FGFR1 or 3 mRNA expression levels (RNAscope score of 3+ or 4+) in archival or\n             fresh tumor biopsy specimen\n\n          -  Documented locally advanced (T4, any N; or any T, N2-3) or metastatic urothelial\n             carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis,\n             ureters, urethra, meeting all of the following criteria:\n\n          -  No prior systemic treatment for locally advanced or metastatic urothelial carcinoma.\n             For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation\n             for urothelial carcinoma, a treatment-free interval > 12 months between the last\n             treatment administration and the date of recurrence is required in order to be\n             considered treatment-naïve in the metastatic setting. Prior local intra-vesical\n             chemotherapy or prior local immunotherapy is allowed.\n\n          -  Ineligibility for cisplatin-based chemotherapy as defined by any one of the following\n             criteria:\n\n               -  Impaired renal function (GFR > 30 but < 60 mL/min/1.73 m2) according to the\n                  modification of diet in renal disease (MDRD) abbreviated formula\n\n               -  Hearing loss (measured by audiometry) of 25 dB at two contiguous frequencies\n\n               -  Grade ? 2 peripheral neuropathy (i.e. sensory alteration or paresthesia including\n                  tingling)\n\n          -  Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1.\n\n        Exlusion criteria:\n\n          -  Active symptomatic or untreated brain metastases as determined by CT or MRI evaluation\n             during screening and prior radiographic assessment.\n\n          -  History of autoimmune disease, including but not limited to myasthenia gravis,\n             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,\n             inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid\n             syndrome, granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré\n             syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.\n\n          -  History or current condition of an uncontrolled cardiovascular disease including any\n             of the following conditions:\n\n               -  Congestive heart failure (CHF) NYHA Class 2 or greater, unstable angina (symptoms\n                  of angina at rest) or\n\n               -  New-onset angina (within last 3 months before the first study drug\n                  administration)\n\n               -  Myocardial infarction (MI) within past 6 months before the first study drug\n                  administration\n\n               -  Unstable cardiac arrhythmias requiring anti-arrhythmic therapy.\n\n          -  Patients with known coronary artery disease, congestive heart failure not meeting the\n             above criteria, or known left ventricular ejection fraction < 50% must be on a stable\n             medical regimen that is optimized in the opinion of the treating physician, in\n             consultation with a cardiologist if appropriate.\n\n          -  Current diagnosis of any retinal disorders including retinal detachment, retinal\n             pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion.\n\n          -  Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g.\n             parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis,\n             paraneoplastic hypercalcemia).\n\n          -  Concomitant therapies that are known to increase serum calcium or phosphate levels\n             (i.e. antacids, phosphate-containing laxatives oral/rectal, potassium phosphate) and\n             that cannot be discontinued or switched to a different medication before the first\n             study drug administration\n\n          -  Treatment with systemic corticosteroids or other systemic immunosuppressant\n             medications within 2 weeks before the first study drug administration, or anticipated\n             requirement for systemic immunosuppressive medications during the trial.
Inclusion Criteria Stage 1\n\n          -  ECOG Performance Status of 0 or 1\n\n          -  Metastatic or locally advanced, histologically documented TNBC (absence of HER2, ER,\n             and PR expression)\n\n          -  Radiologic/objective evidence of recurrence or disease progression after one line of\n             chemotherapy for metastatic breast cancer MBC\n\n          -  Availability of a representative tumor specimen that is suitable for determination of\n             PD-L1 and/or additional biomarker status via central testing\n\n          -  Eligible for capecitabine monotherapy\n\n          -  Adequate hematologic and end-organ function, laboratory test results, obtained within\n             14 days prior to initiation of study treatment.\n\n          -  Negative HIV test at screening\n\n          -  Negative hepatitis B surface antigen .\n\n          -  Negative hepatitis C virus (HCV) antibody test at screening or positive HCV antibody\n             test followed by a negative HCV RNA test at screening\n\n        Inclusion Criteria for Stage 1 and Stage 2\n\n          -  Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1\n             (RECIST v1.1)\n\n          -  Tumor accessible for biopsy\n\n          -  For patients receiving therapeutic anticoagulation: stable anticoagulant regimen\n             during the 14 days prior to initiation of study treatment\n\n          -  For women of childbearing potential: agreement to remain abstinent (refrain from\n             heterosexual intercourse) or use contraceptive measures as outlined for each specific\n             treatment arm\n\n          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use\n             contraceptive measures, and agreement to refrain from donating sperm, as outlined for\n             each specific treatment arm\n\n        Inclusion criteria stage 2\n\n          -  ECOG Performance Status of 0, 1, or 2\n\n          -  Patients randomly allocated to the control arm during Stage 1: ability to initiate\n             Stage 2 treatment within 3 months after experiencing unacceptable toxicity, provided\n             that Medical Monitor approval for entry into Stage 2 is obtained, or disease\n             progression per RECIST v1.1 while receiving control treatment\n\n          -  Patients randomly allocated to an experimental arm during Stage 1: ability to initiate\n             Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related\n             to atezolizumab, disease progression per RECIST v1.1, or loss of clinical benefit as\n             determined by the investigator (see Section 3.1.1.1 for details) while receiving Stage\n             1 treatment\n\n          -  Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage\n             1 (if deemed clinically feasible by the investigator)\n\n        Exclusion Criteria for Stage 1\n\n          -  Prior treatment with any of the protocol-specified study treatments\n\n          -  Treatment with investigational therapy within 28 days prior to initiation of study\n             treatment\n\n          -  Inability to swallow medication or malabsorption condition that would alter the\n             absorption of orally administered medications\n\n          -  Treatment with sorivudine or its chemically related analogues, such as brivudine\n\n          -  History of severe and unexpected reactions to fluoropyrimidine therapy\n\n        Exclusion Criteria for Stage 1 and Stage 2\n\n          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent\n             drainage procedures (once monthly or more frequently)\n\n          -  Uncontrolled tumor-related pain\n\n          -  Symptomatic, untreated, or actively progressing CNS metastases\n\n          -  History of leptomeningeal disease\n\n          -  Active or history of autoimmune disease or immune deficiency\n\n          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis\n             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of\n             active pneumonitis on screening chest computed tomography (CT) scan History of\n             radiation pneumonitis in the radiation field (fibrosis) is permitted.\n\n          -  Active tuberculosis\n\n          -  Severe infection within 4 weeks prior to initiation of study treatment\n\n          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation\n             of study treatment\n\n          -  Significant cardiovascular disease\n\n          -  Prior allogeneic stem cell or solid organ transplantation\n\n          -  History of malignancy other than breast cancer within 2 years prior to screening, with\n             the exception of those with a negligible risk of metastasis or death\n\n          -  Treatment with systemic immunosuppressive medication (including, but not limited to,\n             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and\n             anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study\n             treatment, or anticipation of need for systemic immunosuppressive medication during\n             the course of the study\n\n          -  Pregnancy or breastfeeding, or intention of becoming pregnant during the study
INCLUSION CRITERIA:\n\n          1. Age: Men and women aged ? 18 years,\n\n          2. Signed written informed consent,\n\n          3. Any histologic type of locally advanced or metastatic NSCLC,\n\n          4. Life expectancy of ? 12 weeks,\n\n          5. Measurable or evaluable (cytologically or radiologically detectable disease such as\n             ascites, peritoneal deposits, or lesions which do not fulfill RECIST 1.1 criteria for\n             measurable disease) lesions according to RECIST v1.1 criteria for phase 1 portion. For\n             phase 2, all patients must have RECIST 1.1 measurable disease,\n\n          6. Physiologic function:\n\n               -  Hematologic function: Absolute neutrophil count (ANC) ? 1.5 × 109/L, platelet\n                  count ? 100 × 109/L, and hemoglobin ? 9 g/dL (may have been transfused),\n\n               -  Hepatic function: Total bilirubin level ? 1.5 × the upper limit of normal (ULN)\n                  range and aspartate aminotransferase (AST) and alanine aminotransferase (ALT)\n                  levels ? 2.5 × ULN,\n\n               -  Renal function: Estimated creatinine clearance ? 30 mL/min according to the\n                  Cockcroft-Gault formula (or local institutional standard method).\n\n          7. Pregnancy and contraception:\n\n               -  Pregnancy test: Negative serum or urine pregnancy test at screening for women of\n                  childbearing potential,\n\n               -  Contraception: Highly effective contraception for both male and female subjects\n                  throughout the study and for 90 days after last avelumab treatment administration\n                  if the risk of conception exists.\n\n          8. Ability to comply with protocol requirements,\n\n          9. Willingness to consent and ability to undergo a trucut biopsy to obtain a fresh\n             metastasis or primary tumor biopsy in case no adequate tumoral tissue is available,\n             and to undergo fibroscopy to obtain a biopsy from normal bronchial mucosa,\n\n         10. No serious or medically uncontrolled concomitant conditions that are likely to make\n             the patient unfit for SPRING combination therapy, as per investigator assessment,\n\n         11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.\n\n        EXCLUSION CRITERIA:\n\n          1. Patients with documented oncogenic aberrations at enrollment: EGFR, ALK, ROS1 when\n             available, MET exon 14 skipping when available.\n\n             Note: For Phase 1 portion, all patients with adenocarcinoma histology must have\n             documentation of results for druggable oncogenic aberrations (EGFR mutations, ALK\n             rearrangements, and ROS1 when available) prior to enrollment on the study.\n\n          2. For Phase 1 portion, >2 lines of prior therapy in the metastatic setting.\n\n          3. For the dose escalation phase of the study or until the MTD for the combination\n             regimen has been determined, patients with moderate hepatic impairment defined as AST,\n             ALT, alkaline phosphatase (ALP) >5 times ULN, which would be grade 3 or higher.\n             However patients with liver metastases with AST/ALT ? 5 x ULN can be included in the\n             study.\n\n          4. For Phase 2 portion, any prior therapy in the metastatic setting.\n\n        Clinical exclusion criteria for Phase 1 and Phase 2 studies:\n\n          1. Documented untreated central nervous system metastases (indicated by clinical\n             symptoms, cerebral edema, steroid requirement, or progressive disease in the prior\n             four weeks),\n\n          2. Participants with a history of myocardial infarction within the last 2 years or with\n             significant cardiac arrhythmias uncontrolled by medication or pacemaker,\n\n          3. Participants with any history of interstitial lung disease,\n\n          4. Prior clinically significant toxicities from anticancer agents or radiotherapy which\n             have not regressed to Grade ? 1 severity (NCI-CTCAE version 4.03) apart from\n             peripheral neuropathy and alopecia,\n\n          5. History of any second malignancy in the last two years; patients with prior history of\n             in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with a\n             history of other malignancies are eligible if they have been continuously disease-free\n             for at least two years,\n\n          6. Autoimmune condition requiring medical intervention,\n\n          7. Uncontrolled concomitant illness, active infection requiring i.v. antibiotics,\n\n          8. Participants who are at risk for, or who have a history of arterial thromboembolic\n             events within the past 12 months and/or venous thromboembolic events within the past 6\n             months, or have had any recent active gastrointestinal bleeding,\n\n          9. Prior > G3 hemoptysis, major blood vessel involvement, and/or central cavitations,\n\n         10. Known or suspected drug hypersensitivity to any drug used in the combination,\n\n         11. Difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or\n             conditions that may hamper compliance and/or absorption of the oral drugs,\n\n         12. Any condition (e.g., known or suspected poor compliance, psychological instability,\n             geographical location, etc.) that, in the judgment of the investigator may affect the\n             patient's ability to sign the informed consent and undergo study procedures,\n\n         13. Taking another experimental drugs within 28 days prior to day 1 of the protocol\n             medications in this study,\n\n         14. Pregnant or breast-feeding women,\n\n         15. Both male and female patients of reproductive potential must agree to use a reliable\n             method of birth control, during the study and for 3 months following the last dose of\n             study drug,\n\n         16. Patients currently taking strong CYP3A4 inducers and inhibitors.\n\n         17. Patients currently taking proton pump inhibitors due to their impact on the\n             disposition of palbociclib during the dose escalation phase,\n\n         18. Other anticancer agents and anticoagulants are excluded (except for low doses of\n             anticoagulants used for access lines)\n\n         19. A time period of at least three weeks or five drug half-lives, whichever is shorter\n             must have elapsed from last non-investigational therapy before day 1 of treatment on\n             this study,\n\n         20. Specific exclusion criteria for administration of avelumab, in combination:\n\n               -  IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, EXCEPT for the\n                  following: a. intranasal, inhaled, topical steroids, or local steroid injection\n                  (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic\n                  doses ? 10 mg/day of prednisone or equivalent; c. Steroids as premedication for\n                  hypersensitivity reactions (e.g., CT scan premedication).\n\n               -  AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when\n                  receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo,\n                  psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive\n                  treatment are eligible.\n\n               -  ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell\n                  transplantation.\n\n               -  INFECTIONS: Active infection requiring systemic therapy.\n\n               -  HIV/AIDS: Known history of testing positive for HIV or known acquired\n                  immunodeficiency syndrome.\n\n               -  HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at\n                  screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening\n                  test positive).\n\n               -  VACCINATION: Vaccination within 4 weeks of the first dose of avelumab and while\n                  on trials is prohibited except for administration of inactivated vaccines.\n\n               -  HYPERSENSITIVITY TO STUDY DRUG: Known prior severe hypersensitivity to\n                  investigational product or any component in its formulations, including known\n                  severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade\n                  ? 3).\n\n               -  CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular\n                  disease: cerebral vascular accident/stroke (< 6 months prior to enrollment),\n                  myocardial infarction (< 6 months prior to enrollment), unstable angina,\n                  congestive heart failure (? New York Heart Association Classification Class II),\n                  or serious cardiac arrhythmia requiring medication.\n\n               -  OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI\n                  CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ? 2, or\n                  other Grade ? 2 not constituting a safety risk based on investigator's judgment\n                  are acceptable.\n\n               -  Other severe acute or chronic medical conditions including colitis, inflammatory\n                  bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions\n                  including recent (within the past year) or active suicidal ideation or behavior;\n                  or laboratory abnormalities that may increase the risk associated with study\n                  participation or study treatment administration or may interfere with the\n                  interpretation of study results and, in the judgment of the investigator, would\n                  make the patient inappropriate for entry into this study.
PART A DOSE ESCALATION\n\n        Inclusion Criteria: PART A Dose Escalation\n\n          1. 18-70 years of age\n\n          2. Histologically confirmed WHO grade IV glioblastoma\n\n          3. Unequivocal evidence of a tumor recurrence (any number of recurrences) or progression\n             after an initial treatment regimen (prior to enrollment on this study) consisting of\n             surgical intervention (tumor resection), radiation, and temozolomide chemotherapy (per\n             Stupp protocol), as assessed by MRI of the brain with and without contrast within 30\n             days prior to the initiation of injections of VBI-1901.\n\n          4. Recovery from the effects of surgery.\n\n          5. Corticosteroid (dexamethasone or equivalent) dosage ? 4mg daily that has been stable\n             or decreasing for at least 5 days.\n\n          6. Recovery from prior therapy toxicity defined as resolution of all treatment-related\n             adverse events (AEs) to Grade ? 1 or pre-treatment baseline (except alopecia).\n\n          7. Karnofsky performance status (KPS) score ? 70%.\n\n          8. Adequate organ function, including the following:\n\n               1. Absolute neutrophil count (ANC) ? 1,000/?L, platelets ? 100,000/?L\n\n               2. Serum creatinine < 1.5 × the upper limit of normal (ULN)\n\n               3. Bilirubin < 1.5 × ULN\n\n               4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN\n\n          9. Women of childbearing potential: negative urine pregnancy test within 14 days prior to\n             the start of VBI-1901 treatment.\n\n         10. Female subjects of childbearing potential and sexually active male subjects must agree\n             to use an acceptable form of contraception for heterosexual activity (i.e., oral\n             contraceptives, double barrier methods, hormonal injectable, transdermal, or implanted\n             contraceptives, tubal ligation, or vasectomy of their sexual partner(s) for > 30 days\n             before Screening, during the study, and for 60 days after the last dose of study\n             drug).\n\n         11. Female subjects without childbearing potential (spontaneous amenorrhea for > 12 months\n             or surgically sterilized by tubal ligation, hysterectomy, or bilateral oophorectomy >\n             6 months before Screening) are eligible for inclusion without contraceptive use\n             restriction.\n\n         12. Able and willing to comply with protocol requirements, including being able to have an\n             MRI in the opinion of the Investigator.\n\n         13. Written consent has been obtained.\n\n         14. Tumor specimen available for central pathological review.\n\n        Exclusion Criteria: PART A Dose Escalation\n\n          1. Contrast-enhancing residual tumor that is associated with either diffuse sub-\n             ependymal or leptomeningeal dissemination.\n\n          2. Requirement of systemic corticosteroid therapy > 4 mg/day of dexamethasone or\n             equivalent or requirement of increasing dose of systemic corticosteroids during the 7\n             days prior to the start of VBI-1901 treatment.\n\n          3. Evidence of HCMV viremia in serum of > 18,200 (4.3Log10) IU/mL using FDA approved\n             COBAS® AmpliPrep/COBAS® TaqMan® HCMV test (Roche).\n\n          4. Surgical resection or major surgical procedure within 4 days prior to the start of\n             VBI- 1901, or stereotactic biopsy within 7 days prior to the start of VBI-1901.\n\n          5. Active infection requiring intravenous antibiotics or antiviral.\n\n          6. History of cancer (other than GBM or prostate) within the past 2 years that could\n             negatively impact survival and/or potentially confound tumor response assessments\n             within this study.\n\n          7. Known immunosuppressive disease or active systemic autoimmune disease such as systemic\n             lupus erythematosus, human immunodeficiency virus infection, Hepatitis B virus or\n             Hepatitis C virus infections. Subjects with vitiligo, type 1 diabetes mellitus,\n             hypothyroidism due to autoimmune condition only requiring hormone replacement therapy,\n             psoriasis not requiring systemic therapy, or conditions not expected to recur in the\n             absence of an external trigger are permitted to enroll.\n\n          8. Immunosuppressive agent within 4 weeks prior to the start of VBI-1901 treatment.\n\n          9. Evidence of intra-tumoral or peri-tumoral hemorrhage on baseline, other than those\n             that are ?Grade 1 and either post-operative or stable on at least 2 consecutive MRI\n             scans.\n\n         10. Any condition which in the investigator's opinion makes the subject unsuitable for\n             study participation.\n\n         11. Lack of family or social support structure that would preclude continued participation\n             in the study.\n\n        PART B\n\n        Inclusion Criteria: Part B\n\n          1. 18-70 years of age.\n\n          2. Histologically confirmed WHO grade IV glioblastoma.\n\n          3. Unequivocal evidence of a first tumor recurrence with measurable disease, defined as 1\n             cm but no greater than 3 cm of enhancing tissue measured in 2 planes (axial, coronal,\n             or sagittal) after an initial treatment regimen (prior to enrollment on this study)\n             consisting of surgical intervention (tumor resection), radiation, and temozolomide\n             chemotherapy (per Stupp protocol), as assessed by MRI of the brain with and without\n             contrast within 30 days prior to the initiation of injections of VBI-\n\n        1901.\n\n        4. At least 12 weeks since treatment per Stupp protocol prior to first dose of VBI-1901.\n\n        5. Recovery from the effects of surgery.\n\n        6. Corticosteroid (dexamethasone or equivalent) dosage ? 4mg daily that has been stable or\n        decreasing for at least 5 days.\n\n        7. Recovery from prior therapy toxicity, defined as resolution of all treatment-related\n        adverse events (AEs) to Grade ? 1 or pre-treatment baseline (except alopecia).\n\n        8. Karnofsky performance status (KPS) score ? 70%.\n\n        9. Adequate organ function, including the following:\n\n          1. Absolute neutrophil count (ANC) ? 1,000/?L, platelets ? 100,000/?L;\n\n          2. Serum creatinine < 1.5 × the upper limit of normal (ULN);\n\n          3. Bilirubin < 1.5 × ULN;\n\n          4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN.\n\n             10. Women of childbearing potential must have a negative urine pregnancy test within\n             14 days prior to the start of VBI-1901 treatment.\n\n             11. Female subjects of childbearing potential and sexually active male subjects must\n             agree to use an acceptable form of contraception for heterosexual activity (i.e., oral\n             contraceptives, double barrier methods, hormonal injectable, transdermal, or implanted\n             contraceptives, tubal ligation, or vasectomy of their sexual partner(s) for > 30 days\n             before Screening, during the study, and for 60 days after the last dose of study\n             drug).\n\n             12. Female subjects without childbearing potential (spontaneous amenorrhea for > 12\n             months or surgically sterilized by tubal ligation, hysterectomy, or bilateral\n             oophorectomy > 6 months before Screening) are eligible for inclusion without\n             contraceptive use restriction.\n\n             13. Able and willing to comply with protocol requirements, in the opinion of the\n             Investigator.\n\n             14. Written consent has been obtained.\n\n             15. Tumor specimen available for central pathological review.\n\n        Exclusion Criteria: Part B\n\n          1. Contrast-enhancing residual tumor that is any of the following:\n\n               1. Greater than 3 cm in 2 planes (axial, coronal, or sagittal);\n\n               2. Multi-focal (defined as two separate areas of contrast enhancement measuring at\n                  least 1 cm in 2 planes that are not contiguous on either fluid-attenuated\n                  inversion recovery (FLAIR) or T2 sequences);\n\n               3. Associated with either diffuse sub-ependymal or leptomeningeal dissemination.\n\n          2. Requirement of systemic corticosteroid therapy > 4 mg/day of dexamethasone or\n             equivalent or requirement of increasing dose of systemic corticosteroids during the 7\n             days prior to the start of VBI-1901 treatment.\n\n          3. Evidence of HCMV viremia in plasma of >18,200 (4.3log10) IU/mL using FDA approved\n             COBAS® AmpliPrep/COBAS® TaqMan® HCMV test (Roche).\n\n          4. Prior treatment involving immunotherapy, including oncolytic viruses, therapeutic\n             vaccination, or biologics (e.g. monoclonal antibodies) presumed to have\n             immunomodulatory effects.\n\n          5. Surgical resection or major surgical procedure within 14 days prior to the start of\n             VBI- 1901, or stereotactic biopsy within 14 days prior to the start of VBI-1901.\n\n          6. Radiation therapy, local therapy (except for surgical re-resection), or systemic\n             therapy following first recurrence/progressive disease. Excluded local therapies\n             include stereotactic radiation boost, implantation of carmustine biodegradable wafers\n             (Gliadel), intratumoral or convection- enhanced delivery administered agents, etc.\n\n          7. Active infection requiring intravenous antibiotics or antivirals.\n\n          8. History of cancer (other than GBM or prostate) within the past 2 years that has\n             metastatic or local recurrence potential and could negatively impact survival and/or\n             potentially confound tumor response assessments within this study.\n\n          9. Known immunosuppressive disease or active systemic autoimmune disease such as systemic\n             lupus erythematosus, human immunodeficiency virus infection, Hepatitis B virus or\n             Hepatitis C virus infections. Subjects with vitiligo, type 1 diabetes mellitus,\n             hypothyroidism due to autoimmune condition only requiring hormone replacement therapy,\n             psoriasis not requiring systemic therapy, or conditions not expected to recur in the\n             absence of an external trigger are permitted to enroll.\n\n         10. Immunosuppressive agent within 4 weeks prior to the start of VBI-1901 treatment.\n\n         11. Evidence of intra- or peri-tumoral hemorrhage on baseline MRI scan, other than those\n             that are ?Grade 1 and either post-operative or stable on at least 2 consecutive MRI\n             scans.\n\n         12. Any condition which in the investigator's opinion makes the subject unsuitable for\n             study participation.\n\n         13. Lack of family or social support structure that would preclude continued participation\n             in the study.
Inclusion Criteria: All subjects\n\n          1. Histologically confirmed diagnosis of B-cell follicular lymphoma based on the WHO 2008\n             classification of tumors of hematopoietic and lymphoid tissue.\n\n          2. ?2 prior systemic treatments for follicular lymphoma.\n\n          3. Previously received an anti-CD20 antibody and an appropriate alkylator-based\n             combination therapy.\n\n          4. Disease progression within 12 months after completion of most recent therapy or\n             refractory disease.\n\n          5. Presence of measurable disease.\n\n          6. Availability of archival tissue confirming diagnosis.\n\n          7. ECOG performance status of 0,1 or 2.\n\n          8. Life expectancy ?6 months.\n\n          9. Adequate bone marrow function.\n\n         10. Adequate renal and hepatic function.\n\n         11. Females of childbearing potential and non-sterile males must agree to use highly\n             effective methods of birth control throughout the course of study and at least up to\n             90 days after last dosing, or 18 months after the last dose of obinutuzumab, whichever\n             is longer.\n\n         12. Male subjects are eligible if vasectomized or if they agree to the use of barrier\n             contraception in combination with other methods during the study treatment period and\n             for ? 90 days after the last dose of BGB-3111.\n\n         13. Ability to provide the written informed consent and can understand and comply with the\n             requirements of the study.\n\n        Exclusion Criteria: All subjects\n\n          1. Prior exposure to a BTK inhibitor.\n\n          2. Known central nervous system involvement by leukemia or lymphoma.\n\n          3. No evidence of transformation from follicular lymphoma to other aggressive histology.\n\n          4. No allogeneic hematopoietic stem cell transplantation within 12 months of enrollment\n\n          5. Prior malignancy within the past 5 years, except for basal or squamous cell skin\n             cancer, superficial bladder cancer, carcinoma in situ of the cervix of breast, or\n             localized Gleason score 6 prostate\n\n          6. Clinically significant cardiovascular disease.\n\n          7. Major surgery or significant injury ? 4 weeks prior to start of study treatment.\n\n          8. Active fungal, bacterial or viral infection requiring systemic treatment.\n\n          9. History of severe bleeding disorder.\n\n         10. History of stroke or intracranial hemorrhage within 6 months before first study drug.\n\n         11. Severe or debilitating pulmonary disease.\n\n         12. Known human immunodeficiency virus (HIV) or active hepatitis B or C.\n\n         13. Unable to swallow capsules or significant gastrointestinal disease that would\n             interfere with drug absorption.\n\n         14. Requires ongoing treatment with a strong CYP3A inhibitor or inducer\n\n         15. Pregnant or nursing females.\n\n         16. Vaccination with live vaccine within 35 days prior to first dose.\n\n         17. Ongoing drug or alcohol addiction.\n\n         18. Hypersensitivity to BGB-3111, known ingredients of BGB-3111 or obinutuzumab.\n\n         19. Participation in another therapeutic trial.
Inclusion criteria\n\n        1.Provision of informed consent prior to any study specific procedures 2.Patients must be\n        male or female ?18 years of age. 3.Progressive cancer at the time of study entry with a\n        life expectancy of ?16 weeks 4.Histologically or cytologically confirmed TNBC with evidence\n        of metastatic disease as per ASCO-CAP HER2 guideline recommendations 2013 5.Patients must\n        have received at least 1 and no more than 2 prior lines of treatment for metastatic disease\n        with an anthracycline (eg, doxorubicin, epirubicin) and/or a taxane (eg, paclitaxel,\n        docetaxel) unless contraindicated, in either the neo-adjuvant, adjuvant or metastatic\n        setting.\n\n        6.Confirmed presence of qualifying HRR mutation or absence of any HRR mutation in tumour\n        tissue by the Lynparza HRR assay.\n\n        7.At least one measurable lesion that can be accurately assessed at baseline by computed\n        tomography (CT) (magnetic resonance imaging [MRI] where CT is contraindicated) and is\n        suitable for repeated assessment as per RECIST 1.1.\n\n        8.Patients must have normal organ and bone marrow function measured within 28 days prior to\n        randomisation as defined by protocol 9.ECOG PS 0-1 within 28 days of randomisation.\n        10.Patients must be willing to comply with the protocol requirements Exclusion criteria\n\n          1. Cytotoxic chemotherapy, hormonal or non hormonal targeted therapy within 21 days of\n             Cycle 1 Day 1 is not permitted. Palliative radiotherapy must have been completed 21 or\n             more days before Cycle 1 Day 1. The patient can receive a stable dose of\n             bisphosphonates or denosumab for bone metastases, before and during the study as long\n             as these were started at least 5 days prior to study treatment.\n\n          2. More than 2 prior lines of cytotoxic chemotherapy for metastatic disease.\n\n          3. Previous randomisation in the present study.\n\n          4. Previous treatment with a PARP inhibitor (including olaparib) or other DDR inhibitor\n             (unless treatment was for less than 3 weeks duration and at least 12 months have\n             elapsed between the last dose and randomisation. Patients that did not tolerate prior\n             treatment are excluded).\n\n          5. Exposure to a small molecule IP within 30 days or 5 half-lives (whichever is longer)\n             prior to randomisation.The minimum washout period for immunotherapy shall be 42 days.\n\n          6. Patients with MDS/AML or with features suggestive of MDS/AML.\n\n          7. Patients with second primary cancer, EXCEPTIONS: adequately treated non melanoma skin\n             cancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ\n             (DCIS), stage 1 grade 1 endometrial carcinoma, or other solid tumours curatively\n             treated with no evidence of disease for ? 5 years prior to study entry.\n\n          8. Mean resting corrected QTc interval using the Fridericia formula (QTcF) >470\n             msec/female patients and >450 msec for male patients or congenital long QT syndrome.\n\n          9. Any of the protocol specified cardiac diseases currently or within the last 6 months\n             defined by New York Heart Association (NYHA) ? Class 2:\n\n         10. Concomitant use of known strong cytochrome P (CYP) 3A inhibitors or use of known\n             strong or moderate CYP3A inducers.\n\n         11. Persistent toxicities (? CTCAE grade 2) caused by previous cancer therapy, excluding\n             alopecia and CTCAE grade 2 peripheral neuropathy.\n\n         12. Major surgery within 2 weeks of starting study treatment: patients must have recovered\n             from any effects of any major surgery.\n\n         13. Immunocompromised patients, eg,human immunodeficiency virus (HIV) patients.\n\n         14. Patients with known active hepatitis (B or C).\n\n         15. Patients considered a poor medical risk due to a serious, uncontrolled medical\n             disorder, non malignant systemic disease or active, uncontrolled infection.\n\n         16. Patients with symptomatic uncontrolled brain metastases.\n\n         17. Patients unable to swallow orally administered medication and patients with\n             gastrointestinal disorders likely to interfere with absorption of the study\n             medication.\n\n         18. Patients with a known hypersensitivity to olaparib, AZD1775, AZD6738, or any of the\n             excipients of the products.\n\n         19. Pregnant or breast feeding women.
Inclusion Criteria:\n\n        For inclusion in this study, patients must fulfil the following criteria:\n\n          -  Has read and understands the informed consent form (ICF) and has given written\n             informed consent prior to any study procedures.\n\n          -  Female or male aged ?18 years.\n\n          -  Has completed 1 of the parent AZD1775 clinical pharmacology studies (ie, D6014C00002,\n             D6014C00003, D6014C00004, D6014C00005, or D6014C00006) and in the Investigator's\n             opinion will continue to benefit from treatment with AZD1775. Patients who discontinue\n             early from the parent study will be considered by the Sponsor and treating physician\n             on a case-by-case basis.\n\n          -  Any prior radiation must have been completed at least 7 days prior to the start of\n             study treatment, and patients must have recovered from any acute effects prior to the\n             start of study treatment.\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 to 1.\n\n          -  Baseline laboratory values within 7 days of study treatment initiation in the CA\n             study:\n\n               -  Absolute neutrophil count (ANC) ?1500/?L.\n\n               -  Haemoglobin ?9 g/dL.\n\n               -  Platelets ?100,000/?L.\n\n               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ?3 x upper\n                  limit of normal (ULN) or ?5 x ULN if known hepatic metastases.\n\n               -  Serum bilirubin within normal limits or ?1.5 x ULN in patients with liver\n                  metastases; or total bilirubin ?3.0 x ULN with direct bilirubin within normal\n                  limits in patients with well documented Gilbert's Syndrome.\n\n               -  Serum creatinine ?1.5 x ULN, or measured creatinine clearance (CrCl) calculated\n                  by Cockcroft-Gault method ?45 mL/min (confirmation of creatinine clearance is\n                  only required when creatinine is >1.5 x ULN) CrCl (glomerular filtration rate) =\n                  (140-age) x (weight/kg) x Fa (72 x serum creatinine mg/dL) where F = 0.85 for\n                  females and F = 1 for males.\n\n          -  Female patients who are of non-childbearing potential and fertile women of\n             childbearing potential (WoCBP) who agree to use adequate contraceptive measures that\n             are in place during screening (or consent), for the duration of the study, and for 1\n             month after treatment stops; who are not breastfeeding; and who have a negative serum\n             or urine pregnancy test prior to the start of study treatment.\n\n          -  Male patients must be willing to use barrier contraception (ie, condoms) for the\n             duration of the study and for 3 months after study treatment discontinuation.\n\n          -  Willingness and ability to comply with the study and the follow-up procedures.\n\n        Exclusion Criteria:\n\n        Patients must not enrol in this study if any of the following exclusion criteria are\n        fulfilled:\n\n          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca\n             personnel and/or personnel at the study centre).\n\n          -  Previous enrolment and received study treatment in the present study. Patients can,\n             however, be re-screened if the reason for the screen failure no longer exists.\n\n          -  Concurrent enrolment in another clinical study, unless it is an observational\n             (non-interventional) clinical study or the follow-up period of an interventional\n             study.\n\n          -  Must not have received another systemic anti-cancer therapy in the interval following\n             participation in the AZD1775 clinical pharmacology study and the start of treatment on\n             the CA protocol.\n\n          -  Not developed any clinical findings suggestive of brain metastasis. Patients continue\n             to be neurological stable and remain off systemic corticosteroids following treatment\n             of known brain metastases.\n\n          -  Did not tolerate AZD1775 in the parent study in the opinion of the Investigator.\n\n          -  Where a course of palliative radiotherapy was indicated, the last fraction must have\n             been delivered before the start of study treatment on the CA study.\n\n          -  Major surgical procedures ?28 days of beginning study treatment, or minor surgical\n             procedures ?7 days. No waiting period required following port-a-cath placement or\n             other central venous access placement.\n\n          -  Grade >1 toxicities from prior therapy, according to the Common Terminology Criteria\n             for Adverse Events (CTCAE), excluding alopecia or anorexia.\n\n          -  Continue to be able to swallow oral medication, did not undergo placement of a\n             percutaneous endoscopic gastrostomy tube and did not require total parenteral\n             nutrition.\n\n          -  Has had prescription or non-prescription drugs or other products known to be sensitive\n             to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be\n             moderate to strong inhibitors/inducers of CYP3A4 between the parent study and entry\n             into this CA study. Co administration of aprepitant or fosaprepitant during this study\n             is prohibited.\n\n          -  Has consumed herbal preparations between the parent study and entry into this CA\n             study.\n\n          -  Has consumed grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade,\n             or other products containing grapefruit or Seville oranges between the parent study\n             and entry into the CA study.\n\n          -  Any known hypersensitivity or contraindication to AZD1775 or to the components\n             thereof.\n\n          -  Any of the following cardiac diseases currently or within the last 6 months as defined\n             by the New York Heart Association ?Class 2:\n\n               -  Unstable angina pectoris.\n\n               -  Congestive heart failure.\n\n               -  Acute myocardial infarction.\n\n               -  Conduction abnormality not controlled with pacemaker or medication.\n\n               -  Significant ventricular or supraventricular arrhythmias (patients with chronic\n                  rate-controlled atrial fibrillation in the absence of other cardiac abnormalities\n                  are eligible).\n\n          -  AZD1775 should not be given to patients who have a history of Torsades de pointes\n             unless all risk factors that contributed to Torsades have been corrected. AZD1775 has\n             not been studied in patients with ventricular arrhythmias or recent myocardial\n             infarction.\n\n          -  Patient with mean resting QTc interval (specifically QTc calculated using the\n             Fridericia formula [QTcF]) >450 ms for males and >470 ms for females from 3\n             electrocardiograms (ECGs) performed within 2 to 5 minutes apart during screening, or\n             congenital long QT syndrome.\n\n          -  Pregnant or lactating female patients.\n\n          -  Serious, symptomatic active infection at the time of study entry, or another serious\n             underlying medical condition that would impair the ability of the patient to receive\n             study treatment.\n\n          -  Active infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV).
Inclusion Criteria\n\n        Subjects must fulfil all of the following requirements:\n\n          1. A histologically or cytologically confirmed cancer that is metastatic and is approved\n             to be treated with Nivolumab or Atezolizumab with the following origins: melanoma,\n             NSCLC, HNSCC, RCC, and urothelial cancer, as well as the following:\n\n               1. Subjects must not be considered eligible for a potentially curative resection.\n\n               2. Subjects who are eligible for PD-1/PD-L1 therapy or who have exhausted all\n                  standard therapies for their disease except for immunotherapy.\n\n                  either c) or d)\n\n               3. Subjects progressed on their prior treatment before initiating treatment on\n                  current study.\n\n                  Or\n\n               4. Subjects, who are currently being treated with PD-1 or PD-L1 inhibitors Nivolumab\n                  or Atezolizumab and have achieved at least stable disease (SD), and who, in the\n                  judgment of their treating physicians, could benefit from the addition of\n                  DSP-7888 vaccine to improve or maintain their response.\n\n             In expansion part only: All subjects who are candidates for immunotherapy including\n             PD-1/PD-L1 inhibitors are eligible to enroll in the study. Subjects must have at least\n             1 target lesion based on RECIST criteria and other supporting disease specific\n             evaluation criteria.\n\n          2. Subjects must be positive for at least 1 of the following human leukocyte antigens\n             (HLA):\n\n               1. HLA-A*02:01\n\n               2. HLA-A*02:06\n\n               3. HLA-A*24:02\n\n          3. ? 18 years of age.\n\n          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          5. Either archival tumor tissue must be available or subject must consent to undergo a\n             tumor biopsy before administration of first dose.\n\n          6. Females of childbearing potential must have a negative serum pregnancy test.\n\n          7. Male or female subjects of child-producing potential must agree to use contraception\n             or use prevention of pregnancy measures (true abstinence) during the study and for 150\n             days after the last dose.\n\n          8. Total bilirubin of ? 2.0 mg/dL (? 3.0 mg/dL for subjects with known Gilbert's\n             syndrome)\n\n          9. Aspartate aminotransferase (AST) ? 3.0 × the upper limit of normal (ULN) or < 5 × ULN\n             if considered to be due to liver metastases.\n\n         10. Alanine transaminase (ALT) ? 3.0 × the upper limit of normal (ULN) or < 5 × ULN if\n             considered to be due to liver metastases.\n\n         11. Glomerular Filtration Rate > 40 mL/min.\n\n         12. Multigated acquisition (MUGA) scan or echocardiogram with left ventricular ejection\n             fraction (LVEF) > 40%.\n\n         13. Life expectancy ? 3 months.\n\n         14. Subjects must be willing to provide a personally signed and dated informed consent\n             document.\n\n        Exclusion Criteria\n\n        Subjects with any of the following will be excluded from the study:\n\n          1. Anticancer chemotherapy (including molecular targeted drugs), immunotherapy, or\n             investigational agents within 7 days of the first dose of DSP-7888; radiotherapy\n             within 4 weeks of the first dose of DSP-7888. Subjects may begin DSP-7888 on a date\n             determined by the Investigator and medical monitor for the Sponsor provided that all\n             treatment related adverse events (AEs) have resolved or have been deemed irreversible.\n             This exclusion is not applied to subjects who meet the inclusion criterion 1d.\n\n          2. In expansion part only: Subjects progressed on their prior checkpoint inhibitors\n             (PD-1/PD-L1) treatment before initiating treatment on current study.\n\n          3. Major surgery within 4 weeks prior to study treatment.\n\n          4. Subject has received a live vaccine within 30 days prior to the first dose.\n\n          5. Any known, untreated brain metastases. Subjects with treated brain metastases must be\n             clinically stable for 4 weeks after completion of treatment for brain metastases and\n             have radiographic image documentation of stability. Subjects must have no clinical\n             symptoms from brain metastases and not have required systemic corticosteroids > 10\n             mg/day prednisone or equivalent for at least 2 weeks prior to the first dose of study\n             drug.\n\n          6. Subject has multifocal glioblastoma.\n\n          7. Pregnant or breastfeeding.\n\n          8. Subject has an active autoimmune disease requiring immunosuppression with the\n             exception of subjects with isolated vitiligo, resolved childhood asthma or atopic\n             dermatitis, controlled hypoadrenalism or hypopituitarism, and euthyroid subjects with\n             a history of Grave's disease.\n\n             a. Subjects with controlled hyperthyroidism must be negative for thyroglobulin and\n             thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to study\n             drug administration.\n\n          9. Subject has interstitial lung disease or active, non-infectious pneumonitis.\n\n         10. Known hypersensitivity to a component of protocol therapy.\n\n               1. Subjects with known hypersensitivity to any of the components of DSP-7888 Dosing\n                  Emulsion.\n\n               2. Subjects with known hypersensitivity to Nivolumab or Atezolizumab are excluded\n                  from receiving combination therapy that includes the agent to which they are\n                  hypersensitive.\n\n         11. Uncontrolled concurrent illness including, but not limited to, ongoing or active\n             infection, clinically significant non-healing or healing wounds, symptomatic\n             congestive heart failure, unstable angina pectoris, severe and/or uncontrolled cardiac\n             arrhythmia, significant pulmonary disease, uncontrolled infection or psychiatric\n             illness/social situations that would limit compliance with study requirements.\n\n         12. Subjects with a history of another primary cancer with the exception of: a) curatively\n             resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ;\n             c) localized prostate cancer not requiring systemic therapy; and d) any another cancer\n             from which the subject has been disease free for ? 2 years that, in the opinion of the\n             Investigator and medical monitor for the Sponsor, will not affect subject outcome in\n             the setting of the current diagnosis.\n\n         13. Patient has a QTcF (QT corrected based on Fridericia's equation) interval > 480 msec\n             (CTCAE = Grade 2) or other factors that increase the risk of QT prolongation or\n             arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT\n             interval syndrome) at screening. (Patients with bundle branch block and a prolonged\n             QTc interval should be reviewed by the Medical Monitor for potential inclusion.)\n\n         14. Subject has a medical history of frequent or sustained ventricular ectopy.\n\n         15. Subject has, in the opinion of the treating Investigator, any concurrent conditions\n             that could pose an undue medical hazard or interfere with the interpretation of the\n             study results.\n\n         16. Known history of human immunodeficiency virus (HIV) infection, active hepatitis B, or\n             untreated hepatitis C; patients who have completed a course of anti-viral treatment\n             for hepatitis C are eligible.\n\n         17. Subject has baseline signs and symptoms consistent with clinically significant,\n             decreased pulmonary function: (1) blood saturation oxygen level (SpO2) < 90% at rest\n             on room air; (2) dyspnea at rest or required supplemental oxygen within 2 weeks of\n             study enrollment.
Inclusion Criteria:\n\n          -  Patient has histologically or cytologically proven advanced (unresectable) or\n             metastatic cancer as outlined below according to study part and disease type:\n\n          -  Part A: Patients with previously treated advanced or metastatic cancer. Patient may\n             have received no more than 4 lines of treatment for advanced or metastatic cancer.\n             Hormonal treatment will not be considered a prior line of treatment.\n\n          -  Part B: Patients with advanced or metastatic cancer for which treatment with\n             carboplatin-paclitaxel is considered appropriate therapy. Patient may have received no\n             more than 1 prior line of chemotherapy in the metastatic setting. Hormonal treatment\n             will not be considered a prior line of treatment.\n\n          -  Part C: Patients with previously treated advanced or metastatic cancer. Patient may\n             have received no more than 4 lines of treatment for advanced or metastatic cancer.\n             Hormonal treatment will not be considered a prior line of treatment.\n\n          -  Part D: Patients in whom carboplatin-paclitaxel and bevacizumab is considered\n             appropriate therapy. Patient may have received no more than 1 prior line of\n             chemotherapy in the metastatic setting. Hormonal treatment will not be considered a\n             prior line of treatment.\n\n          -  Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.\n\n          -  Patient has adequate organ function\n\n          -  Female patient has a negative serum pregnancy test within 72 hours prior to taking\n             study treatment if of childbearing potential and agrees to abstain from activities\n             that could result in pregnancy from screening through 180 days after the last dose of\n             study treatment, or is of non-childbearing potential.\n\n          -  Male patient agrees to use an adequate method of contraception and not donate sperm\n             starting with the first dose of study treatment through 90 days after the last dose of\n             study treatment. Note: Abstinence is acceptable if this is the established and\n             preferred contraception for the patient.\n\n          -  Patient has measurable lesions by RECIST v1.1.\n\n        For Part A and C, in addition to the general inclusion criteria, patients must also meet\n        the following additional criterion to be considered eligible to participate in this study:\n\n          -  Patient is able to take oral medications.\n\n          -  For patients to be eligible for any parts of the study using niraparib 300 mg as a\n             starting dose, a screening actual body weight ? 77 kg and screening platelet count ?\n             150,000 u/L is necessary.\n\n        Exclusion Criteria:\n\n        (Patients will not be eligible for the study entry if any of the following criteria are\n        met)\n\n          -  Patient has known active central nervous system metastases, carcinomatous meningitis,\n             or both.\n\n          -  Patient has a known additional malignancy that progressed or required active treatment\n             within the last 2 years. Exceptions include basal cell carcinoma of the skin, squamous\n             cell carcinoma of the skin that has undergone potentially curative therapy, or in situ\n             cervical cancer.\n\n          -  Patient is considered a poor medical risk due to a serious, uncontrolled medical\n             disorder, nonmalignant systemic disease, or active infection that requires systemic\n             therapy.\n\n          -  Patient has a condition (such as transfusion-dependent anemia or thrombocytopenia),\n             therapy, or laboratory abnormality that might confound the study results or interfere\n             with the patient's participation\n\n          -  Patient is pregnant or expecting to conceive children within the projected duration of\n             the study, starting with the screening visit through 180 days after the last dose of\n             study treatment.\n\n        Note: No data are available regarding the presence of niraparib or its metabolites in human\n        milk, or on its effects on the breastfed infant or milk production. Because of the\n        potential for serious adverse reactions in breastfed infants from niraparib, female\n        patients should not breastfeed during treatment with niraparib and for 1 month after\n        receiving the final dose.\n\n          -  Patient has a known history of human immunodeficiency virus (type 1 or 2 antibodies).\n\n          -  Patient has known active hepatitis B or hepatitis C.\n\n          -  Patient has an active autoimmune disease that has required systemic treatment in the\n             past 2 years.\n\n          -  Patient has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2,\n             anti-CTLA-4 including ipilimumab), or any other antibody or drug specifically\n             targeting T-cell co-stimulation or checkpoint pathways.\n\n          -  Patient has undergone prior treatment with a known PARP inhibitor.\n\n          -  Known history or current diagnosis of MDS or AML.\n\n        For Parts C and D only, patients will not be eligible for study entry if the following\n        additional exclusion criterion is met:\n\n          -  Patient has clinically significant cardiovascular disease (e.g., significant cardiac\n             conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac\n             arrhythmia or unstable angina, New York Heart Association Grade 2 or greater\n             congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or\n             greater peripheral vascular disease, and history of cerebrovascular accident [CVA])\n             within 6 months of enrollment.\n\n          -  Patient has a history of bowel obstruction, including subocclusive disease, related to\n             the underlying disease and history of abdominal fistula, gastrointestinal perforation,\n             or intra abdominal abscesses. Evidence of recto-sigmoid involvement by pelvic\n             examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction.\n\n          -  Patient has proteinuria as demonstrated by urine protein: creatinine ratio ?1.0 at\n             screening or urine dipstick for proteinuria ?2 (patients discovered to have ?2\n             proteinuria on dipstick at baseline should undergo 24-hour urine collection and must\n             demonstrate <2 g of protein in 24 hours to be eligible).\n\n          -  Patient is at increased bleeding risk due to concurrent conditions (e.g., major\n             injuries or surgery within the past 28 days prior to start of study treatment, history\n             of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or\n             clinically significant hemorrhage within the past 3 months).\n\n          -  Patient has a known hypersensitivity to bevacizumab components or excipients
Inclusion and Exclusion Criteria - Part 1 Inclusion Criteria - Part 1\n\n        • Subject has provided informed consent prior to initiation of any study-specific\n        activities/procedures or subject's legally acceptable representative has provided informed\n        consent prior to any study-specific activities/procedures being initiated when the subject\n        has any kind of condition that, in the opinion of the investigator, may compromise the\n        ability of the subject to give written informed consent.\n\n          -  Age ? 18 at time of informed consent\n\n          -  Biopsy-proven DLBCL excluding DLBCL that represents transformation of indolent NHL\n             Note: Lymphoblastic Lymphoma and Burkitt Lymphoma histology are not eligible\n\n          -  Subject has ? 1 characteristic feature of high-risk DLBCL:\n\n             o High-risk first complete remission (defined as interim PET-CT positive or < complete\n             remission to frontline chemotherapy AND achieved complete remission to\n             platinum-containing salvage)\n\n             o Relapse within 1 year of diagnosis\n\n               -  Secondary aaIPI > 1 (see Appendix D)\n\n               -  Partial response/partial metabolic response after minimum of 2 cycles of\n\n               -  platinum-containing salvage chemotherapy\n\n               -  C-myc rearrangement\n\n          -  aHSCT with high-dose chemotherapy following first (or later) salvage treatment.\n\n          -  PET-CT negative (Deauville score ? 3) 90 days (± 30 days) post aHSCT\n\n          -  Available relapsed and/or diagnostic pathology formalin-fixed paraffin-embedded (FFPE)\n             tumor block or slide samples at the time of enrollment including the successful\n             identification of malignant clone sequences by the central laboratory.\n\n          -  MRD plasma sample collected ? 3 weeks from post aHSCT PET-CT scan\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status ? 2.\n\n          -  Adequate organ function determined ? 3 weeks prior to enrollment defined as follows:\n\n             o Hematological: Absolute neutrophil count (ANC) ? 1.0 x 109/L Platelet count ? 75 x\n             109/L Hemoglobin ? 8 g/dL\n\n             o Renal: Creatinine clearance ? 50 mL/min Cockcroft-Gault equation\n\n             o Hepatic: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x\n             upper limit of normal (ULN) Total bilirubin < 2 x ULN (unless Gilbert's Disease or if\n             liver involvement with lymphoma)\n\n          -  Subject will be available to complete all protocol-required study visits or\n             procedures, and/or to comply with all required study procedures to the best of the\n             subject's and investigator's knowledge including but not limited to:\n\n          -  Completion of up to a 24-month run-in period\n\n          -  Completion of all regularly scheduled study visits including blood draws for\n\n          -  MRD assessment, clinical disease state assessment, PET-CT scans (ie, at time of MRD\n             positivity or relapse), assignment to treatment with blinatumomab\n\n        Other Inclusion Criteria may apply\n\n        Exclusion Criteria - Part 1\n\n        • Clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia,stroke,\n        severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain\n        syndrome, and psychosis\n\n          -  Evidence of CNS involvement with DLBCL\n\n          -  Current autoimmune disease or history of autoimmune disease with potential of CNS\n             involvement\n\n          -  Prior anti-CD19 directed therapies\n\n          -  Prior alloHSCT\n\n          -  Received radiation ? 2 weeks prior to enrollment\n\n          -  Known infection with human immunodeficiency virus or chronic infection with hepatitis\n             B virus (hepatitis B surface antigen positive) or hepatitis C virus (anti-hepatitis C\n             virus positive)\n\n          -  History of malignancy other than DLBCL within the past 3 years with the following\n             exceptions:\n\n             o Malignancy treated with curative intent and with no known active disease present for\n             ? 3 years before enrollment and felt to be at low risk for recurrence by the treating\n             physician\n\n             o Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of\n             disease\n\n             o Adequately treated cervical carcinoma in situ without evidence of disease\n\n               -  Adequately treated breast ductal carcinoma in situ without evidence of disease\n\n               -  Prostatic intraepithelial neoplasia without evidence of prostate cancer\n\n               -  Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in\n                  situ\n\n          -  Subject has known hypersensitivity to immunoglobulins or any of the products or\n             components to be administered during dosing.\n\n          -  History or evidence of any other clinically significant disorder, condition or disease\n             (with the exception of those outlined above) that, in the opinion of the investigator\n             or Amgen physician, if consulted, would pose a risk to subject safety or interfere\n             with the study evaluation, procedures or completion.\n\n          -  Women who are pregnant or breastfeeding or planning to become pregnant or breastfeed\n             while receiving blinatumomab and for an additional 48 hours after the last treatment\n             dose of blinatumomab. (Females of child bearing potential should only be included\n             after a negative highly sensitive urine or serum pregnancy test.)\n\n          -  Women of childbearing potential unwilling to use an acceptable method of effective\n             contraception while receiving blinatumomab and for an additional 48 hours after last\n             dose of blinatumomab. Note: The pregnancy, breastfeeding and contraceptive\n             requirements are specific to blinatumomab. The investigator is responsible for\n             providing the subject (male and female) with pregnancy and breastfeeding (female only)\n             avoidance requirements for other medications given during the study.\n\n          -  Currently receiving treatment in another investigational device or drug study or less\n             than 30 days since ending treatment on another investigational device or drug study.\n             Other investigational procedures while participating in this study are excluded.\n\n        Inclusion and Exclusion Criteria - Part 2 Inclusion Criteria - Part 2\n\n          -  MRD-positive assessment (by NGS analysis) at enrollment or at any time during the\n             run-in 1 period\n\n          -  PET-CT negative (defined by Deauville criteria ? 3) at run-in 2 performed ? 3 weeks\n             from MRD-positive assessment at run-in 1. Historical PET-CT are allowed if performed ?\n             6 weeks from day 1 (first dose of blinatumomab) and subject has no clinical signs or\n             symptoms suggestive of disease progression (eg, increase in lactate dehydrogenase\n             [LDH] not otherwise explained)\n\n          -  Adequate organ function determined ? 2 week prior to treatment assignment with\n             blinatumomab as follows:\n\n               -  Hematological:\n\n        ANC ? 1.0 x 109/L Hemoglobin ? 8 g/L Platelet count ? 75 x 109/L o Renal: Creatinine\n        clearance ? 50 mL/min Cockcroft-Gault equation\n\n        o Hepatic: AST and ALT < 3 x ULN Total bilirubin < 2 x ULN (unless Gilbert's Disease or if\n        liver involvement with lymphoma)\n\n        Exclusion Criteria - Part 2 Subject has active infection requiring systemic therapy Any\n        change in the part 1 eligibility criteria during the run-in period.\n\n        Other Exclusion Criteria may apply
Inclusion Criteria:-\n\n          -  Participants with histologically confirmed advanced ovarian cancer or triple negative\n             breast cancer who in the opinion of the Investigator are appropriate for this study\n\n          -  Measurable disease by RECIST criteria version 1.1 prior to study drug administration\n\n          -  Performance status of 0 or 1 on the eastern Cooperative Oncology Group (ECOG) scale\n\n          -  Life expectancy, in the opinion of the Investigator, of at least 3 months\n\n          -  Disease-free of active second/secondary or prior malignancies for => 2 years with the\n             exception of squamous cell carcinoma of the skin, or carcinoma in situ of the cervix\n             or breast\n\n          -  Willing to provide the protocol specified tumor biopsies\n\n          -  Acceptable hematologic status, liver and renal function\n\n          -  Participants who have received prior treatment with CD137 agonists or immune\n             checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1\n             therapeutic antibodies, may be enrolled, provided the following requirements are met:\n\n               -  Minimum of 5 months from the last dose of anti-PD-1, anti-CTLA-4, anti-PD- L1 or\n                  CD137 agonist treatment\n\n               -  No history of severe immune-related adverse effects from CD137 agonist,\n                  anti?CTLA-4, anti-PD-1 or anti-PD-L1 (NCI CTCAE Grade 3 and 4). Any toxicity\n                  related to the therapy must have resolved completely, no residual toxicity as\n                  assessed by NCI CTCAE (v4.03)\n\n          -  Agree to use protocol defined methods of contraception\n\n        Exclusion Criteria:\n\n          -  Participants with history of prior malignancy except solid tumor treated curatively\n             more than 3 years ago without evidence of recurrence\n\n          -  Asymptomatic or symptomatic, untreated, or actively progressing central nervous system\n             (CNS) metastases\n\n          -  History of leptomeningeal disease\n\n          -  Uncontrolled tumor-related pain\n\n          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent\n             drainage procedures. Participants with indwelling catheters are allowed.\n\n          -  Uncontrolled or symptomatic hypercalcemia\n\n          -  New York Heart Association Class III or IV cardiac disease, pericarditis, myocardial\n             infarction within the past 6 months, unstable arrhythmia\n\n          -  Fredericia-corrected QT interval (QTcF) > 470 milli seconds (msec) (female) or > 450\n             msec (male), or history of congenital long QT syndrome. Any electrocardiogram (ECG)\n             abnormality, including pericarditis, which in the opinion of the Investigator would\n             preclude safe participation in the study.\n\n          -  Active, uncontrolled bacterial, viral, or fungal infections within 7 days of study\n             entry requiring systemic therapy\n\n          -  Known clinically important respiratory impairment\n\n          -  History of major organ transplant\n\n          -  History of an autologous or allogeneic bone marrow transplant\n\n          -  Serious non-malignant disease that could compromise protocol objectives in the opinion\n             of the Investigator and/or the Sponsor\n\n          -  Pregnant or nursing women\n\n          -  Any systemic anticancer therapy within 3 weeks prior to Cycle 1 Day 1\n\n          -  Any radiation treatment to metastatic site within <= 14 days of Cycle 1 Day 1\n\n          -  Major surgical procedure, open biopsy, or significant traumatic injury within 30 days\n             prior to Cycle 1 Day 1 or anticipation of need for major surgical procedure during the\n             course of the study\n\n          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to\n             chimeric or humanized antibodies or fusion proteins\n\n          -  Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster\n             ovary cells or any component of the atezolizumab formulation\n\n          -  Active or history of autoimmune disease\n\n          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced\n             pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic\n             organizing pneumonia), or evidence of active pneumonitis on screening chest computed\n             tomography (CT) scan. History of radiation pneumonitis in the radiation field\n             (fibrosis) is permitted\n\n          -  Positive test for Human immunodeficiency virus (HIV)\n\n          -  Active hepatitis B or hepatitis C\n\n          -  Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or\n             anticipation that such a live, attenuated vaccine will be required during the study\n\n          -  Treatment with investigational therapy within 28 days prior to initiation of study\n             treatment\n\n          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation\n             of study treatment\n\n          -  Consumption of agents which strongly inhibit CYP3A4 enzyme, within 7 days prior to the\n             first dose of study treatment and during the study\n\n          -  Consumption of agents which strongly induce CYP3A4 enzyme, within 14 days prior to the\n             first dose of study treatment and during the study\n\n          -  Treatment with systemic immuno-stimulatory agents within 4 weeks or five half-lives of\n             the drug (whichever is shorter) prior to the first dose of study treatment\n\n          -  Treatment with systemic corticosteroids or other systemic immunosuppressive\n             medications within 2 weeks prior to the first dose of study treatment, or, anticipated\n             requirement for systemic immunosuppressive medications during the trial\n\n          -  History of allergic reactions attributed to components of the formulated product(s)\n\n          -  Unwillingness or inability to comply with procedures required in this protocol
Inclusion Criteria:\n\n          1. Fully understand the study and voluntarily sign the informed consent form;\n\n          2. 18-75 years of age\n\n          3. Body weight ? 45kg\n\n          4. Histologically or cytologically documented, locally advanced or metastatic solid\n             malignancy (except squamous NSCLC) that has progressed on approved systemic therapy,\n             the last dose of prior systemic anti-cancer therapy must have been administered ? 4\n             weeks prior to initiation of study treatment, and for whom no effective therapy or\n             standard of care exists.\n\n          5. Have measurable disease per RECIST Version 1.1 (expansion phase only)\n\n          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          7. Expected survival of more than 12 weeks;\n\n          8. For female patients of childbearing potential and male patients with partners of\n             childbearing potential, agreement (by patient and partner) to use a highly effective\n             form(s) of contraception that results in a low failure rate ( < 1% per year) when used\n             consistently and correctly, and to continue its use for 90 days after the last dose of\n             fruquintinib.\n\n        Exclusion Criteria:\n\n        Patients will be excluded from the study, if any of the following criteria is met:\n\n          1. Absolute neutrophil count (ANC) < 1.5×109/L, platelet count < 100 ×109/L, or\n             hemoglobin < 90 g/L;\n\n          2. Serum total bilirubin > 1.5 times the upper limit of normal (ULN);\n\n          3. Alanine aminotransferase (ALT) aspartate aminotransferase (AST) > 1.5 ULN in patients\n             without hepatic metastases or ALT, AST > 3 ULN in patients with hepatic metastases;\n\n          4. Serum potassium, calcium, or magnesium levels out of the normal laboratory reference\n             range, and clinically significant in the investigator's judgment.\n\n          5. Serum creatinine clearance < 60 mL/min;\n\n          6. Urine dipstick for proteinuria > 2 +. Patients discovered to have ? 1 + proteinuria on\n             dipstick urinalysis at baseline should undergo a 24-hour urine collection and must\n             demonstrate ? 1 g of protein in 24 hours;\n\n          7. Uncontrolled hypertension, defined as: systolic blood pressure ? 140 mmHg and/or\n             diastolic blood pressure ? 90mmHg;\n\n          8. International Normalized Ratio (INR) > 2 or activated partial thromboplastin time\n             (aPTT) > 1.5 ULN, except if the patient is currently receiving or intending to receive\n             anti-coagulants for therapeutic purposes (prophylactic use is allowed).\n\n          9. Risk of, or active hemorrhage: history or presence of active gastric/duodenal ulcer or\n             ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, or any\n             other condition that could possibly result in gastrointestinal tract hemorrhage or\n             perforation;\n\n         10. History or presence of hemorrhage from any other site (e.g., hemoptysis or\n             hematemesis) within 2 months prior to screening\n\n         11. History of a thromboembolic event (including DVT, pulmonary embolism, stroke and/or\n             transient ischemic attack) within 12 months prior to screening;\n\n         12. Patients with squamous non-small-cell lung cancer (NSCLC);\n\n         13. Clinically significant cardiovascular disease, including but not limited to acute\n             myocardial infarction or coronary artery bypass surgery within 6 months prior to\n             enrollment, severe or unstable angina pectoris, New York Heart Association Class\n             III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left\n             ventricular ejection fraction (LVEF) < 50%;\n\n         14. Mean corrected QT interval using the Fredericia method (QTcF) > 480 msec or any\n             factors that increase the risk of QTc prolongation or risk of arrhythmic events such\n             as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or\n             unexplained sudden death under 40 years of age in a next of kin relative.\n\n         15. Concomitant medications with a known risk of causing QT prolongation and/or Torsades\n             de Pointes (See list in Appendix E; source list is continuously updated online at\n             www.qtdrugs.org ).\n\n         16. Systemic anti-neoplastic therapies within 4 weeks prior to the initiation of\n             investigational treatment, including chemotherapy, radical radiotherapy,\n             hormonotherapy, bio-therapy and immunotherapy;\n\n         17. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the\n             initiation of study treatment;\n\n         18. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks before the first dose of\n             study treatment (3 weeks for St John's Wort). See Appendix F for a list of such\n             medications.\n\n         19. Surgery prior to enrollment within 28 days prior to the initiation of study treatment\n             or unhealed surgical incision;\n\n         20. Toxicity from a previous anti-tumor treatment that does not return to Grade 0 or 1\n             (except for alopecia);\n\n         21. Known human immunodeficiency virus (HIV), hepatitis A, B or C infection except for\n             fully recovered Hepatitis A. Previous medical history of hepatitis B virus (HBV)\n             infection regardless of drug control, HBV DNA ?104 ×copy number or ?2000 IU/mL;\n\n         22. Known clinically significant history of liver disease, including hepatitis or\n             cirrhosis; current alcohol abuse.,\n\n         23. Evidence of ongoing or active infection requiring intravenous antibiotics;\n\n         24. Women who are pregnant or lactating;\n\n         25. Central nervous system (CNS) metastatic disease or prior cerebral metastasis;\n\n         26. Inability to take medication orally, dysphagia or an active gastric ulcer resulting\n             from previous surgery (e.g., gastric bypass) or a severe gastrointestinal disease, or\n             any other condition that investigators believe may affect absorption of the\n             investigational product;\n\n         27. Received investigational treatment in another clinical study within 4 weeks prior to\n             the initiation of investigational treatment;\n\n         28. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory\n             result, or any other condition that investigators suspect may prohibit use of the\n             investigational product, affect interpretation of study results, or put the patient at\n             undue risk of harm.
Inclusion Criteria:\n\n          -  Signed a written informed consent form(s).\n\n          -  ECOG performance status 0-1.\n\n          -  Women of childbearing potential must use adequate contraception (hormonal or barrier\n             method of birth control; abstinence).\n\n        HLA INCLUSION\n\n        • Pathologically confirmed advanced/metastatic solid tumors such as one of the following\n        indications:\n\n          -  Pathologically confirmed diagnosis of stage IIIB/IV recurrent NSCLC\n\n          -  Pathologically confirmed diagnosis of stage III/IV recurrent or metastatic HNSCC (oral\n             cavity, pharynx, larynx)\n\n        MAIN SCREENING & LEUKAPHERESIS INCLUSION\n\n          -  Pathologically confirmed advanced/metastatic solid tumors such as one of the following\n             indications:\n\n               -  Pathologically confirmed diagnosis of stage IIIB/IV recurrent NSCLC\n\n               -  Pathologically confirmed diagnosis of stage III/IV recurrent or metastatic HNSCC\n                  (oral cavity, pharynx, larynx)\n\n          -  HLA phenotype positive NOTE: Patients who were previously HLA-typed for participation\n             in other Immatics' sponsored clinical trials and were HLA phenotype positive may enter\n             IMA201-101 main screening\n\n          -  Patient's tumor must express specified biomarkers. NOTE: Patients who were previously\n             screened for participation in other Immatics' sponsored clinical trials and whose\n             biomarkers are positive for IMA201-101 based on IMA_Detect may enter IMA201-101\n             screening\n\n          -  Recommended acceptable organ and marrow function, defined per protocol\n\n          -  Measurable disease\n\n          -  At least one lesion (metastasis or primary tumor) being considered accessible for a\n             biopsy.\n\n          -  Adequate hepatic function, as defined per protocol\n\n          -  Serum creatinine within 1.5 x normal range for age OR creatinine clearance with a\n             recommended GFR ? 50 mL/min/1.73m2.\n\n          -  Adequate pulmonary function, defined per protocol and oxygen saturation >92% on room\n             air.\n\n          -  Acceptable coagulation status: INR ?2.0 x ULN and PTT ?2.0 x ULN.\n\n          -  Confirmed availability of production capacities for the patient's ACTengine IMA201\n             product prior to the leukapheresis.\n\n        TREATMENT INCLUSION:\n\n        Patients may enter the treatment phase if:\n\n          -  Disease recurs/progresses\n\n          -  Disease becomes refractory or previous anti-cancer treatment is no longer warranted\n\n               -  Available IMA201 T-cell product that was produced for the patient and passed all\n                  release tests.\n\n               -  Adequate hepatic function per protocol.\n\n               -  Serum creatinine within 1.5 x normal range for age or creatinine clearance with a\n                  recommended GFR ? 50 mL/min/1.73m2.\n\n               -  Measurable disease\n\n               -  Male patients must agree to use effective contraception or be abstinent while on\n                  study and for 90 days after the infusion of IMA201.\n\n        Exclusion Criteria:\n\n        • Pregnant or is breastfeeding.\n\n        HLA EXCLUSION:\n\n          -  History of other malignancies (except for adequately treated basal or squamous cell\n             carcinoma or carcinoma in situ) within the last 3 years.\n\n          -  Serious autoimmune disease\n\n        MAIN SCREENING EXCLUSION:\n\n          -  Any condition contraindicating leukapheresis.\n\n          -  Brain metastases.\n\n          -  HIV infection, active Hepatitis B or C infection\n\n          -  Concomitant therapy indicated with any of the following: interferons or other\n             non-study immunotherapy regimens; immunosuppressive agents; other investigational\n             therapies; or chronic use of systemic corticosteroids.\n\n          -  Severe immune-related toxicities related to checkpoint inhibitors defined per\n             protocol.\n\n          -  Cardiac conditions per protocol\n\n          -  Prior stem cell transplantation or solid organ transplantation.\n\n          -  Concurrent severe and/or uncontrolled medical disease that could compromise\n             participation in the study\n\n          -  Active diverticulitis, intra-abdominal abscess or gastrointestinal (GI) obstruction.\n\n          -  History of other malignancies (except for adequately treated basal or squamous cell\n             carcinoma or carcinoma in situ) within the last 3 years.\n\n          -  Serious autoimmune disease\n\n          -  History of hypersensitivity to cyclophosphamide, fludarabine or IL-2.\n\n          -  History of or current immunodeficiency disease or prior treatment compromising immune\n             function\n\n          -  Patients with active pneumonitis.\n\n          -  Investigator's judgment\n\n        TREATMENT EXCLUSION\n\n          -  Received chemotherapy, surgery, or radiotherapy (for therapeutic purposes) within 3\n             weeks (4 weeks for monoclonal antibodies or investigational drugs, 1 week for tyrosine\n             kinase inhibitor (TKI) (e.g. erlotinib, gefitinib) or the patient has not recovered\n             (from grade ?2 side effects of the previous therapy) prior to lymphodepletion regimen.\n\n          -  Active pneumonitis.\n\n          -  Patient unable to tolerate lymphodepletion, low-dose IL-2 and/or ACTengine IMA201\n             treatment.\n\n          -  Severe immune-related toxicities related to checkpoint inhibitors defined per\n             protocol.\n\n          -  Investigator's judgment
Inclusion Criteria:\n\n        -Part A - single-agent dose-escalation part: Patients with histologically confirmed solid\n        tumors or non-Hodgkin's lymphoma (NHL).\n\n        Part B - single-agent expansion part:\n\n          -  Patients with DNA Damage Response (DDR) defects or Mismatched Repair (MMR) deficiency\n             putative biomarker-positive advanced solid tumors of the following histologies: i)\n             castration-resistant prostate cancer (CRPC); ii) lung cancer, including\n             adenocarcinoma, squamous carcinoma, or small cell lung cancer (SCLC); iii) colorectal\n             cancer (CRC) and iv) gynecological tumors (ovarian cancer, endometrial cancer, or\n             cervical cancer).\n\n          -  Patients with advanced mantle cell lymphoma (MCL). Patients with diffuse large B cell\n             lymphoma (DLBCL) known to be positive for DDR defects.\n\n          -  Part C (dose escalation in combination with radium-223 dichloride)\n             Castration-resistant prostate cancer with symptomatic bone metastases (positive bone\n             scan the last 3 months) and no known visceral metastatic disease.\n\n        The following inclusion criteria apply to ALL (dose-escalation and expansion) patients:\n\n          -  Patients with tumors resistant or refractory to standard treatment and for which, in\n             the opinion of the investigator, experimental treatment with BAY1895344 may be of\n             benefit, or patients who refused standard treatment\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.\n\n          -  Adequate bone marrow function as assessed by the following laboratory tests\n\n               1. Part A + B: Hemoglobin (HB) >=8.5 g/dL; patients with chronic erythropoietin\n                  treatment consistent with institutional guidelines can be included Part\n                  C:Hemoglobin ?9.0 g/dL\n\n               2. Platelet count >=100,000/mm*3\n\n               3. Absolute neutrophil count (ANC) >=1500/mm*3\n\n        Exclusion Criteria:\n\n          -  Known hypersensitivity to the study drugs or excipients of the preparations or any\n             agent given in association with this study\n\n          -  History of cardiac disease: congestive heart failure New York Heart Association (NYHA)\n             class >II, unstable angina (angina symptoms at rest), new-onset angina (within the\n             past 6 months before study entry), myocardial infarction within the past 6 months\n             before study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy (beta\n             blockers, calcium channel blockers, and digoxin are permitted)\n\n          -  Moderate or severe hepatic impairment, i.e. Child-Pugh class B or C\n\n          -  Patients with known human immunodeficiency virus (HIV) infection\n\n          -  Patients who have an active hepatitis B virus (HBV) or hepatitis C virus (HCV)\n             infection requiring treatment. Patients with chronic HBV or HCV infection are eligible\n             at the investigator's discretion provided that the disease is stable and sufficiently\n             controlled under treatment.\n\n          -  Infections of CTCAE(Common Terminology Criteria for Adverse Events Version) Grade 2\n             not responding to therapy or active clinically serious infections of CTCAE Grade >2
Inclusion Criteria\n\n          1. Histologic confirmation of metastatic NSCLC. For subjects with EGFR mutations, prior\n             therapy must have included an EGFR tyrosine kinase inhibitor. Subjects must not have\n             ALK rearrangement.\n\n          2. Availability of archival (diagnostic) specimens or willing to undergo a pre-treatment\n             biopsy.\n\n          3. Subjects with treated brain metastases must have been treated with surgery and/or\n             radiation therapy ? 21 days pre-study and must be clinically stable with no\n             requirement for steroids.\n\n          4. Laboratory parameters for vital functions should be in the normal range.\n\n          5. ECOG Performance Status ? 2.\n\n        Exclusion Criteria\n\n        Subjects may not enter the study if they fulfill any of the following criteria:\n\n          1. Treatment with an investigational agent within 4 weeks of starting treatment or prior\n             treatment with a checkpoint inhibitor (CTLA-4, PD-1 or PD-L1 antibodies).\n\n          2. Active, suspected or prior documented autoimmune disease, clinically significant\n             cardiovascular disease, or clinically uncontrolled hypertension.\n\n          3. History of pneumonitis or interstitial lung disease, or any unresolved immune-related\n             adverse events following prior therapy.\n\n          4. Major surgery within 4 weeks of starting treatment (or scheduled for surgery during\n             the projected course of the study) or prior cancer vaccine treatment or allogeneic\n             bone marrow transplantation.\n\n          5. Subjects who are immunosuppressed, including those with known immunodeficiency or have\n             active infection including tuberculosis or other serious illnesses.\n\n          6. Skin disease (e.g., psoriasis) that may prevent intradermal administration of the\n             vaccine into the target areas.
Inclusion Criteria\n\n        Part A Dose Escalation: Patients must have histological or cytological confirmation of a\n        solid tumour known to harbour KRAS mutations (e.g., NSCLC, mCRC, pancreatic or\n        cholangiocarcinoma), and have progressed despite standard therapy(ies), or are intolerant\n        to standard therapy(ies), or have a tumour for which no standard therapy(ies) exists.\n\n        Part B Expansion: Patients in Part B must have measurable disease as measured by Response\n        Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1\n\n        Group 1. Patients must have histological or cytological confirmation of locally advanced or\n        metastatic KRASm+ NSCLC, who have failed prior therapy and for whom no current therapy is\n        available.\n\n        Group 2. Patients must have histological or cytological confirmation of locally advanced or\n        metastatic KRASm+ NSCLC, who have failed prior therapy and for whom no current therapy is\n        available. At study entry patients must be clinically suitable for mandatory baseline and\n        on-treatment tumour biopsies.\n\n          1. Signed written informed consent\n\n          2. ? 18 years old\n\n          3. All patients must have KRAS mutations identified in tumour tissue samples from a prior\n             test conducted by a clinical laboratory that has received international or country\n             specific certification. Mutations may include but are not limited to:\n\n             NSCLC KRAS mutations in codons G12/13, Q61, and A59\n\n             mCRC KRAS mutations in codons G12/13 (Exon 2), Q61, A59 (Exon 3), K117, and A146 (Exon\n             4)\n\n             Patient must agree to the collection of archival tumour tissue sample for biomarker\n             analysis. If an archived tumour sample is not available a fresh tumour biopsy can be\n             used.\n\n          4. Adequate organ system function as indicated by:\n\n               1. Absolute neutrophil count (ANC) ? 1.5 x 10^9/L\n\n               2. Platelets ? 100 x 10^9/L\n\n               3. Haemoglobin ? 9g/dL\n\n               4. Activated partial thromboplastin time (aPTT) ? 1.5 times the upper limit of\n                  normal (ULN)\n\n               5. Total bilirubin ? 1.5 mg/dL\n\n               6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 3.0 times\n                  the ULN if no liver involvement or ? 5 times the ULN with liver involvement.\n\n               7. Creatinine ? 1.5 times the ULN or creatinine clearance ? 60 mL/min as calculated\n                  by the Cockcroft-Gault method, or 24 hour measured urine creatinine clearance ?\n                  60 mL/min.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1\n\n          6. Life expectancy ? 12 weeks\n\n          7. Male patients with female partners of child-bearing potential must be willing to use\n             one highly effective form of contraception and must use a condom during their\n             participation in this study and for 7 months following the last dose of the study\n             drug. Male patients must refrain from donating sperm during their participation in the\n             study and at least for 7 months after the last treatment.\n\n          8. Female patients must use a highly effective contraceptive measure from screening until\n             18 weeks after the last dose of drug. All methods of contraception (with the exception\n             of total abstinence) should be used in combination with the use of a condom by a male\n             sexual partner for intercourse. Female patients should not be breast-feeding and must\n             have a negative pregnancy test prior to start of dosing if of childbearing potential\n             or must have evidence of non-childbearing potential by fulfilling one of the following\n             criteria at screening:\n\n        Post-menopausal women defined as aged more than 50 years and amenorrhoeic for at least 12\n        months following cessation of all exogenous hormonal treatment.\n\n        Documentation of irreversible surgical sterilisation by hysterectomy, bilateral\n        oophorectomy, or bilateral salpingectomy, but not tubal ligation.\n\n        Exclusion Criteria:\n\n          1. Patients who have received chemotherapy, radiotherapy, hormonal therapy, immunotherapy\n             or investigational drugs within 21 days or 5 half lives (whichever is shorter) from\n             enrolment.\n\n          2. With the exception of alopecia, any unresolved toxicities from prior therapy greater\n             than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events\n             (CTCAE) Grade 1 at the time of enrolment.\n\n          3. Unresolved immunotherapy-related hepatotoxicity from previous therapy.\n\n          4. Major surgery (excluding placement of vascular access) ? 21 days from beginning of the\n             enrolment or minor surgical procedures ? 7 days. No waiting is required following\n             implantable port and catheter placement.\n\n          5. Patients receiving full-dose anti-coagulation therapies.\n\n          6. Has active or prior documented autoimmune disease within the past 2 years with the\n             exception of vitiligo, Grave's disease, and/or psoriasis not requiring systemic\n             treatment.\n\n          7. Has a history of atypical Haemolytic Uremic Syndrome.\n\n          8. Patients with leptomeningeal metastases.\n\n          9. Previously untreated brain metastases. Patients who have received radiation or surgery\n             for brain metastases are eligible if therapy was completed at least 3 weeks prior to\n             enrolment and there is no evidence of central nervous system disease progression or\n             mild neurologic symptoms, and no requirement for chronic corticosteroid therapy.\n\n         10. Evidence of severe or uncontrolled systemic diseases, including uncontrolled\n             hypertension, active bleeding diatheses, or active infection including hepatitis B,\n             hepatitis C and human immunodeficiency virus (HIV).\n\n         11. Any of the following cardiac criteria:\n\n               1. Congestive heart failure (CHF) per New York Heart Association (NYHA)\n                  classification > Class II.\n\n               2. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.\n\n               3. Unstable angina or new-onset angina.\n\n               4. QT interval (QTcF) >470 ms on screening electrocardiogram (ECG) by Fridericia's\n                  formula.\n\n         12. History of hypersensitivity to active or inactive excipients of AZD4785 or drugs with\n             a similar chemical structure or class to AZD4785.\n\n         13. Judgment by the Investigator that the patient should not participate in the study if\n             the patient is unlikely to comply with study procedures, restrictions and\n             requirements.\n\n         14. Psychological, familial, sociological, or geographical conditions that do not permit\n             compliance with the protocol.
Key Inclusion Criteria:\n\n        For Phase 1\n\n          -  Patients with a locally advanced or metastatic solid tumor who:\n\n               -  have progressed on or are intolerant to standard therapy, or\n\n               -  no standard therapy exists, or in the opinion of the Investigator, are not\n                  candidates for or would be unlikely to tolerate or derive significant clinical\n                  benefit from standard therapy, or\n\n               -  decline standard therapy\n\n          -  Prior MKIs with anti-RET activity are allowed. However, prior treatment with a\n             selective RET inhibitor(s) is prohibited.\n\n          -  A RET gene alteration is not required initially. Once adequate PK exposure is\n             achieved, evidence of RET gene alteration in tumor and/or blood is required as\n             identified through molecular assays, as performed for clinical evaluation.\n\n          -  Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as\n             appropriate to tumor type.\n\n          -  Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.\n\n          -  Adequate hematologic, hepatic and renal function.\n\n          -  Life expectancy of at least 3 months.\n\n        For Phase 2\n\n        As for phase 1 with the following modifications:\n\n          -  For Cohorts 1 and 3 Subjects must have received prior standard therapy appropriate for\n             their tumor type and stage of disease, or in the opinion of the Investigator, would be\n             unlikely to tolerate or derive clinical benefit from appropriate standard of care\n             therapy.\n\n          -  Cohorts 1-4: enrollment will be restricted to patients with evidence of a RET gene\n             alteration in tumor. However, a positive germline DNA test for a RET gene mutation is\n             acceptable in the absence of tumor tissue testing for patients with MTC.\n\n          -  Cohorts 1-4: at least one measurable lesion as defined by RECIST 1.1 or RANO, as\n             appropriate to tumor type and not previously irradiated.\n\n          -  Cohort 4: radiographic PD within the previous 14 months.\n\n        Note: Patients otherwise eligible for cohort 4 who do not demonstrate radiographic PD\n        within the previous 14 months may be enrolled to cohort 5 if a compelling rationale is\n        provided by the investigator and approved by the Sponsor.\n\n        Cohort 5: (up to 50 patients):\n\n          -  Cohorts 1-4 without measurable disease;\n\n          -  MTC not meeting the requirements for Cohorts 3 or 4;\n\n          -  Other RET-altered solid tumor or other RET alteration/activation (any solid tumor,\n             excluding synonymous, frameshift, or nonsense mutations);\n\n          -  cfDNA positive for a RET gene alteration not known to be present in a tumor sample.\n\n        Key Exclusion Criteria (Phase 1 and Phase 2):\n\n          -  Phase 2 Cohorts 1-4: an additional known oncogenic driver.\n\n          -  Prior treatment with a selective RET inhibitor\n\n          -  Investigational agent or anticancer therapy within 5 half-lives or 2 weeks (whichever\n             is shorter) prior to planned start of LOXO-292. In addition, no concurrent\n             investigational anti-cancer therapy is permitted. LOXO-292 may be started within less\n             than 5 half-lives or 2 weeks of prior therapy if considered by the Investigator to be\n             safe and within the best interest of the patient, with prior Sponsor approval.\n\n          -  Major surgery (excluding placement of vascular access) within 4 weeks prior to planned\n             start of LOXO-292.\n\n          -  Radiotherapy with a limited field of radiation for palliation within 1 week of planned\n             start of LOXO-292, with the exception of patients receiving radiation to more than 30%\n             of the bone marrow or with a wide field of radiation, which must be completed at least\n             4 weeks prior to the first dose of study treatment.\n\n          -  Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of\n             starting study treatment with the exception of alopecia and Grade 2, prior\n             platinum-therapy related neuropathy.\n\n          -  Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated\n             spinal cord compression. Patients are eligible if neurologically stable and without\n             increase in steroid dose for 14 days prior to the first dose of LOXO-292 and no CNS\n             surgery or radiation has been performed for 28 days, 14 days if stereotactic\n             radiosurgery.\n\n          -  Clinically significant active cardiovascular disease or history of myocardial\n             infarction within 6 months prior to planned start of LOXO-292 or prolongation of the\n             QT interval corrected (QTcF) > 470 msec on all 3 ECGs during Screening.\n\n          -  Required treatment with certain strong CYP3A4 inhibitors or inducers.
Inclusion Criteria Part 1 (CMP-001 + pembrolizumab):\n\n          1. Histopathologically confirmed diagnosis of metastatic, or unresectable, malignant\n             melanoma. Ocular melanoma subjects are not eligible.\n\n          2. Male and female subjects age 18 or older\n\n        3a. Subjects who are currently receiving treatment with any anti-PD-1/PD-L1 antibody,\n        either alone or in combination and who are progressing. Subjects must have received at\n        least 4 doses of anti-PD-1/PD-L1 before enrolling into the CMP-001-001 study.\n\n        OR\n\n        3b. Subjects who have previously received any anti-PD-1/PD-L1 therapy, alone or in\n        combination and progressed, regardless of the best overall response to prior\n        anti-PD-1/PD-L1 based therapy. Subjects must have received at least 4 doses of\n        anti-PD-1/PD-L1.\n\n        4. Subjects must have at least one tumor lesion with a longest diameter of ?0.5 cm that can\n        be easily palpated or detected by ultrasound to facilitate intratumoral injection of\n        CMP-001 (i.e., tumor in skin, muscle, subcutaneous tissue or accessible lymph node).\n\n        5. Subjects must have measurable disease by RECIST Version 1.1. 6. Capable of understanding\n        and complying with protocol requirements. 7. A life expectancy of greater than 24 weeks at\n        Screening. 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. 9.\n        Most recent laboratory values (within 3 weeks prior to Week 1 Day 1 (W1D1)) before study\n        entry meet the following standards:\n\n          -  Bone marrow function: neutrophil count ?1,000/mm3, platelet count ? 75,000/mm3 and\n             hemoglobin concentration > 8.0 g/dL.\n\n          -  Liver function: total bilirubin ? 1.5 times the upper limit of normal (ULN) ranges of\n             each institution, with the following exception: patients with Gilbert Disease serum\n             bilirubin > 3X ULN AND aspartate aminotransferase (AST) and alanine aminotransferase\n             (ALT) ? 3 times the ULN range of each institution.\n\n          -  LDH ?2.0 times the ULN range of each institution\n\n          -  Renal function: serum creatinine ? 1.5 times the ULN range of each institution. 10.\n             The subject must sign a written informed consent form prior to the initiation of any\n             study procedures. Adult subjects unable to provide written informed consent on their\n             own behalf will not be eligible for the study.\n\n        Part 1 Dose Expansion Phase subjects must also meet the following inclusion criterion:\n\n        11. At least one additional lesion that is measurable and is not intended for injection (to\n        allow an assessment of systemic antitumor effect). These lesions not intended for injection\n        may be located in any metastatic site.\n\n        Exclusion Criteria Part 1 (CMP-001 + pembrolizumab):\n\n          1. Pregnant or breastfeeding.\n\n          2. Received investigational therapy (e.g. small molecule or biologic) within 30 days\n             prior to the start of CMP-001 dosing on W1D1. However, if an investigational therapy\n             has a short half-life, a reduced wash out period may be acceptable with Sponsor\n             approval.\n\n          3. Received treatment with anti-CTLA-4 antibody within 30 days prior to the start of\n             CMP-001 dosing on W1D1.\n\n          4. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or\n             hepatitis C virus (HCV). If there is no known or documented history of HIV, Hepatitis\n             B or Hepatitis C, the site is not required to do additional testing for these values\n             at Screening.\n\n          5. Developed autoimmune disorders of Grade 4 while on prior immunotherapy. Subjects who\n             developed autoimmune disorders of Grade ? 3 may enroll if the disorder has resolved to\n             Grade ? 1 and the subject has been off systemic steroids at doses > 10mg/day for at\n             least two weeks.\n\n          6. Require systemic pharmacologic doses of corticosteroids greater than the equivalent of\n             10 mg/day; replacement doses, topical, ophthalmologic and inhalational steroids are\n             permitted. Subjects who have a history of adrenal insufficiency and are receiving\n             greater than 10 mg/day coticosteroid may be eligible but only after Sponsor\n             consultation. Subjects who are currently receiving steroids at a dose of ?10 mg/day do\n             not need to discontinue steroids prior to enrollment.\n\n          7. Active (i.e., symptomatic or growing) central nervous system (CNS) metastases. However\n             subjects with active CNS metastases are eligible for the trial if\n\n               -  the metastases have been treated by surgery and/or radiotherapy,\n\n               -  the subject is off corticosteroids > 10 mg/day and is neurologically stable for\n                  at least 2 weeks prior to Screening.\n\n               -  brain MRI completed within 3 months of screening (required for all subjects).\n\n          8. Any concurrent uncontrolled illness, including mental illness or substance abuse,\n             which in the opinion of the Investigator, would make the subject unable to cooperate\n             or participate in the trial.\n\n          9. Severe uncontrolled cardiac disease within 6 months of Screening, including but not\n             limited to uncontrolled hypertension; unstable angina; myocardial infarction (MI) or\n             cerebrovascular accident (CVA).\n\n         10. Requires prohibited treatment (i.e., non-protocol specified anticancer\n             pharmacotherapy, surgery or conventional radiotherapy for treatment of malignant\n             tumor).\n\n         11. Women of child-bearing potential who are unable or unwilling to use an acceptable\n             method of contraception.\n\n        Inclusion Criteria - Part 2: CMP-001 Monotherapy\n\n        Subjects must meet all of the following inclusion criteria to be eligible:\n\n          1. Histopathologically confirmed diagnosis of metastatic, or unresectable, malignant\n             melanoma. Ocular melanoma subjects are not eligible.\n\n          2. Male or female subjects age 18 or older.\n\n          3. Previously received any anti-PD-1/PD-L1 therapy, alone or in combination. Subjects\n             must have received a minimum of 4 doses of anti-PD-1/PD-L1 therapy prior to study\n             entry.\n\n          4. Subjects must have at least one tumor lesion with a longest diameter of ?0.5 cm that\n             can be easily palpated or detected by ultrasound to facilitate intratumoral injection\n             of CMP-001 (i.e., tumor in skin, muscle, subcutaneous tissue or accessible lymph\n             node).\n\n          5. Subjects must have measurable disease by RECIST Version 1.1.\n\n          6. Capable of understanding and complying with protocol requirements.\n\n          7. A life expectancy of greater than 24 weeks at Screening.\n\n          8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to\n\n          9. Most recent laboratory values (within 3 weeks prior to first CMP-001 injection at Week\n             1 Day 1 (W1D1)) before study entry meet the following standards:\n\n               -  Bone marrow function: neutrophil count ?1,000/mm3, platelet count ?75,000/mm3 and\n                  hemoglobin concentration > 8.0 g/dL.\n\n               -  Liver function: total bilirubin ? 1.5 times the upper limit of normal (ULN)\n                  ranges of each institution, aspartate aminotransferase and alanine\n                  aminotransferase ? 3 times the ULN range of each institution.\n\n               -  LDH ?2.0 times the ULN range of each institution.\n\n               -  Renal function: serum creatinine ?1.5 times the ULN range of each institution.\n\n         10. The subject must sign a written informed consent form prior to the initiation of any\n             study procedures. Adult subjects unable to provide written informed consent on their\n             own behalf will not be eligible for the study.\n\n        Exclusion Criteria Part 2: (CMP-001 Monotherapy)\n\n          1. Pregnant or breastfeeding.\n\n          2. Received investigational therapy (e.g. small molecule or biologic) within 30 days\n             prior to the start of CMP-001 dosing on W1D1. Received prior therapy with an\n             anti-PD1/PD-L1 or anti-CTLA-4 within 45 days prior to the start of CMP-001 dosing on\n             W1D1. However, if an investigational therapy has a short half-life, a reduced wash out\n             period may be acceptable with Sponsor approval.\n\n          3. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or\n             hepatitis C virus (HCV). If there is no known or documented history of HIV, Hepatitis\n             B or Hepatitis C, the site is not required to do additional testing for these values\n             at Screening.\n\n          4. Subjects who developed autoimmune disorders of Grade ? 3 may enroll if the disorder\n             has resolved to Grade ?1 and the subject has been off systemic steroids at doses >10\n             mg/day for at least 2 weeks.\n\n          5. Require systemic pharmacologic doses of corticosteroids greater than the equivalent of\n             10 mg/d; replacement doses, topical, ophthalmologic and inhalational steroids are\n             permitted. Subjects who have a history of adrenal insufficiency and are receiving\n             greater than 10 mg/day of corticosteroid may be eligible but only after Sponsor\n             consultation. Subjects who are currently receiving steroids at a dose of ? 10 mg/day\n             do not need to discontinue steroids prior to enrollment.\n\n          6. Active (i.e., symptomatic or growing) central nervous system (CNS) metastases.\n             However, subjects with active CNS metastases are eligible for the trial if:\n\n               -  the metastases have been treated by surgery and/or radiotherapy.\n\n               -  the subject is off corticosteroids >10 mg/day and is neurologically stable for at\n                  least 2 weeks prior to Screening.\n\n               -  brain MRI completed within 3 months of screening (required for all subjects).\n\n          7. Any concurrent uncontrolled illness, including mental illness or substance abuse,\n             which in the opinion of the Investigator, would make the subject unable to cooperate\n             or participate in the trial.\n\n          8. Severe uncontrolled cardiac disease within 6 months of Screening, including but not\n             limited to uncontrolled hypertension; unstable angina; myocardial infarction (MI) or\n             cerebrovascular accident (CVA).\n\n          9. Requires prohibited treatment (i.e., non-protocol specified anticancer\n             pharmacotherapy, surgery or conventional radiotherapy for treatment of malignant\n             tumor).\n\n         10. Women of childbearing potential who are unable or unwilling to use an acceptable\n             method of contraception.
Inclusion Criteria:\n\n        Patients with NSCLC:\n\n          1. Has histologically- or pathologically-confirmed recurrent/metastatic NSCLC.\n\n          2. If has adenocarcinoma, required to have previously been tested for anaplastic lymphoma\n             kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations,\n             with results available for collection in this study, and, if positive, has been\n             treated with prior EGFR or ALK therapy.\n\n          3. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and\n             experienced documented, unequivocal progressive disease by either RECIST 1.1 or\n             clinical assessment.\n\n          4. Patients with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been\n             previously treated with a PD-1/PD-L1-blocking antibody\n\n             Patients in Expansion Phase, Cohorts 2 and 3\n\n          5. Previously treated with a PD-1/PD-L1-blocking antibody and experienced experienced\n             documented, unequivocal radiographic progression of disease by irRECIST, or similar\n             criteria during or within 12 weeks after last dose of such treatment. Patients must\n             have received at least 6 weeks of PD-1/PD-L1 therapy for Cohort 3.\n\n             Patients with Melanoma:\n\n          6. In addition to having been previously treated with a PD-1/PD-L1-blocking antibody\n             (inclusion #5), has a histologically- or cytologically-confirmed diagnosis of\n             unresectable or metastatic melanoma and experienced unequivocal progressive disease\n             during treatment with a BRAF inhibitor if BRAF V600 mutation-positive. Treatment with\n             BRAF inhibitor may occur AFTER treatment with the checkpoint inhibitor.\n\n             Patients in Expansion Phase, Cohort 4 (Colorectal Cancer)\n\n          7. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and\n             experienced documented, unequivocal progressive disease by either RECIST 1.1 or\n             clinical assessment. Must have documented mismatch repair-proficient colon cancer as\n             determined by either immunohistochemistry for mismatch repair proteins or PCR-based\n             functional microsatellite instability. Patients with colorectal cancer enrolled in\n             Cohort 4 should not have been previously treated with a PD-1/PD-L1-blocking antibody\n             (i.e., pembrolizumab, nivolumab, MEDI36MEDI4376, or GNE PDL1 [MPDL3280A])\n\n             All Patients\n\n          8. Aged 18 years or older on the day written informed consent is given.\n\n          9. If has brain metastases, must have stable neurologic status following local therapy\n             for at least 4 weeks without the use of steroids or on stable or decreasing dose of\n             ?10 mg daily prednisone (or equivalent), and must be without neurologic dysfunction\n             that would confound the evaluation of neurologic and other AEs.\n\n         10. Evidence of locally recurrent or metastatic disease based on imaging studies within 28\n             days before the first study drug dose:\n\n               -  At least 1 measurable lesion ?20 mm by conventional techniques or ?10 mm by\n                  spiral CT scan or MRI, with the last imaging performed within 28 days before the\n                  first study drug dose. If there is only 1 measurable lesion and it is located in\n                  previously irradiated field, it must have demonstrated unequivocal progression\n                  according to RECIST, version 1.1.\n\n         11. If receiving radiation therapy, has a 2-week washout period following completion of\n             the treatment prior to receiving the first study drug dose and continues to have at\n             least 1 measureable lesion, per above criterion.\n\n         12. ECOG performance status of 0 or 1.\n\n         13. Has acceptable, applicable laboratory parameters.\n\n         14. Female subjects must not be pregnant.\n\n         15. If male, agrees to use an adequate method of contraception\n\n        15. Experienced resolution of toxic effect(s) of the most recent prior chemotherapy to\n        Grade 1 or less (except alopecia). If patient underwent major surgery or radiation therapy\n        of >30 Gy, they must have recovered from the toxicity and/or complications from the\n        intervention.\n\n        17. Willing to have fresh tumor samples collected during screening and at other time points\n        designated as mandatory, per the Schedule of Study Assessments.\n\n        18. Able to understand and give written informed consent and comply with study procedures.\n\n        Exclusion Criteria:\n\n        Patients meeting any of the following criteria are not eligible for study participation:\n\n          1. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form\n             of immunosuppressive therapy within 7 days prior to the first dose of study drug. The\n             use of physiologic doses of corticosteroids may be approved after consultation with\n             the Sponsor.\n\n          2. Active autoimmune disease that has required systemic treatment in past 2 years (i.e.,\n             with disease modifying agents, corticosteroids, or immunosuppressive drugs).\n             Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid\n             replacement therapy for adrenal or pituitary insufficiency) is not considered a form\n             of systemic treatment.\n\n          3. History of interstitial lung disease (ILD).\n\n          4. Allergy to benzamide or inactive components of entinostat.\n\n          5. History of allergies to any active or inactive ingredients of pembrolizumab or severe\n             hypersensitivity (>= Grade 3) to pembroluzumab.\n\n          6. History or current evidence of any condition, therapy, or laboratory abnormality that\n             might confound the results of the study, interfere with the patient's participation\n             for the full duration of the study, or is not in the best interest of the patient to\n             participate, in the opinion of the treating Investigator, including, but not limited\n             to:\n\n               -  Myocardial infarction or arterial thromboembolic events within 6 months prior to\n                  baseline or severe or unstable angina, New York Heart Association (NYHA) Class\n                  III or IV disease, or a QTc interval > 470 msec.\n\n               -  Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or\n                  uncontrolled systemic infection.\n\n               -  Another known additional malignancy that is progressing or requires active\n                  treatment (excluding adequately treated basal cell carcinoma, squamous cell of\n                  the skin, cervical intraepithelial neoplasia [CIN]/cervical carcinoma in situ or\n                  melanoma in situ, or ductal carinoma in situ of the breast). Prior history of\n                  other cancer is allowed, as long as there is no active disease within the prior 5\n                  years.\n\n               -  Has a history of (non-infectious) pneumonitis that required steroids or current\n                  pneumonitis.\n\n               -  Active infection requiring systemic therapy.\n\n               -  Known active central nervous system (CNS) metastases and/or carcinomatous\n                  meningitis.\n\n             Note: Patients with previously treated brain metastases may participate provided they\n             are stable (without evidence of progression by imaging [using the identical imaging\n             modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the\n             first dose of study drug and any neurologic symptoms have returned to baseline), have\n             no evidence of new or enlarging brain metastases, and are not using steroids for at\n             least 2 weeks prior to the first dose of study drug or are on stable or decreasing\n             dose of ?10 mg daily prednisone (or equivalent). This exception does not include\n             carcinomatous meningitis which is excluded regardless of clinical stability.\n\n          7. Known psychiatric or substance abuse disorders that would interfere with cooperation\n             with the requirements of the study.\n\n          8. Currently participating and receiving study therapy or has participated in a study of\n             an investigational agent and received study therapy or used an investigational device\n             within 4 weeks of the first dose of treatment.\n\n          9. Received a live virus vaccination within 30 days of the first dose of treatment.\n\n         10. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to baseline or who\n             has not recovered (i.e., ?Grade 1 or at baseline) from AEs due to agents administered\n             more than 4 weeks earlier.\n\n         11. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2\n             weeks prior to study baseline or who has not recovered (i.e., ?Grade 1 or at baseline)\n             from AEs due to a previously administered agent.\n\n             Note: Patients with ?Grade 2 neuropathy or ?Grade 2 alopecia are an exception to this\n             criterion and may qualify for the study.\n\n             Note: If patient underwent major surgery, they must have recovered adequately from the\n             toxicity and/or complications from the intervention prior to starting therapy.\n\n         12. Received transfusion of blood products (including platelets or red blood cells) or\n             administration of colony stimulating factors (including granulocyte-colony stimulating\n             factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF], or\n             recombinant erythropoietin) within 4 weeks prior to the first dose of study drug.\n\n         13. Currently receiving treatment with any other agent listed on the prohibited medication\n             list such as valproic acid, or other systemic cancer agents within 14 days of the\n             first dose of treatment.\n\n         14. If female, is pregnant, breastfeeding, or expecting to conceive, or if male, expect to\n             father children within the projected duration of the study, starting with the\n             screening visit through 120 days after the last dose of study drug.\n\n         15. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).\n\n         16. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C\n             (e.g., hepatitis C virus ribonucleic acid [qualitative]).\n\n         17. For CRC expansion cohort, no prior history of malignant bowel obstruction requiring\n             hospitalization in the 6 months prior to enrollment\n\n         18. For the CRC expansion cohort, no history of uncontrolled ascites, defined as\n             symptomatic ascites and/or repeated paracenteses for symptom control in the past 3\n             months
Inclusion Criteria:\n\n        For both portions of the study, participants must satisfy all of the following inclusion\n        criteria to be enrolled in the study:\n\n          -  Written Institutional Review Board/Ethics Committee-approved informed consent form\n             (ICF), signed by participant or legally authorized representative.\n\n          -  Participants must be determined to have histologically confirmed unresectable, locally\n             advanced or metastatic adenocarcinoma of the intra- and/or extra-hepatic bile ducts\n             and/or gallbladder. Participants must have sufficient tissue with architectural\n             integrity, including tumor and associated stroma, available for retrospective\n             biomarker testing.\n\n          -  One or more lesions measurable on computed tomography (CT) scan/magnetic resonance\n             imaging (MRI) scan per Response Evaluation Criteria in Solid Tumors (RECIST) version\n             1.1 (v1.1).\n\n          -  Participants having Eastern Cooperative Oncology Group (ECOG) Performance Status of 0\n             to 1.\n\n          -  Life expectancy ?3 months.\n\n          -  Males and females aged ?18 years.\n\n          -  Screening clinical laboratory values within pre-determined parameters\n\n          -  Female participants of childbearing potential (WOCBP) must have a negative urine or\n             serum pregnancy test within 7 days before Day 1 (first dose of study medication).\n\n          -  For WOCBP and for men, agreement to use a highly effective contraceptive method from\n             the time of screening throughout the study until 5 months (WOCBP) or 6 months (men)\n             after administration of the last dose of any study medication. Highly effective\n             contraceptive methods consist of prior sterilization, intrauterine device (IUD),\n             intrauterine hormone releasing system (IUS), oral or injectable contraceptives,\n             barrier methods, and/or true sexual abstinence.\n\n        Exclusion Criteria:\n\n        Participants are ineligible for enrollment if they meet any of the following exclusion\n        criteria:\n\n          -  Clinical evidence of deep vein thrombosis or pulmonary embolism present during the\n             screening period\n\n          -  New York Heart Association Class III or IV cardiac disease, atrial fibrillation,\n             unstable angina, or myocardial infarction within the past 12 months before screening.\n\n          -  Participants with known brain metastases\n\n          -  History of cerebrovascular accident or transient ischemic attack\n\n          -  History of active bleeding within the last 3 months prior to screening requiring\n             transfusion.\n\n          -  Participants must have received no previous radiotherapy, surgery, chemotherapy or\n             investigational therapy for treatment of metastatic or locally advanced disease.\n\n          -  Active hepatitis B virus (HBV) infection, defined as having a positive hepatitis B\n             surface antigen (HBsAg) test at screening\n\n          -  Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody\n             test at screening\n\n          -  History of:\n\n               1. Idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis\n                  obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of\n                  active pneumonitis on screening chest CT scan. History of radiation pneumonitis\n                  in the radiation field (fibrosis) is permitted.\n\n               2. Or known cases of hepatobiliary diseases (e.g., primary biliary cholangitis,\n                  primary sclerosing cholangitis, history of immune-mediated cholangitis);\n\n                  Participants with cholangitis attributed to infectious etiology (e.g., ascending\n                  cholangitis, bacterial cholangitis) are eligible if the infection has been fully\n                  resolved prior to the screening visit.\n\n               3. Or known cases of drug-induced hepatobiliary toxicities.\n\n          -  Active or history of autoimmune diseases\n\n          -  Uncontrolled hypercalcemia
Inclusion Criteria:\n\n        Male or female patients with a diagnosis of CML-CP ? 18 years of age\n\n        Patients must meet all of the following laboratory values at the screening visit:\n\n          -  < 15% blasts in peripheral blood and bone marrow\n\n          -  < 30% blasts plus promyelocytes in peripheral blood and bone marrow\n\n          -  < 20% basophils in the peripheral blood\n\n          -  ? 50 x 109/L (? 50,000/mm3) platelets\n\n          -  Transient prior therapy related thrombocytopenia (< 50,000/mm3 for ? 30 days prior to\n             screening) is acceptable\n\n          -  No evidence of extramedullary leukemic involvement, with the exception of\n             hepatosplenomegaly\n\n        BCR-ABL ratio ? 1% IS according to central laboratory at the screening examination\n\n        Prior treatment with a minimum of 2 prior ATP-binding site TKIs (i.e. imatinib, nilotinib,\n        dasatinib, radotinib or ponatinib)\n\n        Failure or intolerance to the last previous TKI therapy at the time of screening (adapted\n        from the 2013 ELN Guidelines Bacarrani 2013)\n\n          -  Failure is defined for CML-CP patients (CP at the time of initiation of last therapy)\n             as follows. Patients must meet at least 1 of the following criteria.\n\n          -  Three months after the initiation of therapy: No CHR or > 95% Ph+ metaphases\n\n          -  Six months after the initiation of therapy: BCR-ABL ratio > 10% IS and/or > 65% Ph+\n             metaphases\n\n          -  Twelve months after initiation of therapy: BCR-ABL ratio > 10% IS and/or > 35% Ph+\n             metaphases\n\n          -  At any time after the initiation of therapy, loss of CHR, CCyR or PCyR\n\n          -  At any time after the initiation of therapy, the development of new BCR-ABL mutations\n\n          -  At any time after the initiation of therapy, confirmed loss of MMR in 2 consecutive\n             tests, of which one must have a BCR-ABL ratio ? 1% IS\n\n          -  At any time after the initiation of therapy, new clonal chromosome abnormalities in\n             Ph+ cells: CCA/Ph+\n\n          -  Intolerance is defined as:\n\n          -  Non-hematologic intolerance: Patients with grade 3 or 4 toxicity while on therapy, or\n             with persistent grade 2 toxicity, unresponsive to optimal management, including dose\n             adjustments (unless dose reduction is not considered in the best interest of the\n             patient if response is already suboptimal)\n\n          -  Hematologic intolerance: Patients with grade 3 or 4 toxicity (absolute neutrophil\n             count [ANC] or platelets) while on therapy that is recurrent after dose reduction to\n             the lowest doses recommended by manufacturer\n\n        Exclusion Criteria:\n\n        Known presence of the T315I or V299L mutation at any time prior to study entry Known second\n        chronic phase of CML after previous progression to AP/BC Previous treatment with a\n        hematopoietic stem-cell transplantation Patient planning to undergo allogeneic\n        hematopoietic stem cell transplantation\n\n        Cardiac or cardiac repolarization abnormality, including any of the following:\n\n          -  History within 6 months prior to starting study treatment of myocardial infarction\n             (MI), angina pectoris, coronary artery bypass graft (CABG)\n\n          -  Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete\n             left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type\n             II and third degree AV block)\n\n          -  QTcF at screening ?450 ms (male patients), ?460 ms (female patients)\n\n          -  Long QT syndrome, family history of idiopathic sudden death or congenital long QT\n             syndrome, or any of the following:\n\n          -  Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or\n             hypomagnesemia, history of cardiac failure, or history of clinically\n             significant/symptomatic bradycardia\n\n          -  Concomitant medication(s) with a known risk to prolong the QT interval and/or known to\n             cause Torsades de Pointes that cannot be discontinued or replaced 7 days prior to\n             starting study drug by safe alternative medication.\n\n          -  Inability to determine the QTcF interval\n\n          -  Severe and/or uncontrolled concurrent medical disease that in the opinion of the\n             investigator could cause unacceptable safety risks or compromise compliance with the\n             protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, pulmonary\n             hypertension)\n\n          -  History of acute pancreatitis within 1 year of study entry or past medical history of\n             chronic pancreatitis\n\n          -  History of acute or chronic liver disease\n\n          -  Treatment with medications that meet one of the following criteria and that cannot be\n             discontinued at least one week prior to the start of treatment with study treatment\n\n          -  Moderate or strong inducers of CYP3A\n\n          -  Moderate or strong inhibitors of CYP3A and/or P-gp\n\n          -  Substrates of CYP3A4/5, CYP2C8, or CYP2C9 with narrow therapeutic index\n\n          -  Women of child-bearing potential, defined as all women physiologically capable of\n             becoming pregnant, unless they are using highly effective methods of contraception\n             during dosing and for 3 days after last dose of ABL001. Highly effective contraception\n             methods include:\n\n          -  Total abstinence (when this is in line with the preferred and usual lifestyle of the\n             subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation\n             methods) and withdrawal are not acceptable methods of contraception\n\n          -  Female sterilization (have had surgical bilateral oophorectomy (with or without\n             hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking\n             study treatment). In case of oophorectomy alone, only when the reproductive status of\n             the woman has been confirmed by follow up hormone level assessment\n\n          -  Male sterilization (at least 6 months prior to screening). The vasectomized male\n             partner should be the sole partner for that subject.\n\n          -  Use of oral, injected or implanted hormonal methods of contraception or placement of\n             an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal\n             contraception that have comparable efficacy (failure rate <1%), for example hormone\n             vaginal ring or transdermal hormone contraception.\n\n          -  In case of use of oral contraception women should have been stable on the same pill\n             for a minimum of 3 months before taking study treatment.\n\n          -  Women are considered post-menopausal and not of child bearing potential if they have\n             had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile\n             (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral\n             oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at\n             least six weeks ago. In the case of oophorectomy alone, only when the reproductive\n             status of the woman has been confirmed by follow up hormone level assessment is she\n             considered not of child bearing potential.\n\n          -  Sexually active males unless they use a condom during intercourse while taking the\n             drug during treatment and for 3 days after stopping treatment and should not father a\n             child in this period. A condom is required to be used also by vasectomized men as well\n             as during intercourse with a male partner in order to prevent delivery of the drug via\n             semen.
Inclusion Criteria\n\n        Each subject eligible to participate in this study must meet or have all the following\n        criteria:\n\n          1. Is 18 years of age or older.\n\n          2. Can provide written informed consent or have their legal representatives provide\n             written informed consent\n\n          3. Have documented histological or cytological evidence of invasive cancer of the breast,\n             defined by one of the following:\n\n               -  ER+ breast cancer, defined as positive if ? 1% by IHC and HER2 normal, defined as\n                  IHC 0-1+ or IHC 2+(and FISH<2), or FISH < 2.0\n\n               -  TNBC, defined as ER-/PgR- if 0 % by IHC and HER2 normal, defined as IHC 0-1+ or\n                  IHC 2+(and FISH<2), or FISH < 2.0\n\n          4. ECOG PS of 0 or 1 for Females, 0, 1, or 2 for Males.\n\n          5. Undergoing or willing to undergo gonadal suppression:\n\n               -  Female subjects with ER+/HER2 normal tumors must be post-menopausal defined by\n                  local practice. Ovarian suppression with a LHRH analogue to achieve cessation of\n                  regular menses is allowed on study\n\n               -  Male subjects must be undergoing or willing to undergo gonadal suppression whilst\n                  on study drug and continue with the LHRH analogue for the duration of the study\n\n          6. Subjects must have adequate hematopoietic function as evidenced by:\n\n               -  WBC ? 3,000/?l\n\n               -  ANC ? 1,500/?l\n\n               -  Platelet count ? 100,000/?l\n\n               -  HGB ? 9 g/dl and not transfusion dependent\n\n          7. Adequate liver function, including all the following:\n\n               -  Total serum bilirubin ?2.0 x ULN unless the subject has documented Gilbert\n                  syndrome;\n\n               -  Aspartate and alanine aminotransferase (AST & ALT) ?3.0 x ULN or ?5.0 x ULN if\n                  subject has liver metastasis;\n\n               -  Alkaline phosphatase ?3.0 x ULN or ?5 x ULN in case of bone metastasis and/or\n                  hepatic metastasis\n\n          8. Subjects must have adequate renal function as evidenced by a serum creatinine of ? 2.0\n             mg/dl.\n\n          9. Potassium (K+) ?3.5 mEq/L\n\n         10. Women of child-bearing potential must have a negative serum or urine pregnancy test\n             within 72 hours of C1D1.\n\n         11. Women of child-bearing potential and male subjects with a female partner of\n             childbearing potential must use 2 acceptable methods of birth control (one of which\n             must include a condom as a barrier method of contraception) starting at Screening and\n             continuing throughout the study period and for 3 months after final study drug\n             administration i. Two acceptable forms of birth control include:\n\n        1. Condom (barrier method of contraception), and 2. One of the following:\n\n          1. Oral, injected or implanted hormonal contraception\n\n          2. Placement of an intrauterine device (IUD) or intrauterine system (ISU)\n\n          3. Additional barrier methods of contraception: Occlusive cap (diaphragm or\n             cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.\n\n          4. Vasectomy or surgical castration ? 6 months prior to Screening. 12. Able to swallow\n             study medication 13. Able to comply with study requirements\n\n        Exclusion Criteria\n\n          1. Received any investigational agent within 5 half-lives of the agent in question; if\n             the half-life is not known, ? 28 days of C1D1.\n\n          2. Received palliative radiotherapy ? 2 weeks of C1D1\n\n          3. Received any other therapeutic treatment for breast cancer ? 2 weeks of C1D1, except\n             for hormonal therapies.\n\n          4. Symptomatic CNS metastases.\n\n          5. History of another invasive malignancy ? 3 years of C1D1.\n\n          6. A QTcF interval >470 msec on the Screening ECG. If the ECG QTcF interval is >470 msec,\n             then the mean QTcF of a triplicate ECGs can be used and if the mean is <470 msec, the\n             subject may be enrolled.\n\n          7. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia, ventricular\n             fibrillation, atrial fibrillation with rapid ventricular response, torsades de\n             pointes, second degree or third degree atrioventricular heart block without a\n             permanent pacemaker in place).\n\n          8. Class III or IV Congestive Heart Failure (CHF) as defined by the New York Heart\n             Association (NYHA) functional classification system within the previous 6 months\n\n          9. Initiated a bone modifying agent (e.g. denosumab) ? 28 days of C1D1.\n\n         10. Any medical condition that could preclude their participation in the study, pose an\n             undue medical hazard, or which could interfere with the interpretation of the study\n             results.\n\n         11. A history of seizure ? 2 years of C1D1 or those who require prophylactic anti-seizure\n             medications.\n\n         12. A history of loss of consciousness or transient ischemic attack ? 12 months before\n             C1D1.\n\n         13. Known active HIV, Hepatitis B, or Hepatitis C infections.\n\n         14. Known or suspected hypersensitivity to seviteronel, or any components of the\n             formulation.\n\n         15. Any other condition which in the opinion of the investigator would preclude\n             participation in the study.
Inclusion Criteria:\n\n        Dose Escalation and Dose Expansion Cohorts\n\n        Patients must meet all of the following criteria to be eligible for participation in the\n        study:\n\n          1. Female patients, ? 18 years of age at the time of obtaining informed consent.\n\n          2. Patients with a documented (histologically- or cytologically-proven) breast cancer\n             that is locally advanced or metastatic.\n\n          3. Patients with a malignancy that is either relapsed/refractory to standard therapy or\n             for which no standard therapy is available.\n\n          4. Patients with a malignancy that is currently not amenable to surgical intervention due\n             to either medical contraindications or non-resectability of the tumor.\n\n          5. Patients with measurable or non-measurable disease according to the Response\n             Evaluation Criteria In Solid Tumor (RECIST, v1.1).\n\n          6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of\n             0 or 1 (see APPENDIX B: Performance Status Evaluation).\n\n          7. Life expectancy of greater than or equal to 3 months.\n\n          8. Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1\n             severity or lower, except for stable sensory neuropathy (less than or equal to Grade\n             2).\n\n          9. Patients who are either not of childbearing potential or who agree to use a medically\n             effective method of contraception during the study and during 3 months after the last\n             dose of study drug. (See Appendix H: Forms of contraception).\n\n         10. Patients with the ability to understand and give written informed consent for\n             participation in this trial, including all evaluations and procedures as specified by\n             this protocol.\n\n        Dose expansion Cohort - TNBC\n\n          1. Patients with conditions as follows:\n\n               -  ER <10%, PR <10% by IHC assay; And\n\n               -  HER2 negative based on ASCO CAP guideline\n\n          2. Patients with measurable disease according to the response evaluation criteria in TNBC\n             (RECIST, v1.1)\n\n          3. Patients with measurable disease that can be easily accessed for biopsy.\n\n          4. Relapsed (recurrence or disease progression after achieving a documented clinical\n             response to first- or second-line treatment) or refractory (disease progression while\n             receiving first line or second line treatment). In the case of TNBC, prior initial\n             therapy with at least one known active regimen for TNBC including, but not limited to,\n             any combination of anthracyclines, taxanes, platinum agents, Ixabepilone, and/or\n             cyclophosphamide is required.\n\n        Exclusion Criteria:\n\n        Dose Escalation and Dose Expansion Cohorts Patients meeting any of the following criteria\n        are ineligible for participation in the study.\n\n          1. Women who are pregnant or lactating. Women of child-bearing potential (WOCBP) not\n             using adequate birth control see Appendix H: Forms of contraception.\n\n          2. Patients with known central nervous system (CNS) or leptomeningeal metastases not\n             controlled by prior surgery, radiotherapy or requiring corticosteroids to control\n             symptoms, or patients with symptoms suggesting CNS involvement for which treatment is\n             required.\n\n          3. Patients with primary brain tumors.\n\n          4. Patients with any hematologic malignancy. This includes leukemia (any form), lymphoma,\n             and multiple myeloma.\n\n          5. Patients with any of the following hematologic abnormalities at baseline. (Patients\n             may have received a red blood cell product transfusion prior to study, if clinically\n             warranted.):\n\n               -  Absolute neutrophil count (ANC) < 1,500 per mm3\n\n               -  Platelet count < 100,000 per mm3\n\n               -  Hemoglobin < 8.0 gm/dL\n\n          6. Patients with any of the following serum chemistry abnormalities at baseline:\n\n               -  Total bilirubin ? 1.5 × the ULN for the institution value\n\n               -  AST or ALT ? 3 × the ULN for the institution value (? 5 × if due to hepatic\n                  involvement by tumor)\n\n               -  Creatinine ? 1.5 × ULN for the institution value (or a calculated creatinine\n                  clearance < 60 mL/min/1.73 m2* )\n\n          7. Patients with a significant active cardiovascular disease or condition, including:\n\n               -  Congestive heart failure (CHF)requiring therapy\n\n               -  Need for antiarrhythmic medical therapy for a ventricular arrhythmia\n\n               -  Severe conduction disturbance\n\n               -  Unstable angina pectoris requiring therapy\n\n               -  QTc interval > 450 msec (males) or > 470 msec (females)\n\n               -  QTc interval ? 300 msec\n\n               -  History of congenital long QT syndrome or congenital short QT syndrome\n\n               -  LVEF < 50% as measured by echocardiography or MUGA scan\n\n               -  Uncontrolled hypertension (per the Investigator's discretion)\n\n               -  Class III or IV cardiovascular disease according to the New York Heart\n                  Association's (NYHA) Functional Criteria (see APPENDIX C: New York Heart\n                  Association's Functional Criteria).\n\n               -  Myocardial infarction (MI) within 6 months prior to first study drug\n                  administration\n\n          8. Patients with a known or suspected hypersensitivity to any of the components of\n             OTS167.\n\n          9. Patients with a known history of human immunodeficiency virus (HIV) or active\n             infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).\n\n         10. Patients with any other serious/active/uncontrolled infection, any infection requiring\n             parenteral antibiotics, or unexplained fever > 38ºC within 1 week prior to first study\n             drug administration.\n\n         11. Patients with inadequate recovery from any prior surgical procedure, or patients\n             having undergone any major surgical procedure within 4 weeks prior to first study drug\n             administration.\n\n         12. Patients with any other life-threatening illness, significant organ system\n             dysfunction, or clinically significant laboratory abnormality, which, in the opinion\n             of the Investigator, would either compromise the patient's safety or interfere with\n             evaluation of the safety of the study drug.\n\n         13. Patients with a psychiatric disorder or altered mental status that would preclude\n             understanding of the informed consent process and/or completion of the necessary\n             studies.\n\n         14. Patients with the inability or with foreseeable incapacity, in the opinion of the\n             Investigator, to comply with the protocol requirements.\n\n         15. Any anti-neoplastic agent or monoclonal antibody therapy for the primary malignancy\n             (standard or experimental) within 2 weeks prior to first study drug administration.\n\n         16. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a\n             limited field of radiation for palliation within 1 week of the first dose of study\n             treatment. If acute symptoms of radiation have fully resolved, the extent and timing\n             of radiotherapy for eligibility can be discussed between Investigator and Sponsor.\n\n         17. Patients requiring surgery for the primary or metastatic primary malignancy.\n\n         18. Herbal preparations or related over the counter (OTC) preparations/supplements\n             containing herbal ingredients within 1 week prior to first study drug administration\n             and during study.\n\n         19. Systemic hormonal therapy which is not related to breast cancer treatment (standard or\n             experimental) within 1 week prior to first study drug administration and during study.\n             The following therapies are allowed:\n\n               -  Hormonal therapy (e.g., Megace) for appetite stimulation\n\n               -  Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations\n\n               -  Oral replacement glucocorticoid therapy for adrenal insufficiency\n\n               -  Low-dose maintenance steroid therapy for other conditions (excluding steroid\n                  tapers for brain edema/metastases/radiation)\n\n               -  Hormonal contraceptive therapy (for WOCBP must be combined with non-hormonal\n                  contraceptive equivalent to a double-barrier method)\n\n         20. Any other investigational treatments during study. This includes participation in any\n             medical device or therapeutic intervention clinical trials.\n\n             Dose expansion Cohort - TNBC\n\n         21. Patients with only lesions that cannot be accessed for biopsy.
Inclusion Criteria:\n\n        Main inclusion criteria all patients, Part 1 and Part 2:\n\n          -  Male or female, at least 18 years of age at the time of informed consent\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1\n\n          -  Life expectancy >3 months assessed during Screening\n\n          -  Documented (histologically- or cytologically-proven) epithelial malignancy that is\n             locally advanced or metastatic, having received all therapy known to confer clinical\n             benefit\n\n        Additional inclusion criteria applicable to Part 2 ONLY:\n\n          -  Epithelial malignancy (tumor types to be determined), measurable according to RECIST\n             v1.1 that has been confirmed by computed tomography (CT) or magnetic resonance imaging\n             (MRI) within 4 weeks prior to C1/D1\n\n          -  Willingness to undergo a pre-and post-dosing biopsy (total of 2 biopsies) from primary\n             or metastatic tumor site(s) considered safe for biopsy\n\n        Exclusion Criteria:\n\n          -  Any antineoplastic agent for the primary malignancy (standard or investigational)\n             without delayed toxicity within 4 weeks or 5 plasma half-lives (whichever is shortest)\n             prior to C1/D1, except nitrosoureas and mitomycin C within 6 weeks prior to C1/D1.\n\n          -  Part 2 ONLY: Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless\n             there is documented progression of the lesion following radiotherapy\n\n          -  Immunosuppressive or systemic hormonal therapy (>10 mg daily prednisone equivalent)\n             within 2 weeks prior to C1/D1 with exceptions\n\n          -  Use of hematopoietic growth factors within 2 weeks prior to C1/D1\n\n          -  Active second malignancy or history of another malignancy within the last 3 years,\n             with allowed exceptions\n\n          -  Central nervous system (CNS) malignancies including:\n\n               1. Primary malignancies of the CNS\n\n               2. Known, untreated CNS or leptomeningeal metastases, or spinal cord compression;\n                  patients with any of these not controlled by prior surgery or radiotherapy, or\n                  symptoms suggesting CNS metastatic involvement for which treatment is required\n\n          -  Inadequate recovery from an acute toxicity associated with any prior antineoplastic\n             therapy\n\n          -  Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery from any\n             prior surgical procedure\n\n          -  Non-healing wounds on any part of the body\n\n          -  Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within\n             4 weeks prior to C1/D1, unless adequately treated and stable\n\n          -  Active uncontrolled bleeding or a known bleeding diathesis\n\n          -  Significant gastrointestinal abnormalities\n\n          -  Significant cardiovascular disease or condition\n\n          -  Abnormal hematologic, renal or hepatic function
Inclusion Criteria:\n\n          -  Acute leukemia: Patients with refractory or relapsed AML, other than acute\n             promyelocytic leukemia (APL).\n\n          -  Patients with a monosomal or complex karyotype may enroll at the time of day 14 biopsy\n             after induction chemotherapy, if residual disease is identified.\n\n          -  Patients must express HLA-A2.01 and myeloid blasts must express PRAME.\n\n          -  Absolute lymphocyte count (ALC) > 300/mm^3 or cluster of differentiation (CD)3+ >150\n             cells/ mm^3.\n\n          -  Patients who have relapsed and are greater than 100 days after a stem cell transplant\n             are eligible unless they have active GVHD requiring systemic immunosuppressive\n             therapy, defined as a need for > 10 mg prednisone or equivalent/day and active use of\n             a calcineurin inhibitor.\n\n          -  Relapsed or refractory AML or MDS.\n\n               -  AML patients must have > 5% bone marrow blasts at study entry, without\n                  alternative causality (e.g. bone marrow regeneration).\n\n                  a. Relapsed or refractory AML according to the Modified International Working\n                  Group Criteria for AML.\n\n                    1. Relapsed: Bone marrow blasts ?5 percent; or reappearance of blasts in the\n                       blood\n\n                    2. Refractory: Failure to achieve complete remission (CR) or complete remission\n                       with incomplete blood count recovery (CRi) after induction chemotherapy\n\n               -  MDS patients:\n\n                    1. High Grade MDS (RAEB-2) with 10-19% blasts, not responding to\n                       hypomethylation therapy or\n\n                    2. RAEB-1 or RAEB-2 MDS recurrence after initial response.\n\n          -  Age ? 18 years.\n\n          -  Life expectancy of at least 2 months.\n\n          -  Karnofsky performance status: > 60%.\n\n          -  Informed consent has been obtained\n\n          -  Patients who have come off previous cancer therapy for at least 14 days for prior\n             cytotoxic agents, and prior to D0, except when hydroxyurea is given only when needed\n             to control hyperleukocytosis. Persistent clinically significant toxicities from prior\n             chemotherapy must not be greater than Grade 1 (CTCAE 4.03) at the time of enrollment.\n             Salvage/lymphodepleting chemotherapeutic agents may be given up to 3 days prior to T\n             cell reinfusion if necessary to control rapidly growing disease.\n\n          -  Able to meet local institutional criteria for T cell apheresis collection.\n\n          -  Renal function:\n\n               1. All patients must have a calculated creatinine clearance > 40 mL/min according to\n                  Cockcroft-Gault Equation.\n\n               2. Routine urinalysis must show no clinically significant abnormalities.\n\n          -  Subject has adequate organ function as measured by:\n\n             i. Adequate LFTs: Total bilirubin ? 3.0 x the institutional upper normal limits (ULN)\n             with direct bilirubin < 1.6 x ULN.\n\n        ii. Alanine transaminase (ALT)/aspartate transaminase (AST) and Alkaline Phosphatase ? 5 x\n        ULN.\n\n        iii. Cardiac: left ventricular ejection fraction at rest must be ? 40%.\n\n        iv. Pulmonary: forced expiratory volume (FEV) 1, forced vital capacity (FVC), carbon\n        monoxide diffusing capacity (DLCO) ? 50% predicted (corrected for hemoglobin).\n\n          -  Acceptable coagulation status:\n\n               -  International normalized Ratio (INR)/ Prothrombin Time (PT) ? 1.5 times ULN.\n\n               -  Partial thromboplastin time (PTT) < 1.5 times ULN.\n\n          -  For fertile men and women, agreement to use effective contraceptive methods during the\n             study and for 3 months after administration of BPX-701.\n\n        Exclusion Criteria:\n\n        Patients who have any of the following are not eligible for enrollment (initiation of\n        BPX-701 infusion) in this study:\n\n          -  Inadequate lymphocyte count for collection.\n\n          -  Bovine product allergy.\n\n          -  History of prior malignancy other than: i) those associated with the current disease,\n             ii) previously treated with a curative intent therapy less than 1 year ago and except\n             superficial skin cancers.\n\n          -  Participation in any investigational drug study < 28 days prior to D0 (BPX-701\n             infusion).\n\n          -  Uncontrolled leptomeningeal leukemic disease.\n\n          -  Uncontrolled disseminated intravascular coagulation.\n\n          -  Other serious illness or medical conditions, which in the investigator's opinion could\n             hamper patient's understanding of the study, compliance to study treatment, and/or\n             safety or interpretation of study results. These conditions include (but are not\n             restricted to):\n\n               1. Congestive heart failure or angina pectoris (New York Heart Association Class III\n                  or IV) except when it is medically controlled. Uncontrolled hypertension or\n                  malignant arrhythmias.\n\n               2. Presence of significant neurologic or psychiatric disorders impairing the ability\n                  to obtain consent.\n\n               3. Uncontrolled bacterial, viral or fungal infection.\n\n               4. Known HIV, hepatitis B virus (HBV), hepatitis C virus (HCV) positivity or subject\n                  not meeting the selection criteria as defined for the Foundation for the\n                  Accreditation of Cell Therapy (FACT) and American Association of Blood Banks\n                  (AABB).\n\n          -  Unwillingness or inability to comply with procedures required in this protocol.
Inclusion Criteria:\n\n        Subject must meet all of the following applicable inclusion criteria to participate in this\n        study:\n\n          -  Written informed consent and HIPAA authorization for release of protected health\n             information obtained from the subject prior to performing any protocol-related\n             procedures, including screening evaluations. NOTE: HIPAA authorization may be included\n             in the informed consent or obtained separately.\n\n          -  Age ? 18 years at the time of consent.\n\n          -  ECOG Performance Status of 0-1 within 28 days prior to registration for protocol\n             therapy.\n\n          -  Females of childbearing potential and males must be willing to use an effective method\n             of contraception (hormonal or barrier method of birth control; abstinence) from the\n             time consent is signed until 12 weeks after treatment discontinuation.\n\n          -  Females of childbearing potential must have a negative serum pregnancy test within 14\n             days prior to registration for protocol therapy. NOTE: Female subjects are considered\n             of child bearing potential unless they are surgically sterile (they have undergone a\n             hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are ?60\n             years old and naturally postmenopausal for at least 12 consecutive months.\n\n          -  Histological evidence of persistent residual esophageal adenocarcinoma including\n             gastroesophageal junction adenocarcinoma following definitive concurrent\n             chemoradiotherapy (carboplatin and paclitaxel or cisplatin and 5-FU) in the surgical\n             sample (esophagus or lymph node or both) obtained at the time of esophagectomy. NOTE:\n             Persistent residual disease is defined as follows (modified from College of American\n             Pathologists Guidelines):\n\n               -  No residual tumor (Grade 0, complete response, 0% tumor). This group will not be\n                  included in this study.\n\n               -  Marked response (Grade 1, 0-<10% residual tumor)\n\n               -  Moderate response (Grade 2, 10-50% residual tumor)\n\n               -  No definite response (Grade 3, >50% residual tumor)\n\n          -  Minimum of 1 month and maximum of 3 months from surgical resection with no evidence of\n             disease progression at the time of enrollment.\n\n          -  Must have adequately recovered from surgery as judged by the treating investigator.\n\n          -  Subject is willing and able to comply with the protocol for the duration of the study\n             including undergoing treatment and scheduled visits and examinations including follow\n             up.\n\n        Exclusion Criteria:\n\n        Subjects meeting any of the criteria below may not participate in the study:\n\n          -  Prior therapy with a PD-1, PD-L1, or CTLA-4 inhibitor or cancer-specific vaccine\n             therapy.\n\n          -  Evidence of active autoimmune disease requiring systemic treatment within preceding 3\n             months or a documented history of clinically severe autoimmune disease, or a syndrome\n             that requires systemic steroids or immunosuppressive agents. Exceptions to this rule\n             include vitiligo, resolved childhood asthma/atopy, requirement of intermittent\n             bronchodilators or local steroid injections, hypothyroidism stable on hormone\n             replacement, psoriasis not requiring systemic treatment (within the past 2 years),\n             Graves's disease and Sjogren's syndrome.\n\n          -  Prior malignancy is not allowed except for adequately treated basal cell or squamous\n             cell skin cancer, in situ cervical cancer, Gleason score ? 7 prostate cancers, or\n             other cancer for which the subject has been disease-free for at least 3 years.\n\n          -  Active or prior documented inflammatory bowel disease (e.g. Crohn's disease,\n             ulcerative colitis).\n\n          -  Presence of interstitial lung disease or history of pneumonitis requiring treatment\n             with corticosteroids.\n\n          -  Patients with diagnosis of primary immunodeficiency.\n\n          -  Patients receiving chronic systemic corticosteroid therapy or other immunosuppressive\n             therapy within 28 days prior to registration for protocol therapy. Exceptions include\n             intranasal and inhaled corticosteroids or systemic corticosteroids at physiological\n             doses, which are not to exceed 10 mg/day of prednisone, or an equivalent\n             corticosteroid.\n\n          -  History of allogeneic organ or stem cell transplant.\n\n          -  Receipt of live attenuated vaccine within 30 days prior to registration for protocol\n             therapy.\n\n          -  Mean QT interval corrected for heart rate (QTc) > 470 msec calculated from 3 ECGs by\n             Bazett's Correction.\n\n          -  Ventricular arrhythmias requiring medication(s).\n\n          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic\n             congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac\n             arrhythmia, active peptic ulcer disease or gastritis, or active bleeding diatheses.\n\n          -  History of psychiatric illness/social situations that would limit compliance with\n             study requirements or compromise the ability of the subject to give written informed\n             consent.\n\n          -  Known HIV infection or chronic hepatitis B or C.\n\n          -  Known history of previous clinical diagnosis of tuberculosis.\n\n          -  Clinically significant infections as judged by the treating investigator. Clinically\n             significant is defined as an active infection requiring IV antibiotics.\n\n          -  Because there is an unknown but potential risk for adverse events in nursing infants\n             secondary to treatment of the mother, breastfeeding should be discontinued. In\n             addition, breast milk cannot be stored for future use while the mother is being\n             treated on study.\n\n          -  Treatment with any investigational agent within 28 days prior to registration for\n             protocol therapy.\n\n          -  History of hypersensitivity to durvalumab or any excipient.\n\n          -  Any condition that, in the opinion of the investigator, would interfere with\n             evaluation of study treatment or interpretation of patient safety or study results.\n\n          -  Previous enrollment in the present study.
Inclusion Critera\n\n          1. Female ? 18 years of age\n\n          2. Histologically proven diagnosis of:\n\n             a. Endometrial and other uterine cancers with tumors of all histologies i. Recurrent\n             Stage I to II endometrial and other uterine cancers, after at least one prior line of\n             standard therapy, requiring further treatment with platinum-based chemotherapy ii.\n             Advanced Stage III to IV endometrial and other uterine cancers requiring treatment\n             with platinum-based chemotherapy b. Ovarian Cancer: Platinum-sensitive or\n             platinum-resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal\n             cancer treated with at least one prior line of platinum-based chemotherapy and\n             requiring further treatment.\n\n             Platinum-sensitive is defined as cancer progression ? 6 months after platinum-based\n             chemotherapy. Platinum-resistant is defined as cancer progression < 6 months after\n             platinum-based chemotherapy.\n\n             Histologic cell types eligible are endometrioid adenocarcinoma, serous adenocarcinoma,\n             undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma,\n             adenocarcinoma not otherwise specified. c. Cervical cancer: recurrent or metastatic\n             cervical cancer that is not amenable to curative treatment with surgery and/or\n             radiation therapy and has not been previously treated with chemotherapy for\n             recurrence.\n\n             Histologic cell types eligible are squamous cell carcinoma, adenosquamous carcinoma or\n             adenocarcinoma\n\n          3. Have measureable disease defined by RECIST 1.1 confirmed by CT or MRI scan within 28\n             days of enrollment.\n\n          4. Life expectancy of ? 3 months at the time of enrollment.\n\n          5. Able to take orally administered study medication.\n\n          6. Have adequate baseline function and performance status within 28 days of enrollment:\n\n               1. Bone marrow function: absolute neutrophil count (ANC) ? 1,500/mm3, platelets ?\n                  100,000/mm3\n\n               2. Renal function: creatinine ? 1.5 x institutional upper limit normal (ULN) or if\n                  creatinine is > 1.5 x ULN, creatinine clearance must be > 50 mL/min.\n\n               3. Hepatic function: bilirubin ? 1.5 x ULN or ? 3.0 x ULN for subjects with Gilbert\n                  Syndrome; AST and ALT ? 3.0 × ULN.\n\n               4. Coagulation profile: international normalized ratio (INR) is ? 1.5 and an aPTT or\n                  PTT < 1.2 x ULN\n\n               5. ECOG performance ? 2\n\n          7. Women of child-bearing potential must agree to use contraceptive measures starting 1\n             week before C1D1 until 4 weeks after the last dose of study treatment and have a\n             negative serum pregnancy test within 28 days of enrollment.\n\n          8. Provide written informed consent and authorization permitting release of Protected\n             Health Information.\n\n          9. Ability and willingness to comply with the study protocol for the duration of the\n             study and with follow-up procedures.\n\n        Exclusion Criteria\n\n          1. Serious, non-healing wound, ulcer or bone fracture.\n\n          2. Major surgical procedure within 28 days or minor surgical procedure performed within 7\n             days prior to C1D1 (a major surgical procedure is defined as requiring general\n             anesthesia).\n\n          3. (Intentionally left blank)\n\n          4. Active bleeding or pathologic conditions that carry high risk of bleeding, such as\n             known bleeding disorder, coagulopathy, or tumor involving major vessels.\n\n          5. History or evidence upon physical examination of central nervous system (CNS) disease\n             including primary brain tumor; seizures not controlled with standard medical therapy;\n             and history of cerebrovascular accident (CVA, stroke), transient ischemic attack\n             (TIA), or subarachnoid hemorrhage within 6 months of enrollment.\n\n             a. Subjects with metastatic CNS tumors may participate in this study if the subject is\n             > 28 days from therapy completion (including radiation and/or surgery), is clinically\n             stable at the time of study enrollment, and is not receiving corticosteroid therapy.\n\n          6. Proteinuria on urinalysis within 28 days of enrollment. Subjects discovered to have a\n             urine protein of 1+ on dipstick or ? 30 mg/dl at baseline should undergo a 24-hour\n             urine collection and demonstrate < 1000 mg protein per 24 hours or spot urine protein\n             (mg/dL) to creatinine (mg/dL) ratio must be <1.0 to allow participation in the study.\n\n          7. Clinically significant cardiovascular disease including uncontrolled hypertension;\n             myocardial infarction or unstable angina within 6 months prior to enrollment; New York\n             Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix E);\n             serious cardiac arrhythmia requiring medication; and Grade II or greater peripheral\n             vascular disease.\n\n          8. Women who are pregnant or nursing.\n\n          9. (Intentionally left blank)\n\n         10. Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or\n             hypocalcaemia.\n\n         11. Hemoptysis within 3 months prior to enrollment.\n\n         12. Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver\n             dysfunction.\n\n         13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in\n             cases of mitomycin C, nitrosourea, lomustine) prior to enrollment.\n\n         14. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19\n             within 14 days prior to enrollment and during the study unless there is an emergent or\n             life-threatening medical condition that required it.\n\n         15. Known history of human immunodeficiency virus infection (HIV).\n\n         16. Active bacterial infections requiring systemic antibiotics (excluding uncomplicated\n             urinary tract infection).\n\n         17. Other invasive malignancies, with the exception of non-melanoma skin cancer, who had\n             (or have) any evidence of other cancer present within the last 5 years prior to\n             enrollment or whose previous cancer treatment contraindicates this protocol therapy.\n\n         18. History of non-malignant gastrointestinal bleeding, gastric stress ulcerations, or\n             peptic ulcer disease within the past 3-months prior to enrollment that in the opinion\n             of the investigator may place the subject at risk of side effects on an\n             anti-angiogenesis product.\n\n         19. History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).\n\n         20. Intra-abdominal abscess within the last 3 months of enrollment.\n\n         21. Pre-existing uncontrolled hypertension as documented by two baseline blood pressure\n             readings taken at least five minutes apart, defined as systolic BP >160 mm Hg or\n             diastolic BP > 90 mm Hg pressure.\n\n         22. QTc > 470 msec on screening ECG per Fridericia's formula.\n\n         23. History of or existing risk factors for Torsades de pointes (TdP) (e.g., heart\n             failure, hypokalemia, family history of Long QT Syndrome).\n\n         24. Concurrent use of concomitant medications that prolong the QT/QTc interval.\n\n         25. Baseline echocardiogram (within 56 days of enrollment) with left ventricular ejection\n             fraction (LVEF) < 50%.\n\n         26. History of difficulty swallowing, malabsorption, active partial or complete bowel\n             obstruction, or other chronic gastrointestinal disease or condition that may hamper\n             compliance and/or absorption of AL3818.\n\n         27. History of pancreatitis; history of renal disease that includes histologically\n             confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal\n             nephropathy or other renal insufficiencies.\n\n         28. Treatment with an investigational agent within 28 days of enrollment.\n\n         29. Known recreational substance abuse.\n\n         30. Anticoagulation therapy with warfarin. Subjects treated with heparin, low molecular\n             weight heparin, or any other anticoagulant may be included provided the subject has\n             been on a stable therapeutic dose of the anticoagulant for at least 14 days prior to\n             enrollment.\n\n         31. Known hypersensitivity to AL3818 or components of the formulation.
Inclusion Criteria:\n\n        For a subject to be eligible for this study, she must meet all of the following criteria:\n\n          1. Female subjects 18 years of age or older\n\n          2. Subjects may be enrolled with previous histologically proven diagnosis of the\n             following:\n\n             a. Endometrial Cancer: Patients must have recurrent or persistent endometrial\n             carcinoma, which is refractory to curative therapy or established treatments.\n\n             i. Histologic diagnosis will be reviewed by the treating institution ii. Patients with\n             the following histologic epithelial cell types are eligible: Endometrioid\n             adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell\n             adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified,\n             mucinous adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma.\n\n             iii. Initial treatment may have included chemotherapy, chemotherapy and radiation\n             therapy, and/or consolidation/maintenance therapy; antiangiogenic therapy (e.g.\n             bevacizumab) as part of adjuvant therapy is allowed. Chemotherapy administered in\n             conjunction with primary radiation as a radio-sensitizer will be counted as a systemic\n             chemotherapy regimen.\n\n             iv. Patients should have received no more than two prior cytotoxic or non-cytotoxic\n             therapies for management of recurrent or persistent disease (excluding endocrine\n             therapies which will not count in the number of regimens)\n\n             b. Ovarian cancer: Patients must have recurrent or persistent ovarian, fallopian tube\n             or primary peritoneal cancer, which is refractory to established treatments.\n\n             i. Patients with the following histologic epithelial cell types are eligible:\n             Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear\n             cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise\n             specified.\n\n             ii. Patients must have received at least one prior platinum-based chemotherapeutic\n             regimen for the management of primary disease containing carboplatin, cisplatin, or\n             another organoplatinum compound.\n\n             iii. This initial therapy may have included high-dose therapy, consolidation, or\n             extended therapy administered after surgical or non-surgical assessment.\n\n             iv. Antiangiogenic therapy (e.g. bevacizumab) as part of adjuvant therapy is allowed.\n\n             v. Patients should have received no more than two prior cytotoxic or non-cytotoxic\n             therapies for management of recurrent or persistent disease\n\n             c. Cervix cancer: Subjects diagnosed with histologically confirmed squamous cell\n             carcinoma of the cervix.\n\n             i. Patients must have received at least one prior platinum based chemotherapeutic\n             regimen for the management of primary disease containing carboplatin, cisplatin or\n             another organoplatinum compound. The initial therapy may have included high-dose\n             therapy, consolidation or extended therapy administered after surgical or non-surgical\n             assessment. Antiangiogenic therapy (e.g. bevacizumab) as part of adjuvant therapy is\n             allowed. Chemotherapy administered in conjunction with primary radiation as a\n             radio-sensitizer will be counted as a systemic chemotherapy regimen.\n\n             ii. Patients should have received no more than two prior cytotoxic or non-cytotoxic\n             standard therapies for management of recurrent or persistent disease.\n\n             d. Other uterine cancers: Subjects diagnosed with other uterine cancers, such as\n             Leiomyosarcoma, and have received no more than two prior cytotoxic or non-cytotoxic\n             standard therapies for management of recurrent or persistent disease.\n\n          3. For Phase 2a only, all patients must express at least one FGFr 1, 2 or 3 amplification\n             (or mutation) from archived tissue or new biopsy. For non-amplified patients, approval\n             of the site coordinator or the sponsor is required prior to enrollment.\n\n          4. All patients must have measurable disease. Measurable disease is defined as at least\n             one lesion that can be accurately measured in at least one dimension (longest\n             dimension to be recorded). Each lesion must be ? 20mm when measured by conventional\n             techniques, including palpation, plain x-ray, CT, and MRI, or ? 10mm when measured by\n             spiral CT.\n\n          5. Life expectancy ? 3 months\n\n          6. Subject must be suitable for oral administration of study medication\n\n          7. Patients must have signed an approved informed consent and authorization permitting\n             release of personal health information.\n\n          8. Patient must have adequate:\n\n               1. Bone Marrow Function: Absolute neutrophil count (ANC) greater then or equal to\n                  1,500/mm3, equivalent to Common Toxicity Criteria (CTC) grade 1. Platelets\n                  greater than or equal to 100,000/mm3\n\n               2. Renal Function: Creatinine less than or equal to 1.5 x institutional upper limit\n                  normal (ULN), CTC grade 1. Note: If creatinine is greater than 1.5 x ULN,\n                  creatinine clearance must be greater than >50 mL/min.\n\n               3. Hepatic Function: Bilirubin less than or equal to 1.5 x ULN (CTC grade 1) or less\n                  than or equal to 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT less\n                  than or equal to 3.0 ×ULN.\n\n               4. Coagulation profile: PT such that international normalized ratio (INR) is ? 1.55\n                  (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of\n                  therapeutic warfarin or low molecular weight heparin) and a PTT < 1.2 times\n                  control.\n\n          9. ECOG performance status ? 2.\n\n         10. Subjects of child-bearing potential must agree to use contraceptive measures starting\n             1 week before the administration of the first dose of AL3818 until 4 weeks after\n             discontinuing study drug.\n\n         11. Subjects of child-bearing potential must have a negative serum pregnancy test prior to\n             study entry and cannot be lactating.\n\n         12. Ability and willingness to comply with the study protocol for the duration of the\n             study and with follow-up procedures.\n\n        Exclusion Criteria\n\n        Subjects who meet any of the following criteria will be excluded from participation in the\n        study:\n\n          1. Subjects who have received prior treatment with an FGFr inhibitor or antagonist of\n             FGFr. Prior anti-VEGF or anti-angiogenic therapy is allowed in the adjuvant treatment\n             setting Prior anti-VEGF or anti-angiogenic therapy for the treatment of recurrent\n             disease is not allowed.\n\n          2. Patients who have received prior antiangiogenic therapy, including bevacizumab,\n             sorafenib, sunitinib, in the setting of advanced disease.\n\n          3. Patients with serious, non-healing wound, ulcer or bone fracture.\n\n          4. Patients with active bleeding or pathologic conditions that carry high risk of\n             bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major\n             vessels.\n\n          5. Patient with history or evidence upon physical examination of CNS disease, including\n             primary brain tumor, seizures not controlled with standard medical therapy, any brain\n             metastases or history of cerebrovascular accident (CVA, stroke) transient ischemic\n             attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment\n             on this study.\n\n          6. However, patients with metastatic CNS tumors may participate in this trial, if the\n             patient is > 4 weeks from therapy completion (including radiation and/or surgery), is\n             clinically stable at the time of study entry and is not receiving corticosteroid\n             therapy.\n\n          7. Patients with proteinuria. Patients discovered to have a urine protein of 1+ on\n             dipstick or ? 30 mg/dl at baseline should undergo a 24-hour urine collection, which\n             must be an adequate collection and must demonstrate < 1000 mg protein/24 hr to allow\n             participation in the study.\n\n          8. Patients with clinically significant cardiovascular disease; this includes:\n             Uncontrolled hypertension; Myocardial infarction or unstable angina within 6 months\n             prior to registration; New York Heart Association (NYHA) Grade II or greater\n             congestive heart failure (Appendix F); Serious cardiac arrhythmia requiring\n             medication; Grade II or greater peripheral vascular disease (Appendix F).\n\n          9. Patients who are pregnant or nursing. To date, no fetal studies of AL3818 in animals\n             or humans have been performed. Therefore, AL3818 should not be administered to\n             pregnant women. Subjects will be apprised of the large potential risk to a developing\n             fetus. It is not known whether AL3818 is excreted in human milk. Because many drugs\n             are excreted in human milk, AL3818 should not be administered to nursing women. Women\n             of childbearing potential must agree to use contraceptive measures during study\n             therapy and for at least 3 months after completion of AL3818 therapy. Because many\n             drugs are excreted in human milk.\n\n         10. Patients with uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.\n\n         11. Hemoptysis within 3 months prior to first scheduled dose of AL3818.\n\n         12. Patients with acute or chronic liver disease, active hepatitis A or B with known\n             cirrhosis or liver dysfunction.\n\n         13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks in\n             cases of mitomycin C, nitrosourea, lomustine) prior to first scheduled dose of AL3818\n             or a major surgical procedure within 28 days or minor surgical procedure performed\n             within 7 days prior to first scheduled dose of AL3818.\n\n         14. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19\n             who cannot be switched to other alternative medications (See Appendix E).\n\n         15. Known history of human immunodeficiency virus infection (HIV).\n\n         16. Subjects with active bacterial infections (other than uncomplicated urinary tract\n             infection) and/or receiving systemic antibiotics.\n\n         17. Patients with other invasive malignancies, with the exception of non-melanoma skin\n             cancer, who had (or have) any evidence of other cancer present within the last 5 years\n             or whose previous cancer treatment contraindicates this protocol therapy.\n\n         18. History of non-malignant GI bleeding, gastric stress ulcerations, or peptic ulcer\n             disease within the past 3-months that in the opinion of the investigator may place the\n             patient at risk of side effects on an anti-angiogenesis product.\n\n         19. History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).\n\n         20. Intra-abdominal abscess within the last 3 months.\n\n         21. History of uncontrolled hypertension that is not well managed by medication, as\n             documented by 2 baseline evaluations taken one hour apart with systolic blood pressure\n             >160 mm or diastolic blood pressure >90 mm Hg pressure, or that in the opinion of the\n             investigator may place the patient at risk when taking a VEGF inhibitor.\n\n         22. Pre-existing uncontrolled hypertension as documented by 2 baseline BP readings taken\n             at least one hour apart, defined as systolic bloodpressure (BP) >160 mm Hg or\n             diastolic BP > 90 mm Hg pressure.\n\n         23. QTcF>470 msec on screening ECG.\n\n         24. A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family\n             history of Long QT Syndrome).\n\n         25. The use of concomitant medications that prolong the QT/QTc interval.\n\n         26. Baseline echocardiogram (within 2 months) with left ventricular ejection fraction\n             (LVEF) < 50%.\n\n         27. History of difficulty swallowing, malabsorption, active partial or complete bowel\n             obstruction, or other chronic gastrointestinal disease or condition that may hamper\n             compliance and/or absorption of AL3818.\n\n         28. History of pancreatitis and/or renal disease that includes histologically confirmed\n             glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy,\n             or other renal insufficiencies.\n\n         29. Treatment with an investigational agent within the longest time frame of either 5\n             half- lives or 30 days of initiating study drug.\n\n         30. Known recreational substance abuse.\n\n         31. Known hypersensitivity to anti-angiogenic agents.
Criteria:\n\n          -  Histologically and/or cytologically confirmed malignant pleural mesothelioma.\n\n          -  Unresectable disease (defined as the participant not being a candidate for curative\n             surgery).\n\n          -  Measurable disease, defined as at least 1 lesion (measurable) that can be accurately\n             assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI)\n             and is suitable for repeated assessment (modified RECIST for pleural mesothelioma).\n\n          -  Available unstained archived tumor tissue sample in sufficient quantity to allow for\n             analyses. At least fifteen unstained slides or a tumor block (preferred). NOTE: A fine\n             needle aspiration sample is not sufficient to make the patient eligible for\n             enrollment. Given the complexity of mesothelioma pathological diagnosis and that these\n             will be newly diagnosed patients it is expected that they will have a core needle\n             biopsy or surgical tumor biopsy as part of their initial diagnostic work up.\n\n          -  Age ? 18 years.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.\n\n          -  Ability to understand and willingness to sign Institutional Review Board\n             (IRB)-approved informed consent.\n\n          -  Willing to provide archived tumor tissue and blood samples for research.\n\n          -  Adequate organ function as measured by the following criteria, obtained ? 2 weeks\n             prior to registration:\n\n               -  Absolute Neutrophil Count (ANC) ? 1500/mm³\n\n               -  Hemoglobin ?9.0 g/dL\n\n               -  Platelets ?100,000/mm³\n\n               -  Serum creatinine clearance (CL)>60 mL/min by the Cockcroft-Gault formula or by\n                  24-hour urine collection for determination of creatinine clearance. NOTE:\n                  Patients with a creatinine Cl ? 45 mL/min however ? 60 mL/min may be considered\n                  for enrollment provided they fulfill all other eligibility criteria, these\n                  subjects will receive pemetrexed carboplatin concurrent with durvalumab during\n                  the combination phase of treatment. Patients with a creatinine CL<45 mL/min\n                  should not be enrolled.\n\n               -  Albumin ? 2.8 g/dL\n\n               -  Total Bilirubin ? 1.5x Upper Limit of Normal (ULN)\n\n               -  Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ? 2.5x ULN (? 5x\n                  ULN in patients with liver metastases)\n\n          -  Women must either be of non-reproductive potential or must have a negative serum\n             pregnancy test upon study entry.\n\n          -  Women must not be pregnant or breastfeeding.\n\n          -  Patient is willing and able to comply with the protocol for the duration of the study\n             including undergoing treatment and scheduled visits and examinations including\n             follow-up.\n\n          -  Patient must not have involvement in the planning and/or conduct of the study. No\n             previous enrollment in the present study.\n\n          -  Patients may not have participated in another clinical study with an investigational\n             product during the last 4 weeks.\n\n          -  Patients must not have any prior systemic therapy (chemotherapy, immunotherapy,\n             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal\n             antibodies, and other investigational agent) for mesothelioma.\n\n          -  No previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or any other\n             agent targeting immune checkpoints.\n\n          -  Patients must not have non-pleural mesothelioma e.g. mesothelioma arising in\n             peritoneum, tunica vaginalis or any serosal surface other than the pleura.\n\n          -  Patients must not have an active second malignancy other than non-melanoma skin cancer\n             or cervical carcinoma in situ.\n\n          -  Patients must not have mean QT interval corrected for heart rate (QTc) ?470 ms\n             calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction.\n\n          -  Patients must not have symptomatic or uncontrolled brain metastases requiring\n             concurrent treatment, inclusive of but not limited to surgery, radiation and/or\n             corticosteroids (prednisone >10 mg or equivalent). Surgery, radiation and/or\n             corticosteroids (any dose >10 mg prednisone equivalent) must have been completed ? 2\n             weeks prior to registration.\n\n          -  Patients must not have uncontrolled seizures.\n\n          -  Patients must not have current or prior use of immunosuppressive medication within 28\n             days before the first dose of durvalumab, with the exceptions of intranasal and\n             inhaled corticosteroids or systemic corticosteroids at physiological doses, which are\n             not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Standard\n             steroid premedication given prior to chemotherapy or as prophylaxis for imaging\n             contrast allergy should not be counted for this criterion.\n\n          -  No active or prior documented autoimmune or inflammatory disorders (including\n             inflammatory bowel disease, diverticulitis with the exception of diverticulosis,\n             celiac disease, irritable bowel disease; Wegner syndrome) within the past 2 years.\n             Subjects with vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic\n             treatment (within the past 3 years) are not excluded.\n\n          -  No history of primary immunodeficiency.\n\n          -  No history of allogeneic organ transplant.\n\n          -  No history of hypersensitivity to durvalumab, cisplatin, carboplatin, pemetrexed or\n             any of their excipients.\n\n          -  No uncontrolled intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable\n             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active\n             bleeding diatheses including any subject known to have psychiatric illness/social\n             situations that would limit compliance with study requirements or compromise the\n             ability of the subject to give written informed consent.\n\n          -  No active infection including tuberculosis (clinical evaluation including: physical\n             examination findings, radiographic findings, positive PPD test, etc.), hepatitis B\n             (known positive HBV surface antigen [HBsAg] result), hepatitis C, or human\n             immunodeficiency virus (positive HIV 1/2 antibodies as defined by a positive ELISA\n             test). Patients with a past or resolved HBV infection (defined as the presence of\n             hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients\n             positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction\n             is negative for HCV RNA. HIV testing is not required in absence of clinical suspicion.\n\n          -  No known history of leptomeningeal carcinomatosis.\n\n          -  Patients must not have received live attenuated vaccination within 30 days prior to\n             study entry or within 30 days of receiving durvalumab.\n\n          -  Patients must not have any condition that, in the opinion of the investigator, would\n             interfere with evaluation of study treatment or interpretation of patient safety or\n             study results.
Inclusion Criteria (Escalation and Expansion Phases)\n\n        Patients must meet the following criteria to be eligible to enroll in the study:\n\n          1. Patients must have histologically confirmed solid tumors or hematologic malignancies.\n             Eligible patients include the following:\n\n             a) GIST patients must have a KIT and PDGFRA mutation and must have progressed on or\n             had an intolerability to at least 1 line of systemic anticancer therapy: i. Patients\n             with a pre-existing resistance mutation to an approved line of therapy are eligible.\n             For example, imatinib resistant mutations including KIT Exon 17 and PDGFRA D842V.\n\n             b) SM patients must have a confirmed diagnosis (confirmed by a central independent\n             pathologist) of advanced SM according to 2016 World Health Organization (WHO) criteria\n             for SM and must have documented KIT mutant disease. SM patients must also have a\n             normal karyotype.\n\n             Advanced SM includes: ASM, SM-AHN, wherein the AHN does not require immediate\n             alternative therapy, such as acute myeloid leukemia. AHNs that are eligible include:\n             low grade myelodysplastic syndrome (MDS) with a high SM burden who require treatment\n             for SM only, myeloproliferative neoplasms (MPNs), MDS/MPN, and HES/CEL], and MCL i.\n             Patients with advanced SM must present with at least 1 eligible C-Finding (organ\n             damage) as outlined in Table 3 of the 2013 International Working\n             Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European\n             Competence Network on Mastocytosis (ECNM) consensus response criteria (Appendix 10.5);\n             please see below for MCL exception) (#iii).\n\n             ii. Patients with imatinib-sensitive KIT mutations must have progressed on or were\n             intolerant to a tryosine kinase inhibitor.\n\n             iii. Patients with histopathologically-confirmed MCL without a C-finding are eligible.\n\n             iv. Patients with symptomatic SSM are eligible. By definition, SSM patients must have\n             at least 2 B-findings, and clinically significant symptom burden (eg, flushing,\n             diarrhea, etc.) despite maximal treatment with approved agents to treat mediator\n             symptoms, such as antihistamines and cromolyn sodium. Patients must have a normal\n             karyotype.\n\n             v. Patients with hematologic malignancies featuring clonal expansion of eosinophils\n             driven by genomic alterations of KIT or PDGFR (eg, HES or CEL) must have a diagnosis\n             confirmed by a central independent pathologist and are eligible if they have\n             progressed on or are intolerant of imatinib therapy. Patients with de novo imatinib\n             resistant mutations, such as but not limited to KIT D816V or PDGFRA D842V, are\n             eligible without prior imatinib therapy.\n\n             c) Malignant glioma patients with genomic alterations potentially conferring\n             sensitivity to DCC-2618 including, but not limited to, amplification and/or mutations\n             of PDGFRA and/or KIT.\n\n             i. Patients must not require use of enzyme-inducing antiepileptic drugs. ii. Patients\n             that require steroids must be on a stable dose for 2 weeks prior to the first dose of\n             study drug.\n\n             d) Other solid tumor patients that have alterations in genes encoding kinases that are\n             targets of DCC-2618. This includes KIT, PDGFR (A or B), TIE2, CSF1R, and VEGFR2.\n             Patients must have received approved treatments known to provide clinical benefit\n             prior to study entry.\n\n             e) If signs or symptoms suggest CNS metastases, a brain MRI must be performed to\n             confirm absence of CNS disease within 1 week prior to receiving study drug.\n\n          2. Patients with known CNS metastases may participate provided that:\n\n               1. they are stable (ie, without evidence of progression by magnetic resonance\n                  imaging [MRI]) for at least 4 weeks prior to the first dose study drug (patients\n                  with active disease may be eligible following discussion between the Investigator\n                  and the Sponsor),\n\n               2. all neurologic symptoms have been stable for 2 weeks prior to the first dose of\n                  study drug,\n\n               3. patients must not require use of enzyme-inducing antiepileptic drugs,\n\n               4. patients that require steroids must be on a stable dose for 2 weeks prior to the\n                  first dose of study drug.\n\n          3. Patients with solid tumors (with the exception of glial tumors and tumors that are\n             anatomically inaccessible) must have an archival tumor biopsy sample as long as no\n             anticancer therapy was administered since the sample was collected; otherwise, a\n             current biopsy is required. In the case of glial tumors and anatomically inaccessible\n             tumors, the most recent archival tissue is required.\n\n          4. Male or female patients ?18 years of age.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ?2.\n\n          6. Female patients of childbearing potential must have a negative serum beta?human\n             chorionic gonadotropin (?-hCG) pregnancy test within 28 days prior to the start of\n             study drug. For clinical sites in the UK, pregnancy testing must occur within 7 days\n             prior to the start of study drug.\n\n          7. Patients of reproductive potential must agree to follow the contraception requirements\n             outlined in Section 6.8.11.\n\n          8. The patient is capable of understanding and complying with the protocol and has signed\n             the informed consent document. A signed informed consent form must be obtained before\n             any study?specific procedures are performed. Standard procedures performed as part of\n             the practice of medicine prior to consent (eg, imaging, physical exam) can be used to\n             determine eligibility if completed within 28 days prior to the initial dose of study\n             drug.\n\n          9. Patients with solid tumors must have at least 1 measurable lesion according to RECIST\n             Version 1.1 (non-nodal lesions must be ?1.0 cm in the long axis or ?double the slice\n             thickness in the long axis; nodal lesions must be ?1.5 cm in the short axis) or\n             Response Assessment in Neuro-Oncology Criteria (RANO).\n\n             a) A non-brain lesion in a previously irradiated area is eligible to be considered as\n             measurable disease as long as there is objective evidence of progression of the lesion\n             before study enrollment.\n\n         10. Adequate organ function and bone marrow function as indicated by the following central\n             laboratory screening assessments performed within 14 days prior to the first dose of\n             study drug. Local laboratory values obtained after screening and prior to Cycle 1 Day\n             1 dosing that do not meet the criteria below must be discussed with the Sponsor:\n\n               1. Solid Tumor Patients: Bone Marrow Function: Absolute neutrophil count (ANC)\n                  ?1500/?L; hemoglobin ?9 g/dL; platelet count ?75,000/?L.\n\n               2. All Patients:\n\n             i. Hepatic Function: Serum direct bilirubin ?1.5 times the upper limit of normal (ULN)\n             (?3 × ULN if this elevation is solely due to ASM/MCL); aspartate transaminase\n             (AST)/alanine transaminase (ALT), ?3 × ULN (?5 × ULN in the presence of hepatic\n             metastases or if this elevation is solely due to ASM/MCL).\n\n             ii. Renal Function: Serum creatinine ?2.0 × ULN or creatinine clearance ?50 mL/min\n             based either on urine collection or Cockcroft Gault estimation.\n\n             iii. Coagulation Profile: Prothrombin time (PT) - international normalized ratio\n             (INR)/partial thromboplastin time (PTT) ?1.5 × ULN. Patients on a stable, maintenance\n             regimen of anticoagulant therapy for at least 30 days prior to study drug\n             administration may have PT/INR measurements >1.5 × ULN if, in the opinion of the\n             Investigator, the patient is suitable for the study. An adequate rationale must be\n             provided to the Sponsor prior to enrollment.\n\n             c) SM patients with one or more inadequate organ function laboratory value may be\n             eligible if both the Investigator and Sponsor deem it to be disease-related and the\n             abnormality qualifies as a C-Finding (see Appendix 10.5).\n\n         11. Resolution of all toxicities from prior therapy to ?Grade 1 (or baseline) within 1\n             week prior to the first dose of study drug (excluding alopecia and ?Grade 3 clinically\n             asymptomatic lipase, amylase, and creatine phosphokinase laboratory abnormalities).\n\n        Exclusion Criteria (Escalation and Expansion Phases)\n\n        Patients meeting any of the following criteria will be excluded from the study:\n\n          1. GIST patients with wild type or unknown KIT or PDGFRA status.\n\n          2. Patients with SM or other hematologic malignancies will be excluded if the following\n             apply:\n\n               1. SM patients with wild type KIT mutational status.\n\n               2. SM patients with neutropenia accompanied by fever or infection, or\n                  thrombocytopenia associated with clinically significant bleeding.\n\n                    -  Patients with an infection that is well controlled with antibiotics are\n                       eligible if there is an immediate need for treatment\n\n               3. SM-AHN patients diagnosed with:\n\n             i. SM with MDS (SM-MDS) who require treatment for MDS. ii. Patients requiring\n             immediate treatment for AHN. d) Patients with leukemias, with the exception of MCL and\n             CEL, that have progressed after imatinib.\n\n             e) Eosinophilic myeloproliferative neoplasm patients: i. Lacking a mutation that is a\n             known target of DCC-2618. This includes, but is not limited to, fusions/mutations of\n             FGFR1, JAK2, and ABL.\n\n          3. Has a known additional malignancy that is progressing or required active treatment\n             within 3 years of the first dose of study treatment. Exceptions include basal cell\n             carcinoma of the skin, squamous cell carcinoma of the skin that has undergone\n             potentially curative therapy, or other in situ cancers.\n\n          4. Treatment with anticancer therapy, including investigational therapy, within 2 weeks\n             prior to the administration of study drug, with the exception of hydroxyurea that is\n             allowed to control white blood cell count. For prior therapies with a half-life longer\n             than 3 days, the interval must be at least 28 days prior to the first administration\n             of study drug.\n\n          5. New York Heart Association class III and IV heart disease, active ischemia or any\n             other uncontrolled cardiac condition such as angina pectoris, clinically significant\n             cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart\n             failure.\n\n          6. Arterial thrombotic or embolic events such as cerebrovascular accident (including\n             ischemic attacks) or hemoptysis within 6 months before start of study drug.\n\n          7. Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg,\n             pulmonary embolism) within the 3 months before start of study drug. Patients with\n             venous thrombotic events ?3 months before start of study drug on stable\n             anticoagulation therapy are eligible.\n\n          8. Baseline prolongation of the rate-corrected QT interval based on repeated\n             demonstration of QT interval corrected by Fridericia's formula (QTcF) >450 ms in males\n             or >470 ms in females or history of long QT interval corrected (QTc) syndrome.\n\n          9. LVEF <50% or below the lower limit of normal (whichever is higher).\n\n         10. Major surgery within 4 weeks of the first dose of study drug; following major\n             surgeries >4 weeks prior to the first dose of study drug, all surgical wounds must be\n             healed and free of infection or dehiscence.\n\n         11. Any other clinically significant comorbidities, such as uncontrolled pulmonary\n             disease, active infection, or any other condition, which in the judgment of the\n             Investigator, could compromise compliance with the protocol, interfere with the\n             interpretation of study results, or predispose the patient to safety risks.\n\n         12. Malabsorption syndrome or other illness that could affect oral absorption.\n\n         13. Known human immunodeficiency virus or active hepatitis C infection only if the patient\n             is taking medications that are described in Section 5.8.2.2, active hepatitis B, or\n             active hepatitis C infection.\n\n         14. If female, the patient is pregnant or lactating.\n\n         15. Known allergy or hypersensitivity to any component of the investigational drug\n             product.
Inclusion Criteria:\n\n        All Patients (Stages 1 and 2):\n\n          1. The patient is ?18 years old\n\n          2. The patient has an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2\n\n          3. The patient has adequate baseline organ function, including cardiac, renal, and\n             hepatic function:\n\n               -  Left ventricular ejection fraction (LVEF) ? institutional lower limit of normal\n                  as measured by multigated acquisition scan or 2-dimensional (2-D) echocardiogram\n                  within 28 days prior to start of therapy and no clinically significant\n                  abnormalities on a 12-lead electrocardiogram (ECG)\n\n               -  Serum creatinine ?1.5 mg/dL (or ?114 µmol/L)\n\n               -  Serum albumin ?3.2 g/dL (or ?32 g/L) in the absence of receipt of (IV) albumin\n                  within the previous 72 hours\n\n               -  Bilirubin ?1.5 mg/dL (or ?26 µmol/L)\n\n               -  Aspartate transaminase (AST) and alanine transaminase (ALT) ?2.5 times the upper\n                  limit of normal (ULN)\n\n               -  CPK ?2.5 times the ULN\n\n          4. If a woman of child bearing potential, the patient has a negative serum or urine\n             pregnancy test within 1 week prior to SL-401 treatment (intervals shorter than 1 week\n             are acceptable, if required by institutional guidelines)\n\n          5. The patient has signed informed consent prior to initiation of any study-specific\n             procedures or treatment\n\n          6. The patient is able to adhere to the study visit schedule and other protocol\n             requirements, including follow-up for response assessments\n\n          7. The patient agrees to use acceptable contraceptive methods for the duration of time in\n             the study, and to continue to use acceptable contraceptive methods for 2 months after\n             the last SL-401 infusion\n\n          8. Patient has an absolute neutrophil count (ANC) ?0.5×10?/L\n\n        Additional Inclusion Criteria Specific to Patients with MF and CMML (Stages 1 and 2)\n\n        Exclusion Criteria:\n\n        All Patients (Stages 1 and 2):\n\n          1. Patient has persistent clinically significant toxicities Grade ?2 from previous\n             chemotherapy not readily controlled by supportive measures (excluding alopecia,\n             nausea, and fatigue)\n\n          2. Patient has received treatment with chemotherapy, wide-field radiation, or biologic\n             therapy within 14 days of study entry\n\n          3. Patient has received treatment with another investigational agent within 14 days of\n             study entry or concurrent treatment with another investigational agent.\n\n          4. Patient has previously received treatment with SL-401 or has a known hypersensitivity\n             to any components of the drug product\n\n          5. Patient has an active malignancy and/or cancer history (excluding myeloproliferative\n             disorders and concomitant myeloid malignancies as specified in the inclusion criteria)\n             that can confound the assessment of the study endpoints. Patients with a past cancer\n             history (within 2 years of entry) and/or ongoing active malignancy or substantial\n             potential for recurrence must be discussed with the Sponsor before study entry.\n             Patients with the following neoplastic diagnoses are eligible: non-melanoma skin\n             cancer, carcinoma in situ (including superficial bladder cancer), cervical\n             intraepithelial neoplasia, or organ-confined prostate cancer with no evidence of\n             progressive disease\n\n          6. Patient has clinically significant cardiovascular disease (e.g., uncontrolled or any\n             New York Heart Association Class 3 or 4 congestive heart failure, uncontrolled angina,\n             history of myocardial infarction or stroke within 6 months of study entry,\n             uncontrolled hypertension or clinically significant arrhythmias not controlled by\n             medication)\n\n          7. Patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic\n             obstructive pulmonary disease, pulmonary hypertension) that, in the Investigator's\n             opinion, would put the patient at significant risk for pulmonary complications during\n             the study\n\n          8. Patient has known active or suspected disease involvement of the central nervous\n             system (CNS). If suspected due to clinical findings, CNS disease should be ruled out\n             with relevant imaging and/or examination of cerebrospinal fluid\n\n          9. Patient is receiving immunosuppressive therapy, with the exception of corticosteroids\n             as specified in the inclusion criteria and tacrolimus, for treatment or prophylaxis of\n             graft-versus-host disease (GVHD). If the patient has been on immunosuppressive\n             treatment or prophylaxis for GVHD, the treatment(s) must have been discontinued at\n             least 14 days prior to study drug and there must be no evidence of Grade ?2 GVHD\n\n         10. Patient has uncontrolled intercurrent illness including, but not limited to,\n             uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness\n             that would limit compliance with study requirements\n\n         11. Patient is pregnant or breast feeding\n\n         12. Patient has known human immunodeficiency virus (HIV)\n\n         13. Patient has evidence of active or chronic Hepatitis B or Hepatitis C infection.\n\n         14. Patient is oxygen-dependent\n\n         15. Patient has any medical condition that in the Investigator's opinion place the patient\n             at an unacceptably high risk for toxicities\n\n        Additional Exclusion Criteria Specific to Patients with MF and CMML (Stages 1 and 2)
Inclusion Criteria: All subjects\n\n          1. Age ? 18 years old.\n\n          2. Confirmed diagnosis of glioblastoma (WHO Grade IV).\n\n          3. Ability to undergo serial MRIs.\n\n          4. ECOG status ? 1.\n\n          5. Adequate bone marrow function.\n\n          6. Adequate renal and hepatic function.\n\n          7. Females of childbearing potential and non-sterile males must agree to use highly\n             effective methods of birth control throughout the course of study and at least up to\n             90 days after last dosing.\n\n          8. Ability to swallow whole capsules.\n\n             Subjects in Arms A and B (not Arm C) must also meet inclusion criteria 8 - 10:\n\n          9. No previous treatment for GB except surgery.\n\n         10. Able to start radiation therapy ? 49 days after surgery but ? 14 days after a biopsy\n             or ?28 days after an open biopsy or craniotomy with adequate wound healing.\n\n         11. Documented unmethylated MGMT promoter status.\n\n             Subjects in Arm C must also meet inclusion criteria # 12 - 14:\n\n         12. No prior systemic chemotherapy other than TMZ for GB.\n\n         13. Progressive disease > 2 months after completion of first line therapy.\n\n         14. At least one measurable lesion by mRANO.\n\n             Subjects in Arm C Phase 2, Cohort C1 must also meet criteria # 15. This is not\n             applicable to subjects enrolled in Arm C, Ph 1b.\n\n         15. Documentation of unmethylated MGMT promoter status.\n\n             Subjects in Arm C Phase 2, Cohort C2 must also meet Criteria #16. This is not\n             applicable to subjects enrolled in Arm C Phase 1b.\n\n         16. Documentation of methylated MGMT promoter status.\n\n        Exclusion Criteria: All subjects\n\n          1. Prior chemotherapy, biologic therapy, immunotherapy or investigational agents ?21 days\n             prior to start of study treatment.\n\n          2. Toxicity of ? Grade 2 from prior therapy.\n\n          3. Major surgery or significant other injury ? 4 weeks prior to start of study treatment.\n\n          4. History of other active malignancies within 2 years with exception of (i) adequately\n             treated in situ cancer of the cervix, (ii) non-melanoma skin cancer, or (iii)\n             localized adequately treated cancer with curative intent or malignancy diagnosed > 2\n             years ago with no evidence of disease and no treatment ? 2 years prior to study\n             treatment.\n\n          5. Uncontrolled seizure disorder.\n\n          6. Active infection requiring systemic treatment.\n\n          7. Known human immunodeficiency virus (HIV) or active viral hepatitis.\n\n          8. Active, clinically significant cardiac disease or any Class 3 or 4 cardiac disease,\n             ventricular arrhythmia or CVA ? 6 months prior to start of treatment.\n\n          9. Active clinically significant gastrointestinal disease.\n\n         10. Active bleeding disorder ? 6 months prior to start of treatment.\n\n         11. Need for therapeutic anti-coagulation with heparin, warfarin or other anticoagulants.\n\n         12. Use of any medications or food known to be strong or moderate cytochrome P450, family\n             3, subfamily A (CYP3A) inhibitors or strong inducers.\n\n         13. Pregnant or nursing females.\n\n         14. Significant intercurrent illness that may result in subject's death prior to death\n             from glioblastoma.\n\n         15. Known hypersensitivity to any component of TMZ or decarbazine (DTIC). [Subjects in\n             Arms B and C only.]
Inclusion Criteria:\n\n        To be eligible for the study, patients must meet ALL of the following criteria prior to\n        enrollment in the study:\n\n          1. Must be ? 18 years of age at the time of consent.\n\n          2. Must have recurrent, metastatic, or persistent squamous cell carcinoma, adenosquamous\n             carcinoma, or adenocarcinoma of the cervix that is not amenable to curative treatment\n             with surgery and/or radiation therapy and for which no other therapies are expected to\n             have significant benefit, in the opinion of the Investigator.\n\n          3. Must have at least 1 lesion that is resectable for TIL generation. The resected TIL\n             generating lesion(s) should yield at least 1.5 cm in diameter post-resection of tumor\n             tissue. Following resection for TIL generation, must have a remaining measurable\n             target lesion as defined by RECIST v1.1\n\n          4. Must have had at least 1 and no more than 3 prior systemic chemotherapeutic treatments\n             (such as carboplatin/cisplatin, paclitaxel, and bevacizumab except where there are\n             contraindications) for cervical carcinoma. Patients must have progressive disease\n             while receiving or after the completion of the most recent prior treatment.\n\n          5. Any prior therapy directed at the malignant tumor must be discontinued at least 28\n             days prior to tumor resection. Radiation therapy may have been received up to 28 days\n             prior to tumor resection for lesions not expected to be used for TIL generation or\n             target lesions.\n\n          6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          7. Patients must be seronegative for the human immunodeficiency virus (HIV). Patients\n             with positive serology for hepatitis B virus surface antigen (HBsAg), hepatitis B core\n             antibody (anti-HBc), or hepatitis C virus (anti-HCV) indicating acute or chronic\n             infection may be enrolled if the viral load by polymerase chain reaction (PCR) is\n             undetectable with/without active treatment.\n\n          8. Patients of childbearing potential must be willing to practice an approved method of\n             birth control starting at the time of informed consent and for 1 year after the\n             completion of the study treatment regimen.\n\n        Exclusion Criteria:\n\n          1. Patients who have received an organ allograft or prior cell transfer therapy except\n             for prior LN-145 therapy.\n\n          2. Patients who are on a systemic steroid therapy > 10 mg of prednisone daily or other\n             steroid equivalent.\n\n          3. Patients who currently have prior therapy-related toxicities greater than Grade 1\n             according to NCI-CTCAE v4.03; except for peripheral neuropathy, alopecia, or vitiligo\n             prior to enrollment/resection.\n\n          4. Patients who have a contraindication to or history of hypersensitivity reaction to any\n             component or excipients of the TIL therapy and the other study drugs.\n\n          5. Patients with active systemic infections, coagulation disorders or other active major\n             medical illnesses of the cardiovascular, respiratory, or immune system.\n\n          6. Patients with symptomatic and/or untreated brain metastases (of any size and any\n             number).\n\n          7. Patients who have any form of primary or acquired immunodeficiency syndrome, such as\n             severe combined immunodeficiency disease or acquired immune deficiency syndrome\n             (AIDS).\n\n          8. Patients who have a diagnosis of end-stage renal disorder requiring hemodialysis.\n\n          9. Patients who have a left ventricular ejection fraction (LVEF) < 45% or who are New\n             York Heart Association (NYHA) Class 2 or higher.\n\n         10. Patients who have a forced expiratory volume in 1 second (FEV1) of less than or equal\n             to 60% of predicted normal.\n\n         11. Patients who have received a live or attenuated vaccine within 28 days of the NMA-LD\n             regimen.\n\n         12. Patients whose cancer requires immediate treatment or who would otherwise suffer a\n             disadvantage by participating in this study.\n\n         13. Patients who have received prior treatment with immunotherapy (eg, anti-PD-1\n             anti-PD-L1, or anti-CTLA4 antibodies)
Patient Inclusion Criteria\n\n        Patients must meet all of the following inclusion criteria to be eligible for enrollment\n        into the study:\n\n          -  Histologically or cytologically confirmed metastatic or unresectable solid tumor.\n\n          -  Has failed treatment with all standard therapies for their malignancy.\n\n          -  Adequate Karnofsky Performance Status.\n\n          -  An expected survival of at least 3 months.\n\n          -  Adequate organ and bone marrow function.\n\n          -  Signed informed consent form for study participation prior to screening.\n\n        Patient Exclusion Criteria\n\n        Patients presenting with any of the following will be excluded in the study:\n\n          -  Clinically significant disease as defined by the protocol.\n\n          -  Surgical therapy or other therapies within period as defined by the protocol.\n\n          -  Any condition that will interfere with compliance with the protocol as determined by\n             investigator.
Inclusion Criteria:\n\n          1. Patients must have a histologically confirmed diagnosis of malignant PEComa that is\n             either metastatic or locally advanced and for which surgery is not a recommended\n             option.\n\n          2. Patients must have available tumor block along with the corresponding pathology report\n             (or approximately 30 unstained slides, with a minimum of 16 slides), and/or fresh\n             biopsy to allow retrospective centralized confirmation of malignant PEComa and for\n             mTOR pathway analysis and biomarker analysis.\n\n          3. Patients must have one or more measurable target lesions by CT scan or MRI. Measurable\n             disease by RECIST v1.1.\n\n          4. Patients must not have been previously treated with an mTOR inhibitor.\n\n          5. Prior treatment (investigational or other), chemotherapy, radiotherapy, surgery, or\n             other therapeutic agents (except mTOR inhibitors) is allowed, if completed after 5\n             half-lives or ?28 days prior to enrollment, whichever is shorter.\n\n          6. Eligible patients, 18 years or older, with Eastern Cooperative Oncology Group (ECOG)\n             performance status 0 or 1.\n\n          7. Patients must have the following blood chemistry levels at screening (obtained\n\n             ?14 days prior to enrollment (local laboratory):\n\n               1. total bilirubin ?1.5 x upper limit of normal (ULN) mg/dl\n\n               2. AST ?2.5 x ULN (?5 x ULN if attributable to liver metastases)\n\n               3. serum creatinine ?1.5 x ULN\n\n          8. Adequate biological parameters as demonstrated by the following blood counts at\n             screening (obtained ?14 days prior to enrollment, local laboratory):\n\n               1. Absolute neutrophil count (ANC) ?1.5 × 109/L;\n\n               2. Platelet count ?100,000/mm3 (100 × 109/L);\n\n               3. Hemoglobin ?9 g/dL.\n\n          9. Serum triglyceride <300 mg/dL; serum cholesterol < 350 mg/dL.\n\n         10. Male or non-pregnant and non-breast feeding female:\n\n               -  Females of child-bearing potential must agree to use effective contraception\n                  without interruption from 28 days prior to starting IP and while on study\n                  medication and have a negative serum pregnancy test (? -hCG) result at screening\n                  and agree to ongoing pregnancy testing during the course of the study, and after\n                  the end of study treatment.\n\n               -  Male patients must practice abstinence or agree to use a condom during sexual\n                  contact with a pregnant female or a female of childbearing potential while\n                  participating in the study, even if he has undergone a successful vasectomy.\n\n         11. Life expectancy of >3 months, as determined by the investigator.\n\n         12. Ability to understand and sign informed consent.\n\n         13. Willingness and ability to comply with scheduled visits, laboratory tests, and other\n             study procedures.\n\n        Exclusion Criteria:\n\n        A patient will not be eligible for inclusion in this study if any of the following criteria\n        apply:\n\n          1. Patients with lymphangioleiomyomatosis (LAM) are excluded.\n\n          2. Known active uncontrolled or symptomatic central nervous system (CNS) metastases. A\n             patient with controlled and asymptomatic CNS metastases may participate in this study.\n             As such, the patient must have completed any prior treatment for CNS metastases ?28\n             days (including radiotherapy and/or surgery) prior to start of treatment in this study\n             and should not be receiving chronic corticosteroid therapy for the CNS metastases.\n\n          3. Active gastrointestinal bleeding, if transfusion dependent.\n\n          4. Pre-existing thyroid abnormality is allowed provided thyroid function can be\n             controlled with medication.\n\n          5. Uncontrolled serious medical or psychiatric illness. Patients with a \currently\n             active\ second malignancy other than non-melanoma skin cancers, carcinoma in situ of\n             the cervix, resected incidental prostate cancer (staged pT2 with Gleason Score ? 6 and\n             postoperative PSA <0.5 ng/mL), or other adequately treated carcinoma-in-situ are\n             ineligible. Patients are not considered to have a \currently active\ malignancy if\n             they have completed therapy and are free of disease for ?1 year).\n\n          6. Liver-directed therapy within 2 months of enrollment. Prior treatment with\n             radiotherapy (including radio-labeled spheres and/or cyberknife, hepatic arterial\n             embolization (with or without chemotherapy) or cyrotherapy/ablation) is allowed if\n             these therapies did not affect the areas of measurable disease being used for this\n             protocol.\n\n          7. Recent infection requiring systemic anti-infective treatment that was completed\n\n             ?14 days prior to enrollment (with the exception of uncomplicated urinary tract\n             infection or upper respiratory tract infection).\n\n          8. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy.\n\n          9. Unstable coronary artery disease or myocardial infarction during preceding 6 months.\n\n         10. Receiving any concomitant antitumor therapy.\n\n         11. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary\n             hypertension.\n\n         12. The use of certain medications and illicit drugs within 5 half-lives or 28 days,\n             whichever is shorter prior to the first dose of study drug and for the duration of the\n             study will not be allowed.\n\n         13. Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to receiving\n             the first dose of ABI-009. Additionally, use of any known CYP3A4 substrates with\n             narrow therapeutic window (such as fentanyl, alfentanil, astemizole, cisapride,\n             dihydroergotamine, pimozide, quinidine, terfanide) within the 14 days prior to\n             receiving the first dose of ABI-009.
INCLUSION CRITERIA\n\n        -Patients must be greater than or equal to 12 months and ? 21 years of age at the time of\n        study enrollment.\n\n        Patients must have one of the following:\n\n        Leukemia\n\n          -  Bone marrow involvement defined as ALL ? 25% blasts (M2 or M3) with or without\n             extramedullary involvement.\n\n          -  Refractory bone marrow involvement defined as MRD ? 0.1% blasts done at a COG-approved\n             MRD testing lab after most recent treatment regimen. in the bone marrow (M23) and any\n             CNS status. OR\n\n          -  Newly diagnosed patients (T or B-cell ALL) with refractory bone marrow involvement\n             after Consolidation therapy are eligible.\n\n          -  First relapse B-cell ALL patients are eligible with refractory disease.\n\n          -  Second or greater relapse B-cell patients are eligible at time of relapse or with\n             refractory disease.\n\n          -  First or greater relapse T-cell ALL patients are eligible at time of relapse or with\n             refractory disease.\n\n          -  Isolated CNS 2 or 3 patients with < 0.1% MRD bone marrow involvement are not eligible.\n\n        Lymphoma\n\n          -  Patient must have relapsed or refractory lymphoblastic lymphoma or peripheral T-cell\n             lymphoma.\n\n          -  Patient must have histologic verification of disease at original diagnosis.\n\n          -  Patient must have evaluable or measurable disease documented by clinical or\n             radiographic criteria or bone marrow disease present at study entry.\n\n          -  Patients may have CNS 2 or 3 disease\n\n        Karnofsky greater than or equal to 50% for patients > 16 years of age and Lansky greater\n        than or equal to 50 for patients ? 16 years of age.\n\n        Patients must have fully recovered from the acute toxic effects of all prior anti-cancer\n        chemotherapy.\n\n        Patients with leukemia or lymphoma who relapse while receiving maintenance chemotherapy\n        will not be required to have a waiting period before enrollment onto this study.\n\n        At least 14 days must have elapsed after the completion of cytotoxic therapy, with the\n        exception of hydroxyurea.\n\n        Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth\n        factor (e.g. Neulasta) or 7 days for short-acting growth factor.\n\n        Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent.\n        For agents that have known adverse events occurring beyond 7 days after administration,\n        this period must be extended beyond the time during which adverse events are known to\n        occur. The duration of this interval must be discussed with the study chair\n\n        Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g.\n        tumor vaccines. or chimeric antigen receptor T cell (CART) therapy or tumor vaccines.\n\n        Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the\n        last dose of a monoclonal antibody. (ie: Rituximab = 66 days, Epratuzumab = 69 days).\n        Patients must have been off blinatumomab infusion for at least 4 days and all drug-related\n        toxicity must have resolved to grade 2 or lower as outlined in the inclusion and exclusion\n        criteria\n\n        XRT: At least 14 days after local palliative XRT (small port); At least 84 days must have\n        elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of\n        pelvis; At least 42 days must have elapsed if other substantial marrow radiation.\n\n        Stem Cell Infusion: No evidence of active graft vs. host disease and at least 84 days must\n        have elapsed after transplant or stem cell infusion.\n\n        Adequate Bone Marrow Function Defined as: Blood counts are not required to be normal prior\n        to enrollment on trial. However, platelet count must be greater than or equal to 20,000/mm3\n        to initiate therapy (may receive platelet transfusions). Patients should not be known to be\n        refractory to red blood cell or platelet transfusions.\n\n        Adequate Renal Function Defined as:\n\n          -  Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2 or\n\n          -  Normal serum creatinine based on age and gender.\n\n        Adequate Liver Function Defined as:\n\n          -  Total bilirubin (sum of conjugated + unconjugated) must be less than or equal to 1.5 x\n             normal per institutional normal values for age.\n\n          -  SGPT (ALT) and SGOT (AST) must be less than 3 x institutional upper limit of normal\n             (Grade 1 or less per CTCAE 4).\n\n             --GGT must be less than 2.5 x institutional upper limit of normal (Grade 1 or less per\n             CTCAE 4).\n\n          -  Serum albumin greater than or equal to 2 g/dL.\n\n          -  The hepatic requirements may be waived for patients with elevations clearly due to\n             leukemic infiltration after consultation with the Study Chair or Vice Chair.\n\n          -  Fasting or non-fasting serum triglyceride level ? 300 mg/dL and serum cholesterol\n             level ? 300 mg/dL.\n\n        Adequate Cardiac Function Defined As:\n\n          -  Shortening fraction of ? 27% by echocardiogram, or\n\n          -  Ejection fraction of ? 50% by gated radionuclide study.\n\n        Adequate Pulmonary Function Defined as:\n\n          -  Pulse oximetry > 94% on room air (> 90% if at high altitude)\n\n          -  No evidence of dyspnea at rest and no exercise intolerance.\n\n          -  Baseline chest x-ray with no evidence of active infectious disease or pneumonitis.\n\n        Reproductive Function\n\n          -  Female patients of childbearing potential must have a negative urine or serum\n             pregnancy test confirmed prior to enrollment.\n\n          -  Female patients with infants must agree not to breastfeed their infants while on this\n             study.\n\n          -  Male and female patients of child-bearing potential must agree to use an effective\n             method of contraception approved by the investigator during the study.\n\n          -  Random or fasting glucose within the upper limits of normal for age. If the initial\n             blood glucose is non-fasting and above normal limits a fasting glucose can be obtained\n             and must be within the upper limits of normal for age.\n\n        EXCLUSION CRITERIA\n\n          -  Corticosteroids: Patients receiving corticosteroids who have not been on a stable or\n             decreasing dose of corticosteroid for at least 7 days prior to enrollment are not\n             eligible.\n\n          -  Investigational Drugs: Patients who are currently receiving another investigational\n             drug are not eligible. The definition of \investigational\ for use in this protocol\n             means any drug that is not licensed by the FDA, Health Canada or the Therapeutic Goods\n             Administration to be sold in the countries they govern. (United States, Canada and\n             Australia)\n\n          -  Anti-cancer Agents: Patients who are currently receiving or may receive while on\n             therapy, other anti-cancer agents, radiation therapy or immunotherapy are not eligible\n             [except leukemia patients receiving hydroxyurea, which may be continued until 24 hours\n             prior to start of protocol therapy]. Intrathecal chemotherapy (at the discretion of\n             the primary oncologist) may be given up to one week prior to the initiation of study\n             therapy.\n\n          -  Anti-GVHD or agents to prevent organ rejection post-transplant: Patients who are\n             receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host\n             disease post bone marrow transplant or organ rejection post transplant are not\n             eligible for this trial. At least 3 half-lives must have elapsed after the last dose\n             of GVHD meds.\n\n          -  Anticoagulants: Patients who are currently receiving therapeutic anticoagulants\n             (including aspirin, low molecular weight heparin, and others) are not eligible. At\n             least 3 half-lives must have elapsed after the last dose of anticoagulants.\n\n          -  Angiotensin-converting enzyme (ACE) inhibitors: Patients who are currently receiving\n             ACE inhibitors are not eligible due to the development of angioneurotic edema-type\n             reactions in some subjects who received concurrent treatment with temsirolimus + ACE\n             inhibitors. At least 3 half-lives must have elapsed after the last dose of ACE\n             inhibitors.\n\n          -  Calcium Channel Blockers: Patients who are currently receiving Calcium Channel\n             Blockers are not eligible due to the development of angioneurotic edema-type reactions\n             in some subjects who received concurrent treatment with temsirolimus + Calcium Channel\n             Blockers. At least 3 half-lives must have elapsed after the last dose of Calcium\n             Channel Blockers.\n\n          -  Enzyme inducing Anti-convulsants: Patients who are currently receiving enzyme inducing\n             anticonvulsants (ie phenytoin, phenobarbitol, or carbamazepine) are not eligible.\n             Stabilizing on a non-hepatic inducing metabolizing anti-convulsant (ie: gabapentin or\n             levetiracetam) prior to study entry is acceptable. At least 3 half-lives must have\n             elapsed after the last dose of enzyme inducing anti-coagulants.\n\n          -  Patients receiving treatment with azoles such as fluconazole or voriconazole which are\n             potent inhibitors of temsirolimus metabolism. At least 3 half-lives must have elapsed\n             after the last dose of azoles.\n\n          -  Patient with Burkiett's leukemia and /or lymphoma are not eligible.\n\n        Infection Criteria\n\n        Patients are excluded if they have:\n\n          -  Positive blood culture within 48 hours of study enrollment;\n\n          -  Fever above 38.2 within 48 hours of study enrollment with clinical signs of infection.\n             Fever that is determined to be due to tumor burden is allowed if patients have\n             documented negative blood cultures for at least 48 hours prior to enrollment and no\n             concurrent signs or symptoms of active infection or hemodynamic instability.\n\n          -  A positive fungal culture within 30 days.\n\n          -  Active fungal, viral, bacterial, or protozoal infection requiring IV treatment.\n             Chronic prophylaxis therapy to prevent infections is allowed.\n\n        Patients with Down syndrome and Fanconi Anemia are excluded.\n\n        Patients will be excluded if they have significant concurrent disease, illness, psychiatric\n        disorder or social issue that would compromise patient safety or compliance with protocol\n        treatment or required observations, interfere with consent, study participation, follow up,\n        or interpretation of study results.\n\n        Patients with known optic nerve and/or retinal involvement (because it may not be possible\n        to safely delay irradiation) are not eligible. Patients presenting with visual disturbances\n        by history or physical exam should have an ophthalmological exam and, if indicated, an MRI\n        to determine optic nerve or retinal involvement.
Inclusion Criteria (Parts B & C):\n\n          -  18 years or older\n\n          -  Histologically confirmed unresectable Stage III or Stage IV malignant melanoma, or\n             other solid tumor malignancies\n\n          -  Failed to respond to or relapsed following standard treatment, declined or was not\n             eligible for standard treatment.\n\n          -  Expected survival of at least 12 weeks.\n\n          -  Eastern Cooperative Oncology Group performance status score of 0 or 1 is required.\n\n          -  Evidence of adequate organ function by standard laboratory tests.\n\n        Exclusion Criteria (Parts B & C):\n\n          -  Evidence of progression of central nervous system (CNS) metastases or symptomatic CNS\n             metastases within 35 days prior to dosing.\n\n          -  Ocular melanoma which has not metastasized or presence of a non-solid tumor.\n\n          -  A history of any major surgery within 4 weeks prior to dosing.\n\n          -  Any history of antitumor therapy completed within 28 days prior to dosing.\n\n          -  Subjects with active autoimmune disease or history of known or suspected autoimmune\n             disease, with the exception of subjects with isolated vitiligo, resolved childhood\n             asthma/atopy, psoriasis not requiring systemic treatment and controlled thyroid\n             disorders.\n\n          -  Clinically significant heart disease, defined as NYHA Class III or IV.\n\n          -  Any significant systemic infection requiring IV antibiotics.\n\n          -  Known to be human immunodeficiency virus (HIV) positive, have hepatitis B surface\n             antigen (HBsAg), or hepatitis C antibodies (HCAb) unless HCV RNA undetected/negative.\n\n          -  Treatment with any other anti-human GITR monoclonal antibody (mAb) or immunomodulatory\n             therapy 42 days prior to dosing (30 days for Interleukin-2 & Interferon-?, 7 days for\n             Topical Imiquimod).\n\n          -  Adverse events from prior anti-cancer therapy that have not resolved to grade ?1\n             except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy.\n\n          -  Use of any investigational drugs within 30 days prior to dosing.\n\n          -  Any condition that requires or is likely to require treatment with pharmacologic doses\n             of systemic corticosteroids. Subjects are permitted to receive physiologic replacement\n             of corticosteroid therapy (? 10 mg prednisone daily).
Inclusion Criteria (main):\n\n          -  Patients with advanced and/or metastatic cancer who have no available standard therapy\n             or who are not candidates for available standard therapy, and for whom, in the opinion\n             of the investigator, experimental therapy with GEN1029 may be beneficial.\n\n          -  Patient must be ? 18 years of age\n\n          -  Patients must have measurable disease according to Response Evaluation Criteria In\n             Solid Tumors (RECIST) version 1.1\n\n          -  Have an acceptable hematological status\n\n          -  Have an acceptable renal function\n\n          -  Have an acceptable liver function\n\n          -  Have an Eastern Cooperative Oncology Group performance status of 0 or 1\n\n          -  Body weight ? 40kg\n\n          -  Patients both females and males, of childbearing or reproductive potential must agree\n             to use adequate contraception from screening visit until six months after last\n             infusion of GEN1029\n\n        Exclusion Criteria (main):\n\n          -  Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for\n             at least 8 weeks prior to first GEN1029 administration\n\n          -  Have clinically significant cardiac disease\n\n          -  Uncontrolled hypertension defined as systolic blood pressure ?160 mmHg and/or\n             diastolic blood pressure ?100 mmHg, despite optimal medical management\n\n          -  Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new\n             (younger than 6 months) or progressive brain metastases or stroke\n\n          -  History of organ allograft (except for corneal transplant) or autologous or allogeneic\n             bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of\n             Investigational Medicinal Product (IMP)\n\n          -  Have received a cumulative dose of corticosteroid ? 150 mg prednisone (or equivalent\n             doses of corticosteroids) within two weeks before the first GEN1029 administration\n\n          -  History of ? grade 3 allergic reactions to monoclonal antibody therapy as well as\n             known or suspected allergy or intolerance to any agent given in the course of this\n             trial\n\n          -  Radiotherapy within 14 days prior to first GEN1029 administration\n\n          -  Any prior therapy with a compound targeting DR4 or DR5\n\n          -  History of chronic liver disease or evidence of hepatic cirrhosis
Inclusion Criteria:\n\n        Patients must meet all the following inclusion criteria to be eligible for enrollment into\n        the study:\n\n          1. Age ? 18 years;\n\n          2. Life expectancy > 12 weeks;\n\n          3. Present with histologically confirmed intracranial (supratentorial) unmethylated MGMT\n             promotor status GBM (WHO Grade lV astrocytoma) with a MGMT status that has been\n             confirmed by validated PCR or validated alternate genomic analysis;\n\n          4. Have undergone maximal surgical resection of their tumor and within 6 weeks of surgery\n             received initial treatment with XRT/TMZ which consisted of XRT by external beam to a\n             partial brain field in daily fractions of 2.0 Gray (Gy), to a planned total dose to\n             the tumor of 60.0 Gy, in conjunction with TMZ oral QD 75 mg/m2 in accordance with the\n             Stupp regimen;\n\n          5. Must have measurable disease, according to RANO criteria for inclusion in the\n             expansion cohort. Patients with non-measurable disease can be included in the\n             dose-escalation cohorts;\n\n          6. KPS ? 70;\n\n          7. Cranial magnetic resonance imaging (MRI) must have been performed within 7 days prior\n             to or on the day of the Randomization/Week 1 Visit;\n\n          8. Stable or decreasing corticosteroid dose within 7 days prior to the first dose;\n\n          9. Adequate bone marrow/hematological function within 7 days prior to Day 1;\n\n         10. Adequate liver and renal function within 14 days prior to Day 1;\n\n         11. International normalized ratio (INR) or prothrombin time (PT) (secs) and activated\n             partial thromboplastin time (aPTT) within 7 days prior to randomization:\n\n         12. Patients must be willing to forego other drug therapy against the tumor while enrolled\n             in the study.\n\n        Exclusion Criteria:\n\n          1. Previous radiotherapy to the brain or cytotoxic drug therapy (including Gliadel®\n             wafers) in addition to the required postoperative radiation plus TMZ, non-cytotoxic\n             drug therapy, or experimental drug therapy directed against the brain tumor prior to\n             this regimen, will be excluded. Patients may have received or be receiving\n             corticosteroids, analgesics, and other drugs to treat symptoms or prevent\n             complications but the dose must be stable at treatment start. NOTE: 5 aminolevulinic\n             acid-mediated photodynamic therapy administered prior to surgery to aid in optimal\n             surgical resection is not considered a chemotherapy agent;\n\n          2. Any prior or anticipated concomitant treatment involving a medical device (such as\n             Optune®) applying tumor treating fields (TTF);\n\n          3. QT interval time of ? 470 msec;\n\n          4. Undetermined/indeterminate MGMT status;\n\n          5. Diabetic patients; prediabetic patients treated with metformin;\n\n          6. Use of any CYP3A4 inducing or inhibiting agents;\n\n          7. Significant medical illnesses;\n\n          8. Women who are pregnant or who are lactating;\n\n          9. Diagnosed with infratentorial GBM, a tumor outside of brain or gliomatosis cerebri;\n\n         10. Evidence of recent hemorrhage on postoperative MRI of the brain;\n\n         11. Any previous malignancy; except for adequately controlled limited basal cell carcinoma\n             of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix, or one\n             which has been absent for ?3 years;
Inclusion Criteria:\n\n        Subjects must meet all of the following inclusion criteria to be eligible for enrollment\n        into the Intensive and Non Intensive study (unless where indicated):\n\n          1. Subjects with untreated AML according to the World Health Organization (WHO) 2016\n             Classification2, including those with:\n\n               -  AML arising from MDS or another antecedent hematologic disease (AHD).\n\n               -  AML after previous cytotoxic therapy or radiation (secondary AML).\n\n          2. 18 years of age (In Japan, 20 years of age).\n\n          3. Adequate Organ Function as defined by the following:\n\n               -  Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) 3\n                  x upper limit of normal (ULN), excluding subjects with liver function\n                  abnormalities due to underlying malignancy.\n\n               -  Total serum bilirubin 2 x ULN (except subjects with documented Gilbert's\n                  syndrome).\n\n               -  Estimated creatinine clearance 30 mL/min as calculated using the standard method\n                  for the institution.\n\n          4. QTc interval 470 msec using the Fridericia correction (QTcF).\n\n          5. All anti cancer treatments (unless specified) should be discontinued 2 weeks from\n             study entry, for example: targeted chemotherapy, radiotherapy, investigational agents,\n             hormones, anagrelide or cytokines.\n\n               -  For control of rapidly progressing leukemia, all trans retinoic acid (ATRA),\n                  hydroxyurea, and/or leukopheresis may be used before and for up to 1 week after\n                  the first dose of glasdegib.\n\n          6. Serum or urine pregnancy test (for female subjects of childbearing potential) with a\n             minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin\n             (hCG) negative at screening.\n\n          7. Male and female subjects of childbearing potential and at risk for pregnancy must\n             agree to use at least one highly effective method of contraception throughout the\n             study and for 180 days after the last dose of azacitidine, cytarabine, or\n             daunorubicin; and the last dose of glasdegib or placebo, whichever occurs later.\n\n          8. Female subjects of non childbearing potential must meet at least 1 of the following\n             criteria:\n\n               1. Have undergone a documented hysterectomy and/or bilateral oophorectomy;\n\n               2. Have medically confirmed ovarian failure; or\n\n               3. Achieved postmenopausal status, defined as follows: cessation of regular menses\n                  for at least 12 consecutive months with no alternative pathological or\n                  physiological cause; status may be confirmed by having a serum follicle\n                  stimulating hormone (FSH) level confirming the postmenopausal state.\n\n             All other female subjects (including female subjects with tubal ligations) are\n             considered to be of childbearing potential.\n\n          9. Consent to a saliva sample collection for a germline comparator, unless prohibited by\n             local regulations or ethics committee (EC) decision.\n\n         10. Evidence of a personally signed and dated informed consent document indicating that\n             the patient has been informed of all pertinent aspects of the study.\n\n         11. Subjects who are willing and able to comply with the study scheduled visits, treatment\n             plans, laboratory tests and other procedures (including bone marrow [BM] assessments).\n\n        Exclusion Criteria:\n\n        Subjects with any of the following characteristics/conditions will not be included in the\n        study:\n\n          1. Acute Promyelocytic Leukemia (APL) and APLwith PML RARA, subjects (WHO 2016\n             classification).\n\n          2. AML with BCR ABL1 or t(9;22)(q34;q11.2) as a sole abnormality.\n\n               -  Complex genetics may include t(9;22) cytogenetic translocation.\n\n          3. Subjects with known active CNS leukemia.\n\n          4. Participation in other clinical studies involving other investigational drug(s)\n             (Phases 1 4) within 4 weeks prior study entry and/or during study participation.\n\n          5. Subjects known to be refractory to platelet or packed red cell transfusions per\n             Institutional Guidelines, or a patient who refuses blood product support.\n\n          6. Subjects with another active malignancy on treatment with the exception of basal cell\n             carcinoma, non melanoma skin cancer, cervical carcinoma in situ. Other prior or\n             concurrent malignancies will be considered on a case by case basis.\n\n          7. Any one of the following ongoing or in the previous 6 months: myocardial infarction,\n             congenital long QT syndrome, Torsades de pointes, symptomatic arrhythmias (including\n             sustained ventricular tachyarrhythmia), right or left bundle branch block and\n             bifascicular block, unstable angina, coronary/peripheral artery bypass graft,\n             symptomatic congestive heart failure (CHF New York Heart Association class III or IV),\n             cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism;\n             as well as bradycardia defined as <50 bpms.\n\n          8. Subjects with an active, life threatening or clinically significant uncontrolled\n             systemic infection not related to AML.\n\n          9. Subjects with left ventricular ejection fraction (LVEF) <50% are excluded from the\n             Intensive Chemotherapy Study only.\n\n         10. Cumulative anthracycline dose equivalent of 550 mg/m2 of daunorubicin for the\n             Intensive Chemotherapy Study only.\n\n         11. Known malabsorption syndrome or other condition that may significantly impair\n             absorption of study medication in the investigator's judgment (eg, gastrectomy, lap\n             band, Crohn's disease) and inability or unwillingness to swallow tablets or capsules.\n\n         12. Current use or anticipated requirement for drugs that are known strong CYP3A4/5\n             inducers.\n\n         13. Concurrent administration of herbal preparations.\n\n         14. Major surgery or radiation within 4 weeks of starting study treatment.\n\n         15. Documented or suspected hypersensitivity to any one of the following:\n\n               -  For subjects assigned to intensive chemotherapy, documented or suspected\n                  hypersensitivity to cytarabine (not including drug fever or exanthema, including\n                  known cerebellar side effects) or daunorubicin.\n\n               -  For subjects assigned to non intensive chemotherapy, documented or suspected\n                  hypersensitivity to azacitidine or mannitol.\n\n         16. Known active drug or alcohol abuse.\n\n         17. Other acute or chronic medical or psychiatric condition including recent (within the\n             past year) or active suicidal ideation or behavior or laboratory abnormality that may\n             increase the risk associated with study participation or investigational product\n             administration or may interfere with the interpretation of study results and, in the\n             judgment of the investigator, would make the subject inappropriate for entry into this\n             study.\n\n         18. Pregnant females or breastfeeding female subjects.\n\n         19. Known recent or active suicidal ideation or behavior.\n\n         20. Investigator site staff members directly involved in the conduct of the study and\n             their family members, site staff members otherwise supervised by the investigator, or\n             subjects who are Pfizer employees, including their family members, directly involved\n             in the conduct of the study.
INCLUSION CRITERIA:\n\n        Each patient (male or female) must meet all of the following criteria to be enrolled in\n        this study:\n\n          1. Capable of understanding the written informed consent, provides signed and witnessed\n             written informed consent, and agrees to comply with protocol requirements.\n\n          2. Age 18 years or older (US sites) or 21 years or older (Singapore site) at Baseline.\n\n          3. Bone marrow (BM) cytogenetic analysis with at least 20 metaphase cells, confirmed\n             advanced haematologic malignancies in any of the 4 following disease populations at\n             Screening:\n\n               -  CML-AP, Ph+\n\n               -  CML-BC, Ph+\n\n               -  Ph+ ALL\n\n               -  Ph- ALL with relapsed and refractory disease who have exhausted all available\n                  therapy (for patients who develop T315I mutation related resistance, the\n                  definition requires failure of ponatinib treatment if drug is accessible).\n\n          4. Meets definition for one of the following study subgroups:\n\n             CML-AP:\n\n               -  ? 15% and < 30% blast in peripheral blood or bone marrow, or\n\n               -  ? 20% basophils in peripheral blood or bone marrow or\n\n               -  ? 30% blasts + promyelocytes in peripheral blood or bone marrow (but < 30%\n                  blasts) or\n\n               -  < 100 x 10^9 platelets/L in peripheral blood unrelated to therapy or\n\n               -  Cytogenetic, genetic evidence of clonal evolution and\n\n               -  No extramedullary disease.\n\n             CML-BC:\n\n               -  ? 30% blasts in peripheral blood or bone marrow, or\n\n               -  extramedullary disease other than hepatosplenomegaly.\n\n             Ph+ ALL:\n\n               -  ? 30% blasts in blood or bone marrow and\n\n               -  no prior history of CML.\n\n             Ph- ALL:\n\n               -  ? 10% blasts in bone marrow.\n\n          5. ECOG performance status of 0 to 2 at Baseline.\n\n          6. Life expectancy of at least 3 months at Baseline.\n\n          7. Adequate organ function at Baseline, including the following (noting that repeated\n             tests at Baseline should not be performed unless there are sufficient reasons to\n             assume the patient would meet the inclusion criteria with re testing):\n\n               1. Total bilirubin ? 1.5 x upper limit of normal (ULN), unless resulting from\n                  haemolysis or documented Gilbert syndrome.\n\n               2. Transaminases [aspartate aminotransferase (AST) and/or alanine aminotransferase\n                  (ALT) ? 2.5 x ULN]. [< 5 x ULN if liver infiltration with tumour present]\n\n               3. Prothrombin time (PT) < 1.5 ULN.\n\n               4. Calculated creatinine clearance ? 60 mL/min (Cockcroft and Gault formula).\n\n               5. No clinically relevant abnormalities in the urinalysis results.\n\n               6. Haematology:\n\n                    -  Haemoglobin > 10 g/dL (transfusion allowed to reach the level)\n\n                    -  Neutrophils > 1,000/µL\n\n                    -  Platelets > 75,000/µL.\n\n               7. Pancreatic status:\n\n                    -  Lipase ? 1.5 x ULN\n\n                    -  Amylase ? 1.5 x ULN.\n\n          8. Capable of taking oral medication and following direction regarding taking study drug\n             (either by himself/herself or by caregiver).\n\n          9. Negative serum pregnancy test at Baseline plus a negative urine pregnancy test on Day\n             1, Cycle 1 prior to treatment (applies to females of childbearing potential only).\n\n         10. A minimum of 2 weeks (14 days), or 5 half-lives (whichever is shorter) since last\n             receipt of any anti-cancer therapy (except dasatinib, hydroxyurea, anagrelide or\n             steroids), or 4 weeks from radiation or major surgery to the first administration of\n             the study drug.\n\n         11. All non-haematological AEs of any prior anti-cancer therapy, surgery, or radiotherapy\n             have to be resolved to NCI CTCAE Grade ? 1 (except alopecia) within 2 weeks prior to\n             starting study drug.\n\n         12. Willing to submit the blood samples and bone marrow samples for PK and pharmacodynamic\n             (PD) analyses.\n\n        CML-AP Ph+, CML-BC Ph+, Ph- ALL, and Ph+ ALL patients with relapsed and refractory disease\n        who have exhausted all available therapy.\n\n        Subgroup-specific intolerance definition: [Intolerance to tyrosine kinase inhibitors (TKIs)\n        or other approved treatments for CML-AP, CML-BC and Ph+ ALL; to approved treatments for Ph-\n        ALL] defined as:\n\n          -  Non-haematologic intolerance:\n\n        Patients with Grade 3 or 4 toxicity while on therapy, or with persistent Grade 2 toxicity,\n        unresponsive to optimal management, including dose adjustments (unless a dose reduction is\n        not considered in the best interest of the patient if response is already suboptimal) in\n        absence of: major haematologic response (MaHR) for accelerated phase (AP), blast crisis\n        (BC) or Ph+ ALL patients; complete remission (CR) or complete haematological response with\n        partial haematologic recovery of peripheral blood count (CRh) for Ph- ALL.\n\n          -  Haematologic intolerance:\n\n        Patients with Grade 3 or 4 toxicity [absolute neutrophil count (ANC) or platelets] while on\n        therapy that is recurrent after dose reduction to the lowest dose recommended by drug\n        manufacturers in the absence of: MaHR for AP, BC or Ph+ ALL patients; CR or CRh for Ph-\n        ALL.\n\n        NOTE: For dasatinib, non-haematologic and haematologic intolerance is defined as: CTCAE\n        Grade > 2 requiring discontinuation.\n\n        EXCLUSION CRITERIA:\n\n        Patients meeting any of the following criteria will be excluded from the study:\n\n          1. Is a male patient with sexual partner(s) of childbearing potential who is unwilling to\n             use a highly effective method of contraception, one of which includes a condom.\n             Sexually active male patients must use a condom during intercourse throughout the\n             study and for 12 weeks after the end of treatment and should not father a child in\n             this period. A condom is required to be used also by vasectomised males in order to\n             prevent potential delivery of the study drug via seminal fluid. Female partners of\n             male patients must be advised to also use one of the following contraception methods:\n\n               -  intrauterine device or intrauterine system;\n\n               -  prior sterilisation; or\n\n               -  total abstinence from male/female intercourse.\n\n          2. Is a female patient of childbearing potential, defined as a female physiologically\n             capable of becoming pregnant (including a female whose career, lifestyle, or sexual\n             orientation precludes intercourse with a male partner, and females whose partners have\n             been sterilised by vasectomy or other means), unless they are using a highly effective\n             method for birth control throughout the study and for 12 weeks after the end of\n             treatment. Highly effective methods for birth control include the following:\n\n               -  Total abstinence: This is an acceptable method when this is consistent with the\n                  preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,\n                  calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are\n                  not acceptable methods of contraception.\n\n               -  Female sterilisation: The patient has had a surgical bilateral oophorectomy (with\n                  or without hysterectomy) or tubal ligation at least 6 weeks prior to taking study\n                  drug. In case of an oophorectomy alone, the reproductive status of the patient\n                  must have been confirmed by follow-up hormone level assessment.\n\n               -  Male partner sterilisation: The patient has the appropriate post-vasectomy\n                  documentation of the absence of sperm in the ejaculate. (For female patients on\n                  the study, the vasectomised male partner should be the sole partner for that\n                  patient.) These patients must also agree to the use an intrauterine device or\n                  intrauterine system AND a barrier method of contraception: condom or occlusive\n                  cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, or\n                  cream, or vaginal suppository. Reliable contraception must be maintained\n                  throughout the study and for 12 weeks after study drug discontinuation.\n\n               -  Females considered post-menopausal and not of childbearing potential: The\n                  definition applies to females who have had 12 months of natural (spontaneous)\n                  amenorrhoea with an appropriate clinical profile (e.g., age appropriate, history\n                  of vasomotor symptoms) or 6 months of spontaneous amenorrhoea with serum\n                  follicle-stimulating hormone (FSH) levels > 40 million international units per\n                  milliliter (mIU/mL) (for US only: and estradiol < 20 pg/mL) or have had surgical\n                  bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior to\n                  starting treatment. In the case of oophorectomy alone, only when the reproductive\n                  status of the patient has been confirmed by follow-up hormone level assessment is\n                  she considered not of childbearing potential.\n\n          3. Is a pregnant or nursing (lactating) female, where pregnancy is defined as the state\n             of a female after conception and until the termination of gestation, confirmed by a\n             positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL).\n\n          4. Has dasatinib intolerance (haematologic and non-haematologic). Defined as: CTCAE Grade\n             >2\n\n          5. Has received anti-cancer therapy within 2 weeks or 5 half-lives, whichever is shorter\n             (except for hydroxyurea, steroids, allopurinol, febuxostat, rasburicase, and\n             intravenous hydration), prior to starting study drug or the side effects of such\n             therapy have not resolved to Grade ?1 within 2 weeks prior to starting study drug.\n\n          6. Is receiving concomitant anti-cancer therapy (except for hydroxyurea, steroids,\n             anagrelide, allopurinol, febuxostat, rasburicase, and intravenous hydration during the\n             first week of the study drug[s] administration, or corticosteroids when appropriate).\n\n          7. Has used other investigational drugs within 2 weeks or 5 half-lives (whichever is\n             shorter) prior to the first dose of study drug.\n\n          8. Has undergone autologous or allogenic stem cell transplantation < 60 days prior to the\n             first dose of study drug;\n\n          9. Has any evidence of on-going graft-versus-host disease (GVHD).\n\n         10. Has evidence of another malignancy not in remission or history of such a malignancy\n             within the last 3 years (except for treated basal or squamous cell carcinoma of the\n             skin, or in situ cancer of the cervix).\n\n         11. Has central nervous system (CNS) metastases.\n\n         12. Has significant bleeding disorder unrelated to the disease.\n\n         13. Has a history of long QT syndrome or prolonged QT interval corrected based on\n             Fridericia's method (QTcF) > 450 ms.\n\n         14. Has ECG evidence of complete left bundle branch block, or ventricular pacing.\n\n         15. Has abnormalities in the 12-lead ECG that in the opinion of the Investigator increase\n             the risk of participating in the study (e.g., sinus rhythm with PR interval > 240 ms\n             or second degree or higher atrioventricular (AV) block confirmed by a repeat ECG).\n\n         16. Has blood pressure and heart rate (HR) higher than 160/100 mmHg and 100 beats per\n             minute (bpm), respectively, or lower than 80/50 mm Hg and 45 bpm, respectively,\n             confirmed by a repeat assessment.\n\n         17. Is receiving treatment with drugs known to be associated with Torsade de Pointes.\n\n         18. Has ophthalmic signs or symptoms, such as flashes and colour perception changes.\n\n         19. Has evidence of electrolyte imbalance such as hypokalaemia, hypocalcaemia, and\n             hypomagnesaemia of NCI-CTCAE Grade ? 2 (NCI CTCAE version 4.03).\n\n         20. Has symptomatic chronic heart failure; unstable angina pectoris, cardiac arrhythmia.\n\n         21. Has cardiac left ventricular ejection fraction (LVEF) < 40% (assessed by transthoracic\n             echocardiography).\n\n         22. Has a history of myocardial infarction and/or thromboembolism in the past 6 months.\n\n         23. Has uncontrolled diabetes mellitus, neurologic or psychiatric condition, an ongoing\n             systemic (including opportunistic) clinically significant infections or any other\n             significant or unstable concurrent medical illness that in the opinion of the\n             Investigator would preclude protocol therapy.\n\n         24. Has a known history of human immunodeficiency virus (HIV) sero positivity and/or is\n             receiving combination anti retroviral therapy.\n\n         25. Has a history of gastric bypass surgery or with pre-existing gastrointestinal\n             disorders that may interfere with proper absorption of the drug, as per Investigator's\n             judgement.\n\n         26. Has history of seizure disorders or CNS leukaemia.\n\n         27. Is receiving cytochrome P450 3A4 (CYP3A4) inhibitors within 7 days prior to the first\n             dose of ETC-1907206 or receiving CYP3A4 inducers within 14 days prior to the first\n             dose of ETC-1907206 and dasatinib.\n\n         28. Cannot start treatment with dasatinib 140 mg daily, oral.\n\n         29. Is unwilling or unable to comply with the protocol
Main criteria for inclusion:\n\n        PK Phase:\n\n        To be considered eligible to participate in this study, all of the following requirements\n        must be met:\n\n          -  Patients with histologically or cytologically confirmed diagnosis of metastatic or\n             locally advanced solid tumors that have failed to respond to standard therapy, has\n             progressed despite standard therapy, or for which no standard therapy exists, and who\n             may benefit from treatment with a PARP inhibitor as assessed by the Investigator.\n\n          -  ECOG performance status of 0 to 2.\n\n          -  Adequate organ function as defined below:\n\n               -  Absolute neutrophil count ? 1,500/?L\n\n               -  Platelets ? 100,000/?L\n\n               -  Hemoglobin ? 9 g/dL (5.6 mM)\n\n               -  Serum creatinine ? 1.5 × the upper limit of normal (ULN) or a calculated\n                  creatinine clearance ? 60 mL/min using the Cockcroft-Gault equation or 24-hour\n                  urine creatinine clearance.\n\n               -  Total bilirubin ? 1.5 × ULN except in patients with Gilbert's syndrome. Patients\n                  with Gilbert's syndrome may enroll if direct bilirubin ? 1.5 × ULN of the direct\n                  bilirubin.\n\n               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2.5 × ULN\n                  unless liver metastases are present, in which case, they must be ? 5 × ULN\n\n          -  Patient has recovered to Grade 1 toxicity from prior cancer therapy (a patient with\n             Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may\n             qualify for this study).\n\n          -  Female Patient of childbearing potential is not breastfeeding, has a negative serum\n             pregnancy test within 72 hours prior to taking study drug and agrees to abstain from\n             activities that could result in pregnancy from Screening through 180 days after the\n             last dose of study drug,\n\n          -  Male patient agrees to use an adequate method of contraception and not donate sperm\n             starting with the first dose of study drug through 90 days after the last dose of\n             study drug\n\n        Key Exclusion, PK Phase:\n\n          -  Known diagnosis of immunodeficiency\n\n          -  Symptomatic uncontrolled brain or leptomeningeal metastases.\n\n          -  Major surgery within 3 weeks of starting the study or patient has not recovered from\n             any effects of any major surgery.\n\n          -  Patient is considered a poor medical risk due to a serious, uncontrolled medical\n             disorder; nonmalignant systemic disease; or active, uncontrolled infection.\n\n          -  Known history of myelodysplastic syndrome or acute myeloid leukemia.\n\n          -  Patient is currently receiving a sensitive cytochrome P450 (CYP) 1A2 substrates with a\n             narrow therapeutic index (e.g., tizanidine and theophylline) (Does not apply for\n             Extension Phase).\n\n          -  Patient is currently taking any of the following P-glycoprotein (P-gp) inhibitors:\n             amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan,\n             cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole,\n             ketoconazole, lopinavir and ritonavir, quercetin, quinidine, ranolazine, ticagrelor,\n             and verapamil (Does not apply for Extension Phase).\n\n          -  Patient taking proton pump inhibitors, antacids, or histamine 2 blockers within 48\n             hours prior to study drug administration, and/or within 6 hours after study drug\n             administration (Does not apply for Extension Phase).\n\n          -  Patient has gastric, gastro-esophageal or esophageal cancer; patient is unable to\n             swallow orally administered medication; or patient has gastrointestinal disorders or\n             significant gastrointestinal resection likely to interfere with the absorption of\n             niraparib.\n\n          -  Patient has known active hepatic disease\n\n          -  Patient has a past or current history of chronic alcohol use.\n\n          -  Patient has significant pleural effusion or ascites that is expected to require\n             drainage during the PK Phase (Does not apply for Extension Phase).\n\n        Key Inclusion, Extension Phase:\n\n          -  ECOG performance status of 0 to 2.\n\n          -  Adequate organ function as defined below\n\n               -  Absolute neutrophil count ? 1,500/?L\n\n               -  Platelets ? 100,000/?L\n\n               -  Hemoglobin ? 9 g/dL (5.6 mM)\n\n               -  Serum creatinine ? 1.5 × the ULN or a calculated creatinine clearance ? 60 mL/min\n                  using the Cockcroft-Gault equation or 24-hour urine creatinine clearance\n\n               -  Total bilirubin ? 1.5 × ULN except in patients with Gilbert's syndrome. Patients\n                  with Gilbert's syndrome may enroll if direct bilirubin ? 1.5 × ULN of the direct\n                  bilirubin.\n\n               -  AST and ALT ? 2.5 × ULN unless liver metastases are present, in which case, they\n                  must be ?5 × ULN\n\n          -  Female patient of childbearing potential is not breastfeeding, has a negative serum\n             pregnancy test within 72 hours prior to taking study drug and agrees to abstain from\n             activities that could result in pregnancy from Screening through 180 days after the\n             last dose of study drug.\n\n          -  Male patient agrees to use an adequate method of contraception and not donate sperm\n             starting with the first dose of study drug through 90 days after the last dose of\n             study drug.
Inclusion Criteria:\n\n        - Patients must be ? 1 and ?25 years of age.\n\n        Diagnosis:\n\n        - Patients with AML must have ? 5% blasts (by morphology) in the bone marrow\n\n          -  Patients may have CNS or other sites of extramedullary disease. No cranial irradiation\n             is allowed during the protocol therapy.\n\n          -  Patients with secondary AML are eligible\n\n          -  Patients with Down syndrome and DNA fragility syndromes (such as Fanconi anemia, Bloom\n             syndrome) are excluded.\n\n        Performance Level:\n\n        - Karnofsky >50% for patients >16 years of age and Lansky > 50% for patients ? 16 years of\n        age (See Appendix II for Performance Scales)\n\n        Prior therapy\n\n        - Patients must have fully recovered from the acute toxic effects of all prior\n        chemotherapy, immunotherapy, or radiotherapy prior to entering this study.\n\n          1. Phase 1\n\n             - Any patient with AML in 1st or greater relapse, OR\n\n             - Patients with AML failed to go into remission after first or greater relapse, OR\n\n             - Patients with AML failed to go into remission from original diagnosis after two or\n             more induction attempts.\n\n          2. Cytoreduction with hydroxyurea - Hydroxyurea can be initiated and continued for up to\n             24 hours prior to the start of decitabine/vorinostat. It is recommended to use\n             hydroxyurea in patients with significant leukocytosis (WBC >50,000/L) to control blast\n             count before initiation of systemic protocol therapy.\n\n          3. Patients who relapsed while they are receiving cytotoxic therapy\n\n             - At least 14 days must have elapsed since the completion of the cytotoxic\n             therapy,except Intrathecal chemotherapy.\n\n             Hematopoietic stem cell transplant (HSCT):\n\n             - Patients who have experienced their relapse after a HSCT are eligible, provided they\n             have no evidence of acute or chronic Graft-versus-Host Disease (GVHD).\n\n             Hematopoietic growth factors:\n\n             - It must have been at least 7 days since the completion of therapy with GCSF or other\n             growth factors at the time of enrollment. It must have been at least 14 days since the\n             completion of therapy with pegfilgrastim (Neulasta ®)\n\n             Biologic (anti-neoplastic agent):\n\n             -At least 7 days after the last dose of a biologic agent. For agents that have known\n             adverse events occurring beyond 7 days after administration, this period must be\n             extended beyond the time during which adverse events are known to occur. The duration\n             of this interval must be discussed with the study chair.\n\n             Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after\n             the last dose of monoclonal antibody (i.e. Gemtuzumab = 36 days)\n\n             Immunotherapy: At least 42 days after the completion of any time of immunotherapy,\n             e.g. tumor vaccines or CAR T-cell therapy.\n\n             XRT: Cranio or craniospinal XRT is prohibited during protocol therapy. No washout\n             period is necessary for radiation given to non-CNS chloromas; >90 days must have\n             elapsed if prior TBI, cranio or craniospinal XRT.\n\n             Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior\n             DNMTi (e.g. decitabine) and/or HDACi (e.g. vorinostat) therapy are eligible to\n             participate in this Phase 1 study. At least 7 days must have passed from prior DNMTi\n             or HDACi as a washout period.\n\n             Renal and hepatic function: Patients must have adequate renal and hepatic functions as\n             indicated by the following laboratory values:\n\n             A. Adequate renal function defined as: Patient must have a calculated creatinine\n             clearance or radioisotope GFR ? 70ml/min/1.73m2 OR a normal serum creatinine based on\n             age/gender.\n\n             B. Adequate Liver Function Defined as: Direct bilirubin < 1.5 x upper limit of normal\n             (ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age. The hepatic\n             requirements are waived for patients with known or suspected liver involvement by\n             leukemia. This must be reviewed by and approved by the study chair or vice chair.\n\n             Adequate Cardiac Function Defined as: Shortening fraction of ? 27% by echocardiogram,\n             OR ejection fraction of ? 50% by radionuclide angiogram (MUGA).\n\n             Reproductive Function A. Female patients of childbearing potential must have a\n             negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.\n\n             B. Female patients with infants must agree not to breastfeed their infants while on\n             this study.\n\n             C. Male and female patients of child-bearing potential must agree to use an effective\n             method of contraception approved by the investigator during the study and for a\n             minimum of 6 months after study treatment.\n\n             Exclusion Criteria:\n\n             -No NG or G-Tube administration of Vorinostat is allowed. Capsule must be swallowed\n             whole or given as oral suspension.\n\n             -They are currently receiving other investigational drugs.\n\n             -There is a plan to administer non-protocol chemotherapy, radiation therapy, or\n             immunotherapy during the study period.\n\n             -They have significant concurrent disease, illness, psychiatric disorder or social\n             issue that would compromise patient safety or compliance, interfere with consent,\n             study participation, follow up, or interpretation of study results.\n\n             -They have a known allergy to any of the drugs used in the study.\n\n             -Patients with Down syndrome are excluded.\n\n               -  Patients with DNA fragility syndromes are excluded (e.g. Fanconi Anemia, Bloom\n                  Syndrome)\n\n               -  They are receiving valproic acid (VPA) therapy.\n\n               -  Patients with Acute Promyelocytic Leukemia (APL, APML) are excluded\n\n               -  Patients with documented active and uncontrolled infection at the time of study\n                  entry are not eligible
Inclusion:\n\n        All Patients:\n\n          1. Adequate organ function, determined by:\n\n             Absolute neutrophil count (ANC) ? 1.5 X10^9/L, Platelets ? 100 X10^9/L, Hemoglobin ?\n             9g/dL, aPTT ?1.5 x ULN, Total bilirubin ? 1.5 mg/dL, ALT and AST ? 2.5 x ULN if no\n             liver involvement or ? 5 x ULN with liver involvement, Creatinine < 1.5 x ULN\n             concurrent with creatinine clearance >50 mL/min.\n\n          2. Normotensive or well controlled blood pressure (<140/90).\n\n          3. ECOG perf. status of 0-1.\n\n          4. Ejection fraction (EF) > 50%\n\n          5. Toxicities from prior therapy greater than CTCAE Grade 1 have resolved with the\n             exception of alopecia. Patients with Grade ? 2 neuropathy are eligible.\n\n          6. Male patients must use two forms of contraception. Female partners of child-bearing\n             potential of male patients must use at least one of the two forms of acceptable\n             contraception. Female patients should not be breast-feeding and must have a negative\n             pregnancy test.\n\n          7. Patients with lymphoma must have documented analysis of bone marrow infiltration from\n             biopsy carried out < 3 months of enrollment, or be able to undergo a new bone marrow\n             biopsy if such procedure was performed > 3 months prior to enrollment.\n\n        Part 1a Dose Escalation: Histological or cytological confirmation of malignant solid tumor\n        or lymphoma that is refractory to standard therapy or for which no standard therapy exists.\n\n        Part 1b MTD Dose Expansion: Histologically or cytologically confirmed platinum-resistant or\n        platinum-refractory high grade serous ovarian cancer. Platinum-resistant disease is defined\n        by progression <6 months following the last administered platinum-based regimen, and\n        platinum-refractory is defined by lack of at least a partial response while on\n        platinum-containing regimens. Platinum sensitive disease (recurrent after 6 months) must\n        have been treated with additional platinum containing regimens or PARPi if tBRCAm+ or other\n        HRD+\n\n        Exclusion:\n\n          1. Chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational drugs\n             <21 days or 5 half-lives (whichever is shorter).\n\n          2. More than 5 prior lines of treatment for an advanced solid tumor.\n\n          3. Major surgery ?21 days or minor surgery ?7 days.\n\n          4. Unable to swallow oral medicine or has a GI disorder that would jeopardize intestinal\n             absorption of AZD5153.\n\n          5. Any of the following: Drugs or other products known to be strong or moderate\n             inhibitors/inducers of CYP3A4/5, or CYP3A4/5 sensitive substrates or substrates with a\n             narrow therapeutic range. Drugs that are sensitive substrates of the transporters\n             P-gp, BCRP, OATP1B1, OAT3, MATE1 and MATE2K.\n\n             Herbal preparations, including but not limited to: St. John's wort, kava, ephedra (ma\n             huang), gingko biloba, dehydro-epiandrosterone, yohimbe, saw palmetto, and ginseng.\n\n             Drugs known to prolong QT interval or induce Torsades de Pointes\n\n          6. Refractory nausea and vomiting\n\n          7. Tuberculosis.\n\n          8. Live attenuated vaccine ?28 days.\n\n          9. Spinal cord compression or brain metastases unless asymptomatic, treated and stable\n             and not requiring steroids for at least 4 weeks prior to start.\n\n         10. Evidence of severe or uncontrolled systemic diseases, including uncontrolled\n             hypertension, active bleeding diatheses, or active infection, or other comorbidity\n             that renders the patient unsuitable.\n\n         11. Any of the following:\n\n             Mean resting corrected QT interval (QTcF) >450 msec obtained from 3 electrocardiograms\n             (ECGs).\n\n             Clinically important abnormalities in rhythm, conduction or morphology of resting ECG\n             e.g., complete left bundle branch block, third degree heart block.\n\n             Factors that increase the risk of QTc prolongation or risk of arrhythmic events such\n             as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT\n             syndrome or unexplained sudden death under 40 years of age.\n\n         12. Hypersensitivity to active or inactive excipients of AZD5153 or drugs with a similar\n             chemical structure.\n\n         13. Non-Hodgkin lymphoma (NHL) at high risk for developing tumor lysis syndrome are not\n             eligible for the dose escalation portion of this study.
1. Confirmed diagnosis of HCC by imaging criteria per American Association for the Study\n             of Liver Diseases (AASLD) criteria.\n\n          2. Patients with single or multiple HCC who are unsuitable for surgical resection or RFA,\n             but suitable for embolization.\n\n          3. ECOG score 0-1. Child-Pugh score up to B7.\n\n          4. Patients should have measurable tumor lesion(s) by contrast MRI.\n\n          5. Patients have adequate normal organ function and suitable laboratory criteria.\n\n          6. Men and women of child-bearing age need to commit to using two levels of contraception\n             simultaneously to avoid pregnancy.\n\n        Exclusion Criteria:\n\n          1. Patients who have had a liver transplantation.\n\n          2. Patients who have uncontrolled major medical problems such as cardiac, pulmonary (COPD\n             requiring constant oxygen), renal (creatinine over 2.0) diseases, active infectious\n             diseases (except chronic Hepatitis B or C), or non-healing ulceration.\n\n          3. Patients who have any clinical evidence of hypoxia with O2 saturation less than 92% on\n             room air.\n\n          4. Patients with evidence of arterial insufficiency or microangiopathy in any organ due\n             to any reason, which could lead to distal extremity hypoxia, as evidenced by any\n             gangrenous change in distal limbs or requiring resection for this reason.\n\n          5. Patients with poorly controlled HBV infection.\n\n          6. Patients on interferon treatment need to have at least 2-week washout period from Day\n             1.\n\n          7. Patients with major gastrointestinal bleeding in the prior 2 months of enrollment or\n             known diagnosis of cancer other than HCC.\n\n          8. Pregnant or lactating women.
Inclusion Criteria:\n\n        Cohort A (Solid Tumours)\n\n          -  Age >= 18 years (>=20 years for Japan only) at screening\n\n          -  Signed and dated written informed consent in accordance with GCP (Good Clinical\n             Practice and local legislation prior to admission to the trial\n\n          -  WHO/ECOG (World Health Organization / Eastern Cooperative Oncology Group) performance\n             status 0-1 assessed at screening\n\n          -  Patient must be able to swallow oral capsules.\n\n          -  Male or female patients ready and able to use highly effective methods of birth\n             control during the study and for 12 weeks following the last dose of abemaciclib per\n             ICH (International Conference on Harmonization) M3(R2) that result in a low failure\n             rate of less than 1% per year when used consistently and correctly. A list of\n             contraception methods meeting these criteria is provided in the patient information.\n             Women of childbearing potential must have a negative serum pregnancy test at\n             screening.\n\n          -  Patients with histologically or cytologically confirmed diagnosis of advanced and/or\n             metastatic, measurable or evaluable, non-resectable solid tumours\n\n          -  Patients must have received and failed, or have been intolerant to, all treatment\n             known to confer clinical benefit or have no therapeutic options available as deemed\n             appropriate by their treating physician\n\n          -  Life expectancy >= 3 months in the opinion of the investigator assessed at screening;\n\n        Cohorts B, C, D, F (Breast Cancer):\n\n          -  Age >= 18 years (>=20 years for Japan only) at screening\n\n          -  Signed and dated written informed consent in accordance with GCP and local legislation\n             prior to admission to the trial\n\n          -  WHO/ECOG performance status 0-1 assessed at screening\n\n          -  Patient must be able to swallow oral capsules.\n\n          -  Women who have postmenopausal status due to either surgical/natural menopause or\n             chemical ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1)\n             with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin or\n             radiation-induced ovarian suppression\n\n               -  postmenopausal status defined as meeting one of the following conditions:\n\n                    -  prior bilateral oophorectomy\n\n                    -  age >= 60 years\n\n                    -  age < 60 years and amenorrheic (non-treatment-induced amenorrhea secondary\n                       to tamoxifen, toremifene, ovarian suppression, or chemotherapy) for at least\n                       12 months; and follicle stimulating hormone (FSH) and estradiol within the\n                       postmenopausal range as per institutional reference ranges.\n\n               -  Postmenopausal status due to radiation-induced ovarian suppression must be\n                  confirmed by FSH and estradiol level in the postmenopausal range\n\n          -  Histologically or cytologically proven diagnosis of breast cancer with evidence of\n             locally advanced or metastatic disease not amenable to resection or radiation\n\n          -  HR+ (local lab results at screening or, if not available, at the time of diagnosis) To\n             fulfil the requirement of HR+ disease, the primary tumour or metastatic lesion of the\n             breast cancer must express at least one of the hormone receptors (estrogen receptor\n             [ER] or progesterone receptor [PgR]) by immunohistochemistry (IHC). Estrogen receptor\n             and PgR assays are considered positive if there are at least 1% positive tumour nuclei\n             in the sample as defined in the relevant American Society of Clinical Oncology\n             (ASCO)/College of American Pathologists (CAP) Guidelines (Hammond et al. 2010).\n\n          -  HER2 negative (local lab results at screening or, if not available, at the time of\n             diagnosis) as defined by the most recent American Society of Clinical Oncology\n             (ASCO)/College of American Pathologists (CAP) Guidelines (Hammond et al. 2010).\n\n          -  Previous adjuvant and neoadjuvant chemotherapy is permitted. 0-2 prior lines of\n             chemotherapy for the metastatic setting are allowed.\n\n          -  At least 1 lesion (measurable or non-measurable) that can be accurately assessed at\n             baseline with CT or MRI or PET-CT (CT portion of diagnostic quality) and which is\n             suitable for accurate repeated measurement. For Cohort F only: patients should have at\n             least one measurable lesion.\n\n          -  Cohort B, C, D, F Must be eligible for the corresponding hormonal therapy (letrozole,\n             anastrozole or fulvestrant). For Cohorts B and C previous treatment with fulvestrant\n             or exemestane is allowed. For Cohort D and F prior therapy with non steroidal\n             aromatase inhibitors (anastrozole, letrozole) or exemestane are permitted\n\n          -  Cohort F only: Postmenopausal with locally advanced or metastatic HR+ breast cancer\n             and refractory to aromatase inhibitors therapy and CDK4/6 inhibitor treatment (e.g.,\n             palbociclib or ribociclib) for locally advanced or metastatic breast cancer.Resistance\n             to aromatase inhibitors therapy is defined as the following:\n\n               -  disease recurrence while on, or within 12 months of end of adjuvant treatment\n                  with letrozole, anastrozole, or exemestane;\n\n               -  or disease progression while on, or within one month of end of letrozole,\n                  anastrozole, or exemestane.\n\n        Cohort E (NSCLC (Non-Small Cell Lung Cancer)):\n\n          -  Age >= 18 years (>=20 years for Japan only) at screening\n\n          -  Signed and dated written informed consent in accordance with GCP and local legislation\n             prior to admission to the trial\n\n          -  WHO/ECOG performance status 0-1 assessed at screening\n\n          -  Patient must be able to swallow oral capsules.\n\n          -  Male or female patients ready and able to use highly effective methods of birth\n             control during the study and for 12 weeks following the last dose of abemaciclib per\n             ICH M3 (R2) that result in a low failure rate of less than 1% per year when used\n             consistently and correctly. A list of contraception methods meeting these criteria is\n             provided in the patient information. Women of childbearing potential must have a\n             negative serum pregnancy test at screening.\n\n          -  Histologically or cytologically confirmed diagnosis of stage IV NSCLC.\n\n          -  The participant must have progressed after platinum-based chemotherapy AND\n             immunotherapy (unless deemed inappropriate candidates for immunotherapy by their\n             treating physician) AND have received a maximum of 2 other prior chemotherapy for\n             advanced and/or metastatic disease OR must be judged by the physician as ineligible\n             for further standard second-line chemotherapy. Prior treatment with epidermal growth\n             factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and anaplastic lymphoma kinase\n             (ALK) inhibitors is mandatory in participants whose tumour has EGFR-activating\n             mutations or ALK translocations. Prior targeting agents and neoadjuvant/adjuvant\n             therapies are permitted.\n\n          -  Have adequate organ function including haematology, renal, and liver.\n\n          -  Have measureable disease per Response Evaluation Criteria In Solid Tumours (RECIST)\n             1.1.\n\n        Exclusion Criteria:\n\n        All cohorts:\n\n          -  Any documented active or suspected malignancy or history of malignancy, other than the\n             disease under study, within 3 years prior to screening, except appropriately treated\n             basal cell carcinoma of the skin or in situ carcinoma of uterine cervix or ductal\n             carcinoma in situ (DCIS) if properly treated in opinion of the investigator.\n\n          -  Patients who must or wish to continue the intake of restricted medications or any drug\n             considered likely to interfere with the safe conduct of the trial\n\n          -  Previous treatment in this trial\n\n          -  Currently enrolled in another investigational device or drug study, or less than 21\n             days since ending another investigational device or drug study(s), or receiving other\n             investigational treatment(s).\n\n          -  Chronic alcohol or drug abuse or any condition that, in the investigator's opinion,\n             makes them an unreliable study subject or unlikely to complete the trial\n\n          -  Women who are pregnant, nursing, or who plan to become pregnant while in the trial.\n             Men who plan to father a child while in the trial.\n\n          -  Prior chemotherapy, biological or radiation therapy, androgens, thalidomide, other\n             anticancer agents, or any investigational drug within 21 days; and/or three half-lives\n             for immunotherapy, before starting any of the trial drugs.\n\n          -  Prior anti CDK (Cyclin-dependent Kinase) agents (except cohort F)\n\n          -  Prior radiotherapy to >= 25% of bone marrow regardless of when it was received\n\n          -  Unresolved treatment related toxicity from previous therapy of > CTCAE grade 1 at\n             study entry (except for stable sensory neuropathy ? CTCAE grade 2 and alopecia)\n\n          -  Previous treatment with IGF (Insulin-like Growth Factor)-1R targeting compounds\n\n          -  Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or\n             leptomeningeal disease, as indicated by clinical symptoms, cerebral oedema, and/or\n             progressive growth. History of CNS metastases or cord compression are eligible if they\n             have been definitively treated (e.g. radiotherapy, stereotactic surgery) and are\n             clinically stable, off anticonvulsants and steroids for at least 4 weeks. Patients\n             with brain metastases are eligible if they are asymptomatic or treated at a stable\n             dose of steroids for at least 4 weeks. Patients are not eligible if they have spinal\n             cord compression.\n\n          -  Any evidence of severe or uncontrolled systemic disease as judged by the Investigator.\n\n          -  Inadequate bone marrow reserve or organ function as demonstrated by any of the\n             following: ANC < 1.5 x 109/L, platelets < 100 x 109/L, haemoglobin <90g/L, ALT > 2.5 x\n             ULN or > 5 x ULN in the presence of liver metastases, total bilirubin >1.5 x ULN or >3\n             x ULN in patients with Gilbert's Syndrome, serum creatinine > 1.5 x ULN concurrent\n             with creatinine clearance <= 50 mL/min.\n\n          -  Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi\n             Syndrome or renal tubular acidosis\n\n          -  Refractory nausea and vomiting, chronic GI diseases, inability to swallow the product,\n             or previous significant bowel resection that would preclude adequate absorption of\n             abemaciclib or resulting in baseline Grade 2 or higher diarrhoea.\n\n          -  History of hypersensitivity to active or inactive excipients of xentuzumab,\n             abemaciclib or letrozole/anastrozole/fulvestrant, or loperamide hydrochloride, or\n             drugs with similar chemical structures\n\n          -  Patients with Diabetes Type I or uncontrolled Type II (defined by HgBA1C > 8%)\n\n          -  Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of\n             life threatening complications in the short term including patients with massive\n             uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and\n             over 50% of liver involvement in metastases.\n\n          -  Prior hematopoietic stem cell or bone marrow transplant\n\n          -  Have a personal history of any of the following conditions: syncope of either\n             unexplained or cardiovascular etiology, ventricular arrhythmia (including but not\n             limited to ventricular tachycardia and ventricular fibrillation), or sudden cardiac\n             arrest. Subjects with controlled atrial fibrillation for >30 days prior to study\n             treatment are eligible.\n\n          -  Erythropoietin, G-CSF, and GM-CSF are not allowed within 2 weeks prior to study. The\n             primary prophylactic use of G-CSF is not permitted but it may be used to treat\n             treatment emergent neutropenia.\n\n          -  Have had major surgery (excluding biopsy) < 28 days of the initial dose of any of the\n             study drugs or planned major surgery during study participation.\n\n          -  Have active bacterial, fungal, and/or known viral infection (for example, human\n             immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen, or hepatitis C\n             antibodies). Screening is not required for enrolment.\n\n          -  Patients with baseline Grade >=2 hyperglycaemia or patients with baseline Grade >= 2\n             diarrhoea\n\n          -  Patients needing treatment with CYP3A4 inhibitors/inducers cannot be included in the\n             trial.
Tissue Procurement Inclusion Criteria:\n\n        Subjects will be eligible for tissue procurement for the Vigil manufacturing process, if\n        they meet all of the following criteria:\n\n          1. Histologically confirmed Stage IIIb, IIIc or IV high-grade papillary serous, clear\n             cell, or endometrioid ovarian, fallopian tube or primary peritoneal carcinoma\n\n          2. Age ? 18 years.\n\n          3. Estimated survival ? 6 months.\n\n          4. ECOG Performance Status ? 1\n\n          5. Metastatic disease\n\n          6. Planned standard of care surgical procedure (e.g., tumor biopsy or palliative\n             resection or thoracentesis) and expected availability of a cumulative soft-tissue mass\n             of ~10-30 grams tissue (\grape\ to \golf-ball\ size) or ascites fluid estimated volume\n             ? 500mL (from a primary or secondary paracentesis, yielding in a high volume of tumor\n             cells) for immunotherapy manufacture.\n\n          7. Tumor intended for immunotherapy manufacture is not embedded in bone and does not\n             contain luminal tissue (e.g. bowel, ureter, bile duct).\n\n          8. Presence of at least one additional site of disease that is RECIST 1.1\n             evaluable/measurable.\n\n          9. Ability to understand and the willingness to sign a written informed protocol specific\n             consent for tissue harvest or a parental/guardian informed consent and pediatric\n             assent when appropriate.\n\n        Tissue Procurement Exclusion Criteria:\n\n        Subjects meeting any of the following criteria are not eligible for tissue procurement for\n        the Vigil manufacturing:\n\n          1. Medical condition requiring any form of chronic systemic immunosuppressive therapy\n             (steroid or other) except physiologic replacement doses of hydrocortisone or\n             equivalent (no more than 30 mg hydrocortisone or 10 mg prednisone equivalent daily)\n             for < 30 days duration.\n\n          2. Known history of other malignancy unless having undergone curative intent therapy\n             without evidence of that disease for ? 3 years except cutaneous squamous cell and\n             basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other\n             in situ cancers are allowed if definitively resected.\n\n          3. Brain metastases unless treated with curative intent (gamma knife or surgical\n             resection) and without evidence of progression for ? 2 months.\n\n          4. Any documented history of autoimmune disease with exception of Type 1 diabetes on\n             stable insulin regimen, hypothyroidism on stable dose of replacement thyroid\n             medication, vitiligo, or asthma not requiring systemic steroids.\n\n          5. Known HIV or chronic Hepatitis B or C infection.\n\n          6. Known history of allergies or sensitivities to gentamicin.\n\n          7. History of or current evidence of any condition (including medical, psychiatric or\n             substance abuse disorder), therapy, or laboratory abnormality that might confound the\n             results of the study, interfere with the patient's participation for the full duration\n             of the study, or is not in the best interest of the patient to participate, in the\n             opinion of the treating Investigator.\n\n        Study Enrollment Inclusion Criteria:\n\n        Subjects will be eligible for registration into the trial if they meet all of the following\n        inclusion criteria:\n\n          1. Successful manufacturing of at least 4 vials of Vigil.\n\n          2. One of the following:\n\n               1. Failure to meet the eligibililty criteria for Protocol CL-PTL-119 due to i)\n                  histology of ovarian cancer and failure to achieve a complete clinical response\n                  following primary debulking surgery and standard paclitaxel/carboplatin therapy\n                  OR, ii) a histologic diagnosis of another gynecologic malignancy which is not\n                  ovarian cancer.\n\n               2. Recurrent ovarian cancer.\n\n               3. Randomized on Protocol CL-PTL-119 and were subsequently unblinded at recurrence\n                  and were assigned to the placebo arm.\n\n          3. ECOG performance status (PS) ? 1\n\n          4. Estimated survival ? 6 months.\n\n          5. Measureable or evaluable disease.\n\n          6. Adequate organ and bone marrow function as defined below:\n\n               1. Absolute neutrophil count (ANC) ? 1.5 × 10e9/L (1500 per mm^3)\n\n               2. Platelets >100 × 10e9/L (100,000 per mm^3)\n\n               3. Hemoglobin ?9.0 g/dL (5.59 mmol/L)\n\n               4. Creatinine clearance (CrCL) >50 mL/min by the Cockcroft-Gault formula or by\n                  24-hour urine collection for determination of creatinine clearance:\n\n                  Females:\n\n                  CrCL (mL/min) = Weight (kg) × (140 - Age) × 0.85/72 × serum creatinine (mg/dL)\n\n               5. Serum bilirubin ?1.5 × upper limit of normal (ULN). This will not apply to\n                  patients with confirmed Gilbert's syndrome (persistent or recurrent\n                  hyperbilirubinemia that is predominantly unconjugated in the absence of evidence\n                  of hemolysis or hepatic pathology) who will be allowed in consultation with their\n                  physician.\n\n               6. AST and ALT ?2.5 × ULN in patients with no liver metastasis\n\n               7. AST or ALT ?5 × ULN in patients with liver metastasis\n\n               8. TSH within institutional limits. If TSH is greater or less than institutional\n                  limits patients may participate if their T4 is within normal limits (WNL);\n                  patients may be on a stable dose of replacement thyroid medication; dose\n                  adjustments are allowed if needed\n\n          7. Subject has recovered to CTCAE Grade 1 or better from all adverse events associated\n             with prior therapy or surgery\n\n          8. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to\n             CTCAE Grade 2 or better\n\n          9. Patients with irreversible toxicity that is not reasonably expected to be exacerbated\n             by the IPs may be included (e.g., hearing loss) after consultation with the Principal\n             Investigator\n\n         10. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,\n             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal\n             antibodies, other investigational agent) prior to tissue procurement and at least 21\n             days prior to the first dose of study drug (at least 21 days prior to the first dose\n             of study drug for subjects who have received prior TKIs [e.g., erlotinib, gefitinib\n             and crizotinib] and within 6 weeks for nitrosourea or mitomycin C).\n\n         11. Subjects who are not rendered surgically sterile as a result of surgery for ovarian\n             cancer, must have, negative urine or serum pregnancy test. If the urine test is\n             positive or cannot be confirmed as negative, a negative serum test will be required\n             for study entry.\n\n         12. Ability to understand and the willingness to sign a written informed protocol specific\n             consent.\n\n         13. Willing and able to comply with the protocol for the duration of the study including\n             undergoing treatment and scheduled visits and examinations including follow up.\n\n        Study Enrollment Exclusion Criteria:\n\n        Subjects will NOT be eligible for study registration and enrollment if meeting any of the\n        following criteria:\n\n          1. Have received more than two additional chemotherapy regimens for recurrent ovarian\n             cancer, after their initial treatment with paclitaxel/carboplatin, OR have received\n             more than two additional chemotherapy regimens for the treatment of another\n             gynecologic malignancy\n\n               1. Patients must have fully recovered from chemotherapy associated toxicities prior\n                  to starting treatment on this protocol.\n\n               2. Palliative radiotherapy is permitted provided:\n\n             i. More than 3 weeks have elapsed between the end of radiotherapy and the first dose\n             of study therapy, AND ii. The lung is not in the radiation field, AND iii. The\n             irradiated lesion(s) cannot be used as target lesions.\n\n          2. Participation in another clinical study with an investigational product within the\n             last 3 weeks prior to study start.\n\n          3. Patients with autoimmune diseases are excluded from enrollment with the exception of\n             patients with hypothyroidism on stable thyroxine replacement, and patients with T1DM\n             on stable insulin replacement.\n\n          4. Receipt of steroid therapy within the 2 weeks of the first dose of study therapy.\n\n          5. Live vaccine used for the prevention of infectious disease administered < 30 days\n             prior to the start of study therapy. NOTE: Subjects, if enrolled, should not receive\n             live vaccine during the study and for 5 months after the last dose of atezolizumab.\n\n          6. Post-surgery complication that in the opinion of the treating investigator would\n             interfere with the subject's study participation or make it not in the best interest\n             of the subject to participate.\n\n          7. Mean QT interval corrected for heart rate (QTc) ?470 ms calculated from 3\n             electrocardiograms (ECGs) using Frediricia's Correction.\n\n          8. Female subjects who are pregnant, breast-feeding or of reproductive potential who are\n             not employing an effective method of birth control defined in the protocol. Effective\n             contraception is required for women receiving atezolizumab for 5 months after the last\n             dose.\n\n          9. Any condition that, in the opinion of the investigator, would interfere with\n             evaluation of study treatment or interpretation of patient safety or study results.
Inclusion Criteria:\n\n        For Arm A, B, and C: Histologically confirmed World Health Organization Grade IV\n        glioblastoma. WHO Grade IV gliomas will be allowed on protocol.\n\n        For Arm D and E: WHO Grade IV glioma as per above and tumor must harbor a histone H3 K27M\n        mutation as evidenced by testing any tumor sample with a immunohistochemistry or DNA\n        sequencing test.\n\n        Unequivocal evidence of progressive disease on contrast-enhanced brain computerized\n        tomography (CT) or magnetic resonance imaging (MRI) as defined by Response Assessment in\n        Neuro-Oncology Criteria (RANO), or have documented recurrent glioblastoma on diagnostic\n        biopsy.\n\n        Previous first line therapy with at least radiotherapy and temozolomide.\n\n        For Arm A: Any number of recurrences are allowable. For Arm B: First recurrence (only)\n        glioblastoma who had a complete tumor resection at first diagnosis. For Arm C: Patients\n        must have clinical and/or radiographic evidence of first recurrence of glioblastoma (only)\n        and be eligible for salvage surgical resection as deemed by the site Investigator.\n\n        Must be 12 weeks from radiotherapy. If patients are within 12 weeks of radiotherapy, then\n        the progressive lesion must be outside of the high-dose radiation target volume or have\n        unequivocal evidence of progressive tumor on a biopsy specimen.\n\n        From the projected start of scheduled study treatment, the following time periods must have\n        elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy\n        (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies,\n        or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies.\n\n        All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy, and/or\n        surgery) must be resolved, except for alopecia.\n\n        Male or Female age ?18 years.\n\n        Karnofsky Performance Status (KPS) ? 60% (see Appendix A).\n\n        Adequate organ and marrow function as defined below, all screening labs should be performed\n        within 14 days of treatment initiation:\n\n          -  leukocytes ? 3,000/mcL\n\n          -  absolute neutrophil count ? 1,500/mcL\n\n          -  platelets ? 100,000/mcL\n\n          -  hemoglobin > 8.0 mg/dL\n\n          -  total bilirubin < 2.0 x upper limit of normal\n\n          -  AST (SGOT)/ALT (SGPT) ?2.5 × upper limit of normal creatinine OR creatinine clearance\n             ?60 mL/min/1.73 m2 for patients with creatinine levels above normal.\n\n        CT or MRI within 14 days prior to start of study drug.\n\n        Corticosteroid dose must be stable or decreasing for at least 5 days prior to the scan. For\n        Arm B: Corticosteroid dose must be stable or decreasing for at least 2 weeks prior to study\n        entry.\n\n        The effects of ONC201 on the developing human fetus are unknown. For this reason, women of\n        childbearing potential and men must agree to use adequate contraception (hormonal or\n        barrier method of birth control; abstinence) prior to study entry and for the duration of\n        study participation. Should a woman become pregnant or suspect she is pregnant while she or\n        her partner is participating in this study, she should inform her treating physician\n        immediately. Male subjects should agree to use adequate method of contraception starting\n        with the first dose of study therapy through 120 days after the last dose of therapy.\n\n        Archival tissue for evaluation of correlative objectives (if available). Archival tissue is\n        required for Arms B and C.\n\n        Ability to understand and the willingness to sign a written informed consent document.\n\n        Exclusion Criteria:\n\n        History of allergic reactions attributed to compounds of similar chemical or biologic\n        composition to ONC201 or its excipients.\n\n        Current or planned participation in a study of an investigational agent or using an\n        investigational device.\n\n        Uncontrolled intercurrent illness including, but not limited to, ongoing or active\n        infection or psychiatric illness/social situations that would limit compliance with study\n        requirements.\n\n        Active infection requiring systemic therapy.\n\n        Prior stereotactic radiotherapy, convection enhanced delivery (CED) or brachytherapy must\n        have had a biopsy to confirm radiographic progression is consistent with progressive tumor\n        and not treatment-related necrosis. If the recurrent lesion is outside of any prior\n        high-dose radiation target volume or distant from the prior CED or brachytherapy site,\n        subjects will be considered eligible\n\n        Pregnant women because ONC201 is novel agent with unknown potential for teratogenic or\n        abortifacient effects. Because there is an unknown but potential risk for adverse events in\n        nursing infants secondary to treatment of the mother with ONC201, breastfeeding should be\n        discontinued if the mother is treated with ONC201.\n\n        Known HIV-positive test on combination antiretroviral therapy.\n\n        Known history of cardiac arrhythmias including atrial fibrillation, tachyarrhythmias or\n        bradycardia. Receiving therapeutic agents known to prolong QT interval will be excluded.\n        History of CHF, or MI or stroke in the last 3 months will be excluded.\n\n        Active illicit drug use or diagnosis of alcoholism.\n\n        Prior bevacizumab for treatment of glioblastoma. The rationale for restricting enrollment\n        to patients who have not had prior bevacizumab therapy is that data regarding the efficacy\n        of any therapy after progression on bevacizumab therapy are lacking.\n\n        Tumors with isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations as determined by\n        immunohistochemistry for the IDH1 R132H variant or by direct sequencing. IDH1/2-mutant\n        gliomas have a markedly longer overall survival rate compared to those with IDH1/2-wildtype\n        glioma (Parsons et al., 2008; Yan et al., 2009), indicating IDH1/2-mutant gliomas have a\n        distinct natural history.\n\n        Known additional malignancy that is progressing or requires active treatment within 3 years\n        of start of study drug. Exceptions include basal cell carcinoma of the skin, squamous cell\n        carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative\n        therapy.\n\n        Any surgery (not including minor diagnostic procedures such as lymph node biopsy) within 2\n        weeks of baseline disease assessments; or not fully recovered from any side effects of\n        previous procedures.\n\n        Concomitant use of CYP3A4/5 inhibitors during the treatment phase of the study and within\n        72 hours prior to starting study drug administration.\n\n        Concomitant use of potent CYP3A4/5 inducers, which include enzyme inducing antiepileptic\n        drugs (EIAEDs) (see Appendix B), during the treatment phase of the study and within 2 weeks\n        prior to starting treatment.\n\n        Planned concurrent use Optune™. Prior use of the device is allowable.\n\n        For Arm D: Evidence of leptomeningeal spread of disease.
Inclusion criteria include the following:\n\n          1. Is a male or female, ? 18 years of age, who has provided written informed consent.\n\n          2. Has histologically or cytologically confirmed advanced, unresectable, metastatic solid\n             tumor(s) for which the patients have no available therapy likely to provide clinical\n             benefit.\n\n          3. Must have an archival FFPE tumor sample available, to be provided to the Sponsor upon\n             request.\n\n          4. In the Expansion Phase: patients should be willing to undergo tumor core biopsy\n             procedure at pre-treatment and on Day 4, Cycle 1 if, in the judgment of the\n             investigator, it is considered clinically safe and appropriate to do so. This\n             requirement is optional but preferred for patients in Dose Escalation.\n\n          5. Has adequate organ function.\n\n        Women of childbearing potential must have a negative pregnancy test (urine or serum) within\n        7 days prior to starting the study drug. Both males and females and must agree to use\n        effective birth control during the study if conception is possible during this interval.\n\n        Exclusion:\n\n          1. Has received prior treatment with TAS-119.\n\n          2. Has received treatment with any proscribed treatments within specified time frames\n             prior to study drug administration.\n\n          3. Has a serious illness or medical condition(s).
Inclusion Criteria:\n\n        Note: No waivers of the study inclusion or exclusion criteria will be granted.\n\n          1. Diagnosis of a solid tumor for which the accepted standard of care includesa licensed\n             anti-EGFR therapy;\n\n          2. Tumor progression in patients with RAS wild type metastatic colorectal cancer\n             irrespective of their exposure to licensed anti-EGFR therapy including anti-EGFR\n             antibodies; OR Tumor progression in patients with metastatic colorectal cancer\n             refractory to cetuximab or panitumumab or other anti-EGFR antibodies OR Tumor\n             progression in patients with EGFR-mutated non-small cell lung cancer (NSCLC) who have\n             refused therapy.\n\n             OR Tumor progression or recurrence in patients with squamous cell carcinoma of the\n             head and neck irrespective of their exposure to licensed anti-EGFR therapy including\n             anti-EGFR antibodies.\n\n             OR Patients with locally advanced or metastatic colorectal carcinoma who have\n\n               1. relapsed after standard of care treatment,\n\n               2. proved refractory to standard of care treatment\n\n               3. refused standard of care treatment\n\n               4. been found to be medically unsuitable for standard of care treatment\n\n          3. Completion of written informed consent procedure;\n\n          4. Male or female subjects over 17 years of age\n\n          5. Life expectancy of at least 3 months;\n\n          6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2;\n\n          7. At least one measureable non-irradiated site of disease according to Response\n             Evaluation Criteria in Solid Tumors (RECIST) version 1.1;\n\n          8. Adequate bone marrow function, with absolute neutrophil count (ANC) >1,500/mm3,\n             platelet count >100,000/mm3, and hemoglobin > 10 g/mm3;\n\n          9. Adequate liver function, with bilirubin <1.5 x the upper limit of the normal range\n             (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x the\n             ULN;\n\n         10. Adequate renal function, with serum creatinine <1.5 mg/dL;\n\n         11. Adequate cardiac function, with left ventricular ejection fraction (LVEF) ?50%, normal\n             electrocardiogram, and absence of significant cardiac disease;\n\n         12. In women of childbearing potential (defined as women of reproductive capacity who are\n             pre-menopausal or within 12 months of cessation of menses): negative serum pregnancy\n             test and use of an acceptable non-hormonal method of contraception;\n\n         13. Ability to communicate with the investigator, and understand and comply with the\n             requirements of the protocol;\n\n         14. Agrees to notify the investigator when deviating from the protocol requirements with\n             regard to concomitant medications;\n\n         15. Agrees to stay in contact with the study site for the duration of the study and to\n             provide updated contact information as necessary, and has no current plans to move\n             from the study area for the duration of the study.\n\n        Exclusion Criteria:\n\n          1. Participation in a study of an investigational agent or use of an investigational\n             device at the time of screening or within 4 weeks of enrollment;\n\n          2. Receipt of treatment with a monoclonal antibody (mAb) within 4 weeks of enrollment or\n             not recovered from an adverse event (i.e., event is >Grade 1 or subject has not\n             returned to baseline) due to treatment with a mAb administered >4 weeks before\n             enrollment;\n\n          3. Receipt of chemotherapy, targeted small molecule therapy, or radiation therapy within\n             2 weeks prior to enrollment, or not recovered from an adverse event (i.e., event is\n             >Grade 1 or subject has not returned to baseline) due to a previously-administered\n             agent;\n\n          4. Major surgical procedure or significant traumatic injury within 4 weeks prior to\n             screening;\n\n          5. Diagnosis of an additional malignancy that is progressing and requires treatment;\n             exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the\n             skin, and in situ cervical cancer that has undergone potentially curative therapy;\n\n          6. Active autoimmune disease requiring systemic treatment within the past 3 months, or a\n             documented history of severe autoimmune disease, or a syndrome that requires systemic\n             steroids or immunosuppressive agents (subjects with vitiligo or resolved childhood\n             asthma/atopy are allowed);\n\n          7. Diagnosis of an immune deficiency;\n\n          8. Receipt of systemic steroids or any form of immunosuppressive therapy within 7 days\n             prior to enrollment, with the following exceptions:\n\n               1. Stable doses of topical, ocular, intranasal or inhaled corticosteroids\n\n               2. Doses of systemic steroids that, in the opinion of the investigator, are\n                  pysiologic replacement doses\n\n               3. Systemic steroids as prophylactic treatment for subjects with allergy to contrast\n                  media\n\n               4. Non-absorbed intra-articular steroid injections\n\n               5. Systemic corticosteroids required for control of infusion reactions or AEs if\n                  doses have been tapered to <10 mg prednisone or equivalent for 2 weeks prior to\n                  the first study treatment\n\n          9. Evidence of interstitial lung disease or active, non-infectious pneumonitis;\n\n         10. Active infection requiring systemic therapy;\n\n         11. History of cerebrovascular accident, transient ischemic attack, or subarachnoid\n             hemorrhage within 6 months prior to screening;\n\n         12. Active hepatitis B (i.e., hepatitis B surface antigen [HBsAg] positive) or hepatitis C\n             (i.e., hepatitis C virus [HCV] ribonucleic acid [RNA; qualitative] is detected);\n\n         13. Serious non-healing wound, ulcer, or bone fracture;\n\n         14. Any severe or uncontrolled medical condition or other condition that could affect\n             participation in the study;\n\n         15. Any current medical, psychiatric, occupational, or substance abuse problems that, in\n             the opinion of the investigator, will make it unlikely that the subject will comply\n             with the protocol.
Inclusion Criteria:\n\n        Each participant must meet all of the following inclusion criteria to be enrolled in the\n        study:\n\n          1. Male or female participants 18 years or older.\n\n          2. To be enrolled to the dose escalation (Part A), participants must have\n\n               1. histologically or cytologically confirmed diagnosis of metastatic and/or advanced\n                  solid tumor malignancy or lymphoma, for which no effective standard treatment is\n                  available. However, participants with primary brain tumors or WM will be\n                  excluded.\n\n               2. Radiographically or clinically measurable or nonmeasurable (but evaluable)\n                  disease. Radiographically measurable disease is determined by RECIST (version\n                  1.1) for solid tumors or by International Working Group (IWG) criteria for\n                  malignant lymphoma (2007 IWG).\n\n          3. To be enrolled to the dose expansion cohorts (Part B), participants must meet the\n             following criteria:\n\n               1. Diagnosis of CLL that meets International Workshop on Chronic Lymphocytic\n                  Leukemia (IWCLL) 2008 criteria for Cohort 1; pathologically confirmed diagnosis\n                  of DLBCL for Cohort 2; histologically confirmed diagnosis of B-cell NHL\n                  (follicular lymphoma [FL] [Grade 1, 2, or 3a], small lymphocytic lymphoma (SLL),\n                  lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), marginal zone\n                  lymphoma (MZL) [splenic, nodal, or extra-nodal]) for Cohort 3; histologically\n                  confirmed diagnosis of MCL for Cohort 4; and histologically confirmed diagnosis\n                  of PTLD (early lesion, polymorphic, monomorphic, classical Hodgkin lymphoma-type,\n                  Epstein-Barr virus (EBV) -positive DLBCL of the elderly, DLBCL associated with\n                  chronic inflammation; along with documented or documentable Epstein-Barr\n                  virus-encoded small RNA (EBER) status by tissue in situ hybridization [ISH]) for\n                  Cohort 5; histologically confirmed DLBCL (de novo or transformed disease from\n                  iNHL) for Cohort 6.\n\n               2. Must have received greater than or equal to (>=) 1 prior therapy (excluding\n                  radiation); documented PD (MCL); either treatment naïve to, relapsed/refractory\n                  to, or treatment failure due to other reasons with ibrutinib, idelalisib, or any\n                  other investigational B-cell receptor (BCR) in pathway inhibitors not directly\n                  targeting Spleen tyrosine kinase (SYK); considered not appropriate for treatment\n                  or retreatment with purine analog-based therapy (CLL); or considered ineligible\n                  for at least 1 prior therapy (PTLD); or relapsed or refractory to >= 2 prior\n                  lines of chemotherapy (including standard first line therapy including Rituximab\n                  and an anthracycline [or equivalent if contraindicated] and one additional\n                  systemic multiagent chemotherapy as second-line salvage therapy that may have\n                  included autologous stem cell transplant (ASCT) [unless ineligible for salvage\n                  therapy and ASCT]) and should not have failed more than 4 prior lines of therapy\n                  (DLBCL Cohort 6).\n\n               3. Radiographically or clinically measurable and/or evaluable disease as specified\n                  in the protocol.\n\n          4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.\n\n          5. Participants must have adequate organ function, including bone marrow reserve,\n             hepatic, renal, pancreatic function and controlled blood pressure as described in the\n             protocol.\n\n          6. Female participants who are postmenopausal for at least 1 year, are surgically\n             sterile, or if of childbearing potential who agree to use 2 effective method(s) of\n             contraception during the study treatment period through 6 months after the last dose\n             of study drug or practice true abstinence.\n\n             Male participants, even if surgically sterilized, who agree to practice effective\n             barrier contraception during the study treatment period through 6 months after the\n             last dose of study drug or practice true abstinence.\n\n          7. Voluntary written consent must be given before performance of any study related\n             procedure not part of standard medical care, with the understanding that consent may\n             be withdrawn by the participant at any time without prejudice to future medical care.\n\n          8. Participants must have recovered from the reversible effects of prior anticancer\n             therapy (to Grade less than or equal to (<=) 1).\n\n        Exclusion Criteria:\n\n        Participants meeting any of the following exclusion criteria are not to be enrolled in the\n        study.\n\n          1. Participants with brain metastasis, or participants with central nervous system (CNS)\n             lymphoma or participants with another malignancy within two years of study start, with\n             exceptions as described in the protocol.\n\n          2. Any serious medical or psychiatric illness, including drug or alcohol abuse, that\n             could, in the investigator's opinion, potentially interfere with the completion of\n             treatment according to this protocol.\n\n          3. Life-threatening illness unrelated to cancer; major surgery within 14 days before the\n             first dose of study drug; systemic infection requiring intravenous (IV) antibiotic\n             therapy or other serious infection (bacterial, fungal, or viral) within 21 days before\n             the first dose of study drug.\n\n          4. Female participants who are pregnant or lactating.\n\n          5. Any immunotherapy, chemotherapy, radiotherapy, or investigational therapy within 3-4\n             weeks before the first dose of study treatment, as detailed in the protocol.\n\n          6. For escalation cohort or expansion cohorts excluding PTLD, ASCT within 6 months before\n             Day 1 of Cycle 1, or prior ASCT at any time without full hematopoietic recovery before\n             Day 1 of Cycle 1, or prior allogeneic stem cell transplant at any time.\n\n          7. Treatment with high dose corticosteroids (> daily dose equivalent to 10 milligram (mg)\n             oral prednisone) for anticancer purposes within 7 days before the first dose of\n             TAK-659.\n\n          8. Known human immunodeficiency virus (HIV) positive; known hepatitis B surface\n             antigen-positive; or known or suspected active hepatitis C infection (testing not\n             required).\n\n          9. Evidence of currently uncontrolled cardiovascular conditions as listed in the\n             protocol.\n\n         10. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral\n             absorption or tolerance of TAK-659 including difficulty swallowing tablets; diarrhea >\n             Grade 1 despite supportive therapy.\n\n         11. Lack of suitable venous access for required blood sampling.\n\n         12. Use or consumption of P-glycoprotein (P-gp) inducers/inhibitors and/or strong CYP3A\n             inducers/inhibitors as described in the protocol, and grapefruit-containing food or\n             beverages as described in the protocol.
Inclusion Criteria:\n\n        Patients must meet all of the following inclusion criteria to be eligible for enrollment:\n\n          -  Ability to understand the risks, benefits, and alternative to participation and give\n             informed consent\n\n          -  Have biopsy proven skin cancer on the medial forehead that is amenable to Mohs\n             surgery. Medial forehead is defined as the area superiorly from the hairline,\n             inferiorly at the eyebrow, and laterally to the tip of the lateral brow (see diagram).\n\n          -  Undergoing elective reconstruction of biopsy proven skin cancer that is amenable to\n             Mohs surgery with defect size measuring 1.0 cm or greater\n\n          -  If female, not currently pregnant, no potential for pregnancy, or if of child-bearing\n             age, must agree to use adequate contraception (e.g., hormonal or barrier method of\n             birth control; abstinence) for 30 days after the last dose of study drug. A negative\n             urine pregnancy test is required at study entry for female subjects of childbearing\n             potential: a woman is considered to be of child bearing potential unless she has had a\n             tubal ligation, total hysterectomy, bilateral oopherectomy, or is postmenopausal\n             (without a menstrual period for at least one year)\n\n          -  Agrees to not use disallowed concomitant medications (retinoids)\n\n        Exclusion Criteria:\n\n        The presence of any of the following will exclude a patient from study enrollment.\n\n          -  Pregnant women, women who are breastfeeding, or women of child bearing age who are\n             unwilling to use adequate contraception (described above) during the study period\n\n          -  Current or past history of a neuromuscular disease (such as myasthenia gravis,\n             amyotrophic lateral sclerosis, Eaton-Lambert syndrome)\n\n          -  Currently taking aminoglycosides or other agents interfering with neuromuscular\n             transmission (e.g., curare-like agents)\n\n          -  History of radiation therapy or chemotherapy\n\n          -  History of keloid or other hypertrophic scar formation\n\n          -  Current or past history of scleroderma\n\n          -  Has used botulinum toxin in the forehead area within one year.\n\n          -  Has significant resting eyebrow ptosis\n\n          -  Has used any topical retinoids to the forehead area within the past 4 weeks\n\n          -  Undergo any scar revision procedure for the duration of the study including\n             intralesional kenalog, laser treatment, and/or scar revision surgeries\n\n          -  Any hypersensitivity to any component of abobotulinumtoxinA (i.e. cow milk protein) or\n             any previous hypersensitivity to any botulinum toxin A or related product.\n\n          -  Non-English speaking: These patients are excluded since translation of the informed\n             consent into other languages is time-consuming and expensive as it requires a bona\n             fide translator for the particular language of interest and this type of person may be\n             difficult to locate.\n\n          -  House staff and students, medical students on a clerkship, and employees related to\n             study personnel or who work for any study personnel, and members of the study team are\n             not eligible to participate in this study as a subject.\n\n          -  The investigator feels that for any reason the subject is not eligible to participate\n             in the study
Inclusion Criteria:\n\n          1. Male or female patients age ? 18 years of age at the time of informed consent\n\n          2. HLA-A*0201 positive, confirmed by central laboratory\n\n          3. NY-ESO-1 and/or LAGE-1A positive tumor confirmed by the central laboratory\n\n          4. Arm 1: Patients must be refractory to or intolerant to all existing therapies known to\n             provide clinical benefit for their condition.\n\n          5. Arm 2: Subjects will have received the following previous therapies:\n\n               1. NSCLC — PD-1/PD-L1 inhibitor\n\n               2. Patients with NSCLC and an EGFR or ALK genomic tumor aberration must have disease\n                  progression after treatment with Health Authority-approved agents for these\n                  aberrations\n\n               3. Urothelial cancer — PD-1/PD-L1 inhibitor\n\n               4. Synovial sarcoma — at least one prior chemotherapy regimen\n\n          6. Arm 1 only: Histologically confirmed diagnosis of advanced NSCLC, melanoma, urothelial\n             carcinoma, or synovial sarcoma\n\n          7. Arm 2 only: Histologically confirmed diagnosis of advanced NSCLC, urothelial\n             carcinoma, or synovial sarcoma\n\n          8. Arm 2 only: Disease amenable to biopsy\n\n          9. Arm 2 only: Measurable disease to RECIST v.1.1 criteria\n\n        Exclusion Criteria:\n\n        Impaired baseline organ function as evaluated by out-of-range laboratory values 2. History\n        of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or\n        monoclonal antibodies 3. Clinically significant cardiac disease or impaired cardiac\n        function 4. Presence of symptomatic or untreated central nervous system (CNS) metastases 5.\n        Active infection requiring systemic antibiotic therapy 6. Known history of human\n        immunodeficiency virus infection (HIV) 7. Active hepatitis B virus (HBV) or hepatitis C\n        virus (HCV) infection 8. Malignant disease, other than that being treated in this study 9.\n        Patients receiving systemic steroid therapy or any other systemic immunosuppressive\n        medication. Local steroid therapies are acceptable 10. Systemic anti-cancer therapy within\n        2 weeks of the first dose of study drug.\n\n        11. Major surgery within 2 weeks of the first dose of study drug 12. Radiotherapy within 2\n        weeks of the first dose of study drug, with the exception of palliative radiotherapy to a\n        limited field 13. Use of hematopoietic colony-stimulating growth factors (eg, G-CSF,\n        GM-CSF, M-CSF) ? 2 weeks prior to start of study drug 14. Pregnant, likely to become\n        pregnant, or lactating women
Inclusion Criteria:\n\n          -  Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma\n             using AJCC edition 8\n\n          -  Previously treated for unresectable or metastatic melanoma. Subjects must have at\n             least received the following treatments:\n\n               -  V600BRAF wild-type patients: must have received anti-PD-1/PD-L1 single-agent, or\n                  in combination with anti-CTLA-4 therapy\n\n               -  V600BRAF mutant patients: must have received prior anti-PD-1/PD-L1 single-agent,\n                  or in combination with anti-CTLA-4 therapy. In addition, subjects must have\n                  received prior V600BRAF inhibitor therapy, either single-agent or in combination\n                  with a MEK inhibitor\n\n          -  ECOG performance status 0-2\n\n          -  At least one measurable lesion per RECIST v1.1\n\n          -  At least one lesion, suitable for sequential mandatory tumor biopsies (screening and\n             on-treatment) in accordance with the biopsy guidelines specified in protocol. The same\n             lesion must be biopsied sequentially.\n\n          -  Screening tumor biopsy must fulfill the tissue quality criteria outlined in the\n             protocol, as assessed by a local pathologist\n\n        Key exclusion criteria common to all combination arms:\n\n          -  Subjects with uveal or mucosal melanoma\n\n          -  Presence of clinically active or unstable brain metastasis. Note: Subjects with\n             unstable brain lesions who have been definitively treated with stereotactic radiation\n             therapy, surgery or gamma knife therapy are eligible.\n\n             - Subjects with brain lesions who are untreated (i.e. newly discovered brain lesions\n             during screening) or received whole brain radiation must have documented stable\n             disease as assessed by two consecutive assessments ? 4 weeks apart and have not\n             required steroids for at least ? 4 weeks prior to enrollment.\n\n          -  Use of any live vaccines against infectious diseases within 4 weeks of initiation of\n             study treatment.\n\n          -  Active infection requiring systemic antibiotic therapy.\n\n          -  Systemic chronic steroid therapy (? 10mg/day prednisone or equivalent) or any other\n             immunosuppressive therapy 7 days prior to planned date of first dose of study\n             treatment. Note: Local steroids such as topical, inhaled, nasal and ophthalmic\n             steroids are allowed.\n\n          -  Active, known or suspected autoimmune disease or a documented history of autoimmune\n             disease. Note: Subjects with vitiligo, controlled type I diabetes mellitus on stable\n             insulin dose, residual autoimmune-related hypothyroidism only requiring hormone\n             replacement or psoriasis not requiring systemic treatment are permitted.\n\n          -  Prior allogenic bone marrow or solid organ transplant\n\n          -  History of known hypersensitivity to any of the investigational drugs used in this\n             study
Inclusion Criteria:\n\n        The tumor tissue must have been determined to be KRAS, NRAS, BRAF, PIK3CA (all RAS\n        quadruple) wild-type by CLIA testing.\n\n        The ECOG performance status must be 0, 1 or 2. Patients must have the ability to swallow\n        and retain oral medication. There must be documentation by CT scan, or MRI, that the\n        patient has evidence of measurable metastatic disease per RECIST 1.1 criteria.\n\n        Patients must have an accessible metastatic lesion for pretreatment core biopsy\n        procurement.\n\n        Unless either drug is medically contraindicated, patients must have received oxaliplatin\n        and irinotecan as part of standard chemotherapy regimens. (This includes adjuvant therapy.)\n\n        Specific patient eligibility for quadruple WT and HER2 status:\n\n        Arm 1:\n\n        HER2 amplified confirmed by CLIA testing performed on blood samples, and prior treatment\n        with cetuximab or panitumumab.\n\n        HER2 mutation confirmed by CLIA testing of tumor, and with or without prior treatment with\n        cetuximab or panitumumab.\n\n        Arm 2:\n\n        HER2 WT or HER2 amplified confirmed by CLIA testing of this tumor, and no prior therapy\n        with cetuximab or panitumumab.\n\n        Blood counts performed within 2 weeks prior to study entry must meet the following\n        criteria:\n\n        ANC must be greater than or equal to 1000/mm3. Platelet count must be greater than or equal\n        to 75,000/mm3. Hemoglobin must be greater than or equal to 8 g/dL.\n\n        Adequate hepatic function performed within 2 weeks prior to study entry must be met:\n\n          -  Total bilirubin must be less than or equal to 1.5 x ULN (upper limit of normal) for\n             the lab unless the patient has a bilirubin elevation greater than 1.5 x ULN to 3 x ULN\n             due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin;\n             and\n\n          -  Alkaline phosphatase must be less than or equal to 3 x ULN for the lab with the\n             following exception: for patients with documented liver metastases or bone involvement\n             alkaline phosphatase must be less than or equal to 5 x ULN; and\n\n          -  AST and ALT must be less than or equal to 3 x ULN for the lab with the following\n             exception: for patients with documented liver metastases, AST and ALT must be less\n             than or equal to 5 x ULN.\n\n        Serum creatinine performed within 2 weeks prior to study entry must be less than or equal\n        to 1.5 x ULN for the lab.\n\n        Patients eligible for Arm 1 (neratinib + trastuzumab): Left ventricular ejection fraction\n        must be greater than or equal to 50% or within normal range for the institution (whichever\n        is lowest).\n\n        Female patients and male patients with female partners of reproductive potential must agree\n        to use an effective method of contraception during therapy and for at least 7 months after\n        the last dose of study therapy.\n\n        Exclusion Criteria:\n\n        Diagnosis of anal or small bowel carcinoma. Colorectal cancer histology other than\n        adenocarcinoma, e.g., sarcoma, lymphoma, carcinoid.\n\n        Previous therapy with any HER2 targeting agents (such as trastuzumab, lapatinib, neratinib,\n        etc.) for any malignancy.\n\n        Symptomatic brain metastases or brain metastases requiring chronic steroids to control\n        symptoms.\n\n        Active hepatitis B or hepatitis C with abnormal liver function tests. Malabsorption\n        syndrome, ulcerative colitis, inflammatory bowel disease, resection of the stomach or small\n        bowel, or other disease or condition significantly affecting gastrointestinal function.\n\n        Persistent CTCAE v4.0 greater than or equal to grade 2 diarrhea regardless of etiology.\n\n        CTCAE v4.0 grade 3 or 4 anorexia or nausea related to metastatic disease. CTCAE v4.0\n        greater than or equal to grade 2 vomiting related to metastatic disease.\n\n        Any of the following cardiac conditions: documented congestive heart failure; myocardial\n        infarction within 6 months prior to study entry; unstable angina within 6 months prior to\n        study entry; symptomatic arrhythmia.\n\n        Serious or non-healing wound, skin ulcer, or bone fracture. History of bleeding diathesis.\n        (Patients on stable anticoagulant therapy are eligible.) Symptomatic interstitial lung\n        disease or definitive evidence of interstitial lung disease described on CT scan, MRI, or\n        chest x-ray in asymptomatic patients; dyspnea at rest requiring current continuous oxygen\n        therapy.\n\n        Previous serious hypersensitivity reaction to monoclonal antibodies. (Determination of\n        \serious\ hypersensitivity reaction is at the investigator's discretion.) Other\n        malignancies unless the patient is considered to be disease-free and has completed therapy\n        for the malignancy greater than or equal to 12 months prior to study entry. Patients with\n        the following cancers are eligible if diagnosed and treated within the past 12 months:\n        carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ, and basal\n        cell and squamous cell carcinoma of the skin.\n\n        Psychiatric or addictive disorders or other conditions that, in the opinion of the\n        investigator, would preclude the patient from meeting the study requirements.\n\n        Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be\n        performed within 14 days prior to study entry according to institutional standards for\n        women of childbearing potential.) Use of any investigational agent within 4 weeks prior to\n        study entry. Note: Use of agents known to be strong cytochrome P450 (CYP) 3A4 inducers or\n        inhibitors, and proton pump inhibitors (PPIs) should be avoided for the duration of study\n        therapy.
Inclusion Criteria:\n\n          -  Scheduled to undergo an elective (non-emergent) bowel resection with or without a\n             planned stoma via laparotomy or minimally invasive technique. This includes any\n             subject in which a resection of the small intestine, colon, or rectum is performed for\n             any elected indication.\n\n          -  Has been informed of the nature of the study (either the subject or their legal\n             representative), agrees to its provisions, and has provided written informed consent.\n\n        Exclusion Criteria:\n\n        Subjects will not be eligible for participation in the study if they meet ANY of the\n        following exclusion criteria:\n\n          -  <18 or >80 years of age.\n\n          -  Requires emergency bowel surgery.\n\n          -  Has had 1 or more abdominal surgeries, excluding the current, for inflammatory bowel\n             disease, including, but not limited to, inflammatory bowel disease (IBD), Crohn's\n             Disease, or ulcerative colitis. Note: This does not apply to previous surgery such as\n             hernia repair unrelated to IBD.\n\n          -  American Society of Anesthesiologists (ASA) Class 4 or 5.\n\n          -  Insulin dependent diabetes mellitus.\n\n          -  Known inability to take the study drug orally (i.e. complete small bowel obstruction).\n\n          -  Has contraindications or potential risk factors to taking TXA. These include subjects\n             with:\n\n               1. Known sensitivity to TXA;\n\n               2. Recent craniotomy (past 30 days);\n\n               3. Active cerebrovascular bleed;\n\n               4. Active thromboembolic disease (such as deep vein thrombosis, pulmonary embolism,\n                  cerebral thrombosis, ischemic stroke, or acute coronary syndrome);\n\n               5. Acute promyelocytic leukemia taking all-trans retinoic acid for remission\n                  induction, or\n\n               6. Continuing use of a combined hormonal contraceptive and or combined hormonal\n                  replacement therapy (including combined hormonal pill, patch, or vaginal ring).\n\n          -  Has the following risk factors for thromboembolic disease:\n\n               1. Known medical history of congenital or acquired thrombophilia such as, but not\n                  limited to patients with:\n\n                    -  Sickle cell disease;\n\n                    -  Nephrotic syndrome;\n\n                    -  Factor V Leiden;\n\n                    -  Prothrombin gene mutation;\n\n                    -  Protein C or S deficiency;\n\n                    -  Antithrombin III deficiency;\n\n                    -  Antiphospholipid syndrome.\n\n               2. Stage IV malignant neoplasm;\n\n               3. Neurologic paresis, partial paralysis, or paralysis;\n\n               4. Pacemaker;\n\n               5. History of pulmonary embolism, deep vein thrombosis, cerebrovascular accident, or\n                  rental venous/arterial occlusion;\n\n          -  History of or current seizure disorder.\n\n          -  Patients with myeloproliferative disorders.\n\n          -  Body Mass Index (BMI) >40.\n\n          -  Any other condition that, in the opinion of the Investigator, would preclude the\n             subject from being an appropriate candidate for the study, including severe renal or\n             hepatic impairment.\n\n          -  Planned treatment with alvimopan (Entereg®) during study participation period.\n\n          -  Received any other investigational therapy within 4 weeks prior to Randomization\n\n          -  Chronic opioid usage, defined by the American Pain Society as daily or near-daily use\n             of opioids for at least 90 days.\n\n          -  Female subjects of childbearing potential with a positive urine or serum pregnancy\n             test or who are not taking (or not willing to take) acceptable birth control measures\n             (abstinence, intrauterine devices, contraceptive implants or barrier methods) through\n             Day 30. Additionally, those women who are lactating and insist on breast feeding\n             within 5 days of the last dose of study drug.\n\n          -  Known history of radiation enteritis.
Inclusion Criteria:\n\n        Patients eligible for inclusion in this study have to meet all of the following criteria:\n\n          -  Patient must have had at least one prior line of therapy for their disease and must\n             not be beyond 4th progression/relapse of disease (5 maximum prior lines).\n\n          -  Patient has a pathology confirmed diagnosis of a solid tumor or lymphoma listed in the\n             section \condition\. Patients must have measurable disease as per appropriate\n             guidelines (Solid Tumors by RECIST 1.1 and Diffuse Large B-cell Lymphoma by Revised\n             Response Criteria for Malignant Lymphoma - Cheson et al 2007).\n\n          -  Expansion Cohorts only: Patient must have a site of disease amenable to biopsy, and be\n             a candidate for tumor biopsy according to the treating institution's guidelines.\n             Exceptions may be considered after discussion with the sponsor.\n\n        Exclusion Criteria:\n\n        Patients eligible for this study must not meet any of the following criteria:\n\n          -  History of severe hypersensitivity reactions to other mAbs.\n\n          -  Impaired cardiac function or clinically significant cardiac disease.\n\n          -  Active, known or suspected autoimmune disease or a documented history of autoimmune\n             disease within three years prior to screening with a few exceptions as per protocol.\n\n          -  Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated\n             for skin rash or with replacement therapy for endocrinopathies should not be excluded.\n\n          -  Patient with second primary malignancy within < 3 years of first dose of study\n             treatment.\n\n          -  Prior immunotherapy treatment with PD-1, PD-L1, CTLA-4, or LAG-3 antibodies.\n\n        Other protocol-defined inclusion/exclusion criteria may apply.
Inclusion Criteria:\n\n        Cohort A only\n\n        • Receiving ruxolitinib dose of less than 20 mg daily with no dose increase or no dose\n        modification in the last 8 weeks before screening visit.\n\n        Cohort B only\n\n        • Must have had initial reduction in spleen on ruxolitinib treatment:\n\n          -  Followed by documented evidence of progression in spleen length or volume OR\n\n          -  Discontinued ruxolitinib for hematologic toxicities, after the initial reduction in\n             spleen length or volume.\n\n        All subjects\n\n          -  Confirmed diagnosis of primary myelofibrosis, post-polycythemia vera myelofibrosis, or\n             post-essential thrombocythemia myelofibrosis according to revised World Health\n             Organization 2016 criteria.\n\n          -  Must have palpable spleen of ? 5 cm below the left subcostal margin on physical\n             examination at the screening visit.\n\n          -  Eastern Cooperative Oncology Group performance status of 0, 1, or 2.\n\n          -  Screening bone marrow biopsy specimen available or willingness to undergo a bone\n             marrow biopsy at screening/baseline; willingness to undergo bone marrow biopsy at Week\n             24.\n\n          -  Life expectancy of at least 24 weeks.\n\n          -  Willingness to avoid pregnancy or fathering children\n\n        Exclusion Criteria:\n\n          -  Lack of recovery from all toxicities from previous therapy (except ruxolitinib) to\n             Grade 1 or better.\n\n          -  Previous treatment with itacitinib or JAK1 inhibitors (JAK1/JAK2 inhibitor ruxolitinib\n             is permitted).\n\n          -  Inability to swallow food or any condition of the upper gastrointestinal tract that\n             precludes administration of oral medications.\n\n          -  Recent history of inadequate bone marrow reserve as demonstrated by protocol-defined\n             criteria.\n\n          -  Inadequate liver function at screening and baseline visits as demonstrated by\n             protocol-defined criteria.\n\n          -  Inadequate renal function at screening and baseline visits as demonstrated by\n             protocol-defined criteria.\n\n          -  Active bacterial, fungal, parasitic, or viral infection that requires therapy.\n\n          -  Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of\n             reactivation: HBV DNA and HCV RNA must be undetectable. Subjects cannot be positive\n             for hepatitis B surface antigen or anti-hepatitis B core antibodies. Subjects who have\n             positive anti-HBs as the only evidence of prior exposure may participate in the study\n             provided that there is both 1) no known history of HBV infection and 2) verified\n             receipt of hepatitis B vaccine.\n\n          -  Known human immunodeficiency virus infection.\n\n          -  Clinically significant or uncontrolled cardiac disease.\n\n          -  Active invasive malignancy over the previous 2 years except treated basal or squamous\n             carcinomas of the skin, completely resected intraepithelial carcinoma of the cervix,\n             and completely resected papillary thyroid and follicular thyroid cancers. Subjects\n             with malignancies with indolent behavior such as prostate cancer treated with\n             radiation or surgery may be enrolled as long as they have a reasonable expectation to\n             have been cured with the treatment modality received.\n\n          -  Splenic irradiation within 6 months before receiving the first dose of itacitinib.\n\n          -  Use of any prohibited concomitant medications.\n\n          -  Active alcohol or drug addiction that would interfere with their ability to comply\n             with the study requirements.\n\n          -  Use of any potent cytochrome P450 3A4 inhibitors or inducers within 14 days or 5\n             half-lives (whichever is longer) before the first dose of itacitinib or anticipated\n             during the study.\n\n          -  Use of concomitant treatment of fluconazole at a dose > 200 mg (for ruxolitinib\n             subjects treated in Cohort A only).\n\n          -  Inadequate recovery from toxicity and/or complications from a major surgery before\n             starting therapy.\n\n          -  Currently breastfeeding or pregnant.
-  Patients must have a histologically confirmed diagnosis of invasive breast carcinoma\n             with positive estrogen and/or progesterone receptor status, and negative human\n             epidermal growth factor receptor (HER-2), for whom endocrine therapy is planned.\n\n          -  The HER-2 test result is negative (and should be reported as such), if a single test\n             (or all tests)performed in a tumor specimen show:\n\n               -  Immunohistochemistries (IHC) 1+ negative or IHC 0 negative or\n\n               -  in situ hybridization (ISH) negative using a single probe ISH or dual probe ISH.\n\n          -  Estrogen receptor (ER) and progesterone receptor (PgR) positivity must be assessed\n             according to American Society of Clinial Oncology (ASCO)/College of American\n             Physicians (CAP) guidelines as either ER or PR ? 1% positive nuclear staining. If HER2\n             IHC is 2+, an evaluation for gene amplification must be performed and the gene must\n             not be amplified. Gene amplification evaluation is not required if evaluation by IHC\n             is 0 or 1+ by institutional standards.\n\n          -  Patients must be post-menopausal women with a confirmed diagnosis of metastatic breast\n             cancer (M1). Pathologic confirmation of histology is preferable. In the case of bone\n             metastases only, biopsy-proven metastatic disease of solitary site, or multiple sites\n             of involvement are required. Post-menopausal is defined by one of the following\n             criteria as per National Comprehensive Cancer Network (NCCN) guidelines Version 3.\n             2013:\n\n               -  Prior bilateral oophorectomy and/or hysterectomy\n\n               -  Patients ? 60 years of age\n\n               -  Patients < 60 years of age and amenorrheic for ? 12 months in the absence of\n                  chemotherapy, tamoxifen, toremifene, or ovarian suppression and\n                  follicle-stimulating hormone (FSH) and estradiol in the post-menopausal range\n\n               -  Patients < 60 years of age taking tamoxifen or toremifene must have FSH and\n                  plasma estradiol levels within post-menopausal ranges\n\n          -  Patients must have measurable or evaluable disease. Patients must have a chest and\n             abdominal computerized tomography (CT) and bone scan within 28 days prior to\n             registration. All scans needed for assessment of measurable disease must be performed\n             within 28 days prior to registration. Evaluable disease must be assessed within 28\n             days prior to registration\n\n          -  Patients with a history of prior chemotherapy or hormone therapy or immunotherapy for\n             recurrent or metastatic disease are NOT eligible. Prior adjuvant or neoadjuvant\n             chemotherapy if completed more than 12 months prior to registration is acceptable. Any\n             number of prior hormonal therapy regimens for the adjuvant setting but not for\n             metastatic or recurrent disease is allowed; prior adjuvant or neoadjuvant treatment\n             with an aromatase inhibitor (e.g. anastrozole, letrozole, exemestane) is allowed, if\n             completed more than 12 months prior to randomization.\n\n          -  Patients who have taken luteinizing hormone-releasing hormone (LHRH) analogue as\n             adjuvant therapy are eligible provided they have a) discontinued such therapy at least\n             12 months prior to registration AND b) have not resumed their menstrual periods.\n\n          -  Patients must not have had prior exposure to fulvestrant or mTOR inhibitors (e.g.,\n             rapamycin, everolimus, temsirolimus, deforolimus). Concurrent bisphosphonate therapy\n             is allowed. Patients must not have prior treatment with any investigational drug\n             within 28 days prior to registration and must not be planning to receive any other\n             investigational drug for the duration of the study.\n\n          -  Patients must have an International Normalized Ratio (INR) ? 1.6 within 28 days prior\n             to registration.\n\n          -  Patients must have adequate bone marrow function, as defined by Absolute Neutrophil\n             Count (ANC) of ? 1,500/mL, hemoglobin ? 9 g/dL and a peripheral platelet count ?\n             100,000/ mL, all within 28 days prior to registration.\n\n          -  Patients must have adequate hepatic function obtained within 28 days prior to\n             registration and documented by all of the following:\n\n               -  Bilirubin ? 1.5 mg/dL (or ? 3.0 mg/dL if due to Gilbert's Syndrome)\n\n               -  alanine aminotransferase (ALT) (SGPT) and aspartate aminotransferase (AST) (SGOT)\n                  ? 2.5 x Institutional Upper Limit of Normal (IULN), or ? 5 x IULN if hepatic\n                  metastases are present.\n\n          -  Patients must have adequate renal function with serum creatinine level ? IULN within\n             28 days prior to registration.\n\n          -  Patients must have a fasting cholesterol ? 300 mg/dL and triglycerides ? 2.5 x IULN\n             obtained within 28 days prior to registration. Patients may be on lipid lowering\n             agents to reach these values.\n\n          -  Patients must have a complete history and physical examination within 28 days prior to\n             registration.\n\n          -  Patients with bleeding diathesis (i.e., disseminated intravascular coagulation [DIC],\n             clotting factor deficiency) or long-term anti-coagulant therapy (other than\n             antiplatelet therapy) are NOT eligible.\n\n          -  Patients with presence of life-threatening metastatic visceral disease, defined as\n             extensive hepatic involvement, or any degree of brain or leptomeningeal involvement\n             (past or present), or symptomatic pulmonary lymphangitic spread are not eligible.\n             Patients with discrete pulmonary parenchymal metastases are eligible, provided their\n             respiratory function is not significantly compromised as a result of disease in the\n             opinion of the investigator.\n\n          -  Patients must have a performance status of 0 - 2 by Zubrod criteria.\n\n          -  Patients must not have any Grade III/IV cardiac disease as defined by the New York\n             Heart Association Criteria (i.e., patients with cardiac disease resulting in marked\n             limitation of physical activity or resulting in inability to carry on any physical\n             activity without discomfort), unstable angina pectoris, myocardial infarction within 6\n             months, or serious uncontrolled cardiac arrhythmia.\n\n          -  Patients must not have uncontrolled diabetes (defined as an Hg A1C >7% within 28 days\n             prior to registration).\n\n          -  Patients must not have an organ allograft or other history of immune compromise.\n             Patients must not be receiving chronic, systemic treatment with corticosteroids or\n             other immunosuppressive agent. Topical or inhaled corticosteroids are allowed.\n\n          -  Patients known to be HIV positive may be enrolled if baseline CD4 count is > 500\n             cells/mm3 AND not taking anti-retroviral therapy. Patients with known chronic or\n             active hepatitis are not eligible. Patients must not have any known uncontrolled\n             underlying pulmonary disease.\n\n          -  Patients must be able to take oral medications. Patient may not have any impairment of\n             gastrointestinal function or gastrointestinal disease that may significantly alter the\n             absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting,\n             diarrhea, malabsorption syndrome or small bowel resection).\n\n          -  Patients must not have received immunization with an attenuated live vaccine (e.g.\n             intranasal influenza, MMR, oral polio, varicella, zoster, yellow fever and BCG\n             vaccines) within seven days prior to registration nor have plans to receive such\n             vaccination while on protocol treatment.\n\n          -  Patients must not have taken within 14 days prior to registration, be taking, nor plan\n             to take while on protocol treatment, strong CYP3A4 inhibitors, and/or CYP3A4 inducers.\n\n          -  No other prior malignancy is allowed except for adequately treated basal cell or\n             squamous cell skin cancer, in situ cervical cancer or other cancer for which the\n             patient has been disease-free for 5 years.
Inclusion Criteria:\n\n          1. Patients having histologically confirmed unresectable (Stage III) or metastatic\n             (Stage IV) malignant melanoma with a positive BRAF mutation result determined by\n             Roche CoDx or local CLIA-certified analysis\n\n          2. Patients naïve to a selective BRAF inhibitor therapy or must have progressed after\n             therapy on a selective BRAF inhibitor. For patients entering the protocol progressing\n             on vemurafenib therapy, they must be tolerant of the 960 mg po bid dose.\n\n          3. Tumor biopsies are optional in this study except for patients entering the mandatory\n             biopsy cohorts. Nevertheless tumor biopsies are encouraged, especially in patients\n             with accessible tumors for biopsy to include the collection of formalin-fixed,\n             paraffin-embedded (FFPE) and fresh- frozen tissue (FF) as outlined in the biomarker\n             sections of the protocol. Willingness of patient to give consent of biopsy, should be\n             ascertained\n\n          4. Patients of ? 18 years of age\n\n          5. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 or1\n\n          6. Patients with measurable disease per 'Response Evaluation Criteria In Solid Tumors'\n             (RECIST version 1.1)\n\n          7. Patients must have normal organ and adequate marrow function\n\n          8. Patients with ability to swallow and retain oral medication\n\n          9. Women of childbearing potential and men willing to agree to use adequate\n             contraception (hormonal or barrier method of birth control; abstinence) prior to\n             study entry, during the duration of study participation and for at least 4 weeks\n             after withdrawal from the study, unless they are surgically sterilized.\n\n         10. Negative serum pregnancy test within 10 days prior to commencement of therapy dosing\n             in premenopausal women. Women of non-childbearing potential may be included if they\n             are either surgically sterile or have been postmenopausal for ?1 year.\n\n         11. Ability to understand and the willingness to offer a written Informed Consent\n             document prior to the screening procedures for participation into the study\n\n               -  For Extension phase-\n\n               -  For patients entering the protocol progressing on vemurafenib therapy, they must\n                  be tolerant of the vemurafenib dose selected for the extension phase\n\n        Exclusion Criteria:\n\n          1. Prior malignancy (within the last 2 years) except for adequately treated basal cell\n             or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ\n             prostate cancer or any other cancer for which the patient has been disease-free for\n             at least 2 years\n\n          2. Patients who have received any prior chemotherapy, radiotherapy, biologic/targeted\n             anti-cancer therapy (one week  for BRAF inhibitor for melanoma) or surgery within 4\n             weeks (6 weeks for monoclonal antibodies, radioactive monoclonal antibodies or any\n             radio-or toxin-immunoconjugates) before Day 1 of Investigational product\n             administration and have not recovered (to < Grade 1) from the toxic effects from any\n             prior therapy\n\n          3. Patients having received any other investigational agents within 4 weeks prior to Day\n             1 of Investigational product administration and have not recovered completely (to <\n             Grade 1) from the side effects of the earlier investigational agent\n\n          4. Anticipated administration of any anti-cancer therapies (chemotherapy, radiation\n             therapy, immunotherapy, biological therapy, hormonal therapy, surgery, and/or tumor\n             embolisation) other than those administered in this study such as BRAF inhibitor\n\n          5. Patients with symptomatic or untreated leptomeningeal or brain metastases, or spinal\n             cord compression [patients with previous brain metastases will be allowed to enter\n             the trial if metastases have been surgically removed or all known sites of metastases\n             have been treated with stereotactic high dose radiosurgery. Patients must be off\n             corticosteroids for at least one month and have a stable lesion with verification by\n             imaging (CT/MRI) within 28 days prior to Day 1 of Investigational product\n             administration]\n\n          6. Patients with clinically significant medical condition of malabsorption, inflammatory\n             bowel disease, chronic diarrheal condition, refractory nausea, vomiting or any other\n             condition that will interfere significantly with the absorption of study drugs\n\n          7. Patients with mean QTc interval >480 msec at screening\n\n          8. Treatment with drugs with potential to cause dysrhythmias including but not
Inclusion Criteria:\n\n          1. Patients having histologically confirmed unresectable (Stage III) or metastatic\n             (Stage IV) malignant melanoma with a positive BRAF mutation result determined by\n             Roche CoDx or local CLIA-certified analysis\n\n          2. Patients naïve to a selective BRAF inhibitor therapy or must have progressed after\n             therapy on a selective BRAF inhibitor. For patients entering the protocol progressing\n             on vemurafenib therapy, they must be tolerant of the 960 mg po bid dose.\n\n          3. Tumor biopsies are optional in this study except for patients entering the mandatory\n             biopsy cohorts. Nevertheless tumor biopsies are encouraged, especially in patients\n             with accessible tumors for biopsy to include the collection of formalin-fixed,\n             paraffin-embedded (FFPE) and fresh- frozen tissue (FF) as outlined in the biomarker\n             sections of the protocol. Willingness of patient to give consent of biopsy, should be\n             ascertained\n\n          4. Patients of ? 18 years of age\n\n          5. Patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 or1\n\n          6. Patients with measurable disease per 'Response Evaluation Criteria In Solid Tumors'\n             (RECIST version 1.1)\n\n          7. Patients must have normal organ and adequate marrow function\n\n          8. Patients with ability to swallow and retain oral medication\n\n          9. Women of childbearing potential and men willing to agree to use adequate\n             contraception (hormonal or barrier method of birth control; abstinence) prior to\n             study entry, during the duration of study participation and for at least 4 weeks\n             after withdrawal from the study, unless they are surgically sterilized.\n\n         10. Negative serum pregnancy test within 10 days prior to commencement of therapy dosing\n             in premenopausal women. Women of non-childbearing potential may be included if they\n             are either surgically sterile or have been postmenopausal for ?1 year.\n\n         11. Ability to understand and the willingness to offer a written Informed Consent\n             document prior to the screening procedures for participation into the study\n\n               -  For Extension phase-\n\n               -  For patients entering the protocol progressing on vemurafenib therapy, they must\n                  be tolerant of the vemurafenib dose selected for the extension phase\n\n        Exclusion Criteria:\n\n          1. Prior malignancy (within the last 2 years) except for adequately treated basal cell\n             or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ\n             prostate cancer or any other cancer for which the patient has been disease-free for\n             at least 2 years\n\n          2. Patients who have received any prior chemotherapy, radiotherapy, biologic/targeted\n             anti-cancer therapy (one week  for BRAF inhibitor for melanoma) or surgery within 4\n             weeks (6 weeks for monoclonal antibodies, radioactive monoclonal antibodies or any\n             radio-or toxin-immunoconjugates) before Day 1 of Investigational product\n             administration and have not recovered (to < Grade 1) from the toxic effects from any\n             prior therapy\n\n          3. Patients having received any other investigational agents within 4 weeks prior to Day\n             1 of Investigational product administration and have not recovered completely (to <\n             Grade 1) from the side effects of the earlier investigational agent\n\n          4. Anticipated administration of any anti-cancer therapies (chemotherapy, radiation\n             therapy, immunotherapy, biological therapy, hormonal therapy, surgery, and/or tumor\n             embolisation) other than those administered in this study such as BRAF inhibitor\n\n          5. Patients with symptomatic or untreated leptomeningeal or brain metastases, or spinal\n             cord compression [patients with previous brain metastases will be allowed to enter\n             the trial if metastases have been surgically removed or all known sites of metastases\n             have been treated with stereotactic high dose radiosurgery. Patients must be off\n             corticosteroids for at least one month and have a stable lesion with verification by\n             imaging (CT/MRI) within 28 days prior to Day 1 of Investigational product\n             administration]\n\n          6. Patients with clinically significant medical condition of malabsorption, inflammatory\n             bowel disease, chronic diarrheal condition, refractory nausea, vomiting or any other\n             condition that will interfere significantly with the absorption of study drugs\n\n          7. Patients with mean QTc interval >480 msec at screening\n\n          8. Treatment with drugs with potential to cause dysrhythmias including but not
Inclusion Criteria:\n\n          -  Patients having histologically and/or cytologically confirmed non-haematological\n             malignancy that is metastatic or unresectable and for which standard\n             curative/palliative treatment does not exist or is no longer effective or is not\n             tolerated by patient.\n\n          -  Patients of either sex, of all races and ethnic groups, and more than 18 years of\n             age.\n\n          -  ECOG (Eastern Cooperative Oncology Group) performance status less than 2.\n\n          -  Patients with life expectancy of at least 4 months.\n\n          -  Patients with measurable or evaluable disease per Response Evaluation Criteria In\n             Solid Tumors (RECIST) version 1.1.\n\n          -  Patients must have adequate organ and marrow function as defined below:\n\n          -  Absolute neutrophil count more than equal to 1500/cmm\n\n          -  Platelets more than equal 100,000/cmm\n\n          -  Total bilirubin within normal limits of the institution.\n\n          -  AST/ALT less than equal 2.5 X institutional upper limit of normal (ULN) or less than\n             equal 5 X institutional upper limit of normal (ULN) in the presence of liver\n             metastases\n\n          -  Creatinine less than equal 1.5 X institutional upper limit of normal (ULN)\n\n          -  Women of childbearing potential and men willing to agree to use adequate\n             contraception (hormonal or barrier method of birth control; abstinence) prior to\n             study entry, during the duration of study participation and for at least 4 weeks\n             after withdrawal from the study, unless they are surgically sterilised.\n\n          -  Ability to understand and the willingness to provide a written informed consent\n             document.\n\n        Exclusion Criteria:\n\n          1. Patients who have received any prior chemotherapy, radiotherapy, biologic/targeted\n             anti-cancer therapy or surgery within 4 weeks (3 months for monoclonal antibodies,\n             radioactive monoclonal antibodies or any radio- or toxin- immunoconjugates) before\n             study drug administration and have not recovered (to < Grade 1) from the toxic\n             effects from any prior therapy.\n\n          2. Patients having received any other investigational agents within 4 weeks prior to the\n             date of enrolment and have not recovered completely (to < Grade 1) from the side\n             effects of the earlier investigational agent.\n\n          3. Patients with known brain metastases (except for patients who have previously-treated\n             CNS metastases, are asymptomatic, and have had no requirement for steroids or\n             anti-seizure medication for two months prior to first dose of study drug.)\n\n          4. Patients with a history of myocardial infarction or uncontrolled cardiac dysfunction\n             during the previous 6 months.\n\n          5. Patients with diabetes mellitus requiring insulin therapy at screening or patients\n             with clinically significant diabetic complications, such as neuropathy, retinopathy,\n             peripheral vascular disease or nephropathy.\n\n          6. Clinically significant medical condition of malabsorption, inflammatory bowel\n             disease, or chronic diarrheal condition that might affect the absorption of the\n             investigational agent.\n\n          7. Patients on chronic anticoagulation treatment. Prophylactic anticoagulation with\n             low-molecular heparin is allowed.\n\n          8. Patients with inter-current illness including, but not limited to ongoing or\n             clinically significant active infection, symptomatic congestive heart failure,\n             unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social\n             situations that would limit compliance with study requirements.\n\n          9. Patients with a known history of allergic reaction to any other medication considered\n             to be clinically significant by the investigator.\n\n         10. Women who are pregnant or nursing.\n\n         11. Patients with immune deficiency and at increased risk of lethal infections, for\n             example, known h/o HIV, HBV or HCV.
Inclusion Criteria:\n\n          -  Patients having histologically and/or cytologically confirmed non-haematological\n             malignancy that is metastatic or unresectable and for which standard\n             curative/palliative treatment does not exist or is no longer effective or is not\n             tolerated by patient.\n\n          -  Patients of either sex, of all races and ethnic groups, and more than 18 years of\n             age.\n\n          -  ECOG (Eastern Cooperative Oncology Group) performance status less than 2.\n\n          -  Patients with life expectancy of at least 4 months.\n\n          -  Patients with measurable or evaluable disease per Response Evaluation Criteria In\n             Solid Tumors (RECIST) version 1.1.\n\n          -  Patients must have adequate organ and marrow function as defined below:\n\n          -  Absolute neutrophil count more than equal to 1500/cmm\n\n          -  Platelets more than equal 100,000/cmm\n\n          -  Total bilirubin within normal limits of the institution.\n\n          -  AST/ALT less than equal 2.5 X institutional upper limit of normal (ULN) or less than\n             equal 5 X institutional upper limit of normal (ULN) in the presence of liver\n             metastases\n\n          -  Creatinine less than equal 1.5 X institutional upper limit of normal (ULN)\n\n          -  Women of childbearing potential and men willing to agree to use adequate\n             contraception (hormonal or barrier method of birth control; abstinence) prior to\n             study entry, during the duration of study participation and for at least 4 weeks\n             after withdrawal from the study, unless they are surgically sterilised.\n\n          -  Ability to understand and the willingness to provide a written informed consent\n             document.\n\n        Exclusion Criteria:\n\n          1. Patients who have received any prior chemotherapy, radiotherapy, biologic/targeted\n             anti-cancer therapy or surgery within 4 weeks (3 months for monoclonal antibodies,\n             radioactive monoclonal antibodies or any radio- or toxin- immunoconjugates) before\n             study drug administration and have not recovered (to < Grade 1) from the toxic\n             effects from any prior therapy.\n\n          2. Patients having received any other investigational agents within 4 weeks prior to the\n             date of enrolment and have not recovered completely (to < Grade 1) from the side\n             effects of the earlier investigational agent.\n\n          3. Patients with known brain metastases (except for patients who have previously-treated\n             CNS metastases, are asymptomatic, and have had no requirement for steroids or\n             anti-seizure medication for two months prior to first dose of study drug.)\n\n          4. Patients with a history of myocardial infarction or uncontrolled cardiac dysfunction\n             during the previous 6 months.\n\n          5. Patients with diabetes mellitus requiring insulin therapy at screening or patients\n             with clinically significant diabetic complications, such as neuropathy, retinopathy,\n             peripheral vascular disease or nephropathy.\n\n          6. Clinically significant medical condition of malabsorption, inflammatory bowel\n             disease, or chronic diarrheal condition that might affect the absorption of the\n             investigational agent.\n\n          7. Patients on chronic anticoagulation treatment. Prophylactic anticoagulation with\n             low-molecular heparin is allowed.\n\n          8. Patients with inter-current illness including, but not limited to ongoing or\n             clinically significant active infection, symptomatic congestive heart failure,\n             unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social\n             situations that would limit compliance with study requirements.\n\n          9. Patients with a known history of allergic reaction to any other medication considered\n             to be clinically significant by the investigator.\n\n         10. Women who are pregnant or nursing.\n\n         11. Patients with immune deficiency and at increased risk of lethal infections, for\n             example, known h/o HIV, HBV or HCV.
Main Inclusion Criteria:\n\n          1. Histologically or cytologically confirmed adenocarcinoma of the pancreas\n\n          2. Chemo naïve patients with advanced/metastatic disease\n\n          3. Documented decision justifying non eligibility for surgical resection. The\n             documentation of the non eligibility for surgical resection will be reviewed by an\n             independent committee.\n\n          4. Men and women, age >18 years\n\n          5. Men and women of childbearing potential (entering the study after a confirmed\n             menstrual period and who have a negative pregnancy test), must agree to use two\n             methods (one for the patient and one for the partner) of medically acceptable forms\n             of contraception during the study and for 3 months after the last treatment intake.\n\n          6. Patient should be able and willing to comply with study visits and procedures as per\n             protocol.\n\n          7. Patient should understand, sign, and date the written voluntary informed consent form\n             at the screening visit prior to any protocol-specific procedures performed.\n\n        Main Exclusion Criteria:\n\n          1. Patient treated for a cancer other than pancreatic cancer within 5 years before\n             enrollment, with the exception of basal cell carcinoma or in situ cervical cancer\n\n          2. Any condition that the physician judges could be detrimental to subjects\n             participating in this study; including any clinically important deviations from\n             normal clinical laboratory values or concurrent medical events Previous treatment\n\n          3. Any anti-tumor therapy (any chemotherapy, radiotherapy, immunotherapy, biologic or\n             hormonal therapy) within 6 months prior to baseline\n\n          4. Treatment with any investigational agent within 4 weeks prior to baseline
Main Inclusion Criteria:\n\n          1. Histologically or cytologically confirmed adenocarcinoma of the pancreas\n\n          2. Chemo naïve patients with advanced/metastatic disease\n\n          3. Documented decision justifying non eligibility for surgical resection. The\n             documentation of the non eligibility for surgical resection will be reviewed by an\n             independent committee.\n\n          4. Men and women, age >18 years\n\n          5. Men and women of childbearing potential (entering the study after a confirmed\n             menstrual period and who have a negative pregnancy test), must agree to use two\n             methods (one for the patient and one for the partner) of medically acceptable forms\n             of contraception during the study and for 3 months after the last treatment intake.\n\n          6. Patient should be able and willing to comply with study visits and procedures as per\n             protocol.\n\n          7. Patient should understand, sign, and date the written voluntary informed consent form\n             at the screening visit prior to any protocol-specific procedures performed.\n\n        Main Exclusion Criteria:\n\n          1. Patient treated for a cancer other than pancreatic cancer within 5 years before\n             enrollment, with the exception of basal cell carcinoma or in situ cervical cancer\n\n          2. Any condition that the physician judges could be detrimental to subjects\n             participating in this study; including any clinically important deviations from\n             normal clinical laboratory values or concurrent medical events Previous treatment\n\n          3. Any anti-tumor therapy (any chemotherapy, radiotherapy, immunotherapy, biologic or\n             hormonal therapy) within 6 months prior to baseline\n\n          4. Treatment with any investigational agent within 4 weeks prior to baseline
INCLUSION CRITERIA:\n\n        Patients must meet all of the inclusion criteria outlined below in order to be eligible to\n        participate in the study.\n\n          1. Patients with histologically and/or cytologically confirmed solid tumors who have\n             progressed after receiving approved therapies for their disease and for whom no\n             effective therapies are available.\n\n          2. Surgery and radiotherapy must have been completed at least four weeks prior to study\n             entry, and prior chemotherapy and other anti-cancer therapy, excluding\n             bisphosphonates at a steady dose level, must have been discontinued 2 to 3 weeks\n             previously. All acute toxicities related to these treatments must have resolved.\n\n          3. Aged ? 18 years\n\n          4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.\n\n          5. Written informed consent prior to any study specific screening procedures, which will\n             include mandatory consent to provide a blood sample specifically for pharmacogenomic\n             analysis, with the understanding that the patient may withdraw consent at any time\n             without prejudice. Tumor biopsy for pharmacogenomic (PG) analysis will be voluntary.\n\n          6. Willing and able to comply with the protocol for the duration of the study.\n\n          7. Anticipated life expectancy > three months.\n\n        EXCLUSION CRITERIA:\n\n        Patients with the following characteristics will not be eligible for the study.\n\n          1. Symptomatic or progressive brain tumors or brain or leptomeningeal (CNS) metastases\n             requiring clinical intervention, except if they have completed local therapy and have\n             discontinued the use of corticosteroids for this indication for at least two weeks\n             before starting treatment with E7107.\n\n          2. Any of the following laboratory parameters:\n\n               1. hemoglobin < 9 g/dL (5.6 mM)\n\n               2. neutrophils < 1.5 x 10^9/L\n\n               3. platelets < 100 x 10^9/L\n\n               4. serum bilirubin > 25 ?M (1.5 mg/dL)\n\n               5. liver function tests (defined as AST and ALT) with values > 3 x ULN (5 x ULN if\n                  liver metastases are present)\n\n               6. serum creatinine > 1.5 x ULN or creatinine clearance < 40 mL/min.\n\n          3. Positive history of HIV, active hepatitis B or active hepatitis C or\n             severe/uncontrolled intercurrent illness or infection.\n\n          4. Clinically significant cardiac impairment or unstable ischemic heart disease (greater\n             than Class II according to New York Heart Association (NYHA) classification)\n             including a myocardial infarction within six months of study start.\n\n          5. Bleeding or thrombotic disorders, or using therapeutic dosages of anticoagulants\n\n          6. History of alcoholism, drug addiction, or any psychiatric or psychological condition\n             which, in the opinion of the Investigator, would impair study compliance.\n\n          7. Women who are pregnant or breast-feeding. Women of childbearing potential with either\n             a positive serum pregnancy test at screening, a positive urine pregnancy test at the\n             beginning of any cycle, or no pregnancy test. Women of childbearing potential unless\n             using two forms of contraception, one of which must be a barrier method.\n             Postmenopausal women must be amenorrheic for at least 12 months to be considered of\n             non-childbearing potential.\n\n          8. Fertile men and fertile women who are not willing to use contraception, or fertile\n             men or fertile women with a partner who is not willing to use contraception\n\n          9. Patients with a marked screening or baseline prolongation of QT/QTc interval using\n             the Fridericia formula (ie, repeated demonstration of a QTc interval > 450 msec); a\n             history of additional risk factors for Torsade de Pointe (e.g., heart failure,\n             hypokalaemia, history of Long QT Syndrome).\n\n         10. Patients who have had radiation to >= 25% of their bone marrow (e.g., pelvic\n             radiation).\n\n         11. Patients who have a history of previous Grade 2 or higher hypersensitivity to\n             pladienolide B or derivatives and excipients of the formulation\n\n         12. Patients with significant comorbid disease or condition, which in the Investigator's\n             opinion would exclude the patient from the study\n\n         13. Patients who have received an organ allograft ie, requiring immunosuppressive therapy\n\n         14. Beginning two weeks prior to dosing, patients are not allowed to take drugs that are\n             strong CYP inhibitors (including grapefruit juice and herbal supplements) or inducers\n             (including herbal supplements), or are metabolized by cytochrome P (CYPs) and known\n             to have a narrow
INCLUSION CRITERIA:\n\n        Patients must meet all of the inclusion criteria outlined below in order to be eligible to\n        participate in the study.\n\n          1. Patients with histologically and/or cytologically confirmed solid tumors who have\n             progressed after receiving approved therapies for their disease and for whom no\n             effective therapies are available.\n\n          2. Surgery and radiotherapy must have been completed at least four weeks prior to study\n             entry, and prior chemotherapy and other anti-cancer therapy, excluding\n             bisphosphonates at a steady dose level, must have been discontinued 2 to 3 weeks\n             previously. All acute toxicities related to these treatments must have resolved.\n\n          3. Aged ? 18 years\n\n          4. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.\n\n          5. Written informed consent prior to any study specific screening procedures, which will\n             include mandatory consent to provide a blood sample specifically for pharmacogenomic\n             analysis, with the understanding that the patient may withdraw consent at any time\n             without prejudice. Tumor biopsy for pharmacogenomic (PG) analysis will be voluntary.\n\n          6. Willing and able to comply with the protocol for the duration of the study.\n\n          7. Anticipated life expectancy > three months.\n\n        EXCLUSION CRITERIA:\n\n        Patients with the following characteristics will not be eligible for the study.\n\n          1. Symptomatic or progressive brain tumors or brain or leptomeningeal (CNS) metastases\n             requiring clinical intervention, except if they have completed local therapy and have\n             discontinued the use of corticosteroids for this indication for at least two weeks\n             before starting treatment with E7107.\n\n          2. Any of the following laboratory parameters:\n\n               1. hemoglobin < 9 g/dL (5.6 mM)\n\n               2. neutrophils < 1.5 x 10^9/L\n\n               3. platelets < 100 x 10^9/L\n\n               4. serum bilirubin > 25 ?M (1.5 mg/dL)\n\n               5. liver function tests (defined as AST and ALT) with values > 3 x ULN (5 x ULN if\n                  liver metastases are present)\n\n               6. serum creatinine > 1.5 x ULN or creatinine clearance < 40 mL/min.\n\n          3. Positive history of HIV, active hepatitis B or active hepatitis C or\n             severe/uncontrolled intercurrent illness or infection.\n\n          4. Clinically significant cardiac impairment or unstable ischemic heart disease (greater\n             than Class II according to New York Heart Association (NYHA) classification)\n             including a myocardial infarction within six months of study start.\n\n          5. Bleeding or thrombotic disorders, or using therapeutic dosages of anticoagulants\n\n          6. History of alcoholism, drug addiction, or any psychiatric or psychological condition\n             which, in the opinion of the Investigator, would impair study compliance.\n\n          7. Women who are pregnant or breast-feeding. Women of childbearing potential with either\n             a positive serum pregnancy test at screening, a positive urine pregnancy test at the\n             beginning of any cycle, or no pregnancy test. Women of childbearing potential unless\n             using two forms of contraception, one of which must be a barrier method.\n             Postmenopausal women must be amenorrheic for at least 12 months to be considered of\n             non-childbearing potential.\n\n          8. Fertile men and fertile women who are not willing to use contraception, or fertile\n             men or fertile women with a partner who is not willing to use contraception\n\n          9. Patients with a marked screening or baseline prolongation of QT/QTc interval using\n             the Fridericia formula (ie, repeated demonstration of a QTc interval > 450 msec); a\n             history of additional risk factors for Torsade de Pointe (e.g., heart failure,\n             hypokalaemia, history of Long QT Syndrome).\n\n         10. Patients who have had radiation to >= 25% of their bone marrow (e.g., pelvic\n             radiation).\n\n         11. Patients who have a history of previous Grade 2 or higher hypersensitivity to\n             pladienolide B or derivatives and excipients of the formulation\n\n         12. Patients with significant comorbid disease or condition, which in the Investigator's\n             opinion would exclude the patient from the study\n\n         13. Patients who have received an organ allograft ie, requiring immunosuppressive therapy\n\n         14. Beginning two weeks prior to dosing, patients are not allowed to take drugs that are\n             strong CYP inhibitors (including grapefruit juice and herbal supplements) or inducers\n             (including herbal supplements), or are metabolized by cytochrome P (CYPs) and known\n             to have a narrow
Inclusion Criteria (summary):\n\n          -  Age between 18 and 75 years (inclusive) at screening.\n\n          -  Karnofsky performance status (KPS) of 70 or higher or Eastern Cooperative Oncology\n             Group (ECOG) 0-1 at screening.\n\n          -  Subjects with a histological or cytopathological confirmed diagnosis of a locally\n             advanced or metastatic solid tumor malignancy for which primary treatment is no\n             longer effective or does not offer curative or life-prolonging potential per\n             clinician judgment, with the understanding that DCVax-Direct is not intended as a\n             treatment of last resort.\n\n          -  Not eligible for complete resection due to either tumor location, physician's\n             assessment or subject's choice.\n\n          -  Must have completed at least one recent treatment regimen in the metastatic or\n             advanced setting in the disease currently under treatment to reduce tumor burden.\n\n          -  Any steroid therapy >2 mg dexamethasone or equivalent dose should be stopped or have\n             been tapered down 2 weeks prior to the leukapheresis.\n\n          -  At least one measurable tumor mass, i.e. a lesion that can accurately be measured by\n             CT/MRI in at least one dimension with longest diameter ? 1 cm, that is accessible for\n             injection either with or without imaging (CT/ultrasound) guidance.\n\n          -  Adequate hematological, hepatic, and renal function,\n\n          -  Adequate blood coagulation parameters\n\n          -  Life expectation of >3 months.\n\n        Exclusion Criteria (Summary):\n\n          -  Positive HIV-1, HIV-2, or Human T-lymphotropic virus (HTLV-I/II) tests.\n\n          -  History of current or prior (within the last two years) active clinically significant\n             malignancy other than the tumor type for which DCVax-Direct treatment is considered,\n             and except for primary tumor in the case of metastases and adequately treated basal\n             cell or squamous cell skin cancer or in situ cervical cancer.\n\n          -  Heavily pretreated (HP) subjects are not eligible for this study, unless treatments\n             have occurred more than 1 year in the past.\n\n          -  Presence of brain metastases, unless treated surgically and/or irradiated and\n             clinically stable off steroids or on low dose (< 2 mg per day) steroids for ? 14\n             days, or presence of leptomeningeal disease.\n\n          -  History of immunodeficiency or unresolved autoimmune disease.\n\n          -  Requirement for ongoing immunosuppressants.\n\n          -  Prior active immunotherapy for cancer within the past 2 years.\n\n          -  Ongoing medical need for continuous anti-coagulation or anti-platelet medication.\n\n          -  Known genetic cancer-susceptibility syndromes.\n\n          -  Acute or active uncontrolled infection\n\n          -  Ongoing fever ? 101.5 degrees F/38.6 degrees C at screening.\n\n          -  Unstable or severe intercurrent medical conditions such as unstable angina,\n             uncontrolled arrhythmias, Crohn's Disease, ulcerative colitis etc.\n\n          -  Females of child-bearing potential who are pregnant or lactating or who are not using\n             adequate contraception (surgical, hormonal or double barrier, i.e. condom and\n             diaphragm).\n\n          -  Allergy or anaphylaxis to any of the reagents used in this study.\n\n          -  Inability to obtain informed consent because of psychiatric or complicating medical\n             problems.\n\n          -  Inability or unwillingness to return for required visits and follow-up exams.
Inclusion Criteria (summary):\n\n          -  Age between 18 and 75 years (inclusive) at screening.\n\n          -  Karnofsky performance status (KPS) of 70 or higher or Eastern Cooperative Oncology\n             Group (ECOG) 0-1 at screening.\n\n          -  Subjects with a histological or cytopathological confirmed diagnosis of a locally\n             advanced or metastatic solid tumor malignancy for which primary treatment is no\n             longer effective or does not offer curative or life-prolonging potential per\n             clinician judgment, with the understanding that DCVax-Direct is not intended as a\n             treatment of last resort.\n\n          -  Not eligible for complete resection due to either tumor location, physician's\n             assessment or subject's choice.\n\n          -  Must have completed at least one recent treatment regimen in the metastatic or\n             advanced setting in the disease currently under treatment to reduce tumor burden.\n\n          -  Any steroid therapy >2 mg dexamethasone or equivalent dose should be stopped or have\n             been tapered down 2 weeks prior to the leukapheresis.\n\n          -  At least one measurable tumor mass, i.e. a lesion that can accurately be measured by\n             CT/MRI in at least one dimension with longest diameter ? 1 cm, that is accessible for\n             injection either with or without imaging (CT/ultrasound) guidance.\n\n          -  Adequate hematological, hepatic, and renal function,\n\n          -  Adequate blood coagulation parameters\n\n          -  Life expectation of >3 months.\n\n        Exclusion Criteria (Summary):\n\n          -  Positive HIV-1, HIV-2, or Human T-lymphotropic virus (HTLV-I/II) tests.\n\n          -  History of current or prior (within the last two years) active clinically significant\n             malignancy other than the tumor type for which DCVax-Direct treatment is considered,\n             and except for primary tumor in the case of metastases and adequately treated basal\n             cell or squamous cell skin cancer or in situ cervical cancer.\n\n          -  Heavily pretreated (HP) subjects are not eligible for this study, unless treatments\n             have occurred more than 1 year in the past.\n\n          -  Presence of brain metastases, unless treated surgically and/or irradiated and\n             clinically stable off steroids or on low dose (< 2 mg per day) steroids for ? 14\n             days, or presence of leptomeningeal disease.\n\n          -  History of immunodeficiency or unresolved autoimmune disease.\n\n          -  Requirement for ongoing immunosuppressants.\n\n          -  Prior active immunotherapy for cancer within the past 2 years.\n\n          -  Ongoing medical need for continuous anti-coagulation or anti-platelet medication.\n\n          -  Known genetic cancer-susceptibility syndromes.\n\n          -  Acute or active uncontrolled infection\n\n          -  Ongoing fever ? 101.5 degrees F/38.6 degrees C at screening.\n\n          -  Unstable or severe intercurrent medical conditions such as unstable angina,\n             uncontrolled arrhythmias, Crohn's Disease, ulcerative colitis etc.\n\n          -  Females of child-bearing potential who are pregnant or lactating or who are not using\n             adequate contraception (surgical, hormonal or double barrier, i.e. condom and\n             diaphragm).\n\n          -  Allergy or anaphylaxis to any of the reagents used in this study.\n\n          -  Inability to obtain informed consent because of psychiatric or complicating medical\n             problems.\n\n          -  Inability or unwillingness to return for required visits and follow-up exams.
ENTRY CRITERIA:\n\n        DISEASE CHARATERISTICS:\n\n          -  Muscle invasive or metastatic urothelial cancer of bladder, ureters, renal pelvis,\n             and urethra\n\n          -  Histologically or cytologically confirmed with a clinical plan that would potentially\n             include cisplatin* plus gemcitabine systemic therapy or with disease refractory to a\n             first-line platinum-based therapy (as defined in the protocol).\n\n             * Does not apply to patients screened for Phase II expansion\n\n          -  Surgically incurable\n\n        PRIOR/CONCURRENT THERAPY:\n\n          -  No concurrent radiotherapy, other chemotherapy, or other immunotherapy\n\n          -  Must have recovered from side effects of prior treatments\n\n          -  If prior Proleukin® treatment, must have had a clinical benefit\n\n          -  No use of other investigational agents within 30 days of start or concurrently\n\n        PATIENT CHARACTERISTICS:\n\n        Age\n\n          -  ? 18 years\n\n        Performance Status\n\n          -  ECOG 0 or 1\n\n        Bone Marrow Reserve\n\n          -  Absolute neutrophil count (AGC/ANC) ? 1,500/uL\n\n          -  Platelets ? 100,000/uL\n\n          -  Hemoglobin ? 10g/dL\n\n        Renal Function\n\n          -  Glomerular Filtration Rate (GFR):\n\n               -  ? 50mL/min/1.73m^2 for cisplatin-containing regimen\n\n               -  ? 40mL/min/1.73m^2 for non-cisplatin-containing regimen\n\n        Hepatic Function\n\n          -  Total bilirubin ? 1.5 X ULN\n\n          -  AST, ALT, ALP ? 2.5 X ULN, or ? 5.0 X ULN (if liver metastases exists)\n\n          -  PT INR ? 1.5 X ULN\n\n        Cardiovascular\n\n          -  No congestive heart failure < 6 months\n\n          -  No unstable angina pectoris < 6 months\n\n          -  No myocardial infarction < 6 months\n\n          -  No history of ventricular arrhythmias\n\n          -  No NYHA Class > II CHF\n\n          -  Normal cardiac stress test required for subjects who are ? 50 years old, or have a\n             history of EKG abnormalities, or have symptoms of cardiac ischemia or arrhythmia\n\n          -  No uncontrolled hypertension\n\n        Pulmonary\n\n          -  Not receiving chronic medication for asthma\n\n          -  Normal clinical assessment of pulmonary function\n\n        Hematologic\n\n          -  No evidence of bleeding diathesis or coagulopathy\n\n        Other\n\n          -  Negative serum pregnancy test if female and of childbearing potential\n\n          -  No women who are pregnant or nursing\n\n          -  Subjects, both females and males, with reproductive potential must agree to use\n             effective contraceptive measures for the duration of the study\n\n          -  No known autoimmune disease other than corrected hypothyroidism\n\n          -  No known prior organ allograft or allogeneic transplantation\n\n          -  Not HIV positive\n\n          -  No active systemic infection requiring parenteral antibiotic therapy\n\n          -  No ongoing systemic steroid therapy required\n\n          -  No history or evidence of CNS disease (Controlled brain metastases treated with\n             radiation therapy or surgery where the disease has been clinically stable for a\n             period of a least 3 months before screening is allowed)\n\n          -  No psychiatric illness/social situation\n\n          -  No other illness that in the opinion of the investigator would exclude the subject\n             from participating in the study\n\n          -  Must provide informed consent and HIPAA authorization and agree to comply with all\n             protocol-specified procedures and follow-up evaluations
ENTRY CRITERIA:\n\n        DISEASE CHARATERISTICS:\n\n          -  Muscle invasive or metastatic urothelial cancer of bladder, ureters, renal pelvis,\n             and urethra\n\n          -  Histologically or cytologically confirmed with a clinical plan that would potentially\n             include cisplatin* plus gemcitabine systemic therapy or with disease refractory to a\n             first-line platinum-based therapy (as defined in the protocol).\n\n             * Does not apply to patients screened for Phase II expansion\n\n          -  Surgically incurable\n\n        PRIOR/CONCURRENT THERAPY:\n\n          -  No concurrent radiotherapy, other chemotherapy, or other immunotherapy\n\n          -  Must have recovered from side effects of prior treatments\n\n          -  If prior Proleukin® treatment, must have had a clinical benefit\n\n          -  No use of other investigational agents within 30 days of start or concurrently\n\n        PATIENT CHARACTERISTICS:\n\n        Age\n\n          -  ? 18 years\n\n        Performance Status\n\n          -  ECOG 0 or 1\n\n        Bone Marrow Reserve\n\n          -  Absolute neutrophil count (AGC/ANC) ? 1,500/uL\n\n          -  Platelets ? 100,000/uL\n\n          -  Hemoglobin ? 10g/dL\n\n        Renal Function\n\n          -  Glomerular Filtration Rate (GFR):\n\n               -  ? 50mL/min/1.73m^2 for cisplatin-containing regimen\n\n               -  ? 40mL/min/1.73m^2 for non-cisplatin-containing regimen\n\n        Hepatic Function\n\n          -  Total bilirubin ? 1.5 X ULN\n\n          -  AST, ALT, ALP ? 2.5 X ULN, or ? 5.0 X ULN (if liver metastases exists)\n\n          -  PT INR ? 1.5 X ULN\n\n        Cardiovascular\n\n          -  No congestive heart failure < 6 months\n\n          -  No unstable angina pectoris < 6 months\n\n          -  No myocardial infarction < 6 months\n\n          -  No history of ventricular arrhythmias\n\n          -  No NYHA Class > II CHF\n\n          -  Normal cardiac stress test required for subjects who are ? 50 years old, or have a\n             history of EKG abnormalities, or have symptoms of cardiac ischemia or arrhythmia\n\n          -  No uncontrolled hypertension\n\n        Pulmonary\n\n          -  Not receiving chronic medication for asthma\n\n          -  Normal clinical assessment of pulmonary function\n\n        Hematologic\n\n          -  No evidence of bleeding diathesis or coagulopathy\n\n        Other\n\n          -  Negative serum pregnancy test if female and of childbearing potential\n\n          -  No women who are pregnant or nursing\n\n          -  Subjects, both females and males, with reproductive potential must agree to use\n             effective contraceptive measures for the duration of the study\n\n          -  No known autoimmune disease other than corrected hypothyroidism\n\n          -  No known prior organ allograft or allogeneic transplantation\n\n          -  Not HIV positive\n\n          -  No active systemic infection requiring parenteral antibiotic therapy\n\n          -  No ongoing systemic steroid therapy required\n\n          -  No history or evidence of CNS disease (Controlled brain metastases treated with\n             radiation therapy or surgery where the disease has been clinically stable for a\n             period of a least 3 months before screening is allowed)\n\n          -  No psychiatric illness/social situation\n\n          -  No other illness that in the opinion of the investigator would exclude the subject\n             from participating in the study\n\n          -  Must provide informed consent and HIPAA authorization and agree to comply with all\n             protocol-specified procedures and follow-up evaluations
Inclusion Criteria:\n\n          1. Subjects must have a histologically confirmed diagnosis of glioblastoma multiforme or\n             gliosarcoma;\n\n          2. Measurable disease by RANO criteria;\n\n          3. Disease progression or recurrence following standard of care treatment with\n             temozolomide and radiation;\n\n          4. An interval of at least 4 weeks between prior surgical resection and study\n             enrollment;\n\n          5. An interval of at least 12 weeks between prior radiotherapy or at least 4 weeks from\n             prior chemotherapy, and enrollment in this protocol;\n\n          6. Recovered to Grade 1 or less from the toxic effects of any earlier intervention;\n\n          7. Karnofsky performance status > 60%\n\n        Exclusion Criteria:\n\n          1. Prior anti-angiogenic therapy including VEGF sequestering agents (ie bevacizumab,\n             aflibercept, etc) or VEGFR inhibitors (cediranib, pazopanib, sunitinib, sorafenib,\n             etc);\n\n          2. Prior stereotactic radiotherapy;\n\n          3. Active infection;\n\n          4. Evidence of CNS haemorrhage CTCAE grade 2 or above on baseline MRI;\n\n          5. Subjects who suffered from an acute cardiac event within the last 12 months;\n\n          6. Subjects with active vascular disease, either myocardial or peripheral;\n\n          7. Subjects with proliferative and/or vascular retinopathy;\n\n          8. Subjects with known active second malignancy;
Inclusion Criteria:\n\n          1. Subjects must have a histologically confirmed diagnosis of glioblastoma multiforme or\n             gliosarcoma;\n\n          2. Measurable disease by RANO criteria;\n\n          3. Disease progression or recurrence following standard of care treatment with\n             temozolomide and radiation;\n\n          4. An interval of at least 4 weeks between prior surgical resection and study\n             enrollment;\n\n          5. An interval of at least 12 weeks between prior radiotherapy or at least 4 weeks from\n             prior chemotherapy, and enrollment in this protocol;\n\n          6. Recovered to Grade 1 or less from the toxic effects of any earlier intervention;\n\n          7. Karnofsky performance status > 60%\n\n        Exclusion Criteria:\n\n          1. Prior anti-angiogenic therapy including VEGF sequestering agents (ie bevacizumab,\n             aflibercept, etc) or VEGFR inhibitors (cediranib, pazopanib, sunitinib, sorafenib,\n             etc);\n\n          2. Prior stereotactic radiotherapy;\n\n          3. Active infection;\n\n          4. Evidence of CNS haemorrhage CTCAE grade 2 or above on baseline MRI;\n\n          5. Subjects who suffered from an acute cardiac event within the last 12 months;\n\n          6. Subjects with active vascular disease, either myocardial or peripheral;\n\n          7. Subjects with proliferative and/or vascular retinopathy;\n\n          8. Subjects with known active second malignancy;
Brain lesion size > 3cm 3. Medical History and Concurrent Diseases a) History of whole brain irradiation b) Subjects with an active, known or suspected autoimmune disease c) Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled d) Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. For any prior invasive malignancy, at least 5 years must have elapsed since curative therapy and patients must have no residual sequelae of prior therapy e) Cohort A (asymptomatic): The use of corticosteroids is not allowed within 10 days prior to first treatment (based upon 5 times the expected half life of dexamethasone) except patients who are taking steroids for physiological replacement. If alternative corticosteroid therapy has been used, consultation with the sponsor Medical Monitor is required to determine the washout period prior to initiating study treatment Cohort B (symptomatic): Subjects with neurologic sign and symptoms related to brain metastases who are being treated with a total daily dose of higher than 4 mg dexamethasone or equivalent within 10 prior to the start of treatment with study drug are excluded.
Inclusion Criteria for dose escalation and expansion phase:\n\n          -  Signed written informed consent\n\n          -  Male or female subjects aged greater than or equal to 18 years\n\n          -  Subjects must have histologically or cytologically proven metastatic or locally\n             advanced solid tumors, for which no standard therapy exists or standard therapy has\n             failed. Availability of tumor archival material or fresh biopsies is optional for\n             subjects in dose escalation\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 at trial entry\n             and an estimated life expectancy of at least 3 months\n\n          -  Disease must be measurable with at least 1 uni-dimensional measurable lesion by RECIST\n             1.1, except for subjects with metastatic castrate-resistant prostate cancer (mCRPC) or\n             metastatic breast cancer (MBC) who may be enrolled with objective evidence of disease\n             without a measureable lesion\n\n          -  Adequate hematological, hepatic and renal function as defined in the protocol\n\n          -  Effective contraception for both male and female subjects if the risk of conception\n             exists\n\n          -  Other protocol defined inclusion criteria could apply\n\n        Inclusion Criteria for expansion phase:\n\n          -  Subjects must have relapsed, refractory, or progressive disease following last line of\n             treatment (with the exception of the gastric and gastroesophageal junction (GEJ)\n             cancer cohort, which does not require progression). Availability of tumor archival\n             material or fresh biopsies (excluding bone biopsies) is mandatory for eligibility in\n             the expansion cohorts. For subjects in the MBC cohort, the biopsy or surgical specimen\n             must have been collected within 90 days prior to the first investigational medicinal\n             product (IMP) administration. Specifically, the following will be required:\n\n          -  NSCLC post platinum doublet: Histologically or cytologically confirmed stage IIIB or\n             stage IV NSCLC that has progressed after 1 line of platinum-containing doublet\n             chemotherapy. Subjects should have received only 1 line of platinum-containing\n             treatment for metastatic disease (i.e., adjuvant treatment with a platinum-containing\n             regimen is not sufficient for eligibility because not received in the context of a\n             metastatic disease). Subjects in the NSCLC cohort will only be enrolled in USA\n\n          -  NSCLC first line: Stage IV (per 7th International Association for the Study of Lung\n             Cancer [IASLC] classification) or recurrent NSCLC that is histologically proven.\n             Subjects must not have received treatment for their metastatic or recurrent disease.\n             No activating epidermal growth factor receptor (EGFR) mutation nor ALK\n             translocation/re-arrangement\n\n          -  Gastric and GEJ cancer: Histologically confirmed, unresectable locally advanced or\n             metastatic adenocarcinoma of the gastric and gastro-esophageal junction, treated with\n             first-line chemotherapy combination with or without disease progression. Subjects\n             should have received no more than 1 line of treatment for metastatic disease. Subjects\n             should not have been treated with trastuzumab (but can be Human Epidermal growth\n             factor Receptor 2 [HER2] positive). Subjects who received any platinum containing\n             doublet or triplet as a neoadjuvant chemotherapy strategy, but are not ultimately\n             candidates for surgery will also be eligible, as long as they did not have progressive\n             disease after completion of the neoadjuvant chemotherapy. In addition, subjects with\n             gastric cancer can enter in the study if their white blood cell (WBC) and lymphocyte\n             count is as defined in the protocol\n\n          -  MBC: Subjects must have histologically confirmed locally advanced or MBC and have\n             tumor that is refractory to or progressive after standard of care therapy. Subjects\n             must have received no more than 3 prior lines of cytotoxic therapy for metastatic\n             disease. Subjects must have received a taxane and an anthracycline, unless\n             contra-indicated\n\n          -  Secondary expansion cohorts: Metastatic colorectal cancer (mCRC), Metastatic\n             castrate-resistant prostate cancer (mCRPC), melanoma, ovarian cancer, ACC,\n             mesothelioma, urothelial carcinoma and renal cell carcinoma as defined in the protocol\n\n          -  Efficacy expansion cohorts: Gastric and GEJ cancer (third line), ovarian cancer\n             (platinum Refractory + liposomal doxorubicin), urothelial carcinoma, and HNSCC as\n             defined in the protocol\n\n               -  Other protocol defined inclusion criteria for expansion phase could apply\n\n        Exclusion Criteria for dose escalation and expansion phase:\n\n          -  Concurrent treatment with a non-permitted drug\n\n          -  Prior therapy with specific antibody/drug targeting T cell co-regulatory proteins\n             (immune checkpoints)\n\n          -  Concurrent anticancer treatment, major surgery, or use of any investigational drug\n             within 28 days before the start of trial treatment; or concurrent systemic therapy\n             with immunosuppressive agents, use of hormonal agents within 7 days before the start\n             of trial treatment as defined in the protocol. Note: Subjects receiving bisphosphonate\n             or denosumab are eligible provided treatment was initiated at least 14 days before the\n             first dose of avelumab.\n\n          -  Previous malignant disease other than the target malignancy to be investigated in this\n             trial within the last 5 years with the exception of basal or squamous cell carcinoma\n             of the skin or cervical carcinoma in situ\n\n          -  Rapidly progressive disease (for example, tumor lysis syndrome)\n\n          -  Active or history of central nervous system metastases\n\n          -  Receipt of any organ transplantation including allogeneic stem-cell transplantation\n\n          -  Significant acute or chronic infections as defined in the protocol\n\n          -  Active or history of any autoimmune disease (subjects with diabetes Type 1, vitiligo,\n             psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are\n             eligible) or immunodeficiencies\n\n          -  Known severe hypersensitivity reactions to monoclonal antibodies, any history of\n             anaphylaxis, or uncontrolled asthma\n\n          -  Persisting toxicity related to prior therapy greater than Grade 1 NCI-CTCAE v4.0,\n             however sensory neuropathy less than or equal to Grade 2 is acceptable\n\n          -  Pregnancy or lactation period\n\n          -  Known alcohol or drug abuse\n\n          -  Clinically significant (that is, active) cardiovascular disease\n\n          -  All other significant diseases (for example, inflammatory bowel disease), which, in\n             the opinion of the investigator, might impair the subject's tolerance of trial\n             treatment\n\n          -  Any psychiatric condition that would prohibit the understanding or rendering of\n             informed consent\n\n          -  Legal incapacity or limited legal capacity\n\n          -  Non-oncology vaccine therapies for prevention of infection disease (for example,\n             seasonal flu vaccine, human papilloma virus vaccine) within 4 weeks of study drug\n             administration. Vaccination while on study is also prohibited except for\n             administration of the inactivated influenza vaccine
Inclusion Criteria:\n\n        General Inclusion Criteria:\n\n          -  Histologically or cytologically documented advanced solid tumors\n\n          -  Adequate hematologic and end organ function\n\n          -  Measurable disease by RECIST v1.1\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1\n\n          -  Resolution of any acute, clinically significant treatment-related toxicity from prior\n             therapy to Grade less than or equal to (</=) 1 prior to study entry, with the\n             exception of alopecia\n\n        Eligible Tumor Types:\n\n        Arm A Escalation Cohorts and Arms A and B Biopsy Cohort (Cutaneous/Subcutaneous Lesions)\n\n          -  Histologically or cytologically documented, incurable or metastatic solid malignancy\n             that has failed all available or acceptable standard therapy for which the participant\n             is eligible Arm A and B Safety Expansion Cohorts, Arm B Escalation Cohorts, and Arm B\n             Biopsy Cohort (Liver Lesions)\n\n          -  Histologically or cytologically confirmed metastatic colorectal cancer (mCRC).\n             Participants in the Arm A Safety Expansion Cohort must have mCRC for which established\n             therapies have proved ineffective or intolerable. Participants with malignancies other\n             than mCRC within 5 years prior to Day 1 (except for those with a negligible risk of\n             metastasis or death, such as adequately treated carcinoma in situ of the cervix, basal\n             or squamous cell skin cancer, localized prostate cancer treated surgically with\n             curative intent, or ductal carcinoma in situ treated surgically with curative intent)\n             are not eligible.\n\n        Arm A renal cell carcinoma (RCC) Cohort:\n\n        - Histologically or cytologically confirmed advanced or metastatic RCC with a clear cell\n        component.\n\n        Arm A Tumor Type-Specific Cohort:\n\n        Gastric Cancer:\n\n        - Histologically or cytologically confirmed locally advanced or metastatic adenocarcinoma\n        of the stomach or gastroesophageal junction for which established therapies have proved\n        ineffective or intolerable. The decision may be made to restrict enrollment to participants\n        with a specified tumor PD-L1 status (e.g., immunohistochemistry [IHC] status 0/1 or 2/3)\n\n        Ovarian Cancer:\n\n        - Measurable/assessable ovarian cancer (defined as epithelial ovarian, fallopian tube, or\n        primary peritoneal cancer) that has progressed less than (<) 6 months after completing\n        platinum-based therapy. The following histological types are eligible: Adenocarcinoma NOS,\n        clear cell adenocarcinoma, endometriod adenocarcinoma, malignant Brenner's tumour, mixed\n        epithelial carcinoma, mucinous adenocarcinoma, serous adenocarcinoma, transitional cell\n        carcinoma, undifferentiated carcinoma\n\n        Bladder Cancer:\n\n          -  Histologically or cytologically documented locally advanced (T4b, any N; or any T, N\n             2-3) or metastatic (M1, Stage IV) transitional cell carcinoma of the urothelium\n             (including renal pelvis, ureters, urinary bladder, urethra)\n\n          -  Participants with mixed histologies are required to have a dominant transitional cell\n             pattern\n\n          -  Locally advanced bladder cancer must be inoperable based on involvement of pelvic\n             sidewall or adjacent viscera (clinical stage T4b) or bulky nodal metastasis (N2-N3)\n\n          -  Disease progression during or following treatment with at least one\n             platinum-containing regimen (e.g., GC, MVAC, CarboGem, etc.) for inoperable locally\n             advanced or metastatic urothelial carcinoma or disease recurrence\n\n        Cervical Cancer:\n\n          -  Persistent or recurrent squamous cell carcinoma of the cervix (including adenosquamous\n             tumors)\n\n        Arms C, D, and E Cohorts:\n\n        - Histologically or cytologically documented Stage IIIB (not eligible for definitive\n        chemoradiotherapy), Stage IV, or recurrent non-small cell lung cancer (NSCLC)\n\n        Arm F Cohort:\n\n          -  Histologically confirmed estrogen receptor (ER)-, progesterone receptor (PR)-, and\n             human epidermal growth factor receptor (HER)-negative (triple-negative) adenocarcinoma\n             of the breast that has been treated with systemic cytotoxic therapy. Locally recurrent\n             disease must not be amenable to resection with curative intent\n\n          -  Participants with tumors amenable to excisional, punch, or core needle biopsy are\n             eligible for a separate biopsy expansion cohort\n\n        Tumor molecular status:\n\n        Arm A safety expansion cohort\n\n        - Up to 10 participants with CRC and high microsatellite instability (MSI-H) may be\n        enrolled\n\n        Exclusion Criteria:\n\n        General Exclusions\n\n          -  Any approved anti-cancer therapy, including chemotherapy, hormonal therapy,\n             radiotherapy, or herbal therapy intended as anti-cancer therapy, within 3 weeks prior\n             to initiation of study treatment; the following are allowed: hormonal therapy with\n             gonadotropin-releasing hormone agonists or antagonists for prostate cancer,\n             hormone-replacement therapy, and palliative radiotherapy for bone metastases greater\n             than (>) 2 weeks prior to Day 1\n\n          -  Bisphosphonate therapy for symptomatic hypercalcemia\n\n          -  Known clinically significant liver disease\n\n          -  Known primary central nervous (CNS) malignancy or active CNS metastases (progressing\n             or requiring anticonvulsants or corticosteroids for symptomatic control)\n\n          -  Pregnant or lactating women\n\n          -  Known hypersensitivity to Chinese hamster ovary cell products or any component of the\n             atezolizumab formulation\n\n          -  History of autoimmune disease, idiopathic pulmonary fibrosis, human immunodeficiency\n             virus (HIV), hepatitis B or C infection; history of hepatitis B is allowed if\n             infection has resolved (absence of hepatitis B surface antigen [HBsAg])\n\n          -  Severe infections within 4 weeks prior to Day 1, or signs or symptoms of significant\n             infection within 2 weeks prior to Day 1\n\n          -  Received oral or IV antibiotics within 2 weeks prior to Cycle 1 Day 1\n\n          -  History of myocardial infarction, unstable angina stroke or transient ischemic attack\n             within 6 months prior to Day 1\n\n          -  Administration of a live, attenuated vaccine within 4 weeks before Day 1 or\n             anticipation that such a live attenuated vaccine will be required during the study\n             Bevacizumab-Specific Exclusions (Arms A and B) Exclusion Criteria Unique to Arm A RCC\n             Cohort\n\n          -  Any prior systemic treatment (including tyrosine kinase inhibitors, antibody therapy,\n             immunotherapy, chemotherapy, hormonal therapy, or investigational therapy) for RCC.\n             All treatments, neo-adjuvant, adjuvant, or for locally advanced or metastatic RCC are\n             not permitted\n\n        Arm A Tumor Type-Specific Cohort:\n\n        Gastric Cancer:\n\n        - Prior approved or experimental anti-vascular endothelial growth factor or its receptor\n        (VEGF/VEGFR) therapy (including, for example, bevacizumab or nintedanib). The decision may\n        be made to allocate a specified number of slots to participants who have received prior\n        anti-VEGF/VEGFR therapy\n\n        Ovarian Cancer:\n\n          -  Refractory disease\n\n          -  History of bowel obstruction\n\n          -  >2 prior anticancer regimens\n\n          -  Prior approved or experimental anti-VEGF/VEGFR therapy (including, for example,\n             bevacizumab or nintedanib)\n\n        Cervical Cancer:\n\n        - > 2 prior cytotoxic regimens, not including prior cisplatin-based chemotherapy\n        concomitantly administered with primary pelvic radiation\n\n        Exclusion Criteria Unique to Arm B:\n\n          -  Prior treatment with an oxaliplatin-containing regimen. Oxaliplatin >12 months prior\n             to the diagnosis of metastatic disease is permitted.\n\n          -  Known dihydropyrimidine dehydrogenase deficiency or thymidylate synthase gene\n             polymorphism predisposing the participant for 5-FU toxicity\n\n        Exclusion Criteria Unique to Arms C, D, and E:\n\n          -  Prior chemotherapy for locally advanced or metastatic NSCLC\n\n          -  For participants who received prior adjuvant/neo-adjuvant chemotherapy or\n             chemoradiation for NSCLC, a treatment-free interval >6 months between the last\n             treatment administration and the date of recurrence in required\n\n          -  Participants with a known epidermal growth factor receptor (EGFR) sensitizing mutation\n             must have experienced disease progression during or after treatment with an approved\n             EGFR tyrosine kinase inhibitor\n\n          -  Participants with a known anaplastic lymphoma kinase (ALK) fusion oncogene must have\n             experienced disease progression during or after treatment with crizotinib\n\n          -  For Arm D (carboplatin + pemetrexed), squamous cell histology or evidence of mixed\n             NSCLC histology with a predominance of the squamous cell type\n\n          -  For Arm D (carboplatin + pemetrexed), inability to discontinue treatment with\n             non-steroidal anti-inflammatory drugs (NSAIDs) for 5 days\n\n        Exclusion Criteria Unique to Arm F:\n\n          -  Prior therapy with more than two cytotoxic regimens for metastatic or locally advanced\n             triple-negative breast cancer (TNBC)\n\n          -  Treatment with a taxane-containing regimen within 6 months before enrollment
Inclusion Criteria:\n\n        Subjects must satisfy the following criteria to be enrolled in the study:\n\n          1. Subject is ? 18 years of age the time of signing the informed consent form (ICF).\n\n          2. Documented diagnosis of MDS according to World Health Organization (WHO)/French\n             American British (FAB) classification that meets IPSS R classification of very low,\n             low, or intermediate risk disease, and:\n\n        Ring sideroblast ? 15% of erythroid precursors in bone marrow or ? 5% (but < 15%) if SF3B1\n        mutation is present.\n\n          -  < 5% blasts in bone marrow\n\n          -  Peripheral blood WBC count < 13,000/µL 3. Requires red blood cell RBC transfusions 4.\n             Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 5. Subjects who are\n             refractory/intolerant/ineligible to prior ESA treatment, defined as:\n\n          -  Refractory to prior Erythropoiesis- stimulating agents(ESA) treatment: documentation\n             of non-response or response that is no longer maintained to prior ESA-containing\n             regimen, either as single agent or combination (eg, with G-CSF); ESA regimen must have\n             been either recombinant human erythropoietin (rHu EPO) ? 40,000 IU/wk for at least 8\n             doses or equivalent OR darbepoetin alpha ? 500 ?g Q3W for at least 4 doses or\n             equivalent\n\n          -  Intolerant to prior ESA treatment: documentation of discontinuation of prior\n             ESA-containing regimen, either as single agent or combination (eg, with G-CSF), at any\n             time after introduction due to intolerance or an adverse event\n\n          -  ESA ineligible: low chance of response to ESA base on endogenous serum erythropoietin\n             level > 200 U/L for subjects not previously treated with ESAs\n\n        Exclusion Criteria:\n\n        The presence of any of the following will exclude a subject from enrollment:\n\n          1. Prior therapy with disease modifying agents for underlying MDS disease.\n\n          2. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)\n\n          3. MDS associated with del 5q cytogenetic abnormality\n\n          4. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury\n             or treatment with chemotherapy and/or radiation for other diseases.\n\n          5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies,\n             or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding\n\n             - iron deficiency to be determined by serum ferritin less than or equal to 15 ug/L and\n             additional testing if clinically indicated (eg, calculated transferrin saturation\n             [iron/total iron binding capacity less than or equal to 20%] or bone marrow aspirate\n             stain for iron).\n\n          6. Prior allogeneic or autologous stem cell transplant\n\n          7. Known history of diagnosis of Acute myeloid leukemia (AML)\n\n          8. Use of any of the following within 5 weeks prior to randomization:\n\n               -  anticancer cytotoxic chemotherapeutic agent or treatment\n\n               -  corticosteroid, except for subjects on a stable or decreasing dose for ? 1 week\n                  prior to randomization for medical conditions other than MDS\n\n               -  iron-chelating agents, except for subjects on a stable or decreasing dose for at\n                  least 8 weeks prior to randomization\n\n               -  other RBC hematopoietic growth factors (eg, Interleukin-3)\n\n               -  investigational drug or device, or approved therapy for investigational use. If\n                  the half-life of the previous investigational product is known, use within 5\n                  times the half-life prior to randomization or within 5 weeks, whichever is longer\n                  is excluded.\n\n          9. Prior history of malignancies, other than MDS, unless the subject has been free of the\n             disease (including completion of any active or adjuvant treatment for prior\n             malignancy) for ? 5 years. However, subjects with the following history/concurrent\n             conditions are allowed:\n\n               -  Basal or squamous cell carcinoma of the skin\n\n               -  Carcinoma in situ of the cervix\n\n               -  Carcinoma in situ of the breast\n\n               -  Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,\n                  nodes, metastasis [TNM] clinical staging system)\n\n         10. Major surgery within 8 weeks prior to randomization. Subjects must have completely\n             recovered from any previous surgery prior to randomization
Inclusion Criteria:\n\n          1. Written informed consent and any locally-required authorization (eg, Health Insurance\n             Portability and Accountability Act in the US, EU Data Privacy Directive in the EU)\n             obtained from the patient prior to performing any protocol-related procedures,\n             including pre-screening and screening evaluations\n\n          2. Age ?18 years at time of study entry\n\n          3. Histological or cytological confirmation of locally advanced (stage IIIB) or\n             metastatic (stage IV) solid tumours refractory to standard therapy or for which no\n             standard therapy exists\n\n          4. World Health Organisation Eastern Cooperative Oncology Group (ECOG) performance status\n             0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12\n             weeks\n\n          5. At least 1 lesion, not previously irradiated, that can be accurately measured at\n             baseline as ?10 mm in the longest diameter (except lymph nodes which must have short\n             axis ?15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and\n             which is suitable for accurate repeated assessment as per Response Evaluation Criteria\n             in Solid Tumours (RECIST criteria v1.1)\n\n          6. Female patients and males with partners of childbearing potential should be using\n             highly effective contraceptive measures. Females should not be breastfeeding and must\n             have a negative pregnancy test prior to start of dosing if of childbearing potential\n             or must have evidence of non-childbearing potential by fulfilling 1 of the criteria\n             below at screening.\n\n               -  Postmenopausal defined as aged more than 50 years and amenorrhoeic for at least\n                  12 months following cessation of all exogenous hormonal treatments\n\n               -  Women <50 years old would be considered postmenopausal if they have been\n                  amenorrheic for the past 12 months or more following cessation of exogenous\n                  hormonal treatments. The levels of luteinising hormone (LH) and follicle\n                  stimulating hormone (FSH) must also be in the postmenopausal range (as per the\n                  institution)\n\n               -  Documentation of irreversible surgical sterilisation by hysterectomy and / or\n                  bilateral oophorectomy and/or bilateral salpingectomy but not tubal ligation\n\n          7. Male patients should be willing to use barrier contraception ie, condoms plus\n             spermicide\n\n          8. Mandatory provision of tumour tissue sample available at study entry for exploratory\n             biomarker research. Cytology samples for this exploratory biomarker research will not\n             be acceptable\n\n          9. Patients must have mCRC and, if MSI status is known, non-high MSI status. MSI status\n             will be evaluated based on previous results of local MSI testing, if available.\n             Patients with known MSI-high status will be excluded; patients with MSS, MSI-low, or\n             unknown MSI status may be enrolled\n\n        Exclusion Criteria:\n\n        Patients must not enter the study if any of the following exclusion criteria are fulfilled\n\n          1. Previous enrolment in the present study\n\n          2. Treatment with any of the following:\n\n               -  Cytotoxic chemotherapy or other anticancer drugs within 28 days of the 1st dose\n                  of study treatment or any investigational agents within 5 half-lives of the\n                  product\n\n               -  MEDI4736 or selumetinib in the present study (ie, dosing with MEDI4736 or\n                  selumetinib previously initiated in this study)\n\n               -  Major surgical procedure, (excluding placement of vascular access) or significant\n                  traumatic injury within 4 weeks of the 1st dose of study treatment, or have an\n                  anticipated need for major surgery during the study\n\n               -  Palliative radiotherapy with a wide field of radiation within 4 weeks or\n                  radiotherapy with a limited field of radiation for palliation within 2 weeks of\n                  the 1st dose of study treatment\n\n               -  Prior exposure to immune-mediated therapy, including, but not limited to, other\n                  anti-CTLA- 4 (Cytotoxic T-lymphocyte antigen-4), anti-PD-1 (Programmed cell death\n                  1), anti-PD-L1 (Programmed cell death ligand 1), or anti-PD-L2 (Programmed cell\n                  death ligand 2) antibodies, including therapeutic anticancer vaccines\n\n               -  Receipt of live attenuated vaccine within 30 days prior to the first dose of IP\n\n               -  Concurrent enrolment in another clinical study, unless it is an observational\n                  (non-interventional) clinical study or during the follow-up period of an\n                  interventional study\n\n          3. Any unresolved toxicity NCI CTCAE (National Cancer Institute Common Terminology\n             Criteria for Adverse Events) Grade ?2 from previous anticancer therapy with the\n             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion\n             criteria\n\n               -  Patients with Grade ?2 neuropathy will be evaluated on a case-by-case basis and\n                  may be included after consultation with the medical monitor\n\n               -  Patients with irreversible toxicity not reasonably expected to be exacerbated by\n                  treatment with selumetinib, MEDI4736 or tremelimumab may be included after\n                  consultation with the medical monitor\n\n          4. History of leptomeningeal carcinomatosis and brain metastases or spinal cord\n             compression. Patients with suspected brain metastases at screening should have a CT /\n             MRI of the brain prior to study entry\n\n          5. Active or prior documented autoimmune or inflammatory disorders (including\n             inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the\n             exception of diverticulosis], celiac disease, irritable bowel disease, or other\n             serious GI (Gastrointestinal) chronic conditions associated with diarrhoea, systemic\n             lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [eg, granulomatosis\n             with polyangiitis, Graves' disease; rheumatoid arthritis, hypophysitis, uveitis])\n             within the past 3 years prior to the start of treatment. The following are exceptions\n             to this criterion:\n\n               -  Patients with vitiligo or alopecia\n\n               -  Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone\n                  replacement or psoriasis not requiring systemic treatment\n\n          6. History of active primary immunodeficiency\n\n          7. Current or prior use of immunosuppressive medication within 14 days before the 1st\n             dose of MEDI4736. The following are exceptions to this criterion:\n\n               -  Intranasal, inhaled, topical steroids, or local steroid injections (eg,\n                  intra-articular injection)\n\n               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of\n                  prednisone or its equivalent\n\n               -  Steroids as premedication for hypersensitivity reactions (eg, CT scan\n                  premedication)\n\n          8. As judged by the investigator, any evidence of severe or uncontrolled systemic\n             diseases, including uncontrolled hypertension, renal transplant, active bleeding\n             diatheses, which in the investigator's opinion makes it undesirable for the patient to\n             participate in the study or which would jeopardise compliance with the protocol or\n             active infection including hepatitis B surface antigen (HBsAg), hepatitis C virus\n             (HCV) antibody or human immunodeficiency virus (HIV) or known history of clinical\n             diagnosis of tuberculosis\n\n          9. Screening for chronic conditions is not required\n\n         10. Any of the following cardiac criteria:\n\n               -  Any factors that increase the risk of QT(ECG interval measured from the onset of\n                  the QRS complex to the end of the T wave) interval corrected for heart rate (QTc)\n                  prolongation or risk of arrhythmic events (eg, heart failure, hypokalaemia,\n                  congenital long QT syndrome, family history of long QT syndrome or unexplained\n                  sudden death under 40 years of age) or mean QTc >470 msec\n\n               -  Uncontrolled hypertension (eg, BP ?150/95 mmHg despite medical therapy)\n\n               -  Acute coronary syndrome within 6 months prior to starting treatment\n\n               -  Angina Canadian Cardiovascular Society Grade II-IV (despite medical therapy)\n\n               -  Symptomatic heart failure (New York Heart Association II-IV)\n\n               -  Prior or current cardiomyopathy\n\n               -  Baseline LVEF (Left ventricular ejection fraction) <55% measured by\n                  echocardiography or MUGA. Appropriate correction to be used if a MUGA is\n                  performed.\n\n               -  Atrial fibrillation with a ventricular rate >100 beats per minute at rest\n\n               -  Severe valvular heart disease\n\n         11. Any of the following ophthalmic criteria:\n\n               -  Current or past history of central serous retinopathy, detachment of retinal\n                  pigmented epithelium, or retinal vein occlusion\n\n               -  Intraocular pressure (IOP) >21 mmHg\n\n               -  Uncontrolled glaucoma (irrespective of IOP)\n\n         12. Inadequate bone marrow reserve or organ function as demonstrated by any of the\n             following laboratory values:\n\n               -  Absolute neutrophil count <1.5 x 109/L\n\n               -  Platelet count <100 x 109/L\n\n               -  Haemoglobin <90 g/L\n\n               -  Alanine aminotransferase >2.5 x ULN (upper limit of normal) if no demonstrable\n                  liver metastases or >5 times ULN in the presence of liver metastases\n\n               -  Aspartate aminotransferase >2.5 x ULN if no demonstrable liver metastases or >5\n                  times ULN in the presence of liver metastases\n\n               -  Serum bilirubin ?1.5 x ULN. This will not apply to patients with confirmed\n                  Gilbert's syndrome (persistent or recurrent hyperbilirubinaemia [predominantly\n                  unconjugated bilirubin] in the absence of evidence of haemolysis or hepatic\n                  pathology), who will be allowed in consultation with their physician\n\n               -  Creatinine clearance <50 mL/min (calculated by Cockcroft and Gault equation).\n                  Confirmation of creatinine clearance is only required when creatinine is >1.5\n                  times ULN\n\n         13. Refractory nausea and vomiting, chronic GI diseases, inability to swallow the\n             formulated product or previous significant bowel resection that would preclude\n             adequate absorption of selumetinib\n\n         14. History of hypersensitivity to active or inactive excipients of MEDI4736 or\n             selumetinib or drugs with a similar chemical structure or class to MEDI4736 or\n             selumetinib\n\n         15. Judgment by the investigator that the patient should not participate in the study if\n             the patient is unlikely to comply with study procedures, restrictions, and\n             requirements\n\n         16. Involvement in the planning and conduct of the study (applies to both AZ staff or\n             staff at the study site)\n\n         17. Previous allogeneic bone marrow transplant\n\n         18. Body weight <30 kg
Inclusion:\n\n          1. Male or female 1 to 21 years of age at the time of consent\n\n          2. Steroid-refractory grade B-D aGvHD.\n\n               -  Steroid-refractory is defined as a failure to respond to steroid treatment, with\n                  failure to respond defined as any grade B-D (IBMTR grading) aGvHD that shows\n                  progression ? 3 days, or no improvement by 5 days of treatment with 12 mg/kg/day\n                  methylprednisolone or equivalent in subjects with lower GI or liver disease, or\n                  skin disease associated with bullae. Grade D organ involvement will be limited to\n                  skin and liver.\n\n               -  Steroid refractory may also be defined as a failure to respond to 1 mg/kg/day of\n                  methylprednisolone or equivalent in subjects with disease confined to upper GI\n                  disease or lesser degrees of skin GvHD.\n\n               -  Subjects with lack of complete response after 2 weeks of steroid treatment.\n\n          3. A Lansky scale Performance Status score ? 30.\n\n          4. Laboratory values are within the following limits, assessed within 3 days of the first\n             study treatment:\n\n               -  Absolute neutrophil count > 0.5 × 10^9/L.\n\n               -  Creatinine level < 2 times the upper limit of normal.\n\n          5. For patients with isolated upper GI symptoms, pre-Screening biopsy results to confirm\n             diagnosis of aGvHD.\n\n          6. Female patients of childbearing potential and nonsterilized males who are sexually\n             active with a female partner must be practicing highly effective, reliable, and\n             medically approved contraceptive regimen throughout their participation in the study\n             and for 3 months following the last ECP treatment. Or, for the US only, abstinence may\n             be used in place of an approved contraceptive regimen. Females of childbearing\n             potential are those who have reached the onset of menarche, or 8 years of age,\n             whichever comes first. Approved contraceptive methods for female patients of\n             childbearing potential or nonsterilized males who are sexually active with a female\n             partner are as follows:\n\n               -  Barrier methods of contraception: condom or occlusive cap (diaphragm or\n                  cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.\n\n               -  Established use of oral, injectable, or implanted hormonal methods of\n                  contraception.\n\n               -  Placement of an intrauterine device or intrauterine system.\n\n          7. Signed informed consent/assent is obtained before conducting any study procedures; the\n             parent, legal guardian, or legally authorized representative of a minor must also\n             provide written informed consent.\n\n        Exclusion:\n\n          1. Currently enrolled in another clinical trial for the treatment of aGvHD.\n\n          2. Use of any experimental regimens or medication(s) for aGvHD treatment.\n\n          3. Treatment with > 2.0 mg/kg/day of methylprednisolone equivalents for aGvHD within 30\n             days prior to the first study treatment.\n\n          4. Overt signs of relapse of the underlying condition.\n\n          5. Uncontrolled viral, fungal, or bacterial infection.\n\n          6. Platelet count < 20.0 × 10^9/L, despite platelet transfusion.\n\n          7. Inability to tolerate the extracorporeal volume shifts associated with ECP treatment.\n\n          8. Uncontrolled GI bleeding.\n\n          9. Veno-occlusive liver disease.\n\n         10. Life expectancy < 4 weeks.\n\n         11. Patient requires invasive ventilation or vasopressor support.\n\n         12. Known human immunodeficiency virus (HIV) or hepatitis B or C virus infection (proof of\n             seronegativity within 6 months of screening is required).\n\n         13. Known allergy or hypersensitivity to methoxsalen, Uvadex, or its excipients.\n\n         14. Known hypersensitivity and allergy to heparin and Anticoagulant Citrate Dextrose\n             Formula-A (ACD-A).\n\n         15. Co-existing photosensitive disease (e.g., porphyria, systemic lupus erythematosus,\n             albinism) or aphakia.\n\n         16. Coagulation disorders that cannot be corrected with simple transfusion.\n\n         17. Co-existing melanoma, basal cell, or squamous cell skin carcinoma.\n\n         18. Previous splenectomy.\n\n         19. White blood cell count greater than 25,000 mm3.\n\n         20. Currently being treated with any systemic immunosuppressive or biologic therapy for\n             the treatment of a medical condition other than aGvHD.\n\n         21. Female patient is breastfeeding or pregnant.\n\n         22. Any medical concerns that may pose risk to the patient.\n\n         23. Any psychological, familial, sociological, and/or geographical condition that may\n             potentially hamper compliance with the study protocol and follow-up schedule.
Main Criteria for Inclusion:\n\n          1. Patients with unresectable or metastatic melanoma (Stage IIIc or Stage IV) who\n             progressed following ? 1 lines of prior systemic therapy, including immune checkpoint\n             inhibitor (eg, anti-PD-1), and if BRAF mutation-positive, after BRAF inhibitor\n             systemic therapy. Patients must have no other therapy options that are expected to\n             have significant benefit in the opinion of the Investigator and must have:\n\n               -  At least 1 measurable target lesion, as defined by RECIST 1.1. Lesions in\n                  previously irradiated areas should not be selected as target lesion, unless\n                  treatment was ? 3 months prior, and there has been demonstrated disease\n                  progression in the lesion\n\n               -  At least 1 resectable target lesion to generate TIL of a minimum 1.5 cm in\n                  diameter post-resection; surgical removal with minimal morbidity (defined as any\n                  procedure for which expected hospitalization is ? 3 days)\n\n          2. Patients must be ?18 years and ?70 years of age at the time of consent. Enrollment of\n             patients >70 years of age may be allowed after consultation with the Medical Monitor\n\n          3. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of\n             0 or 1 and an estimated life expectancy of ? 3 months\n\n          4. In the opinion of the Investigator, patient must be able to complete all\n             study-required procedures\n\n          5. Patients of childbearing potential or their partners of childbearing potential must be\n             willing to practice an approved method of birth control during treatment and for 12\n             months after receiving last protocol-related therapy\n\n             Approved methods of birth control are as follows:\n\n               -  Combined (estrogen and progestogen containing) hormonal birth control associated\n                  with inhibition of ovulation: oral; intravaginal; transdermal\n\n               -  Progestogen-only hormonal birth control associated with inhibition of ovulation:\n                  oral; injectable; implantable\n\n               -  Intrauterine device (IUD)\n\n               -  Intrauterine hormone-releasing system (IUS)\n\n               -  Bilateral tubal occlusion\n\n               -  Vasectomized partner\n\n               -  True sexual abstinence when this is in line with the preferred and usual\n                  lifestyle of the patient. Periodic abstinence (eg, calendar ovulation,\n                  symptothermal, post-ovulation methods) is not acceptable.\n\n          6. Patients must have the following hematologic parameters:\n\n               -  Absolute neutrophil count (ANC) ? 1000/mm3\n\n               -  Hemoglobin ? 9.0 g/dL\n\n               -  Platelet count ? 100,000/mm3\n\n          7. Patients must have adequate organ function:\n\n               -  Serum alanine transaminase (ALT)/ serum glutamic-pyruvic transaminase (SGPT) and\n                  aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) ? 3\n                  times the upper limit of normal [ULN]), patients with liver metastasis ? 5 times\n                  ULN\n\n               -  An estimated creatinine clearance (eClCr) ? 40 mL/min using the Cockcroft Gault\n                  formula at Screening\n\n               -  Total bilirubin ? 2 mg/dL: Patients with Gilbert's syndrome must have a total\n                  bilirubin ? 3 mg/dL\n\n          8. Patients must be seronegative for the human immunodeficiency virus (HIV) antibody,\n             hepatitis B antigens, and hepatitis C antibody or antigen\n\n          9. Patients must have recovered from all prior therapy-related adverse events (AEs) to ?\n             Grade 1 (per Common Terminology Criteria for Adverse Events [CTCAE] v4.03), except for\n             alopecia or vitiligo, prior to enrollment (tumor resection), with a washout period\n             from prior anticancer therapy(ies) to the start of planned NMA-LD of a minimum\n             duration detailed as follows:\n\n               -  Targeted therapy: prior targeted therapy with a MEK/BRAF or other-directed agent,\n                  is allowed provided the washout period is a ? 21 days or 5 half-lives, whichever\n                  is longer prior to the start of NMA-LD\n\n               -  Chemotherapy: adjuvant, neoadjuvant or definitive chemotherapy/ chemoradiation is\n                  allowed provided the washout period is ? 21 days or 5 half-lives, whichever is\n                  longer prior to the start of NMA-LD\n\n               -  Immunotherapy: prior checkpoint-targeted therapy with an anti-CTLA-4/anti-PD-1,\n                  other monoclonal antibody (mAb), or vaccine is allowed if disease progression is\n                  confirmed prior to or within the washout period of ? 21 days before the start of\n                  NMA-LD\n\n               -  Palliative radiation therapy is permitted between biopsy and NMA-LD if it does\n                  not involve lesions being selected as target or nontarget\n\n               -  Patients may undergo preplanned procedures if within 2 to 3 weeks prior to the\n                  start of NMA-LD\n\n         10. Patients with documented Grade 2 or higher diarrhea or colitis as a result of previous\n             treatment with immune checkpoint inhibitor(s) must have been asymptomatic for at least\n             6 months and/or had a normal colonoscopy post immune checkpoint inhibitor treatment by\n             visual assessment, prior to start of NMA-LD\n\n         11. Patients must have the ability to understand the requirements of the study, have\n             provided written informed consent, as evidenced by signature on an informed consent\n             form (ICF) approved by an Institutional Review Board/Independent Ethics Committee\n             (IRB/IEC), and agree to abide by the study restrictions and return to the site for the\n             required assessments\n\n         12. Patients have provided written authorization for use and disclosure of protected\n             health information\n\n        Criteria for Exclusion:\n\n          1. Patients with melanoma of uveal/ocular origin\n\n          2. Patients who have received an organ allograft or prior cell transfer therapy that\n             included a nonmyeloablative or myeloablative chemotherapy regimen (not applicable for\n             patients in the retreatment Cohort 3)\n\n          3. Patients with symptomatic and/or untreated brain metastases (of any size and any\n             number)\n\n               -  Patients with definitively treated brain metastases may be considered for\n                  enrollment after discussion with the Medical Monitor, and must be stable for ? 2\n                  weeks prior to the start of NMA-LD\n\n          4. Patients who are pregnant or breastfeeding\n\n          5. Patients who are on a systemic steroid therapy at a dose of > 10 mg of prednisone or\n             equivalent per day\n\n               -  A short course of higher-dose steroid therapy is allowed in cases of exacerbation\n                  of known disease or for treatments of new acute symptoms\n\n          6. Patients who have active medical illness(es) that in the opinion of the Investigator\n             would pose increased risk for study participation that may include active systemic\n             infections, such as syphilis, or any other infections requiring antibiotics,\n             coagulation disorders, or other active major medical illnesses of the cardiovascular,\n             respiratory, or immune system\n\n          7. Patients who have any form of primary immunodeficiency (such as severe combined\n             immunodeficiency disease [SCID] or acquired immunodeficiency syndrome [AIDS])\n\n          8. Patients who have a history of hypersensitivity to any component or excipient of the\n             TIL therapy and other study drugs:\n\n               -  NMA-LD (cyclophosphamide, mesna, and fludarabine)\n\n               -  IL-2\n\n               -  Antibiotics of the aminoglycoside group (ie, streptomycin, gentamicin)\n\n               -  Any component of the TIL infusion product formulation including dimethyl\n                  sulfoxide [DMSO], human serum albumin [HSA], IL-2, and dextran-40\n\n          9. Patients who have a left ventricular ejection fraction (LVEF) < 45% or New York Heart\n             Association (NYHA) functional classification > Class 1 at Screening. All patients must\n             have echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) at Screening. For\n             patients ? 60 years or patients who have a history of ischemic heart disease, chest\n             pain, or clinically significant atrial and/or ventricular arrhythmias, a cardiac\n             stress tests must be performed showing LVEF ?45%, and if any wall movement\n             abnormalities, they must be reversible.\n\n         10. Patients who have obstructive or restrictive pulmonary disease and have a documented\n             FEV1 (forced expiratory volume in 1 second) of ? 60%\n\n         11. Patients who have had another primary malignancy within the previous 3 years (with the\n             exception of carcinoma in situ of the breast, cervix, or bladder, localized prostate\n             cancer and nonmelanoma skin cancer that has been adequately treated)\n\n         12. Patients who have been shown to be BRAF mutation positive (V600), but have not\n             received prior systemic therapy with a BRAF-directed kinase inhibitor\n\n         13. Patients who have received a live or attenuated vaccine within 28 days of the start of\n             NMA-LD\n\n         14. Patients whose cancer requires immediate attention or who would otherwise suffer a\n             disadvantage by participating in this trial\n\n         15. Patients protected by the following constraints:\n\n               -  Hospitalized persons without consent or persons deprived of liberty because of a\n                  judiciary or administrative decision\n\n               -  Adult persons with a legal protection measure or persons who cannot express their\n                  consent\n\n               -  Patients in emergency situations who cannot consent to participate in the trial
ENTRY CRITERIA:\n\n        DISEASE CHARACTERISTICS:\n\n          -  Histologic confirmation of non-muscle invasive bladder cancer of the transitional cell\n             carcinoma high-grade subtype.\n\n               -  Patients are eligible if the diagnostic biopsy was done within 3 months of\n                  treatment start and a cystoscopy demonstrating no resectable disease was done\n                  within 6 weeks of treatment start. Patients with high-grade Ta and/or T1 disease\n                  should have complete resection before study treatment.\n\n               -  Upper tract imaging within 6 months prior to study entry must not be suspicious\n                  for upper tract malignancy.\n\n          -  No history of or evidence of muscle-invasive, locally advanced, metastatic and/or\n             extravesical bladder cancer or presence of any other cancer.\n\n        PRIOR/CONCURRENT THERAPY:\n\n          -  No prior BCG treatment or known hypersensitivity to BCG. Patients who have received\n             more than a single-dose post-operative treatment of mitomycin-C or gemcitabine are\n             excluded.\n\n          -  No concurrent use of other investigational agents.\n\n        PATIENT CHARACTERISTICS:\n\n        Performance Status • ECOG 0, 1, or 2. Bone Marrow Reserve\n\n          -  Absolute neutrophil count (AGC/ANC) ? 1,000/uL\n\n          -  Platelets ? 100,000/uL\n\n          -  Hemoglobin ? 8g/dL Renal Function\n\n          -  Glomerular Filtration Rate (GFR) > 40mL/min or serum creatinine ? 1.5 x ULN Hepatic\n             Function\n\n          -  Total bilirubin ? 2.0 X ULN\n\n          -  AST, ALT, ALP ? 3.0 X ULN Cardiovascular\n\n          -  No symptomatic congestive heart failure Class III or IV.\n\n          -  No severe/unstable angina pectoris < 6 months.\n\n          -  No myocardial infarction < 6 months. Pulmonary\n\n          -  Adequate pulmonary function without any clinical sign of severe pulmonary dysfunction.\n\n        Other\n\n          -  Currently eligible for intravesical BCG therapy.\n\n          -  Negative serum pregnancy test if female and of childbearing potential.\n\n          -  No women who are pregnant or nursing.\n\n          -  Subjects, both females and males, with reproductive potential must agree to use\n             effective contraceptive measures for the duration of the study.\n\n          -  No known positive HIV status.\n\n          -  No history or evidence of uncontrollable CNS disease.\n\n          -  No psychiatric illness/social situation that would limit compliance with study\n             requirements.\n\n          -  No other illness that in the opinion of the investigator would exclude the patient\n             from participating in this study.\n\n          -  Must provide signed informed consent and HIPPA authorization and agree to comply with\n             all protocol-specified procedures and follow-up evaluations.\n\n          -  No active systemic infection requiring parenteral antibiotic therapy.\n\n          -  No ongoing chronic systemic steroid therapy required.\n\n          -  No concurrent febrile illness, active urinary tract infection, active tuberculosis, a\n             history of hypotension or anaphylactic reactions.
Inclusion Criteria:\n\n        Phase 1 Specific Patient at least 18yrs of age with histologically confirmed CLL/SLL or\n        B-cell Non-Hodgkin lymphoma (DLBCL, FL, MCL, MZL, lymphoplasmacytic lymphoma).\n\n        Phase 2a Inclusion\n\n          -  Histological evidence: FL Grade 1-3A/iNHL, with relapsed or refractory disease (iNHL\n             includes LPL/WM, MZL); aNHL, defined as DLBCL, FL Grade 3B, MCL, and transformed NHL\n             with relapsed disease; CLL/SLL, PTCL, or CTCL (with MF/SS) with relapsed or\n             refractory.\n\n          -  Received BCR and/or BCL2 inhibitors were intolerant or had relapsed/refractory disease\n             afterwards.\n\n          -  Prior treatment for lymphoid malignancy for progressive /refractory disease\n\n          -  ? 1 prior regimen (min 2 cycles) with antibody conjugate, cytotoxic chemotherapy, or\n             TKI alone or in combination.\n\n          -  Measureable disease defined as: ? 1 lesion ? 1.5 cm single dimension via CT, CT/PET\n             with nodal or mass lesions; Quantifiable circulating tumor cells; or for Waldenström's\n             macroglobulinemia presence of IgM l > 2X ULN; For CTCL: mSWAT > 0\n\n          -  Ability to provide diagnostic reports\n\n        General Inclusion\n\n          -  ECOG Score of 0 or 1.\n\n          -  Hematologic ANC > 1000/uL and platelet > 75,000/uL,\n\n          -  Serum creatinine of < 1.5 ULN or calculated CrCl of > 50 mL/min\n\n          -  Bilirubin < 20.0mg/dL (if Gilberts then < 2.5 mg/dL) and AST/AST < 2.5 ULN\n\n        Exclusion Criteria:\n\n          -  Richter's syndrome, Burkitt's lymphoma, or Burkitt-like Lymphoma (transformed DLBCL\n             from Follicular NHL are eligible).\n\n          -  Prior transplant with stem cell infusion 90 days or active graft-versus-host treatment\n             within 8 weeks of Day 1.\n\n          -  Prior therapy with SYK inhibitors.\n\n          -  Chronic treatment with strong CYP3A4 inhibitor/ inducer, acid reducing agent, Proton\n             pump inhibitors\n\n          -  Known lymphomatous involvement of the CNS.\n\n          -  Persistent, unresolved NCI CTCAE v4.0 ? Grade 2, previous drug-related toxicity\n             (except alopecia, erectile impotence, hot flashes, libido, neuropathy).\n\n          -  Prior monoclonal antibody, radioimmunoconjugate, antibody drug conjugate,\n             phototherapy, radiotherapy, chemotherapy, immunotherapy, immunosuppressive therapy, or\n             any test agent within 3 weeks or for alemtuzumab 8 weeks of Day 1.\n\n          -  For CTCL: (TSEBT) within 12 weeks, or initiation of topical steroid, nitrogen mustard,\n             or topical retinoid within 2 weeks. (Stable topical ? 4 weeks prior to Day 1 allowed).\n\n          -  Known carrier or infection for HIV/Hep B or C. HCV ab+ must be PCR-. HBV ab+ must be\n             HBsAg- or undetectable DNA\n\n          -  Active infection requiring systemic treatment,\n\n          -  Significant GI disease, previous major gastric/bowel surgery, difficulty swallowing or\n             malabsorption syndrome.\n\n          -  Major surgery within 4 weeks\n\n          -  Previous malignancies within 2 yrs. unless relapse risk is small (< 5%).\n\n          -  Current use of systemic steroids >20 mg QD prednisone (or equivalent)\n\n          -  Breastfeeding or pregnant (intention to become) females or participation in other\n             clinical trials
Inclusion Criteria:\n\n        Eligibility is determined prior to leukapheresis. Subjects must satisfy the following\n        criteria to be enrolled in the study:\n\n          1. Subject is ? 18 years of age at the time of signing the informed consent form (ICF).\n\n          2. Documented diagnosis of multiple myeloma\n\n               -  Must have received at least 3 prior MM treatment regimens. Note: induction with\n                  or without hematopoietic stem cell transplant and with or without maintenance\n                  therapy is considered a single regimen.\n\n               -  Must have undergone at least 2 consecutive cycles of treatment for each regimen,\n                  unless PD was the best response to the regimen.\n\n               -  Must have received a proteasome inhibitor, an immunomodulatory agent and an\n                  anti-CD38 antibody.\n\n               -  Must be refractory to the last treatment regimen.\n\n          3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.\n\n          4. Subjects must have measurable disease, including at least one of the criteria below:\n\n               -  Serum M-protein greater or equal to 1.0 g/dL\n\n               -  Urine M-protein greater or equal to 200 mg/24 h\n\n               -  Serum free light chain (FLC) assay: involved FLC level greater or equal to 10\n                  mg/dL (100 mg/L) provided serum FLC ratio is abnormal\n\n        Exclusion Criteria:\n\n        The presence of any of the following will exclude a subject from enrollment:\n\n          1. Subjects with known central nervous system involvement with myeloma.\n\n          2. History or presence of clinically relevant central nervous system (CNS) pathology.\n\n          3. Subjects with active or history of plasma cell leukemia.\n\n          4. Subjects with solitary plasmacytomas or non-secretory myeloma without other evidence\n             of measurable disease\n\n          5. Inadequate organ function\n\n          6. Ongoing treatment with chronic immunosuppressants\n\n          7. Previous history of an allogeneic hematopoietic stem cell transplantation or treatment\n             with any gene therapy-based therapeutic for cancer or investigational cellular therapy\n             for cancer or BCMA targeted therapy\n\n          8. Evidence of human immunodeficiency virus (HIV) infection.\n\n          9. Seropositive for and with evidence of active viral infection with hepatitis B virus\n             (HBV)\n\n         10. Seropositive for and with evidence of active viral infection with hepatitis B virus\n             (HBV) and Hepatitis C virus (HCV)\n\n         11. Subjects with a history of class III or IV congestive heart failure (CHF) or severe\n             non-ischemic cardiomyopathy, history of stroke, unstable angina, myocardial\n             infarction, or ventricular arrhythmia within the previous 6 months.\n\n         12. Subjects with second malignancies in addition to myeloma if the second malignancy has\n             required therapy in the last 3 years or is not in complete remission\n\n         13. Pregnant or lactating women.\n\n         14. Subject with known hypersensitivity to any component of bb2121 productThe presence of\n             any of the following will exclude a subject from enrollment:\n\n        1. Subjects with known central nervous system involvement with myeloma. 2. History or\n        presence of clinically relevant central nervous system (CNS) pathology.\n\n        3. Subjects with active or history of plasma cell leukemia. 4. Subjects with solitary\n        plasmacytomas or non-secretory myeloma without other evidence of measurable disease 5.\n        Inadequate organ function 6. Ongoing treatment with chronic immunosuppressants 7. Previous\n        history of an allogeneic hematopoietic stem cell transplantation or treatment with any gene\n        therapy-based therapeutic for cancer or investigational cellular therapy for cancer or BCMA\n        targeted therapy 8. Evidence of human immunodeficiency virus (HIV) infection. 9.\n        Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV)\n        and Hepatitis C virus (HCV) 10. Subjects with a history of class III or IV congestive heart\n        failure (CHF) or severe non-ischemic cardiomyopathy, history of stroke, unstable angina,\n        myocardial infarction, or ventricular arrhythmia within the previous 6 months. 11. Subjects\n        with second malignancies in addition to myeloma if the second malignancy has required\n        therapy in the last 3 years or is not in complete remission 12. Pregnant or lactating\n        women. 13 Subject with known hypersensitivity to any component of bb2121 product,\n        cyclophosphamide, fludarabine, or tocilizumab.
Inclusion Criteria:\n\n        Patients must meet all of the following inclusion criteria in order to be entered into the\n        study:\n\n          1. Age 18 or older\n\n          2. Patient has signed informed consent\n\n          3. Patient must have a diagnosis of hepatocellular cancer confirmed by at least one of\n             the following:\n\n        i. Histological confirmation ii. Magnetic resonance imaging (MRI) result with early\n        enhancement and delayed enhancement washout of at least one solid liver lesion > 1 cm.\n        Patient must also have evidence of cirrhosis or have chronic hepatitis B.\n\n        iii. Contrast enhanced computed tomography (CT) with early enhancement and delayed\n        enhancement washout of at least one solid liver lesion > 1cm. Patient must also have\n        evidence of cirrhosis or have chronic hepatitis B.\n\n        d. Patient must not be suitable for treatment by resection or percutaneous ablation at time\n        of study entry.\n\n        Patients not suitable for ablation due to lesion location may be enrolled\n\n        e. Patient MUST meet at least ONE of the following criteria:\n\n        i. Stage Child-Pugh B 7 ii. Recurrent HCC iii.Performance status ECOG 1\n\n        f. Patient has a life expectancy of at least 6 months\n\n        g. Absence of occlusive thrombus to the main portal trunk\n\n        Exclusion Criteria:\n\n        If patients meet any of the following criteria they may not be entered into the study:\n\n          1. Current or previous treatment with chemo- or radiation therapy or sorafenib\n\n          2. Previous treatment with any form of transarterial embolization for HCC\n\n          3. Patients with current or history of any other cancer except non-melanomatous skin\n             cancer\n\n          4. Female patients who are pregnant, breastfeeding, or premenopausal and not using an\n             effective method of contraceptive\n\n          5. Performance status ECOG > 2\n\n          6. Child-Pugh scores >7\n\n          7. Active gastrointestinal bleeding\n\n          8. Evidence of uncorrectable bleeding diathesis\n\n          9. Extra-hepatic spread of the HCC\n\n         10. Total Bilirubin > 3 mg/dL\n\n         11. >50% tumor involvement of the liver\n\n         12. Infiltrative or diffuse HCC\n\n         13. Encephalopathy not adequately controlled medically\n\n         14. Presence of ascites not controlled medically\n\n         15. Presence of medically relevant localized or systemic infection, other than hepatitis\n             B, C, D, E or G\n\n         16. Any contraindication for MRI (eg. metallic implants)\n\n         17. Allergy to contrast media that cannot be managed with prophylaxis\n\n         18. Allergy to iodized oil\n\n         19. Any contraindication to arteriography\n\n         20. Any contraindication for doxorubicin administration, including the following:\n\n        i. White Blood Cell count (WBC) <3000 cells/mm?\n\n        ii. Absolute Neutrophil <1500 cells/mm?\n\n        iii. Cardiac ejection fraction <50%\n\n        iv. Other condition deemed exclusionary by physician\n\n        u. Any contraindication for hepatic embolization, including the following:\n\n        i. Porto-systemic shunt, or an arteriovenous shunt that cannot be adequately closed prior\n        to chemoembolization\n\n        ii. Hepatofugal blood flow\n\n        iii. Serum creatinine > 2mg/dL\n\n        iv. Uncorrectable impaired clotting\n\n          1. Platelet <50,000/mm?\n\n          2. International Normalized Ratio (INR) > 1.4\n\n          3. Activated Prothrombin Time (aPTT) less than 21 or greater than 40\n\n             v. AST > 5X upper limit of normal for lab\n\n             vi. ALT > 5X upper limit of normal for lab
Inclusion Criteria:\n\n        Subjects must meet all of the following criteria to be eligible for the study:\n\n          1. Phase 1a portion: Histologically confirmed advanced relapsed or refractory solid\n             tumors that have exhausted standard of care therapy or either refuse or are not\n             considered to be candidates for any remaining standard therapy.\n\n          2. Age ?18 years\n\n          3. ECOG performance status 0 or 1 (see Appendix B)\n\n          4. Must have evaluable disease per RECIST 1.1. (see Appendix C)\n\n          5. Subjects must have Formalin-Fixed, Paraffin-Embedded (FFPE) tissue available either\n             archived or fresh core or punch needle biopsied at study entry (two fresh\n             cores/punches preferred whenever possible).\n\n          6. Must have received their last anti-cancer therapy, including radiotherapy,\n             chemotherapy, biologic therapy, or herbal therapy at least 3 weeks or 5 half-lives\n             (for systemic agents), whichever is shorter, from initiation of study treatment.\n\n          7. Platelets >100,000/mL without transfusions in the past 7 days\n\n          8. Total bilirubin within 1.5x institutional upper limit of normal (ULN)\n\n               -  AST (SGOT) and ALT (SGPT) <3 X institutional ULN\n\n               -  Patients with documented liver metastases: AST (SGOT) and/or ALT (SGPT) ? 5 × ULN\n\n               -  Albumin ? 3.0 g/dL\n\n               -  Creatinine <1.5 X institutional ULN OR\n\n               -  Creatinine clearance >50 mL/min/1.73 m2 for subjects with creatinine levels above\n                  institutional normal\n\n        Exclusion Criteria:\n\n        Subjects who meet any of the following criteria will not be eligible for participation in\n        the study:\n\n          1. Currently receiving any therapeutic treatment for their malignancy including other\n             investigational agents\n\n          2. Uncontrolled seizure disorder, active neurologic disease, or active CNS involvement\n             except for individuals who have previously treated CNS metastases, are asymptomatic,\n             and have no requirement for a corticosteroid dose (indicated to reduce brain edema)\n             that is equivalent to a prednisone dose of >10mg orally per day or anti-seizure\n             medication for at least 4 weeks prior to first dose of study drug.\n\n          3. History of a Grade 3 or 4 allergic reaction attributed to humanized or human\n             monoclonal antibody therapy\n\n          4. Significant intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac\n             arrhythmia, or psychiatric illness/social situations that would limit compliance with\n             study requirements\n\n          5. Pregnant women or nursing women\n\n          6. Subjects with congestive heart failure with New York Heart Association Classification\n             III, or IV (see Appendix D)\n\n          7. Known clinically significant gastrointestinal disease including, but not limited to,\n             inflammatory bowel disease
Inclusion Criteria:\n\n        All Treatment Arms:\n\n          1. Male or female participants 18 years or older.\n\n          2. Participants who, in the opinion of the treating physician, have failed standard\n             therapies and for whom a phase 1 trial is an appropriate option.\n\n          3. Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be\n             measurable and of the protocol specified genetic mutational status, where applicable.\n\n          4. Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects\n             (except alopecia) of prior therapy.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.\n\n          6. Expected survival time of at least 3 months in the opinion of the investigator.\n\n          7. Block of banked tumor tissue and/or greater than or equal to (>=) 10 unstained slides.\n             Participants who satisfy all other eligibility criteria but do not have banked\n             tissue/slides may be asked to consent to baseline biopsy.\n\n          8. Suitable vein access for the study-required blood sampling.\n\n          9. Thyroid function tests consistent with stable thyroid function. Note: Participants on\n             a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks\n             before Cycle 1, Day 1 are eligible.\n\n         10. Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by\n             echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before\n             the first dose of MLN2480\n\n         11. Female participants who are post menopausal for at least 1 year, surgically sterile,\n             or agree to practice 2 effective methods of contraception through 120 days (4 months)\n             after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6\n             months for participants in Arms 3 and 4, or agree to practice true abstinence.\n\n         12. Male participants who, even if surgically sterilized, agree to practice effective\n             barrier contraception through 120 days (4 months) after the last dose of study drug\n             for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3,\n             and 4, or agree to practice true abstinence.\n\n         13. Additional inclusion criteria for arm 3 expansion only (MLN2480 + paclitaxel):\n\n             a. Participants with KRAS exon 2 or BRAF non-V600 mutation-positive non small cell\n             lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior\n             cytotoxic-approved regimens.\n\n         14. Additional inclusion criteria for arms 4 and 5 expansion only (MLN2480 + cetuximab;\n             MLN2480 + irinotecan):\n\n               1. Participants with CRC who have received a minimum of 1 but not more than 2 prior\n                  cytotoxic-approved regimens.\n\n        Exclusion Criteria:\n\n        All treatment arms:\n\n          1. Female participants who are pregnant or currently breastfeeding.\n\n          2. History of any serious medical or psychiatric illness that could, in the\n             investigator's opinion, potentially interfere with safe protocol completion.\n\n          3. History of uncontrolled brain metastasis unless: previously treated with surgery,\n             whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days\n             without steroid use (or stable steroid dose established for >= 28 days before the\n             first dose of MLN2480).\n\n          4. Ongoing seizure disorder or a requirement for antieplieptics.\n\n          5. Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4\n             half lives, whichever occurs first, before administration of study drug;\n             immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or\n             radiation therapy <= 3 weeks before administration of study drug.\n\n          6. Chronic therapeutic corticosteroid use with the exception of replacement therapy for\n             adrenal insufficiency or corticosteroid inhalers.\n\n          7. Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C;\n             Prior allogeneic bone marrow or organ transplantation, or active condition of chronic\n             immune suppression is not allowed.\n\n          8. Concomitant use, or administration <= 14 days before first dose of study drug(s), of\n             clinically significant enzyme inducers.\n\n          9. Treatment with gemfibrozil (strong Cytochrome P4502C8 [CYP2C8] inhibitor) within 14\n             days before the first dose of MLN2480.\n\n         10. History of or current illicit drug use, drug abuse, or alcohol abuse.\n\n         11. Major surgery within 14 days before the first dose of study drug.\n\n         12. Inability to comply with study requirements.\n\n         13. Other unspecified reasons that, in the opinion of the investigator or Millennium, make\n             the participant unsuitable for enrollment.\n\n         14. Additional exclusion criteria for arms 3, 5, and 6 expansion only (MLN2480 +\n             paclitaxel; MLN2480 + irinotecan; MLN2480 monotherapy):\n\n             a. Prior treatment with rapidly accelerated fibrosarcoma (RAF), extracellular\n             signal-regulated kinases (MEK), or other inhibitors of the mitogen-activated protein\n             kinase (MAPK) pathway.\n\n         15. Additional exclusion criteria for arm 2 only (MLN2480 + alisertib):\n\n             a. History of uncontrolled sleep apnea syndrome and other conditions that could result\n             in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.\n\n         16. Additional exclusion criteria for arm 3 only (MLN2480 + paclitaxel):\n\n             a. Known hypersensitivity to paclitaxel or its components or other drugs formulated in\n             Cremophor® EL (polyoxyethylated castor oil).\n\n         17. Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan):\n\n               1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the\n                  first dose of irinotecan.
Inclusion Criteria for Phase 1b:\n\n          1. Patients must have histologically or cytologically confirmed advanced solid tumors\n             with a histology and/or molecular alteration of interest as defined in Section 4,\n             detected by a CLIA-certified or equivalently accredited diagnostic laboratory\n\n             • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E\n             mutations) patients must have archival tissue available for analysis by Ignyta; all\n             other patients must send tissue to Ignyta, if tissue is available\n\n          2. Prior Treatment:\n\n               -  Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior\n                  therapies are allowed\n\n               -  NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET\n                  inhibitor-naïve will be enrolled; (any number of other prior therapies are\n                  allowed); all other histologies with RET alterations must be RET inhibitor-naïve\n\n               -  Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or\n                  BRAF V600E mutations) may have had prior TKIs and any number of other prior\n                  therapies\n\n          3. Measurable disease according to RECIST v1.1 for all patients except patients with RET\n             altered tumors; patients with RET altered tumors must have evaluable disease, but are\n             not required to have measurable disease\n\n          4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis\n             are allowed. The use of seizure prophylaxis is allowed. Patients requiring steroids\n             must be at a stable or decreasing dose for at least 2 weeks prior to the start of\n             RXDX-105 treatment.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status ? 2\n\n          6. Able to ingest oral medication\n\n          7. Other inclusion criteria apply\n\n        Exclusion Criteria for Phase 1b:\n\n          1. Treated with systemic anticancer therapy or an investigational agent within 2 weeks or\n             5 half-lives, whichever is shorter, prior to start of study drug treatment (4 weeks\n             for antibody therapy and immunotherapy, and 2 weeks for bevacizumab in colon cancer\n             patients)\n\n          2. Major surgery 21 days or less prior to starting study drug or has not recovered from\n             adverse effects of such therapy\n\n          3. Radiotherapy within 2 weeks prior to start of study drug treatment (palliative\n             radiation or stereotactic radiosurgery within 7 days prior to start of study\n             treatment). Patients must have recovered from all radiotherapy-related toxicities\n\n          4. History of non-pharmacologically induced prolonged QTc interval (e.g., repeated\n             demonstration of a QTc interval > 500 milliseconds from ECGs performed at least 24\n             hours apart)\n\n          5. Major active infection requiring parenteral antibiotics\n\n          6. Severe or unstable medical condition, such as congestive heart failure (New York Heart\n             Association [NYHA] Class III or IV), ischemic heart disease, uncontrolled\n             hypertension, uncontrolled diabetes mellitus, psychiatric condition, as well as an\n             uncontrolled cardiac arrhythmia requiring medication (? Grade 2, according to NCI\n             CTCAE v4.03), myocardial infarction within 6 months prior to starting study treatment,\n             or any other significant or unstable concurrent medical illness that in the opinion of\n             the Investigator would preclude protocol therapy\n\n          7. History of other previous cancer that would interfere with the determination of safety\n             or efficacy of RXDX-105 with respect to the qualifying solid tumor malignancy\n\n          8. Known infection with human immunodeficiency virus (HIV) and active hepatitis B or\n             hepatitis C\n\n          9. Current participation in another clinical study of an investigational agent, vaccine,\n             or device. Concomitant participation in observational studies is acceptable\n\n         10. Presence of a significant gastrointestinal disorder that, in the opinion of the\n             Investigator or Sponsor, could interfere with absorption of RXDX-105 (e.g.,\n             malabsorption syndrome, gastrointestinal surgery)\n\n         11. Known hypersensitivity to any of the components of RXDX-105
Tissue Procurement Inclusion Criteria:\n\n        Patients will be eligible for tissue procurement for the Vigil manufacturing process, if\n        they meet all of the following criteria:\n\n          1. Histologically confirmed Ewing's Sarcoma Family of Tumors (ESFT).\n\n          2. Age ?2 years.\n\n          3. Estimated survival ? 6 months.\n\n          4. Evidence of EWS translocation by FISH or RT-PCR or Next Generation Sequencing (NGS).\n\n          5. Metastatic disease\n\n          6. Refractory or intolerant to at least 1 line of systemic chemotherapy.\n\n          7. Planned standard of care surgical procedure (e.g., tumor biopsy or palliative\n             resection or thoracentesis) and expected availability of a cumulative mass of ~10-30\n             grams tissue (\golf-ball\ size) or pleural fluid estimated volume ? 500mL (must be\n             primary tap) for immunotherapy manufacture.\n\n          8. Tumor intended for immunotherapy manufacture is not embedded in bone and does not\n             contain luminal tissue (e.g. bowel, ureter, bile duct).\n\n          9. Ability to understand and the willingness to sign a written informed consent document\n             for tissue harvest.\n\n        Tissue Procurement Exclusion Criteria:\n\n        Patients meeting any of the following criteria are not eligible for tissue procurement for\n        the Vigil manufacturing:\n\n          1. Medical condition requiring any form of chronic systemic immunosuppressive therapy\n             (steroid or other) except physiologic replacement doses of hydrocortisone or\n             equivalent (no more than 30 mg hydrocortisone or 10 mg prednisone equivalent daily)\n             for < 30 days duration.\n\n          2. Known history of other malignancy unless having undergone curative intent therapy\n             without evidence of that disease for ? 3 years except cutaneous squamous cell and\n             basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other\n             in situ cancers are allowed if definitively resected.\n\n          3. Brain metastases unless treated with curative intent (gamma knife or surgical\n             resection) and without evidence of progression for ? 2 months.\n\n          4. Any documented history of autoimmune disease with exception of Type 1 diabetes on\n             stable insulin regimen, hypothyroidism on stable dose of replacement thyroid\n             medication, vitiligo, or asthma not requiring systemic steroids.\n\n          5. Known history of allergies or sensitivities to gentamicin.\n\n          6. History of or current evidence of any condition (including medical, psychiatric or\n             substance abuse disorder), therapy, or laboratory abnormality that might confound the\n             results of the study, interfere with the patient's participation for the full duration\n             of the study, or is not in the best interest of the patient to participate, in the\n             opinion of the treating Investigator.\n\n          7. Known HIV or chronic Hepatitis B or C infection.\n\n        Study Enrollment Inclusion Criteria:\n\n        Patients will be eligible for registration if they meet all of the following inclusion\n        criteria:\n\n          1. Successful manufacturing of at least 4 vials of Vigil.\n\n          2. Karnofsky performance status (PS) ?80%.\n\n          3. Estimated survival ? 6 months.\n\n          4. Normal organ and marrow function as defined below:\n\n             Absolute granulocyte count ?1,500/mm3 Absolute lymphocyte count ?400/mm3 Platelets\n             ?100,000/mm3 Total bilirubin ? institutional upper limit of normal AST(SGOT)/ALT(SGPT)\n             ?2x institutional upper limit of normal Creatinine <1.5 mg/dL\n\n          5. Subject has recovered to CTCAE Grade 1 or better from all adverse events associated\n             with prior therapy or surgery. Pre-existing motor or sensory neurologic pathology or\n             symptoms must be recovered to CTCAE Grade 2 or better.\n\n          6. If female of childbearing potential, has a negative urine or serum pregnancy test. If\n             the urine test is positive or cannot be confirmed as negative, a negative serum test\n             will be required for study entry.\n\n          7. Ability to understand and the willingness to sign a written informed protocol specific\n             consent.\n\n        Study Enrollment Exclusion Criteria:\n\n        Measureable disease is not a requirement for enrollment onto the trial.\n\n        In addition to the procurement exclusion criteria, patients will NOT be eligible for study\n        registration and randomization if meeting any of the following criteria:\n\n          1. Any anti-neoplastic therapy between tissue procurement for Vigil manufacture and start\n             of study therapy.\n\n          2. Live vaccine used for the prevention of infectious disease administered < 30 days\n             prior to the start of study therapy.\n\n          3. Post-surgery complication that in the opinion of the treating investigator would\n             interfere with the patient's study participation or make it not in the best interest\n             of the patient to participate.
Inclusion Criteria:\n\n          -  Definitive diagnosis of unresectable locally advanced or metastatic RCC with\n             clear-cell histology and/or a component of sarcomatoid carcinoma, with no prior\n             treatment in the metastatic setting\n\n          -  Evaluable Memorial Sloan Kettering Cancer Center risk score\n\n          -  Measurable disease, as defined by RECIST v1.1\n\n          -  Karnofsky performance status greater than or equal to 70%\n\n          -  Adequate hematologic and end-organ function prior to randomization\n\n        Exclusion Criteria:\n\n        Disease-Specific Exclusions:\n\n          -  Radiotherapy for RCC within 14 days prior to treatment\n\n          -  Active central nervous system disease\n\n          -  Uncontrolled pleural effusion, pericardial effusion, or ascites\n\n          -  Uncontrolled hypercalcemia\n\n          -  Any other malignancies within 5 years except for low-risk prostate cancer or those\n             with negligible risk of metastasis or death\n\n        General Medical Exclusions:\n\n          -  Life expectancy less than 12 weeks\n\n          -  Participation in another experimental drug study within 4 weeks prior to treatment\n\n          -  Pregnant or lactating women\n\n          -  Known hypersensitivity to any component of atezolizumab or other study medication\n\n          -  History of autoimmune disease except controlled, treated hypothyroidism or type I\n             diabetes mellitus\n\n          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced\n             pneumonitis, or idiopathic pneumonitis\n\n          -  Positive human immunodeficiency virus test\n\n          -  Active or chronic hepatitis B or C\n\n          -  Severe infections within 4 weeks prior to treatment\n\n          -  Exposure to oral or IV antibiotics within 2 weeks prior to treatment\n\n          -  Live attenuated vaccines within 4 weeks prior to treatment, 28 days prior to\n             randomization, during treatment, or within 5 months following last dose of\n             atezolizumab\n\n          -  Significant cardiovascular disease\n\n          -  Prior allogeneic stem cell or solid organ transplantation\n\n        Exclusion Criteria Related to Medications:\n\n          -  Prior treatment with cluster of differentiation 137 agonists, anti-cytotoxic\n             T-lymphocyte associated protein-4, anti-programmed death (PD)-1, or anti-PD-L1\n             therapeutic antibody or pathway-targeting agents\n\n          -  Treatment with immunostimulatory agents for non-malignant conditions within 6 weeks or\n             immunosuppressive agents within 2 weeks prior to treatment\n\n        Bevacizumab- and Sunitinib-Specific Exclusions:\n\n          -  History of hypertensive crisis or hypertensive encephalopathy\n\n          -  Baseline electrocardiogram showing corrected QT interval greater than 460 milliseconds
Inclusion Criteria:\n\n          -  Eastern Cooperative Oncology Group performance status 0 or 1\n\n          -  Histologically or cytologically confirmed, Stage IV non-squamous NSCLC\n\n          -  Participants with no prior treatment for Stage IV non-squamous NSCLC\n\n          -  Known PD-L1 status as determined by immunohistochemistry assay performed on previously\n             obtained archival tumor tissue or tissue obtained from a biopsy at screening\n\n          -  Measurable disease as defined by RECIST v1.1\n\n          -  Adequate hematologic and end organ function\n\n        Exclusion Criteria:\n\n        Cancer-Specific Exclusions:\n\n          -  Active or untreated central nervous system metastases\n\n          -  Malignancies other than NSCLC within 5 years prior to randomization, with the\n             exception of those with a negligible risk of metastasis or death treated with expected\n             curative outcome\n\n        General Medical Exclusions:\n\n          -  Pregnant or lactating women\n\n          -  History of autoimmune disease\n\n          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced\n             pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening\n             chest computed tomography scan. History of radiation pneumonitis in the radiation\n             field (fibrosis) is permitted\n\n          -  Positive test for human immunodeficiency virus\n\n          -  Active hepatitis B or hepatitis C\n\n          -  Severe infection within 4 weeks prior to randomization\n\n          -  Significant cardiovascular disease\n\n          -  Illness or condition that interferes with the participant's capacity to understand,\n             follow and/or comply with study procedures\n\n        Exclusion Criteria Related to Medications:\n\n          -  Prior treatment with cluster of differentiation 137 agonists or immune checkpoint\n             blockade therapies, anti-programmed death-1, and anti-PD-L1 therapeutic antibodies
Inclusion Criteria\n\n        Subjects will be eligible for tissue procurement for the Vigil manufacturing process if\n        they meet all of the following criteria:\n\n          1. Presumptive Stage IIIb, IIIc or IV high-grade papillary serous/clear cell/endometrioid\n             ovarian, fallopian tube or primary peritoneal cancer.\n\n          2. No chemotherapy prior or investigational agents prior to tissue acquisition for Vigil\n             manufacture.\n\n          3. No other malignancy (excluding surgically cured nonmelanoma carcinomas of the skin and\n             carcinoma in situ cervix) unless in remission for ? 2 years.\n\n          4. Anticipated availability of a cumulative mass of ~30 grams tissue (\golf-ball\ size or\n             approximately 3cm disease on CT scan) at time of diagnostic laparoscopy or primary\n             surgical debulking. Infiltrating lumen (bowel, fallopian tube, urethra) tissue should\n             not be used as Vigil immunotherapy material to minimize risk of bacterial\n             contamination.\n\n          5. ECOG performance status (PS) 0-2 prior to diagnostic laparoscopy or debulking\n             laparotomy.\n\n          6. No prior history of hypersensitivity reactions (HSR) with taxanes or platinums.\n\n          7. No prior history of allergies or sensitivities to gentamicin.\n\n          8. Female, 18 years of age or older.\n\n          9. Ability to understand and the willingness to sign a written informed consent document\n             for tissue harvest.\n\n        Subjects will be registered in this study if they meet all of the following inclusion\n        criteria:\n\n          1. Histologically confirmed Stage IIIb, IIIc or IV high-grade papillary serous/clear\n             cell/endometrioid ovarian, fallopian tube or primary peritoneal.\n\n          2. Completion of primary surgical debulking including hysterectomy and bilateral salpingo\n             oophorectomy, and at least 5 but no more than 8 cycles of platinum / taxane adjuvant\n             chemotherapy or chemotherapy as per Category 1 recommendations of the NCCN guidelines,\n             including 5-8 cycles adjuvant intraperitoneal + intravenous (IP/IV) chemotherapy, or\n             5-8 cycles of intravenous chemotherapy divided and administered as neoadjuvant and\n             adjuvant therapy flanking primary debulking surgery.\n\n          3. Clinically defined complete response (cCR) following completion of primary surgical\n             debulking and eligible chemotherapy. cCR defined as no evidence of malignancy on chest\n             x-ray (CT scan is acceptable) and CT scan or MRI of the abdomen and pelvis, normal\n             physical examination, CA-125 antigen level ? 35 U/ml (assessed ? 2 weeks following\n             removal of catheter in subjects receiving intraperitoneal/intravenous chemotherapy)\n             and no findings on physical examination or symptoms suggestive of active cancer.\n\n          4. Subjects must have initiated adjuvant chemotherapy no more than 8 weeks following\n             primary debulking surgery.\n\n          5. Successful manufacturing of at least 4 doses (vials) of Vigil and placebo.\n\n          6. Recovered from all clinically relevant toxicities related to prior therapy (including\n             neuropathy ?Grade 2).\n\n          7. ECOG performance status (PS) 0-1.\n\n          8. Normal organ and marrow function as defined below: Absolute granulocyte count ?\n             1,500/mm^3, Absolute lymphocyte count ? 500/mm^3, Platelets ? 75,000/mm^3, Total\n             bilirubin ? 2 mg/dL, AST(SGOT)/ALT(SGPT)? 2x institutional upper limit of normal,\n             Creatinine < 1.5 mg/dL\n\n          9. Ability to understand and the willingness to sign a written informed protocol specific\n             consent.\n\n        Exclusion Criteria:\n\n        Subjects will be excluded from this study if they meet any of the following criteria (at\n        the time of tissue procurement or at randomization):\n\n          1. Surgery involving general anesthesia, radiotherapy, immunotherapy, or investigational\n             agents within 4 weeks prior to randomization.\n\n          2. Histologically confirmed papillary serous adenocarcinoma of the uterus or disease\n             involving myometrium/endometrium.\n\n          3. Systemic immunosuppressive therapy within 14 days of randomization.\n\n          4. Subjects requiring chronic steroid or immunosuppressive regimens are excluded except\n             inhaled / intranasal steroids and short term systemic steroids <30 days duration and\n             ?0.25 mg/kg prednisone-equivalent per day are allowed.\n\n          5. Congestive heart failure (NYHA Class II, III, or IV), unstable angina, ventricular or\n             hemodynamically significant atrial arrhythmia, or cardiovascular disease such as\n             stroke or myocardial infarction (current or within the past 6 months).\n\n          6. Psychiatric illness/social situations that would limit compliance with study\n             requirements.\n\n          7. Subjects with history of brain metastases.\n\n          8. Subjects with known HIV or chronic Hepatitis B or C infection.\n\n          9. Prior solid organ or bone marrow transplant.\n\n         10. History of or active autoimmune disease (e.g., autoimmune neutropenia,\n             thrombocytopenia, or hemolytic anemia, systemic lupus erythematosus, Sjogren's\n             syndrome, scleroderma, myasthenia gravis, Goodpasture's syndrome, Addison's disease,\n             Hashimoto's thyroiditis, or Graves disease). Persons with vitiligo are not excluded.\n             Diabetics are not excluded if the condition is well controlled.
Inclusion Criteria:\n\n        Among other criteria, patients must meet all of the following conditions to be eligible for\n        the study:\n\n          -  Unresectable, histologically-confirmed advanced (Stage III or Stage IV) melanoma\n\n          -  Disease progression during or after the last anticancer therapy received. For Cohort\n             3, progression must have occurred during the PD-1 targeted CPI (checkpoint inhibitor)\n             treatment and the investigator has deemed it appropriate to continue treatment with\n             the PD-1 targeted CPI beyond confirmed disease progression\n\n          -  No more than one prior chemotherapy-containing regimen for advanced disease.\n\n          -  Prior treatments received must include at least one CPI inhibitor (e.g., anti-CTLA-4,\n             PD-1-, PD-L1-targeted immunotherapy) and for patients with a BRAF mutation at least\n             one BRAF- or MEK-targeted therapy, unless patients are not candidates for, or refused,\n             these therapies. For cohort 3, prior treatment received must include a PD-1 targeted\n             CPI administered during the most recent disease progression and for patients with BRAF\n             mutation at least one BRAF- or MEK-targeted therapy when appropriate\n\n          -  The study site will submit paraffin-embedded tumor tissue obtained from the patient\n             for gpNMB analysis. Patients may require a biopsy if recent tumor tissue is not\n             available. Patients in cohort 2 and 3 must submit a recently obtained biopsy of the\n             skin fold for gpNMB analysis. Patients in Cohort 4 will submit a tumor tissue sample\n             while on study.\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1\n\n          -  Adequate bone marrow, liver and renal function.\n\n        Exclusion Criteria:\n\n        Among other criteria, patients who meet any of the following conditions are NOT eligible\n        for the study:\n\n          -  Previously received glembatumumab vedotin (CR011-vcMMAE, CDX-011) or other\n             MMAE-containing agents\n\n          -  Treatment with the following therapies before the planned start of study treatment:\n\n               1. BRAF or MEK inhibitors within 2 weeks\n\n               2. Monoclonal based therapies within 4 weeks except for the PD-1 targeted checkpoint\n                  inhibitor in cohort 3\n\n               3. Immunotherapy (tumor vaccine, cytokine, or growth factor given to control the\n                  cancer) within 2 weeks\n\n               4. Chemotherapy within 21 days or at least 5 half-lives (whichever is longer)\n\n               5. Investigational therapy within 2 weeks (or at least 5 half-lives, whichever is\n                  longer)\n\n          -  Patients with ocular melanoma\n\n          -  Neuropathy that is moderate (Grade 2) or worse.\n\n          -  Cancer that has spread to the brain or spine will be discussed with the study sponsor\n             and may exclude patients from the trial.\n\n          -  History of another cancer except:\n\n               1. Patients with adequately treated and cured non-melanoma skin cancer or in situ\n                  cancer\n\n               2. Patients with any other cancer from which the patient has been disease-free for ?\n                  3 years\n\n          -  Significant cardiovascular disease\n\n          -  Previously received varlilumab or any other anti-CD27 mAb (Cohort 2 only)\n\n          -  Active systemic infection requiring treatment\n\n          -  Treatment with immunosuppressive medications within 4 weeks or corticosteroids within\n             two weeks\n\n          -  Patients with interstitial lung disease (Cohort 3 only)\n\n          -  Patients with active diverticulitis (Cohort 3 only)\n\n          -  Any non-study vaccination within 4 weeks, or influenza vaccine within 2 weeks, prior\n             to CDX-301 dosing (Cohort 4 only)
Inclusion Criteria\n\n        PART 1\n\n          -  Has locally advanced or metastatic ccRCC and has progressed during treatment with at\n             least one prior therapeutic regimen\n\n          -  Is of age ? 18 years\n\n          -  Has a life expectancy of ? 3 months\n\n          -  Has adequate organ function\n\n          -  If a female patient, must be surgically sterile, post-menopausal, or must agree to use\n             physician-approved method of birth control during the study and for a minimum of 30\n             days after the last study drug administration, or if a male patient with a female\n             partner, must agree to use physician-approved method of birth control during the study\n             and for a minimum of 30 days after the last study drug administration\n\n          -  Able to swallow oral medications\n\n        PART 2 - In addition to PART 1\n\n          -  Received no more than three prior systemic treatment regimens in the advanced or\n             metastatic setting\n\n          -  Must have received at least one but not more than two prior anti-angiogenic therapy\n             regimens\n\n        PART 3 - In addition to PART 1\n\n        • Must have received at least one vascular endothelial growth factor receptor (VEGFR)\n        targeting tyrosine kinase inhibitor\n\n        Exclusion Criteria\n\n        PART 1\n\n          -  Has a history of untreated brain metastasis or history of leptomeningeal disease or\n             spinal cord compression\n\n          -  Has failed to recover from the reversible effects of prior anticancer therapy\n\n          -  Has uncontrolled or poorly controlled hypertension\n\n          -  Is receiving warfarin anticoagulant therapy or expected to require warfarin\n\n          -  Has had any major cardiovascular event within 6 months prior to study drug\n             administration\n\n          -  Has any other clinically significant cardiac, respiratory, or other medical or\n             psychiatric condition that might interfere with participation in the trial or\n             interfere with the interpretation of trial results\n\n          -  Has had major surgery within 4 weeks before first study drug administration\n\n          -  Has known HIV\n\n          -  Has an active infection requiring systemic treatment\n\n          -  Is participating in another therapeutic clinical trial\n\n        PART 2 - In addition to PART 1\n\n          -  Has received prior immunotherapy\n\n          -  Has any active or recent history of a known or suspected autoimmune disease\n\n        PART 3 - In addition to PART 1\n\n          -  Gastrointestinal (GI) disorders\n\n          -  Any history of congenital long QT syndrome
Inclusion\n\n          -  Has read and understands the informed consent form (ICF) and has given written IC\n             prior to any study specific procedures.\n\n          -  Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary\n             peritoneal cancer.\n\n          -  Progressed within 6 months of completing at least 4 cycles of a first-line\n             platinum-containing regimen for Stage III/IV disease. Patients with refractory disease\n             (progression during platinum-containing therapy) are ineligible.\n\n          -  No more than 2-4 prior treatment regimens for Stage III/IV disease, defined as\n             investigational, chemotherapy, hormonal, biologic, or targeted therapy.\n\n          -  Prior doxorubicin (or other anthracycline) at a cumulative dose of ? 360 mg/m² or\n             cumulative epirubicin dose of ? 720 mg/m² (calculated using doxorubicin equivalent\n             doses: 1 mg of doxorubicin = 1 mg PLD = 0.3 mg mitoxantrone = 0.25 mg idarubicin).\n             Subjects without any prior anthracycline exposure can also be included. Applies to Arm\n             D only.\n\n          -  At least 1 measurable lesion according to RECIST v1.1.\n\n          -  Any prior palliative radiation therapy must be completed at least 7 days prior to\n             start of study treatment and patients must have recovered from any acute adverse\n             effects prior to start of study treatment.\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 - 1.\n\n          -  Baseline Laboratory Values:\n\n               1. ANC ?1500/?L\n\n               2. HgB ? 9 g/dL with no blood transfusions in the past 28 days\n\n               3. Platelets ? 100,000/?L\n\n               4. ALT & AST ?3 x ULN or ?5 x ULN if known hepatic metastases\n\n               5. Serum bilirubin within normal limits (WNL) or ?1.5 x the ULN in patients with\n                  liver metastases; or total bilirubin ?3.0 x ULN with direct bilirubin WNL in\n                  patients with well documented Gilbert's Syndrome.\n\n               6. Serum creatinine ?1.5 x the ULN and a calculated creatinine clearance (CrCl) ?45\n                  mL/min by the Cockcroft-Gault method.\n\n          -  Left ventricular ejection fraction (LVEF) WNL of the institution as determined by\n             multiple uptake gated acquisition (MUGA) or echocardiography (ECHO) (applies to Arm D\n             only).\n\n          -  Female patients, ?18, (not of childbearing potential and fertile female patients of\n             childbearing potential) who agree to use adequate contraceptive measures from 2 weeks\n             prior to the study and until 1 month after study treatment discontinuation, who are\n             not breastfeeding, and who have a negative serum or urine pregnancy test within 72\n             hours prior to start.\n\n          -  Predicted life expectancy ? 12 weeks\n\n        Exclusion\n\n          -  Use of a study drug (approved or investigational drug therapy) ?21 days or 5\n             half-lives (whichever is shorter) prior to the first dose of study treatment. For\n             study drugs for which 5 half-lives is ?21 days, a minimum of 10 days between\n             termination of the study drug and administration of study treatment is required.\n\n          -  Major surgical procedures ? 28 days of beginning study, or minor surgical procedures ?\n             7 days. No waiting period following port-a-cath placement, or any other central venous\n             access placement.\n\n          -  Grade >1 toxicity from prior therapy (except alopecia or anorexia).\n\n          -  Known malignant CNS disease other than neurologically stable, treated brain\n             metastases, defined as metastasis having no evidence of progression or haemorrhage\n             after treatment for at least 2 weeks (including brain radiotherapy). Must be off any\n             systemic corticosteroids for the treatment of brain metastases for at least 14 days\n             prior to enrolment.\n\n          -  Patient has had prescription or non-prescription drugs or other products (i.e.\n             grapefruit juice) known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a\n             narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4\n             which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout\n             the study until 2 weeks after last dose of study drug.\n\n          -  Caution should be exercised when inhibitors or substrates of P-gP, substrates of\n             CYP1A2 with a narrow therapeutic range, sensitive substrates of CYP2C19 or CYP2C19\n             substrates with a narrow therapeutic range are administered with AZD1775.\n\n          -  Herbal medications should be discontinued 7 days prior to the first dose of study\n             treatment.\n\n          -  Any of the following cardiac diseases currently or within the last 6 months as defined\n             by New York Heart Association (NYHA) ? Class 2:\n\n               1. Unstable angina pectoris\n\n               2. Congestive heart failure\n\n               3. Acute myocardial infarction\n\n               4. Conduction abnormality not controlled with pacemaker or medication\n\n               5. Significant ventricular or supraventricular arrhythmias (patients with chronic\n                  rate controlled atrial fibrillation in the absence of other cardiac abnormalities\n                  are eligible).\n\n          -  AZD1775 should not be given to patients who have a history of Torsades de pointes\n             unless all risk factors that contributed to Torsades have been corrected. AZD1775 has\n             not been studied in patients with ventricular arrhythmias or recent myocardial\n             infarction.\n\n          -  Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome.\n\n          -  Pregnant or lactating.\n\n          -  Serious active infection at the time of enrolment, or another serious underlying\n             medical condition that would impair the patient's ability to receive study treatment.\n\n          -  Presence of other active cancers, or history of treatment for invasive cancer within 3\n             years. Patients with Stage I cancer who have received definitive local treatment\n             within 3 years, and whom are considered unlikely to recur, are eligible. Patients with\n             previously treated in-situ carcinoma (i.e., non-invasive) are eligible, as are\n             patients with prior non-melanoma skin cancers.
Inclusion Criteria:\n\n          -  Histologically or cytologically documented locally advanced or metastatic solid tumors\n             meeting the following study drug-specific criteria:\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1\n\n          -  Life expectancy greater than or equal to (>/=) 12 weeks\n\n          -  Measurable disease, as defined by RECIST v1.1\n\n          -  Adequate hematologic and end organ function as confirmed by laboratory results within\n             14 days prior to the first study treatment\n\n        Inclusion criteria specific to Arm A: Atezolizumab+ Ipilimumab\n\n          -  Escalation stage: NSCLC participants\n\n          -  Mandatory biopsy cohort: NSCLC or melanoma atezolizumab\n\n          -  Prior atezolizumab-treated cohort: participants with NSCLC or melanoma previously\n             treated with atezolizumab\n\n        Inclusion criteria specific to Arm B: Atezolizumab+ Interferon alfa-2b\n\n          -  Escalation stage: RCC or melanoma participants\n\n          -  Expansion stage: RCC or melanoma participants\n\n          -  Mandatory biopsy cohort: RCC or melanoma participants\n\n          -  Prior immunotherapy-treated cohort: participants with RCC, NSCLC, or melanoma\n             previously treated with programmed death-ligand 1 (PD-L1)/ Programmed death 1 (PD-1)\n\n        Inclusion Criteria Specific to Arm C (Atezolizumab plus PEG-Interferon Alafa-2a):\n\n          -  Cohort 1: participants with RCC\n\n          -  Cohort 2: participants who were previously treated with anti-PD-L1/PD-1 with locally\n             advanced or metastatic solid tumor (e.g., NSCLC, RCC, or melanoma)\n\n        Inclusion Criteria Specific to Arm D (Atezolizumab plus PEG?Interferon Alfa-2a\n        +Bevacizumab)\n\n          -  Cohort 1: participants with metastatic RCC with no prior line of systemic therapy for\n             metastatic disease\n\n          -  Cohorts 2-3: disease progression during or after at least one previous systemic,\n             anti-cancer treatment for locally advanced or metastatic solid tumors; participants\n             with sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic\n             lymphoma kinase (ALK) rearrangements must have failed or are intolerant to prior\n             treatment with EGFR or ALK inhibitors; participants with melanoma with actionable BRAF\n             mutations (e.g., V600) must have failed or are intolerant to prior treatment with BRAF\n             inhibitors\n\n        Inclusion Criteria Specific to Arm E (Atezolizumab +Obinutuzumab)\n\n        - R/M HNSCC participants with at least one prior line of systemic therapy\n\n        Inclusion Criteria Specific to prior Anti?PD-L1/PD-1 Treated Cohorts:\n\n          -  No permanent discontinuation of atezolizumab or other immunotherapies due to a\n             treatment-related adverse event\n\n          -  Recovery from all immunotherapy-related adverse events to Grade less than or equal to\n             (?) 1 or baseline at the time of consent\n\n        Exclusion Criteria:\n\n        General Medical Exclusions:\n\n          -  Pregnant and lactating women\n\n          -  Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3\n             weeks prior to initiation of study treatment, with the following exception: (1)\n             hormone-replacement therapy or oral contraceptives; (2) tyrosine kinase inhibitors\n             (TKIs) that have been discontinued greater than (>) 7 days prior to Cycle 1, Day 1,\n             baseline scans must be obtained after discontinuation of prior TKIs\n\n          -  Investigational therapy within 28 days prior to initiation of study treatment\n\n          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to\n             chimeric or humanized antibodies or fusion proteins\n\n          -  Known hypersensitivity or allergy to Chinese hamster ovary cell products or any\n             component of the atezolizumab formulation\n\n          -  History of or active autoimmune disease\n\n          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced\n             pneumonitis, organizing pneumonia, risk of pulmonary toxicity, or evidence of active\n             pneumonitis on screening chest computed tomography (CT) scan\n\n          -  Prior allogeneic bone marrow transplantation or prior solid organ transplantation\n\n          -  History of human immunodeficiency virus (HIV)\n\n          -  Participants with active hepatitis B\n\n          -  Participants with active hepatitis C\n\n          -  Participants with active tuberculosis\n\n          -  Participants with a history of confirmed progressive multifocal leukoencephalopathy\n\n          -  Any serious medical condition, physical examination finding, or abnormality in\n             clinical laboratory tests that, in the investigator's judgment, precludes the\n             participant's safe participation in and completion of the study\n\n        Cancer-Specific Exclusions:\n\n          -  Active or untreated central nervous system (CNS) metastases, as determined by CT or\n             magnetic resonance imaging (MRI) evaluation during screening and prior radiographic\n             assessments\n\n          -  Spinal cord compression not definitively treated with surgery and/or radiation or\n             previously diagnosed and treated spinal cord compression without evidence that disease\n             has been clinically stable for >/= 2 weeks prior to screening\n\n          -  Leptomeningeal disease\n\n          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent\n             drainage procedures (once monthly or more frequently); participants with indwelling\n             catheters are allowed.\n\n          -  Uncontrolled tumor-related pain\n\n          -  Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of\n             bisphosphonate therapy or denosumab\n\n          -  History of other malignancy within 2 years prior to screening, except for\n             appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma,\n             Stage I uterine cancer, localized prostate cancer treated with curative intent, ductal\n             carcinoma in situ treated surgically with curative intent, or other cancers with a\n             similar outcome\n\n        Exclusion Criteria Related to Medications:\n\n          -  Prior treatment with cluster of differentiation 137 (CD137) agonists or immune\n             checkpoint blockade therapies (Note: Participants enrolled in the prior\n             anti?PD-L1/PD-1 treated cohorts with melanoma may have received prior anti-cytotoxic\n             T-lymphocyte-associated protein 4 treatment or other immunotherapies)\n\n          -  Treatment with systemic immunostimulatory agents within four weeks or five half-lives\n             of the drug, whichever is shorter, prior to Cycle 1, Day 1\n\n          -  Treatment with systemic immunosuppressive medications within 2 weeks prior to Cycle 1,\n             Day 1 (the use of inhaled corticosteroids and mineralocorticoids is allowed)\n\n        Exclusion Criteria Specific to Interferon Alpha Therapy (Arms B?D):\n\n          -  History of depression, suicidal ideation or behavior, bipolar disorder, or psychosis\n\n          -  Hypersensitivity to interferon alpha or any component of the product\n\n        Exclusion Criteria Specific to Bevacizumab (Arm D)\n\n          -  Inadequately controlled hypertension\n\n          -  Prior history of hypertensive crisis or hypertensive encephalopathy\n\n          -  Significant vascular disease within 6 months prior to Day 1\n\n          -  History of hemoptysis\n\n          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of\n             therapeutic anticoagulation)\n\n          -  History of tracheoesophageal fistula, gastrointestinal perforation, or intra-abdominal\n             abscess within 6 months prior to Day 1\n\n          -  Clinical signs or symptoms of gastrointestinal obstruction or requirement for routine\n             parenteral hydration, parenteral nutrition, or tube feeding\n\n          -  Evidence of abdominal free air that is not explained by paracentesis or recent\n             surgical procedure\n\n          -  Proteinuria, as demonstrated by urine dipstick or > 1.0 gram of protein in a 24-hour\n             urine collection\n\n          -  Metastatic disease that involves major airways or blood vessels, or centrally located\n             mediastinal tumor masses of large volume\n\n        Exclusion Criteria Specific Obinutuzumab (Arm E)\n\n          -  Hypersensitivity to obinutuzumab\n\n          -  Prior treatment with obinutuzumab
Inclusion Criteria: Subjects must have histologically or cytologically confirmed metastatic\n        cutaneous or mucosal melanoma, Able to swallow and retain orally administered medication,\n        Adequate hematological, renal, hepatic, and coagulation laboratory assessments Exclusion\n        Criteria: Clinically significant bleeding within 4 weeks of screening, Current use of\n        warfarin, factor Xa inhibitors, and direct thrombin inhibitors, Infection requiring\n        anti-infective treatments within 1 week of study enrollment, Anti-tumor therapy, Major\n        surgery within 28 days
Inclusion Criteria:\n\n        Part A Escalation Cohorts:\n\n        o Histologically or cytologically confirmed advanced malignant solid tumor, limited to\n        melanoma, castrate resistant prostate cancer (CRPC), ovarian cancer (OVCA), renal cell\n        carcinoma, colorectal carcinoma (CRC), pancreatic carcinoma or non-small cell lung\n        carcinoma (NSCLC) that is refractory to, intolerant of, for which no standard of therapy is\n        available or where the patient refuses existing therapies\n\n        Part A Expansion Cohorts, Part B and C Escalation and Expansion Cohorts:\n\n          -  Tumors with all histological diagnosis or tissue origin may be enrolled\n\n          -  Patients must have failed prior standard curative chemotherapy for their disease,\n             refuse existing therapies OR the proposed chemotherapy regimen to which AM0010 is\n             added represents an acceptable standard treatment for their disease.\n\n               -  Measurable or evaluable disease according to irRC or bone metastatic disease\n                  evaluable by Prostate Cancer Working Group 2 criteria (PCWG2) for\n                  castration-resistant prostate cancer (CRPC)\n\n               -  At least 18 years of age\n\n               -  Performance Status of 0 or 1\n\n               -  Adequate organ function\n\n        Exclusion Criteria:\n\n          -  Hematologic malignancies\n\n          -  Pregnant or lactating\n\n          -  Present or history of neurological disorders such as Multiple Sclerosis and Guillain\n             Barre or inflammatory central nervous system/peripheral nervous system (CNS/PNS)\n             disorders\n\n          -  Myocardial infarction within the last 6 months\n\n          -  Unstable angina, or unstable cardiac arrhythmia requiring medication\n\n          -  Surgery within the last 28 days\n\n          -  Systemic fungal, bacterial, viral, or other infection\n\n          -  History of bleeding diathesis within the last 6 months\n\n          -  Positive for human immunodeficiency virus (HIV), hepatitis C, or hepatitis B
Inclusion Criteria:\n\n        - Subjects must satisfy the following criteria to be enrolled in the study:\n\n          1. Adults (age ? 18 years at the time of signing the ICD) with documented diagnosis of MM\n             and measurable disease (serum M-protein ? 0.5 g/dL or urine M-protein ? 200 mg/24\n             hours).\n\n          2. Subjects enrolling in Cohort A (Pom+LD-dex) must have received 2 prior treatment lines\n             of anti-myeloma therapy. Subjects enrolling in Cohort B (Pom+Dara+LD-dex) must have\n             received 1 or 2 prior treatment lines of anti-myeloma therapy.\n\n          3. All subjects must have received prior treatment with LEN or a LEN-containing regimen\n             for at least 2 consecutive cycles as the most recent treatment regimen.\n\n          4. All subjects must have documented disease progression during or after their last\n             antimyeloma therapy.\n\n          5. Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status\n             score of 0, 1, or 2.\n\n          6. Subjects must understand and voluntarily sign an ICD prior to any study related\n             assessments/procedures being conducted.\n\n          7. Subjects must be able to adhere to the study visit schedule and other protocol\n             requirements.\n\n          8. All subjects must provide an adequate bone marrow sample at screening that\n             definitively evaluates the presence or absence of myelodysplastic changes.\n\n          9. Females with child-bearing potential (FCBP†) must agree to use 2 reliable forms of\n             contraception* simultaneously or practice complete abstinence from heterosexual\n             contact for at least 28 days before starting study drug, while participating in the\n             study (including during dose interruptions), and for at least 28 days after study\n             treatment discontinuation and must agree to regular pregnancy testing during this\n             timeframe. For subjects enrolled in Cohort B, pregnancy prevention and testing will\n             continue until 3 months after last dose of daratumumab.\n\n         10. Females must agree to abstain from breastfeeding during study participation and 28\n             days after study drug discontinuation. Female subjects enrolled in Cohort B must agree\n             to abstain from breastfeeding and donating eggs during study participation and until 3\n             months after last dose of daratumumab.\n\n         11. Males must agree to use a latex condom during any sexual contact with FCBP while\n             participating in the study and for 28 days following discontinuation from this study,\n             even if he has undergone a successful vasectomy. Male subjects enrolled in Cohort B\n             must agree to use a latex condom during any sexual contact with FCBP while\n             participating in the study and until 3 months after last dose of daratumumab.\n\n         12. Males must also agree to refrain from donating semen or sperm during the treatment\n             phase and for 28 days after discontinuation from this study treatment. Male subjects\n             enrolled in Cohort B must also agree to refrain from donating semen or sperm during\n             the treatment phase and until 3 months after last dose of daratumumab.\n\n         13. All subjects must agree to refrain from donating blood while on study therapy and for\n             28 days after discontinuation from this study treatment.\n\n         14. All subjects must agree not to share medication.\n\n        Exclusion Criteria:\n\n        The presence of any of the following will exclude a subject from study enrollment:\n\n          1. Any of the following laboratory abnormalities:\n\n               -  Absolute neutrophil count < 1,000/?L\n\n               -  Platelet count < 75,000/?L for subjects in whom < 50% of bone marrow nucleated\n                  cells are plasma cells; or a platelet count < 30,000/?L for subjects in whom ?\n                  50% of bone marrow nucleated cells are plasma cells.\n\n               -  Severe renal impairment (Creatinine Clearance [CrCl] < 30 mL/min) requiring\n                  dialysis.\n\n               -  Corrected serum calcium > 11.5 mg/dL (> 2.8 mmol/L)\n\n               -  Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior red blood cell transfusion or\n                  recombinant human erythropoietin use is permitted)\n\n               -  Serum SGOT/AST or SGPT/ALT > 3.0 x the upper limit of normal (ULN)\n\n               -  Serum total bilirubin > 2.0 mg/dL (34.2 ?mol/L); or > 3.0 x ULN for subjects with\n                  hereditary benign hyperbilirubinemia\n\n          2. Prior history of malignancies, other than MM, unless the subject has been free of the\n             disease for ? 5 years. Allowed exceptions include the following:\n\n               -  Basal or squamous cell carcinoma of the skin\n\n               -  Carcinoma in situ of the cervix or breast\n\n               -  Incidental histological finding of prostate cancer (TNM [tumor, nodes,\n                  metastasis] stage of T1a or T1b)\n\n          3. Previous therapy with pomalidomide or daratumumab\n\n          4. Hypersensitivity to thalidomide, LEN, or dex (this includes ? Grade 3 rash during\n             prior thalidomide or LEN therapy)\n\n          5. Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem\n             cell transplant less than 12 months prior to initiation of study treatment and who\n             have not discontinued immunosuppressive treatment for at least 4 weeks prior to\n             initiation of study treatment and are currently dependent on such treatment.\n\n          6. Subjects with any one of the following:\n\n               -  Congestive heart failure (NY Heart Association Class III or IV)\n\n               -  Myocardial infarction within 12 months prior to starting study treatment\n\n               -  Unstable or poorly controlled angina pectoris, including Prinzmetal's variant\n                  angina pectoris\n\n          7. Subjects who received any of the following within 14 days of initiation of study\n             treatment:\n\n               -  Major surgery (kyphoplasty is not considered major surgery)\n\n               -  Use of any anti-myeloma drug therapy\n\n          8. Use of any investigational agents within 28 days or 5 half-lives (whichever is longer)\n             of treatment, unless approved by the sponsor.\n\n          9. Incidence of gastrointestinal disease that may significantly alter the absorption of\n             Pomalidomide.\n\n         10. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment\n\n         11. Any serious medical condition, laboratory abnormality, or psychiatric illness that\n             would prevent the subject from signing the ICD\n\n         12. Pregnant or breastfeeding females\n\n         13. Known human immunodeficiency virus (HIV) positivity; active infectious hepatitis A, B,\n             or C; or chronic hepatitis B or C\n\n         14. For subjects enrolling in Cohort B - Subject has known allergies, hypersensitivity to\n             mannitol, corticosteroids, monoclonal antibodies or human proteins, or their\n             excipients (refer to the Daratumumab IB), or known sensitivity to mammalian-derived\n             products.
Inclusion Criteria:\n\n          -  Male or female patients, >18 years of age, able to understand and give written\n             informed consent.\n\n          -  Histologically or cytologically confirmed epithelial cancer of one of the following\n             types:\n\n          -  Colorectal\n\n          -  Gastric adenocarcinoma\n\n          -  Esophageal cancer\n\n          -  Hepatocellular carcinoma\n\n          -  Non-small cell lung cancer\n\n          -  Small cell lung cancer\n\n          -  Ovarian epithelial cancer\n\n          -  Cervical Cancer\n\n          -  Endometrial Cancer\n\n          -  Breast cancer\n\n          -  Hormone-refractory prostate cancer\n\n          -  Pancreatic ductal adenocarcinoma\n\n          -  Head and neck cancers- squamous cell\n\n          -  Renal cell cancer (clear cell)\n\n          -  Urothelial cancers\n\n          -  Glioblastoma multiforme\n\n          -  Follicular thyroid cancer\n\n        (Note: Confirmation of Trop-2 expression by immunohistology or other means is not required,\n        but the Sponsor will request tissue specimens from archived materials for determination of\n        Trop-2 expression.)\n\n          -  Stage IV (metastatic) disease.\n\n          -  Refractory to or relapsed after at least one prior standard therapeutic regimen\n             (Appendix 1 lists approved or standard chemotherapeutic agents for each cancer type.\n             Patients who have not received all approved or standard treatments for their cancer\n             must be informed that these alternatives to receiving IMMU-132 are available prior to\n             consenting to participate in this trial.)\n\n          -  Adequate performance status (ECOG 0 or 1)\n\n          -  Expected survival > 6 months.\n\n          -  Measurable disease by CT or MRI.\n\n          -  At least 2 weeks beyond treatment (chemotherapy, investigational drugs including small\n             molecular inhibitors, immunotherapy and/or radiation therapy) or major surgery and\n             recovered from all acute toxicities to Grade 1 or less (except alopecia).\n\n          -  At least 2 weeks beyond high dose systemic corticosteroids (however, low dose\n             corticosteroids < 20 mg prednisone or equivalent daily are permitted).\n\n          -  Adequate hematology without ongoing transfusional support (hemoglobin > 9 g/dL, ANC >\n             1,500 per mm3, platelets > 100,000 per mm3).\n\n          -  Adequate renal and hepatic function (creatinine ? 2.0 x IULN, bilirubin ? 1.5 IULN,\n             AST and ALT ? 3.0 x IULN or 5 x IULN if know liver metastases).\n\n          -  Otherwise, all toxicity at study entry < Grade 1.\n\n        Exclusion Criteria:\n\n        -•Women who are pregnant or lactating.\n\n          -  Women of childbearing potential and fertile men unwilling to use effective\n             contraception during study until conclusion of 12-week post-treatment evaluation\n             period.\n\n          -  Patients with Gilbert's disease.\n\n          -  Patients with brain metastases can be enrolled only if treated, non-progressive brain\n             metastases and off high-dose steroids (>20 mg prednisone or equivalent) for at least 4\n             weeks.\n\n          -  Presence of bulky disease (defined as any single mass > 7 cm in its greatest\n             dimension). Patients with a mass over 7 cm, but otherwise eligible, may be considered\n             for enrollment after discussion and approval with the medical monitor.\n\n          -  Patients with active ? grade 2 anorexia, nausea or vomiting, and/or signs of\n             intestinal obstruction.\n\n          -  Patients with non-melanoma skin cancer or carcinoma in situ of the cervix are\n             eligible, while patients with other prior malignancies must have had at least a 3-year\n             disease-free interval.\n\n          -  Patients known to be HIV positive, hepatitis B positive, or hepatitis C positive.\n\n          -  Known history of unstable angina, MI, or CHF present within 6 months or clinically\n             significant cardiac arrhythmia (other than stable atrial fibrillation) requiring\n             anti-arrhythmia therapy.\n\n          -  Known history of clinically significant active COPD, or other moderate-to-severe\n             chronic respiratory illness present within 6 months.\n\n          -  Prior history of clinically significant bleeding, intestinal obstruction, or GI\n             perforation within 6 months of initiation of study treatment.\n\n          -  Infection requiring intravenous antibiotic use within 1 week.\n\n          -  history of an anaphylactic reaction to irinotecan or ? Grade 3 GI toxicity to prior\n             irinotecan,\n\n          -  Other concurrent medical or psychiatric conditions that, in the Investigator's\n             opinion, may be likely to confound study interpretation or prevent completion of study\n             procedures and follow-up examinations.
Inclusion Criteria:\n\n        In order to be eligible for participation in this trial, the patient must:\n\n          1. Have histologically or cytologically confirmed small cell lung cancer. Confirmation\n             will be done at each participating site.\n\n          2. Have relapsed or progressed after only one prior chemotherapy regimen, which must have\n             been an etoposide-platinum doublet. Eligible patients will be defined as follows:\n\n             \Sensitive\ Disease: Patients who had one previous line of chemotherapy and relapsed\n             after > 60 days of completion of treatment.\n\n             \Refractory\ Disease: Patients with no response to first-line chemotherapy or\n             progression >60 days after completing treatment.\n\n          3. Be ? 18 years of age on day of signing informed consent.\n\n          4. Have a life expectancy of at least 3 months.\n\n          5. Have a performance status of ? 1 on the ECOG Performance Scale.\n\n          6. Have measurable disease based on RECIST 1.1.\n\n          7. Have a tumor tissue specimen available from either a core or excisional biopsy. The\n             tumor specimen should be of adequate size and tumor cellularity to perform whole exome\n             sequencing and immunohistochemistry. In subjects for whom newly obtained samples\n             cannot be obtained (e.g. tumor inaccessible or safety concern), archived tissue may be\n             submitted, if it otherwise satisfies all specimen criteria. Archival samples must have\n             been obtained within 42 days prior to signing consent (please refer to section 12.1 of\n             protocol).\n\n          8. Demonstrate adequate organ function as defined in Table 1.\n\n             Table 1. Adequate Organ Function Laboratory Values System Laboratory Value\n             Hematological Absolute neutrophil count (ANC) ?1,500 /mcL Platelets ?100,000 / mcL\n             Hemoglobin ?8 g/dL (without transfusion) Renal Serum creatinine\n\n             OR\n\n             Glomerular Filtration Rate (GFR) ?1.5 X upper limit of normal (ULN)\n\n             OR\n\n             GFR ?60 mL/min* for patient with creatinine levels > 1.5 X institutional ULN Hepatic\n             Serum total bilirubin ? 1.5 X ULN\n\n             OR\n\n             Direct bilirubin ? ULN for patients with total bilirubin levels > 1.5 ULN AST (SGOT)\n             and ALT (SGPT) ? 2.5 X ULN\n\n             OR\n\n             ? 5 X ULN for patients with liver metastases Albumin ? 2.5 mg/dL\n\n             *GFR should be calculated per institutional standards.\n\n          9. Female patients of childbearing potential should have a negative urine or serum\n             pregnancy within 72 hours of starting treatment. If the urine test is positive or\n             cannot be confirmed as negative, a serum pregnancy test will be required.\n\n         10. Female patients of childbearing potential must be willing to an adequate method of\n             contraception as outlined in Section 14.4.1 - Contraception for the course of the\n             study through 120 days after the last dose of study medication (see Section 13.4.1).\n             Patients of childbearing potential are those who have not been surgically sterilized\n             or have not been free from menses for > 1 year.\n\n             Note: Abstinence is acceptable if this is the usual lifestyle and preferred\n             contraception for the subject.\n\n         11. Male patients must agree to use an adequate method of contraception as outlined in\n             Section 14.4.1 - Contraception - starting with the first dose of study therapy through\n             120 days after the last dose of study therapy. Note: Abstinence is acceptable if this\n             is the usual lifestyle and preferred contraception for the subject.\n\n        Exclusion Criteria:\n\n          -  The patient must be excluded from participating in the trial if the patient:\n\n               1. Is currently participating in or has participated in a study of an\n                  investigational agent or using an investigational device within 14 days of the\n                  first dose of treatment.\n\n               2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or\n                  any other form of immunosuppressive therapy within 7 days prior to the first dose\n                  of trial treatment.\n\n               3. Has had a prior monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or\n                  who has not recovered (i.e., ? Grade 1 or at baseline) from adverse events due to\n                  agents administered more than 14 days earlier.\n\n               4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy\n                  within 2 weeks prior to study Day 1 or who has not recovered (i.e., ? Grade 1 or\n                  at baseline) from adverse events due to a previously administered agent.\n\n                  Note: Patients with ? Grade 2 neuropathy or ? Grade 2 alopecia are an exception\n                  to this criterion and may qualify for the study.\n\n               5. Has undergone major surgery, he/she must have recovered adequately from the\n                  toxicity and/or complications from the intervention prior to starting therapy.\n\n               6. Has a known additional malignancy that is progressing or requires active\n                  treatment.\n\n               7. Has known active central nervous system (CNS) metastases. Patients with\n                  previously treated brain metastases may participate provided they are stable\n                  (without evidence of progression by imaging for at least four weeks prior to the\n                  first dose of trial treatment and any neurologic symptoms have returned to\n                  baseline), have no evidence of new or enlarging brain metastases, and are not\n                  using steroids for at least 7 days prior to trial treatment.\n\n               8. Has known carcinomatous meningitis.\n\n               9. Has an active autoimmune disease requiring systemic treatment in the past 2 years\n                  or a documented history of clinically severe autoimmune disease, or a syndrome\n                  that requires systemic steroids or immunosuppressive agents. Patients with\n                  vitiligo or resolved childhood asthma/atopy would be an exception to this rule.\n                  Patients that require intermittent use of bronchodilators or local steroid\n                  injections would not be excluded from the study. Patients with hypothyroidism\n                  stable on hormone replacement or Sjorgen's syndrome will not be excluded from the\n                  study.\n\n              10. Has evidence of interstitial lung disease, or history of (non-infectious)\n                  pneumonitis that required steroids, or current pneumonitis.\n\n              11. Has an active infection requiring systemic therapy.\n\n              12. Has a history or current evidence of any condition, therapy, or laboratory\n                  abnormality that might confound the results of the trial, interfere with the\n                  patient's participation for the full duration of the trial, or is not in the best\n                  interest of the patient to participate, in the opinion of the treating\n                  investigator.\n\n              13. Has known psychiatric or substance abuse disorders that would interfere with\n                  cooperation with the requirements of the trial.\n\n              14. Is pregnant or breastfeeding, or expecting to conceive or father children within\n                  the projected duration of the trial, starting with the pre-screening or screening\n                  visit through 120 days after the last dose of trial treatment.\n\n              15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-CD137, or\n                  anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including\n                  ipilimumab or any other antibody or drug specifically targeting T-cell\n                  co-stimulation or checkpoint pathways).\n\n              16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).\n\n              17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA\n                  [qualitative] is detected).\n\n              18. Has received a live vaccine within 30 days prior to the planned first dose of\n                  study therapy.\n\n                  Note: Seasonal influenza vaccines for injection are generally inactivated flu\n                  vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®)\n                  are live attenuated vaccines, and are not allowed.\n\n              19. Has a known history of active TB (Bacillus Tuberculosis).\n\n              20. Hypersensitivity to pembrolizumab or any of its excipients.
Inclusion Criteria:\n\n        A subject must satisfy all of the following criteria to be considered for inclusion in the\n        study:\n\n          -  Subjects with histologically or cytologically-confirmed diagnosis of cancer that is\n             recurrent, metastatic, or persistent, who have relapsed from or are refractory to\n             treatment and who also meet the following corresponding requirements for the cohort or\n             phase of the study into which they will enroll:\n\n               -  Dose-escalation Phase: Subjects with advanced solid tumors (any tumor type)\n                  considered to have no standard-of-care treatment for their malignancy with a\n                  curative intent, either as initial therapy or after progressing to prior\n                  therapies; subjects who have been treated previously with a CSF1R inhibitor or an\n                  anti PD1/PDL1 inhibitor may enroll.\n\n               -  Expansion Phase: Subjects with advanced melanoma, non-small-cell lung cancer\n                  (non-squamous; EGFR, ALK wild type), squamous cell carcinoma of the head and\n                  neck, ovarian cancer, or gastrointestinal stromal tumor.\n\n          -  Subjects with melanoma must have a histologically confirmed diagnosis of stage III\n             disease not amenable to local therapy. Melanoma subjects may have received any number\n             of prior lines of therapy for metastatic disease and must have measurable disease per\n             RECISTv1.1. Subjects with melanoma who have received prior treatment with a BRAF/MEK\n             inhibitor are acceptable candidates.\n\n          -  Expansion cohorts: Subjects must have relapsed or been refractory to standard\n             treatment. NSCLC, SCCHN, and Melanoma must show primary progression with\n             antiPD1/anti-PDL1 therapy. They must have tumor accessible for sequential biopsy (core\n             needle biopsy or excision required) and be willing to provide on study tumor tissue\n             biopsy. Subjects for whom newly obtained samples cannot be obtained (e.g. inaccessible\n             or patient safety concern) may submit an archived specimen only upon agreement from\n             the Sponsor.\n\n          -  ECOG performance status 0 or 1.\n\n          -  Adequate organ function as demonstrated by laboratory values.\n\n        Exclusion Criteria:\n\n        A subject who meets any of the following criteria will be disqualified from entering the\n        study:\n\n          -  Disease that is suitable for local therapy administered with curative intent.\n\n          -  Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other\n             form of immunosuppressive therapy within 7 days prior to the first dose of study\n             treatment.\n\n          -  Is currently participating and receiving study therapy or has participated in a study\n             of an investigational agent and received study therapy or used an investigational\n             device within 28 days prior to the first dose of study treatment.\n\n          -  Has had monoclonal antibody within 28 days of first dose of study treatment or has not\n             recovered from AEs due to agents administered more than 28 days earlier.\n\n          -  Has had chemotherapy, targeted small molecule therapy, or radiation therapy within 14\n             days prior to first dose of study treatment or who has not recovered from AEs due to a\n             previously administered agent.\n\n               -  Note: Subjects with ? Grade 2 neuropathy or ? Grade 2 alopecia are an exception\n                  to this criterion and may qualify for the study.\n\n               -  Note: If a subject received major surgery, he or she must have recovered\n                  adequately from the toxicity and/or complications from the intervention prior to\n                  starting study treatment.\n\n          -  Has received transfusion of blood products (including platelets or red blood cells\n             [RBC]) or administration of colony stimulating factors (including granulocyte\n             colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or\n             recombinant erythropoietin) within 28 days prior to Day 1.\n\n          -  Evidence of interstitial lung disease or active, noninfectious pneumonitis.\n\n          -  Has a known additional malignancy that is progressing or requires active treatment.\n             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the\n             skin that has undergone potentially curative therapy, in situ cervical cancer and\n             isolated elevation of prostate-specific antigen. Subjects with a completely treated\n             prior malignancy with no evidence of disease for ? 2 years are eligible.\n\n          -  For Expansion cohort subjects who have previously received an anti-PD-1, anti-PD-L1,\n             or anti?PD-L2 agent or has previously participated in pembrolizumab clinical trials\n             are excluded, except the following tumor types Melanoma, NSCLC and SCCHN (who must\n             show primary progression to anti-PD1/anti-PDL1 therapy).\n\n          -  Radiation therapy within 14 days of first dose of study treatment.\n\n          -  Has active autoimmune disease that has required systemic treatment in past 2 years\n             (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive\n             drugs). Replacement therapy is not considered a form of systemic treatment.\n\n          -  Has an active infection requiring systemic therapy.\n\n          -  Has known central nervous system metastases and/or carcinomatous meningitis.\n\n             o Note: Subjects with previously treated brain metastases may participate if they meet\n             the following criteria: 1) are stable for at least 28 days prior to the first dose of\n             study treatment and if all neurologic symptoms returned to baseline); 2) have no\n             evidence of new or enlarging brain metastases; and 3) have not been using steroids for\n             at least 7 days prior to first dose of study treatment. This exception does not\n             include carcinomatous meningitis, which is excluded regardless of clinical stability.\n\n          -  Uncontrolled intercurrent illness.\n\n          -  Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant\n             small bowel resection that would preclude adequate absorption.\n\n          -  QT interval corrected using Fridericia's formula (QTc) ? 450 msec (males) or ? 470\n             msec (females) at Screening.\n\n          -  Congenital long QT syndrome or patients taking concomitant medications known to\n             prolong the QT interval.\n\n          -  Major surgery within 28 days prior to first dose of study treatment.\n\n          -  Has received a live vaccine administered within 30 days prior to first dose of study\n             treatment.\n\n          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality\n             that might confound the results of the trial, interfere with the subject's\n             participation for the full duration of the trial, or is not in the best interest of\n             the subject to participate, in the opinion of the treating investigator.\n\n          -  Active and clinically significant bacterial, fungal or viral infection, including\n             hepatitis B virus (HBV), hepatitis C virus (HCV), known human immunodeficiency virus\n             (HIV) or acquired immunodeficiency syndrome related illness (HIV testing is not\n             required), including subjects who have an active infection requiring systemic therapy.\n\n          -  Any of the following within 48 weeks (~1 year) prior to first dose of study treatment:\n             myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft,\n             symptomatic congestive heart failure, cerebrovascular accident or transient ischemic\n             attack.\n\n          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the\n             projected duration of the trial, starting with the screening visit through 120 days\n             after the last dose of study treatment.\n\n          -  Has known psychiatric or substance abuse disorders that would interfere with\n             cooperation with the requirements of the trial.\n\n          -  Has had prior exposure to PLX3397.
Inclusion Criteria:\n\n        For the purposes of this study, neoadjuvant and/or adjuvant chemotherapy regimens do not\n        count as a prior line of therapy.\n\n        For Cohorts A and C:\n\n          -  At least one systemic treatment for metastatic breast cancer\n\n          -  Documented disease progression on or after the most recent therapy\n\n          -  Prior treatment must include an anthracycline and a taxane in the neoadjuvant,\n             adjuvant, or metastatic setting\n\n        For Cohort B:\n\n          -  No prior systemic treatment for metastatic breast cancer\n\n          -  Programmed cell death-ligand 1 (PD-L1)-positive mTNBC.\n\n        For Cohort C:\n\n        - PD-L1 strong positive mTNBC\n\n        For all cohorts:\n\n          -  mTNBC confirmed by a central laboratory\n\n          -  For biomarker analysis, adequate newly obtained core or excisional biopsy of a\n             not-previously-irradiated metastatic tumor lesion (mandatory)\n\n          -  Measurable metastatic disease\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          -  Female participants of childbearing potential should be willing to use 2 methods of\n             birth control or be surgically sterile, or abstain from heterosexual activity for the\n             course of the study through 120 days after the last dose of study treatment\n\n          -  Male participants should agree to use an adequate method of contraception starting\n             with the first dose of study treatment through 120 days after the last dose of study\n             treatment\n\n          -  Adequate organ function\n\n        Exclusion Criteria:\n\n          -  Currently participating and receiving study treatment, or has participated in a study\n             of an investigational agent and received study therapy or used an investigational\n             device within 4 weeks prior to study Day 1\n\n          -  Prior anti-cancer monoclonal antibody (mAb) therapy for direct anti-neoplastic\n             treatment within 4 weeks prior to study Day 1\n\n          -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within at\n             least 2 weeks prior to study Day 1\n\n          -  Not recovered (i.e., ? Grade 1 or at baseline) from adverse events due to agents\n             administered within at least 2 weeks prior to study Day 1\n\n          -  Active autoimmune disease requiring systemic treatment in past 2 years\n\n          -  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form\n             of immunosuppressive therapy within 7 days prior to the first dose of study treatment\n\n          -  Known additional malignancy that progressed or required active treatment within the\n             last 5 years. Exceptions include basal cell carcinoma of the skin, squamous cell\n             carcinoma of the skin that has undergone potentially curative therapy, or in situ\n             cervical cancer\n\n          -  Radiographically-detectable central nervous system (CNS) metastases and/or\n             carcinomatous meningitis\n\n          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis\n             or a history of interstitial lung disease\n\n          -  Active infection requiring systemic therapy\n\n          -  Known psychiatric or substance abuse disorders that would interfere with cooperation\n             with the requirements of the study\n\n          -  Pregnant, breastfeeding, or expecting to conceive or father children within the\n             projected duration of the study, starting with the screening visit through 120 days\n             after the last dose of study treatment\n\n          -  Prior therapy with an anti-programmed cell death protein-1 (anti-PD-1), anti-PD-L1,\n             anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor\n             (e.g. cytotoxic T-lymphocyte-associated protein-4 [CTLA-4], OX-40, CD137) or has\n             participated in Merck MK-3475 (pembrolizumab) study\n\n          -  Known history of human immunodeficiency virus (HIV)\n\n          -  Known active Hepatitis B or C\n\n          -  Received a live vaccine within 30 days of planned start of study treatment
Inclusion Criteria:\n\n          -  Must have cancer of the anal canal OR rectal cancer.\n\n          -  Must have metastatic disease or persistent/recurrent loco-regional disease\n\n          -  Prior Therapy: may have received <2 regimens for disease in the metastatic setting. At\n             least one line of therapy.\n\n          -  Be willing and able to provide written informed consent for the trial.\n\n          -  Be ?18 years of age on day of signing informed consent.\n\n          -  Have measurable disease based on RECIST 1.1\n\n          -  Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          -  Demonstrate adequate organ function as defined in protocol.\n\n          -  Females cannot be pregnant or breastfeeding and must take two methods of birth control
Inclusion Criteria: - Age ?18 years; - Written informed consent obtained from the\n        patient/legal representative; - Histologically or cytologically confirmed recurrent or\n        metastatic SCCHN; - Tumor progression or recurrence during or after only one palliative\n        systemic treatment regimen for recurrent or metastatic disease that must have contained a\n        platinum agent OR progression within 6 months of the last dose of platinum given as part of\n        multimodality therapy with curative intent; - Confirmed PD-L1-positive or -negative SCCHN\n        by the Ventana PD-L1 SP263 IHC assay; - WHO/Eastern Cooperative Oncology Group (ECOG)\n        performance status of 0 or 1; At least 1 measurable lesion, - Not previously irradiated; -\n        No prior exposure to immune-mediated therapy; - Adequate organ and marrow function;\n        Evidence of post-menopausal status or negative urinary or serum pregnancy test for female\n        pre-menopausal patients. Exclusion Criteria: - Histologically or cytologically confirmed\n        squamous cell carcinoma of any other primary anatomic location in the head and neck; -\n        Received more than 1 palliative systemic regimen for recurrent or metastatic disease; -Any\n        concurrent chemotherapy, Investigational Product, biologic, or hormonal therapy for cancer\n        treatment; - Receipt of any investigational anticancer therapy within 28 days or 5\n        half-lives; - Receipt of last dose of an approved (marketed) anticancer therapy\n        (chemotherapy, targeted therapy, biologic therapy, mAbs, etc) within 21 days prior to the\n        first dose of study treatment; - Major surgical procedure within 28 days prior to the first\n        dose of Investigational Product; - Any unresolved toxicity NCI CTCAE Grade ?2 from previous\n        anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values\n        defined in the inclusion criterion; - Current or prior use of immunosuppressive medication\n        within 14 days before the first dose of their assigned Investigational Product; - History\n        of allogeneic organ transplantation; - Active or prior documented autoimmune or\n        inflammatory disorders; - Uncontrolled intercurrent illness; - Patients with a history of\n        brain metastases, spinal cord compression, or leptomeningeal carcinomatosis; - Mean QT\n        interval corrected for heart rate (QTc) ?470 ms calculated from 3 electrocardiograms (ECGs)\n        using Fridericia's Correction; - History of active primary immunodeficiency; - Active\n        tuberculosis; - Active infection including hepatitis B, hepatitis C or human\n        immunodeficiency virus (HIV); - Receipt of live, attenuated vaccine within 30 days prior to\n        the first dose of Investigational Product; - Pregnant or breast-feeding female patients; -\n        Known allergy or hypersensitivity to Investigational Product
Inclusion Criteria:\n\n        Cohort A:\n\n          1. Subjects with newly diagnosed, untreated, unmethylated MGMT GBM who are eligible for\n             standard radiation therapy.\n\n             Cohorts B, B2, B3 and C:\n\n          2. First or second recurrence of GBM by diagnostic biopsy or contrast enhanced MRI per\n             modified RANO criteria (122), with last baseline MRI confirmation within 14 days prior\n             to Study Day 1.\n\n             NOTE: Recurrence is defined as progression following therapy (i.e., chemotherapy;\n             radiation). If the subject had a surgical resection for relapsed disease and no\n             anti-tumor therapy was administered for up to 12 weeks, and the subject has further\n             evidence of tumor growth or undergoes another resection, this will be considered as\n             one episode of recurrence.\n\n          3. On Study Day 1, at least 12 weeks from prior radiotherapy (unless progressive disease\n             outside of the radiation field or histopathologic confirmation of unequivocal tumor).\n\n          4. Cohort B, B2, B3: No prior VEGF/VEGFR targeted therapy; Cohort C: No more than one\n             prior bevacizumab regimen.\n\n          5. Recovery from any prior treatment clinically significant, related adverse events to\n             grade ? 1 or pretreatment baseline with the exception of alopecia and laboratory\n             values listed per inclusion criteria.\n\n             Cohorts A, B, B2, B3 and C:\n\n          6. Subjects with measurable or non-measurable disease.\n\n          7. Histopathologic confirmation of glioblastoma.\n\n          8. At the time of Study Day 1, subjects must be at least 4 weeks since major surgical\n             procedure, open biopsy, or significant traumatic injury; there should be no\n             anticipation of need for major surgical procedure during the course of the study.\n\n             There should be no core biopsy or other minor surgical procedure, excluding placement\n             of a vascular access device, within 7 days prior to Study Day 1.\n\n          9. Subjects who have previously been treated with the Optune device are eligible for the\n             study as long as toxicity related to the treatment has resolved to ? Grade 1 or\n             baseline.\n\n         10. ECOG ? 1 or Karnofsky performance status of ? 70.\n\n         11. Adequate hematologic, renal and hepatic function, as defined below:\n\n               -  Absolute Neutrophil Count ? 1000/mm3\n\n               -  Platelet count ? 100,000/mm3\n\n               -  Total bilirubin ? 1.5 x ULN; or if subject has Gilbert syndrome, then total\n                  bilirubin ? 3 x ULN\n\n               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 2.0 x ULN\n\n               -  Creatinine ? 1.5x ULN or creatinine clearance (CrCl) ? 50 mL/min (using the\n                  Cockcroft-Gault formula):\n\n                    -  Female CrCl = (140 - age in years) x weight in kg x 0.85 /72 x serum\n                       creatinine in mg/dL\n\n                    -  Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine\n                       in mg/dL Cohorts B2, B3 and C\n\n               -  Urinary protein quantitative value of ? 30 mg/dL in urinalysis or ?1+ on\n                  dipstick, unless quantitative protein is < 1000 mg in a 24 hour urine sample.\n\n         12. Age must be greater than or equal to 18 years at date of consent.\n\n         13. Written informed consent and any locally required authorization (e.g., Health\n             Insurance Portability and Accountability Act [HIPAA] in the USA) obtained from the\n             subject/legal representative prior to performing any protocol-related procedures,\n             including screening evaluations.\n\n        Exclusion Criteria:\n\n        All Cohorts\n\n          1. Primary tumors localized to the brainstem or spinal cord.\n\n          2. Locally directed therapies including but not limited to stereotactic radiosurgery,\n             re-irradiation, Gliadel, and therapeutics administered by direct injection or\n             convection-enhanced delivery within 6 months of start of study treatment.\n\n          3. Prior exposure to MEDI4736 or other anti-PD-1, anti-PD-L1, anti-CTLA4 antibodies.\n\n          4. Presence of diffuse leptomeningeal disease or extracranial disease.\n\n          5. Active, suspected or prior documented autoimmune disease (including inflammatory bowel\n             disease, celiac disease, irritable bowel syndrome, Wegner's granulomatosis and\n             Hashimoto's thyroiditis). Subjects with vitiligo, type I diabetes mellitus, residual\n             hypothyroidism due to autoimmune condition only requiring hormone replacement,\n             psoriasis not requiring systemic treatment, or conditions not expected to recur in the\n             absence of an external trigger are permitted to enroll.\n\n          6. Known primary immunodeficiency or active HIV.\n\n          7. Known active or chronic viral hepatitis or history of any type of hepatitis within the\n             last 6 months indicated by positive test for hepatitis B surface antigen (HBV sAG) or\n             hepatitis C virus ribonucleic acid (HCV antibody).\n\n          8. History of organ transplant requiring use of immunosuppressive medication.\n\n          9. History of active tuberculosis.\n\n         10. Significant active systemic illness including infections requiring intravenous\n             antibiotics.\n\n         11. Current pneumonitis or interstitial lung disease.\n\n         12. Other invasive malignancy within 2 years prior to entry into the study, except for\n             those treated with surgical therapy only.\n\n         13. History of severe allergic reactions to any unknown allergens or any components of the\n             study drugs.\n\n         14. Any prior Grade ? 3 immune-related adverse event (irAE) or any prior\n             corticosteroid-refractory irAE.\n\n         15. Mental impairment that may compromise the ability to give informed consent and comply\n             with the requirements of the study.\n\n         16. Lack of availability for follow-up assessments.\n\n         17. Lack of availability for Post Study Follow-up contacts to determine relapse and\n             survival.\n\n         18. Women who are breast-feeding or pregnant as evidenced by positive serum pregnancy test\n             (minimum sensitivity 25 IU/L or equivalent units of HCG).\n\n         19. Women of childbearing potential not using a medically acceptable means of\n             contraception for the duration of the study and unsterilized males not willing to\n             abide by requirements for contraception as stated in Section 5.4.\n\n         20. If a subject previously received another investigational treatment, the last dose of\n             investigational treatment was administered within 4 weeks of Day 1 of the study.\n\n         21. Any condition that, in the clinical judgment of the treating physician, is likely to\n             prevent the subject from complying with any aspect of the protocol or that may put the\n             subject at unacceptable risk.\n\n         22. Cohorts B2, B3 and C:\n\n               -  Evidence of hemorrhage on the baseline MRI or CT scan other than those that are ?\n                  grade 1 and either post-operative or stable on at least two consecutive scans\n\n               -  Current use of warfarin sodium or any other Coumadin-derivative anticoagulant.\n                  Participant must be off Coumadin-derivative anticoagulants for at least seven\n                  days prior to starting study drug. Low molecular weight heparin and Factor Xa\n                  antagonists are allowed\n\n               -  History of clinically significant bleeding within 6 months of enrollment\n\n               -  History of arterial thromboembolism within 12 months prior to enrollment\n\n               -  Inadequately controlled hypertension (defined as systolic blood pressure 150\n                  and/or diastolic blood pressure > 90 mmHg on antihypertensive medications)\n\n               -  Any prior history of hypertensive crisis or hypertensive encephalopathy\n\n               -  Clinically significant cardiovascular disease within 12 months prior to\n                  enrollment (or randomization), including myocardial infarction, unstable angina,\n                  grade 2 or greater peripheral vascular disease, cerebrovascular accident,\n                  transient ischemic attack, congestive heart failure, or arrhythmias not\n                  controlled by outpatient medication, percutaneous transluminal coronary\n                  angioplasty/stent\n\n               -  Evidence of bleeding diathesis or coagulopathy\n\n               -  History of abdominal fistula, gastrointestinal perforation, or intra abdominal\n                  abscess within 6 months prior to study enrollment\n\n               -  Serious, non healing wound, ulcer, or bone fracture
Inclusion Criteria: (For all patients unless otherwise specified)\n\n          -  Histologically or cytologically confirmed locally advanced (stage IIIB not amenable to\n             definitive multi-modality therapy including surgery) or metastatic (stage IV) EGFR\n             mutant NSCLC.\n\n          -  Patients with controlled brain metastases\n\n          -  ECOG performance status: Phase I part: 0, 1, or 2; Phase II part: 0 or 1\n\n          -  Presence of at least one measurable lesion according to RECIST 1.1\n\n          -  Patients who are either HBsAg positive or HBV-DNA positive must be willing and able to\n             take antiviral therapy 1-2 weeks prior to 1st dose of EGF816 treatment and continue on\n             antiviral therapy for at least 4 weeks after the last dose of EGF816\n\n          -  Patients must have negative hepatitis C antibody (HCV-Ab) or positive HCV-Ab but\n             undetectable level of HCV-RNA. Note: patients with detectable HCV-RNA are not eligible\n             for the study.\n\n          -  For Phase I: patients must have failed no more than 3 lines of any systemic\n             antineoplastic therapy for advanced NSCLC, including EGFR-TKI\n\n          -  For Phase II: patients must be naïve from any systemic antineoplastic therapy in the\n             advanced setting. Patients who have failed no more than 1 cycle of systemic\n             antineoplastic therapy in the advanced setting are allowed.\n\n        Exclusion criteria: (Applies to all patients unless otherwise specified)\n\n          -  Patients with a history or presence of ILD or interstitial pneumonitis, including\n             clinically significant radiation pneumonitis (i.e. affecting activities of daily\n             living or requiring therapeutic intervention)\n\n          -  Presence or history of another malignancy\n\n          -  Undergone a bone marrow or solid organ transplant\n\n          -  Known history of human immunodeficiency virus (HIV) seropositivity (HIV testing is not\n             mandatory)\n\n          -  Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use\n             at the time of study entry except for control of brain metastases, topical\n             applications, inhaled sprays, eye drops or local injections\n\n          -  Patients with clinically significant, uncontrolled heart disease\n\n          -  Any prior therapies ? 4 weeks prior to the first dose of study treatment\n\n          -  Patients who are receiving treatment with medications that are known to be strong\n             inhibitors or inducers of CYP3A4/5 and cannot be discontinued 1 week prior to the\n             start of EGF816 treatment and for the duration of the study.\n\n          -  Patients who have impairment of GI function or GI disease that may significantly alter\n             the absorption of EGF816 (e.g., ulcerative diseases, uncontrolled nausea, vomiting,\n             diarrhea, or malabsorption syndrome)\n\n          -  Patients who are receiving treatment with any enzyme-inducing anticonvulsant that\n             cannot be discontinued at least 1 week before first dose of study treatment, and for\n             the duration of the study\n\n          -  Women of child-bearing potential, defined as all women physiologically capable of\n             becoming pregnant, unless they are using highly effective methods of contraception\n\n          -  Sexually active males unless they use a condom during intercourse while taking drug\n             and for 3 months after stopping treatment Other protocol-defined inclusion and\n             exclusion criteria may apply.
Inclusion Criteria:\n\n        All Participants:\n\n          -  Confirmed diagnosis of multiple myeloma (MM)\n\n          -  Measurable disease\n\n          -  Archival or newly obtained bone marrow material available. In addition, for\n             participants in the United States (US) and Canada, able to provide newly obtained bone\n             marrow aspirate for biomarker analysis.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          -  Adequate organ function\n\n          -  Female participants of childbearing potential must be willing to use 2 methods of\n             birth control or be surgically sterile, or abstain from heterosexual activity for the\n             course of the study through 120 days after the last dose of study treatment\n\n          -  Male participants must agree to use a latex condom during sexual contact with females\n             of childbearing potential even if they have had a successful vasectomy starting with\n             the first dose of study treatment through 120 days after the last dose of study\n             treatment\n\n          -  Able to swallow capsules and able to take or tolerate oral medications on a continuous\n             basis\n\n        Dose Determination Arm, Dose Confirmation Arm and Cohort 1 Participants:\n\n          -  Failed at least 2 lines of prior therapy (e.g. bortezomib or carfilzomib and either\n             thalidomide, pomalidomide, or lenalidomide)\n\n          -  Prior anti-MM treatments must have included an immunomodulatory (IMiD) treatment\n             (lenalidomide, pomalidomide or thalidomide) AND proteasome inhibitor (bortezomib or\n             carfilzomib) alone or in combination and participant must have failed therapy with an\n             IMiD OR proteasome inhibitor\n\n          -  Must agree to follow the regional requirements for lenalidomide counseling, pregnancy\n             testing, and birth control; willing and able to comply with the regional requirements\n             (for example, periodic pregnancy tests and safety labs)\n\n        Cohort 2 Participants:\n\n          -  MM with relapsing or refractory disease at study entry\n\n          -  Received prior treatment with 1 to 3 lines for MM\n\n          -  Achieved a partial response to at least one prior regimen (defined as ?50% decrease in\n             tumor burden)\n\n          -  Left ventricular ejection fraction of at least 40%\n\n        Exclusion Criteria:\n\n        All Participants:\n\n          -  Currently participating in and receiving study therapy or has participated in a study\n             of an investigational agent or using an investigational device within 4 weeks of the\n             first dose of study treatment\n\n          -  History of repeated infections; primary amyloidosis; hyperviscosity; plasma cell\n             leukemia; polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and\n             skin changes (POEMS) syndrome or Waldenström's macroglobulinemia\n\n          -  Diagnosis of immunosuppressive disorder or on any other immunosuppressive therapy\n             within 7 days prior to the first dose of study treatment\n\n          -  Received a prior monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who\n             has not recovered (i.e. ? Grade 1 or at baseline) from a baseline AE or a Grade 1 AE\n             associated with agents administered more than 4 weeks earlier\n\n          -  Prior anti-MM therapy (including dexamethasone), targeted small molecule therapy, or\n             radiation therapy within 2 weeks prior to study Day 1 or not recovered from AEs due to\n             a previously administered agent\n\n          -  An additional malignancy that is progressing or requires active treatment within the\n             last 5 years\n\n          -  Clinically active central nervous system (CNS) involvement\n\n          -  Active autoimmune disease or a documented history of autoimmune disease, or a syndrome\n             that requires systemic steroids or immunosuppressive agents\n\n          -  Has a history of (non-infectious) pneumonitis that required steroids or current\n             pneumonitis\n\n          -  Active infection requiring intravenous systemic therapy\n\n          -  Known psychiatric or substance abuse disorders that would interfere with cooperation\n             with the requirements of the study\n\n          -  Pregnant or breastfeeding, or expecting to conceive or father children within the\n             projected duration of the study, starting with the pre-screening or screening visit\n             through 120 days after the last dose of study treatment\n\n          -  Prior therapy with an anti-programmed cell death (PD)-1, anti-PD ligand 1\n             (anti-PD-L1), anti-PD-L2, anti-CD137 antibody, or anti-Cytotoxic\n             T-lymphocyte-associated antigen-4 (CTLA-4) agent\n\n          -  Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C\n             Virus (HCV) infection\n\n          -  Clinically significant coagulopathy\n\n          -  Known symptomatic congestive heart failure, unstable angina pectoris, or cardiac\n             arrhythmia\n\n          -  Has had or is planning for allogeneic stem cell transplant\n\n          -  Autologous stem cell transplant within 12 weeks before the first infusion\n\n          -  History of Grade 4 rash associated with thalidomide treatment\n\n          -  Known hypersensitivity to thalidomide, lenalidomide or pomalidomide\n\n          -  Received a live vaccine within 30 days of planned start of study treatment\n\n        Dose Determination Arm, Dose Confirmation Arm and Cohort 1 Participants:\n\n          -  Known gastrointestinal disease that may significantly alter the absorption of\n             lenalidomide\n\n          -  Unable or unwilling to undergo antithrombotic prophylactic treatment\n\n        Cohort 2 Participants:\n\n          -  Smoldering MM (SMM), monoclonal gammopathy of undetermined significance (MGUS), plasma\n             cell leukemia or Waldenström's macroglobulinemia\n\n          -  Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to the\n             first dose of study treatment\n\n          -  Myocardial infarction within 4 months prior to randomization, New York Heart\n             Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of\n             severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick\n             sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3\n             conduction system abnormalities unless participant has a pacemaker.\n\n          -  Known history of allergy to CAPTISOL® (a cyclodextrin derivative used to solubilize\n             carfilzomib)\n\n          -  Hypersensitivity to carfilzomib, bortezomib, boron, or mannitol\n\n          -  Contraindication to any of the required concomitant drugs or supportive treatments,\n             including hypersensitivity to all anticoagulation and antiplatelet options, antiviral\n             drugs, or intolerance to hydration due to pre-existing pulmonary or cardiac impairment\n\n          -  Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to the first\n             dose of study treatment\n\n          -  Pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14\n             days prior to the first dose of study treatment
Inclusion Criteria:\n\n        All Subjects:\n\n          1. Provide signed and dated informed consent prior to study-specific screening procedures\n\n          2. ? 18 years old\n\n          3. Karnofsky performance status (KPS) ? 70\n\n          4. Must have adequate bone marrow and renal/hepatic function within protocol specified\n             limits\n\n          5. Disease-free period of > 2 years from any other previous malignancies, excluding\n             curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or\n             carcinoma in situ of the cervix. Subjects with prostate cancer Stage 1 that do not\n             require treatment may also be included\n\n          6. Women and men must use protocol approved methods of contraception\n\n          7. Must be able and willing to comply with the study visit schedule and study procedures\n\n          8. Must have available archived tumor tissue and willing and able to provide consent for\n             study access to such tissue\n\n             For Phase 1 Subjects Only:\n\n          9. Histologically or cytologically documented diagnosis of solid tumor for which no\n             standard therapy is recognized or have failed or intolerant to the standard-of-care\n             treatment\n\n         10. Inoperable metastatic or locally advanced, unresectable disease\n\n         11. Subjects may have either evaluable or measurable disease\n\n         12. Subjects with treated (surgically excised or irradiated) and stable brain metastases\n             are eligible as long as the subject has adequately recovered from treatment and the\n             treatment was ? 28 days prior to initiation of study drug(s) and baseline brain\n             computed tomography (CT) with contrast or magnetic resonance imaging (MRI) ? 14 days\n             of initiation of study drug is negative for new brain metastases\n\n             For Phase 2 Subjects Only:\n\n         13. Histologically confirmed diagnosis of GBM\n\n         14. Subjects must have documented recurrence after first-line treatment\n\n         15. Prior first-line treatment must have included radiation and temozolomide\n\n         16. Subject is suitable for re-resection, per Investigator discretion, as a component of\n             their clinical care\n\n         17. No more than one prior resection (Note: biopsy does not count as prior resection)\n\n        Exclusion Criteria:\n\n        All Subjects\n\n          1. Subjects who have had recent systemic anticancer therapies, interventional device\n             treatment and/or radiotherapy either within 14 days prior to first dose of study\n             drug(s) or have not recovered (to grade ? 1) from all clinically significant\n             toxicities related to prior therapies\n\n          2. Subjects who have had any major surgery (not including re-resection surgery required\n             in Phase 2) within 28 days prior to first dose of study drug(s), or minor surgery\n             within 14 days prior to first day of study drug(s)\n\n          3. Subjects taking any protocol prohibited medications within 14 days prior to initiating\n             study drug(s) treatment\n\n          4. Subjects who have been treated with an investigational agent or investigational\n             interventional device within 21 days prior to the first dose of study drug(s)\n\n          5. History of significant cardiac disease\n\n          6. Pregnant or breastfeeding\n\n          7. Any other significant co-morbid conditions that in the opinion of the Investigator\n             would impair study participation or cooperation\n\n             For Phase 1 Subjects Only:\n\n          8. Subjects with lymphoma as primary cancer\n\n             For Phase 2 Subjects Only:\n\n          9. Subjects unable or unwilling to consent to the provision of resected tissue after\n             surgery
Inclusion Criteria:\n\n          -  Eastern Cooperative Oncology Group performance status of 0 or 1\n\n          -  Histologically or cytologically confirmed, Stage IV non-squamous NSCLC\n\n          -  Participants with no prior treatment for Stage IV non-squamous NSCLC\n\n          -  Previously obtained archival tumor tissue or tissue obtained from fresh biopsy at\n             screening\n\n          -  Measurable disease, as defined by RECIST v1.1\n\n          -  Adequate hematologic and end organ function\n\n        Exclusion Criteria:\n\n        Cancer-Specific Exclusions:\n\n          -  Active or untreated central nervous system metastases\n\n          -  Malignancies other than NSCLC within 5 years prior to randomization, with the\n             exception of those with a negligible risk of metastasis or death treated with expected\n             curative outcome\n\n        General Medical Exclusions:\n\n          -  Pregnant or lactating women\n\n          -  History of autoimmune disease\n\n          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced\n             pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening\n             chest computed tomography scan. History of radiation pneumonitis in the radiation\n             field (fibrosis) is permitted\n\n          -  Positive test for human immunodeficiency virus\n\n          -  Active hepatitis B or hepatitis C\n\n          -  Severe infection within 4 weeks prior to randomization\n\n          -  Significant cardiovascular disease\n\n          -  Illness or condition that interferes with the participant's capacity to understand,\n             follow and/or comply with study procedures\n\n        Exclusion Criteria Related to Medications:\n\n          -  Prior treatment with cluster of differentiation 137 agonists or immune checkpoint\n             blockade therapies, anti-programmed death-1, and anti-PD-L1 therapeutic antibodies
Inclusion criteria:\n\n        Adult patients aged >=18 years with histologically or cytologically confirmed advanced\n        nonsquamous non-small cell lung cancer (nsNSCLC). Mixed tumors should be categorized\n        according to the predominant histology.\n\n        Note: NSCLC should be predominantly nonsquamous. Recurrent or metastatic disease (Stage IV)\n        with an indication for therapy with paclitaxel + carboplatin + Avastin®.\n\n        Patients harboring tumors with unknown or without activating epidermal growth factor\n        receptor (EGFR) / anaplastic lymphoma receptor tyrosine kinase (ALK) mutation maybe\n        included provided chemotherapy is standard of care. At least one measurable lesion\n        according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 based on independent\n        central review.\n\n        Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.\n\n        Adequate hepatic, renal, and bone marrow function:\n\n        Life expectancy > 6 months based on clinical judgment. Further inclusion criteria apply.\n\n        Exclusion criteria:\n\n        Prior therapy with monoclonal antibodies or small molecule inhibitors against Vascular\n        Endothelial Growth Factor (VEGF) or VEGF receptors, including Avastin®.\n\n        Prior systemic therapy for metastatic disease. Prior systemic anticancer therapy or\n        radiotherapy for locally advanced nsNSCLC if completed <12 months prior to Screening.\n\n        Previous malignancy other than NSCLC in the last 5 years except for basal cell cancer of\n        the skin or pre-invasive cancer of the cervix.\n\n        Symptomatic brain metastasis. Diagnosis of small cell carcinoma of the lung, squamous cell\n        carcinoma of the lung, NSCLC not specified (NS) or NSCLC not otherwise specified(NOS).\n\n        Any unresolved toxicity > Common Toxicity Criteria Grade 1 (except alopecia) from previous\n        anticancer therapy (including radiotherapy).\n\n        History or evidence of inherited bleeding diathesis or coagulopathy with the risk of\n        bleeding. Thrombotic or hemorrhagic event =< 6 months prior to Screening. Further exclusion\n        criteria apply.
ENTRY CRITERIA:\n\n        DISEASE CHARACTERISTICS:\n\n          -  Confirmed diagnosis of relapsed/refractory multiple myeloma after treatment with at\n             least two different previous regimens.\n\n               -  Refractory disease is defined as progressive disease while on therapy or\n                  progression within 60 days of therapy.\n\n               -  Progressive disease is defined by a 25% increase from the lowest response value\n                  in specified tests.\n\n          -  Measurable disease as defined by at least one of the following:\n\n               -  Serum M-protein ? 1g/dL (for IgG, IgM) or 0.5 g/dL (for IgA)\n\n               -  Urine M-protein ? 200mg/24hours\n\n               -  Serum free light chains ? 10 mg/dL and abnormal kappa/lambda ratio\n\n        PRIOR/CONCURRENT THERAPY:\n\n          -  No anti-myeloma treatments within 14 days before the start of study treatment.\n\n          -  Must have recovered from side effects of prior treatments.\n\n        PATIENT CHARACTERISTICS:\n\n        Performance Status\n\n        • ECOG 0, 1, or 2\n\n        Bone Marrow Reserve\n\n          -  Absolute neutrophil count (AGC/ANC) ? 1000/uL\n\n          -  Platelets ? 30,000/uL\n\n          -  Hemoglobin ? 8g/dL\n\n          -  Absolute lymphocytes ? 800/uL\n\n          -  Leukocytes ? 3,000/uL\n\n        Renal Function\n\n        • Glomerular Filtration Rate (GFR) > 40mL/min or Serum creatinine ? 1.5 X ULN\n\n        Hepatic Function\n\n          -  Total bilirubin ? 2.0 X ULN\n\n          -  AST, ALT, ALP ? 3.0 X ULN, or ? 5.0 X ULN (if liver metastases exist)\n\n          -  No positive Hep C serology or active Hep B infection\n\n        Cardiovascular\n\n          -  No congestive heart failure < 6 months\n\n          -  No unstable angina pectoris < 6 months\n\n          -  No myocardial infarction < 6 months\n\n          -  No history of ventricular arrhythmias\n\n          -  No history of supraventricular arrhythmias\n\n          -  No NYHA Class > II CHF\n\n          -  No marked baseline prolongation of QT/QTc interval\n\n        Pulmonary\n\n        • Normal clinical assessment of pulmonary function\n\n        Other\n\n          -  Negative serum pregnancy test if female and of childbearing potential\n\n          -  Women who are not pregnant or nursing\n\n          -  Subjects, both females and males, with reproductive potential must agree to use\n             effective contraceptive measures for the duration of the study\n\n          -  No known autoimmune disease other than corrected hypothyroidism\n\n          -  No known prior organ allograft or allogeneic transplantation\n\n          -  Not HIV positive\n\n          -  No history or evidence of uncontrollable CNS disease\n\n          -  No psychiatric illness/social situation\n\n          -  No other illness that in the opinion of the investigator would exclude the subject\n             from participating in the study\n\n          -  Must provide informed consent and HIPPA authorization and agree to comply with all\n             protocol-specified procedures and follow-up evaluations\n\n          -  No active systemic infection requiring parenteral antibiotic therapy\n\n          -  No on-going chronic systemic corticosteroid (>10 mg daily prednisone equivalent) use\n             or other immunosuppressive therapy (a history of mild asthma not requiring therapy is\n             eligible). Inhaled or topical steroids, and adrenal replacement steroid doses ? 10 mg\n             daily prednisone equivalent, are permitted in the absence of active autoimmune\n             disease.
Inclusion Criteria:\n\n        Patients enrolled in Part A must receive the 99mTc- etarfolatide scan but they do not need\n        to have FR-positive target lesions.\n\n        Parts A and B:\n\n        To qualify for enrollment, the following criteria must be met:\n\n          1. Patient must have the ability to understand and sign an approved informed consent form\n             (ICF).\n\n          2. Patient must be ? 18 years of age.\n\n          3. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0\n             or 1.\n\n          4. Patient must have a life expectancy of > 3 months.\n\n          5. Patient must have at least one measurable lesion per RECIST v1.1 Criteria as assessed\n             on baseline radiologic evaluation obtained no more than 28 days prior to beginning\n             study therapy.\n\n          6. Patients with central nervous system (CNS) metastases that are symptomatic must have\n             received therapy (e.g., surgery, XRT, gamma knife, etc.) and be neurologically stable\n             and off of steroids. The patient should be off steroids at least 14 days before\n             registration. Patients with asymptomatic CNS metastatic disease without associated\n             edema, shift, and a requirement for steroids or anti-seizure medications may be\n             eligible after discussion with the sponsor medical monitor.\n\n          7. Patients must have formalin fixed tissue (biopsy or FNA) available.\n\n          8. Patient must have recovered (to baseline/stabilization) from prior chemo or radio\n             therapy and associated acute toxicities must have resolved to a NCI CTCAE V4 Grade 1\n             or less, with the exception of alopecia.\n\n          9. Patients treated with prior radiation therapy may be eligible if:\n\n               1. Radiotherapy was completed at least 2 weeks before first dose of EC1456 and\n\n               2. Patient has recovered from acute radiation toxicity.\n\n         10. Patients must have adequate organ function:\n\n               1. Bone marrow reserve: Absolute neutrophil count (ANC) ? 1.5 x 109/L; Platelets ?\n                  100 x 109/L; Hemoglobin ? 9 g/dL.\n\n               2. Cardiac:\n\n             i. QTcFridericia (QTcF) < 450 msec on at least 2 of 3 screening ECG's. On site\n             determination of QTcF may be used for screening purposes.\n\n             ii. Left ventricular ejection fraction (LVEF) equal to or greater than the\n             institutional lower limit of normal. LVEF must be evaluated within 28 days prior to\n             C1D1.\n\n             iii. Cardiac Troponin I or T within normal limit. (whichever troponin is done for\n             screening will need to be done throughout the rest of the study).\n\n             c. Hepatic: Total bilirubin ? 1.5 x the upper limit of normal (ULN); Alanine\n             aminotransferase (ALT), aspartate aminotransferase (AST) ? 3.0 x ULN OR ? 5.0 x ULN\n             for patients with liver metastases.\n\n             d. Renal: Serum creatinine ? 1.5 x ULN or for patients with serum creatinine > 1.5\n             ULN, creatinine clearance ? 50 mL/min.\n\n             Patients of childbearing potential:\n\n         11. All women of childbearing potential MUST have a negative urine or serum pregnancy test\n             within 1 week prior to the 99mTc-etarfolatide imaging procedure and within 1 week\n             prior to treatment with EC1456.\n\n         12. Women of child bearing potential must practice an effective method of birth control\n             (i.e., oral, transdermal or injectable contraceptives, intrauterine device [IUD], or\n             double-barrier contraception, such as diaphragm and spermicidal jelly) for the\n             duration of their participation in the trial through 90 days following the last dose\n             of EC1456.\n\n         13. Male patients who are sexually active must practice an effective method of birth\n             control (e.g., condom and spermicidal jelly) for the duration of their participation\n             in the trial through 90 days following the last dose of EC1456.\n\n             Patient and Disease Specific Inclusion Criteria: Part A\n\n             EC1456 dose escalation cohorts (Treatments 1, 2, 3, and 4):\n\n         14. Patients must have pathologically confirmed metastatic or locally advanced solid\n             cancer (preferably TNBC, NSCLC, ovarian, or endometrial cancers due to frequent high\n             FR expression in these cancers) that has failed to respond to standard therapy, is not\n             amenable to standard therapy, or for which standard therapy does not exist.\n\n         15. TNBC and ovarian patients must agree to submit results of BRCA 1/2 status (i.e.,\n             deleterious mutation present, mutation of unknown significance, no mutation detected)\n             if known. BRCA testing is not required for study inclusion.\n\n         16. Patients must have received ? 4 prior lines of systemic anti-cancer therapy (including\n             but not limited to cytotoxic agents, targeted inhibitors, and monoclonal antibodies).\n             Hormonal therapies are not included toward this criterion.\n\n         17. Patients must undergo a 99mTc-etarfolatide SPECT imaging procedure in compliance with\n             the Investigator's Imaging Operations Manual (IIOM). FR expression on 99mTc\n             -etarfolatide SPECT is not required for inclusion in Treatments 1, 2, 3, and 4.\n\n             (Patients who underwent a 99mTc-etarfolatide SPECT/CT imaging procedure as a subject\n             on Endocyte study EC20.12 will not be required to have a repeat scan for participation\n             in study EC1456-01 if the scan was obtained within 4 weeks of cycle 1 day 1 of EC1456\n             administration and has been deemed acceptable by Endocyte Imaging.)\n\n             Part B Only:\n\n             Patient and Disease Specific Inclusion Criteria: Part B\n\n             Patients with FR-positive NSCLC (all subtypes): (Treatments 5, 6, and 7)\n\n         18. Patients with NSCLC (all subtypes) must have received one prior platinum based therapy\n             for advanced or metastatic disease. No additional cytotoxic therapy for advanced or\n             metastatic disease is allowed. Any number of prior targeted therapies (e.g.,\n             inhibitors of ALK, EGFR, and PD-1 or PD-L1) are allowed. Patients with known relevant\n             genomic tumor aberrations (i.e., EGFR, ALK, ROS-1, etc) must have received and\n             progressed on approved therapy for these aberrations. This information must be\n             documented prior to study entry.\n\n         19. Patients must undergo a 99mTc-etarfolatide SPECT imaging procedure in compliance with\n             the Investigator's Imaging Operations Manual (IIOM) and be FR-positive.\n\n        Exclusion Criteria:\n\n        Parts A and B:\n\n        The presence of any of the following will exclude patients from the study:\n\n          1. Systemic anti-cancer treatment, except hormonal treatment, within 28 days prior to\n             EC1456 administration unless there are no remaining or ongoing uncontrolled\n             toxicities. Please contact the medical monitor to discuss requests for less than 28\n             day washout period.\n\n          2. Known hypersensitivity to the components of the study therapy or its analogs.\n\n          3. Carcinomatous meningitis and/or symptomatic central nervous system (CNS) metastases.\n\n          4. Malignancies that are expected to alter life expectancy or may interfere with disease\n             assessment. Patients with adequately treated non-melanoma skin cancer, carcinoma in\n             situ of the cervix, or low-grade (Gleason score ? 6) localized prostate cancer, ductal\n             carcinoma in situ (DCIS), and patients with prior history of malignancy who have been\n             disease free for more than 3 years are eligible.\n\n          5. Serious cardiac illness or medical conditions such as unstable angina, pulmonary\n             embolism, or uncontrolled hypertension.\n\n          6. Patients considered at risk for life-threatening QTc prolongation (i.e., personal or\n             family history of Long QT syndrome, presence of implantable pacemaker or implantable\n             cardioverter defibrillator, etc.).\n\n          7. Use of the following medications within 6 months prior to EC1456 administration:\n             amiodarone, disopyramide, dofetilide, dronedarone, flecanamide, ibutilide, quinidine,\n             or sotalol.\n\n          8. Need for concurrent anti-folate therapy such as methotrexate for rheumatoid arthritis.\n\n          9. Other concurrent chemotherapy, immunotherapy, radiotherapy, or investigational\n             therapy.\n\n         10. Pregnant or lactating women.\n\n         11. Active uncontrolled infections.\n\n         12. Known active Hepatitis B or C infection.\n\n         13. Unable or unwilling to have a pretreatment scan performed with 99mTc-etarfolatide for\n             any reason (such as claustrophobia, an inability to lie supine on an imaging table\n             because of pain or cardiopulmonary disease, etc.).
The following eligibility criteria pertain to patients enrolling into PART 2 of the study:\n\n        Inclusion:\n\n          -  Have a histologically confirmed diagnosis of high grade serous or Grade 2 or Grade 3\n             endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer\n\n          -  Received at least 3 prior chemotherapy regimens. Non-chemotherapy regimens and\n             maintenance therapies administered as single agent treatment will not count as a\n             chemotherapy regimen\n\n          -  Relapsed/progressive disease as confirmed by CT scan\n\n          -  Have biopsiable and measurable disease. Note: biopsy is optional for patients known to\n             harbor a deleterious gBRCA mutation\n\n          -  Have sufficient archival formalin-fixed paraffin-embedded (FFPE) tumor tissue\n             available for planned analyses\n\n        Exclusion:\n\n          -  History of prior cancers except for those that have been curatively treated, with no\n             evidence of cancer currently (provided all chemotherapy was completed >6 months prior\n             and/or bone marrow transplant >2 years prior to first dose of rucaparib).\n\n          -  Prior treatment with any PARP inhibitor\n\n          -  Symptomatic and/or untreated central nervous system metastases\n\n          -  Pre-existing duodenal stent and/or any other gastrointestinal disorder or defect that\n             would, in the opinion of the Investigator, interfere with absorption of rucaparib\n\n          -  Hospitalization for bowel obstruction within 3 months prior to enrollment
ENTRY CRITERIA:\n\n        DISEASE CHARATERISTICS:\n\n          -  Histologically confirmed high-risk (high grade Ta, T1 or carcinoma in situ, tumor >4\n             cm or multi-focal) transitional cell carcinoma s/p TURBT with no remaining resectable\n             disease within 4 weeks of study entry\n\n          -  Intolerant of treatment with BCG or failure (refractory or relapsing) of at least one\n             prior treatment with BCG\n\n          -  Refuse or intolerant of a radical cystectomy\n\n          -  No Evidence of regional and/or distant metastasis\n\n        PRIOR/CONCURRENT THERAPY:\n\n          -  No concurrent radiotherapy, other chemotherapy, or other immunotherapy\n\n          -  No scheduled radiotherapy, chemotherapy, other immunotherapy, or surgery before the\n             scheduled response evaluation\n\n          -  Must have recovered from side effects of prior treatments\n\n          -  No concurrent use of other investigational agents\n\n        PATIENT CHARACTERISTICS:\n\n        Age\n\n        • ? 18 years\n\n        Performance Status\n\n        • ECOG 0, 1, or 2\n\n        Bone Marrow Reserve\n\n          -  Absolute neutrophil count (AGC/ANC) ? 1,000/uL\n\n          -  Platelets ? 100,000/uL\n\n          -  Hemoglobin ? 8 g/dL\n\n        Renal Function\n\n        • Glomerular Filtration Rate (GFR) ? 50mL/min\n\n        Hepatic Function\n\n          -  Total bilirubin ? 2.0 X ULN\n\n          -  AST, ALT, ALP ? 3.0 X ULN\n\n        Cardiovascular\n\n          -  No congestive heart failure < 6 months\n\n          -  No severe/unstable angina pectoris < 6 months\n\n          -  No myocardial infarction < 6 months\n\n          -  No history of ventricular arrhythmias\n\n          -  No NYHA Class > II CHF\n\n          -  No uncontrollable supraventricular arrhythmias\n\n          -  No history of a ventricular arrhythmia\n\n          -  No other clinical signs of severe cardiac dysfunction\n\n          -  Normal Transthoracic Echocardiogram (TTE) is required for patients who have history of\n             EKG abnormalities, CHF, coronary artery disease or other cardiac disease, or have\n             history of having received adriamycin or doxorubicin\n\n          -  No patients with a left ventricular ejection fraction (LVEF) of less than 50%\n\n        Pulmonary\n\n        • Normal clinical assessment of pulmonary function\n\n        Other\n\n          -  Negative serum pregnancy test if female and of childbearing potential\n\n          -  Women who are not pregnant or nursing\n\n          -  Subjects, both females and males, with reproductive potential must agree to use\n             effective contraceptive measures for the duration of the study\n\n          -  No known autoimmune disease other than corrected hypothyroidism\n\n          -  No known prior organ allograft or allogeneic transplantation\n\n          -  Not HIV positive\n\n          -  No active systemic infection requiring parenteral antibiotic therapy\n\n          -  No ongoing systemic steroid therapy required\n\n          -  No history or evidence of uncontrollable CNS disease\n\n          -  No psychiatric illness/social situation\n\n          -  No other illness that in the opinion of the investigator would exclude the subject\n             from participating in the study\n\n          -  Must provide informed consent and HIPAA authorization and agree to comply with all\n             protocol-specified procedures and follow-up evaluations
Inclusion Criteria:\n\n          -  Be at least 12 years of age\n\n          -  Have a documented (medical record) diagnosis of either pheochromocytoma or\n             paraganglioma\n\n          -  Be ineligible for curative surgery for pheochromocytoma\n\n          -  Have failed a prior therapy for pheochromocytoma/paraganglioma or are not candidates\n             for chemotherapy or other curative therapies\n\n          -  Be on stable antihypertensive medication for pheochromocytoma-related hypertension for\n             at least 30 days\n\n          -  Have at least one tumor site by CT or MR or iobenguane I 131 scan\n\n          -  Have an expected survival of at least 6 months\n\n          -  Subjects must agree to use an acceptable form of birth control (abstinence, IUD, oral\n             contraception, barrier and spermicide or hormonal implant) during this study and for 6\n             months following Therapeutic Doses of Ultratrace Iobenguane I 131.\n\n          -  Male subjects must agree not to father a child during the period beginning immediately\n             after administration of the first Therapeutic Dose of Ultratrace Iobenguane I 131\n             during the study and ending six months after administration of the last Therapeutic\n             Dose of Ultratrace Iobenguane I 131.\n\n        Exclusion Criteria:\n\n        Subjects will be excluded if any of the following conditions are observed:\n\n          -  <50% of FDG (if data are available) positive lesions are MIBG avid\n\n          -  Pregnant or nursing females\n\n          -  Active CNS lesions by CT/MR scanning within 3 months of study entry\n\n          -  New York Heart Association class IV heart failure, symptomatic congestive heart\n             failure [New York Heart Association class IV with another medical disorder], unstable\n             angina pectoris, cardiac arrhythmia\n\n          -  Received any previous systemic radiotherapy resulting in marrow toxicity within 3\n             months of study entry or have active malignancy (other than\n             pheochromocytoma/paraganglioma) requiring additional treatment during the active phase\n             or follow up period of the Ultratrace® iobenguane I 131 trial.\n\n          -  Administered prior whole-body radiation therapy\n\n          -  Received external beam radiotherapy to > 25% of bone marrow\n\n          -  Administered prior chemotherapy within 30 days or have active malignancy (other than\n             pheochromocytoma/ paraganglioma) requiring additional treatment during the active\n             phase or follow up period of the Ultratrace iobenguane I 131 trial.\n\n          -  Karnofsky Performance Status is < 60\n\n          -  Platelets < 80,000/?L\n\n          -  Absolute neutrophil count (ANC) < 1,200/?L, Total bilirubin > 1.5 times the upper\n             limit of normal, AST/SGOT or ALT/SGPT > 2.5 times the upper limit of normal\n\n          -  Diagnosed with AIDS or HIV-positive\n\n          -  Active chronic alcohol abuse, chronic liver disease or hepatitis\n\n          -  Renal dysfunction/impairment\n\n          -  Known allergy to iobenguane that has required medical intervention\n\n          -  Received a therapeutic investigational compound and/or medical device/prior\n             chemotherapy within 30 days before admission into this study\n\n          -  Receiving a medication which inhibits tumor uptake of iobenguane I 131\n\n          -  Any medical condition or other circumstances (i.e., uncontrolled current illness\n             including but not limited to, ongoing or active infection or psychiatric\n             illness/social situations that would limit compliance with the study requirements.\n\n          -  Any other condition, that in the opinion of the investigator, may compromise the\n             safety or compliance of the subject or would preclude the subject from successful\n             completion of the study
Criteria for Inclusion:\n\n          1. Female patient ? 18 years\n\n          2. Willing and able to give informed consent\n\n          3. Stage III-IV platinum-sensitive (defined as a lack of progression by RECIST v1.1\n             criteria following completion of standard-of-care chemotherapy, including a minimum of\n             4 cycles of a platinum-containing regimen) epithelial ovarian, fallopian tube or\n             primary peritoneal carcinoma in first remission.\n\n          4. Histologic documentation of diagnosis of carcinoma is required and the following\n             histologic subtypes are eligible: high grade (grade ?3+) serous or endometrioid\n             carcinoma, carcinosarcoma, or poorly-differentiated adenocarcinoma, or mixed\n             (including above subtypes only). Note that synchronous serous or endometrioid uterine\n             or fallopian cancers are allowed.\n\n          5. The patient must have demonstrated an objective response (PR or CR) or stable disease\n             (SD) with the last chemotherapy prior to enrollment and this response must be stable\n             (without progressive disease) before randomization.\n\n          6. Patients must receive their first dose of vaccine within 1 year of completion of their\n             final dose of a chemotherapeutic agent of the platinum-containing regimen\n\n          7. Adequate normal organ and marrow function within 14 days prior to first vaccine\n             administration:\n\n               -  Absolute neutrophil count > 1.5 x 109/L\n\n               -  Platelet > 100 x 109/L\n\n               -  Hemoglobin > 9.0 g/dL\n\n               -  Serum bilirubin < 1.5 times ULN (unless Gilbert's syndrome without concurrent\n                  clinically significant liver disease\n\n               -  AST/ALT < 2.5 ULN unless liver metastasis in which case it must be < 5 x ULN\n\n               -  Serum creatinine CL > 40 mL/min by Cockcroft-Gault formula.\n\n          8. Anti-nuclear antibody (ANA) negative or low-positive institutional range, as\n             determined within 28 days from registration. Intermediate values (usually defined by a\n             titer of ?1:80, or as indicated by institutional range) are acceptable if there are,\n             in the opinion of the Investigator, no early signs of an autoimmune disease.\n\n          9. Female subjects must either be of non-reproductive potential (i.e. post-menopause by\n             history: > 60 years old and no menses for > 12 months naturally or secondary to\n             radiation/chemotherapy; OR serum FSH, LH and estradiol levels in the post-menopausal\n             range; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history\n             of bilateral oophorectomy), or must have a negative serum pregnancy test upon study\n             entry\n\n         10. Life expectancy > 24 weeks\n\n         11. ECOG performance status of 0 or 1\n\n         12. Formalin fixed, paraffin embedded tumor sample from the primary cancer must be sent\n             for central testing.\n\n        Criteria for Exclusion\n\n          1. Histology consistent with non-serous, non-endometrioid (i.e. mucinous or clear cell),\n             or low-grade or borderline serous ovarian carcinoma\n\n          2. Patients with a history of other cancers (other than non-melanoma skin cancers [i.e.\n             basal or squamous cell]) within the past 3 years.\n\n          3. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, targeted\n             therapy, biological/cell therapy, tumor embolization, monoclonal antibodies, other\n             investigational agent) < 28 days prior to the first dose of study drug.\n\n          4. Current or prior use of immunosuppressive medication within 28 days prior to the fist\n             dose of study drug with the exception of topical, intranasal or inhaled\n             corticosteroids or systemic corticosteroids at physiological doses, which are not to\n             exceed 10 mg/day of prednisone, or an equivalent corticosteroid.\n\n          5. Active autoimmune disease requiring therapy within the past 2 years. Note: patients\n             with vitiligo, Grave's disease or psoriasis not requiring systemic treatment within\n             the past 2 years are not excluded.\n\n          6. History of hypersensitivity to GM-CSF\n\n          7. Uncontrolled intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable\n             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active\n             bleeding diatheses including any subject known to have evidence of acute or chronic\n             hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric\n             illness/social situations that would limit compliance with study requirements or\n             compromise the ability of the subject to give written informed consent\n\n          8. Symptomatic thyroid disease, unless negative for thyroid antibodies (TSH receptor,\n             TPO, thyroglobulin).\n\n          9. Subjects who are pregnant or are breast feeding.\n\n         10. Subjects who or of reproductive potential, and are either:\n\n               -  Not abstinent;\n\n               -  Not in an exclusive relationship with a partner who is surgically sterile;\n\n               -  Not employing an effective method of birth control.\n\n         11. Any condition that, in the opinion of the investigator, would interfere with\n             evaluation of study treatment or interpretation of patient safety or study results\n\n         12. Symptomatic or uncontrolled brain metastasis requiring concurrent treatment, inclusive\n             of but not limited to surgery, radiation and/or corticosteroids\n\n         13. Subject with uncontrolled seizures
Inclusion Criteria:\n\n        For patients participating in any part of the trial:\n\n          -  has an advanced solid tumor previously treated with, or inability to tolerate,\n             standard therapy for the disease, or for which a standard therapy does not exist, and\n             as such is considered a candidate for Phase 1 treatment\n\n          -  has adequate organ function: Hgb ?9 g/dL; absolute neutrophil count (ANC) ? 1.5x109/L;\n             plt ? 100,000/?L; AST and ALT < 2.5x ULN (< 5x ULN in patients with liver metastases);\n             total bilirubin < 2.0 mg/dL; serum creatinine ? 1.5x ULN\n\n          -  ECOG performance score 0-2\n\n        For patients participating in any expansion group:\n\n          -  has measurable disease based on RECIST 1.1 as determined by the treating investigator.\n             Tumor lesions in a previously irradiated area are considered measurable if progression\n             has been demonstrated in such lesions\n\n          -  willing to consent for biopsy is strongly recommended but not mandatory\n\n          -  recovery of toxicities related to any prior treatments to at least Grade 1 by CTCAE v\n             4.03. Exceptions are patients with adverse event(s) that are clinically nonsignificant\n             and/or stable on supportive therapy.\n\n        For patients participating in specific expansion groups:\n\n        Cutaneous Melanoma:\n\n          -  unresectable, locally advanced or metastatic (AJCC stage IIIB, IIIC, or IV) cutaneous\n             malignant melanoma\n\n          -  relapsed or progressive disease after or unable to tolerate at least one prior\n             systemic anticancer regimen for metastatic disease involving immunotherapy (anti-PD-1,\n             anti-PD-L1, or anti-CTLA-4)\n\n          -  in tumors with a relevant BRAF mutation, relapsed, refactory, or unable to tolerate at\n             least one prior systemic anticancer regimen for metastic disease involving a BRAF\n             inhibitor\n\n        Uveal Melanoma:\n\n          -  uveal melanoma at metastic stage\n\n        Small Cell Lung Cancer:\n\n          -  extensive disease previously treated with, or inability to tolerate, platinum-based\n             chemotherapy\n\n        Exclusion Criteria:\n\n          -  has primary CNS malignancy\n\n          -  history of untreated brain mets or leptomeningeal disease or spinal cord compression\n\n          -  effects of prior anticancer therapy recovered to grade < 2\n\n          -  known HIV\n\n          -  active infection\n\n          -  major surgery within 2 weeks\n\n          -  history of another malignancy within 2 years prior
Inclusion Criteria:\n\n        Signed informed consent; Histologically confirmed gastric, esophageal, or gastro-esophageal\n        junction adenocarcinoma; disease that is locally advanced (unresectable), metastatic, or\n        locally recurrent disease; Measurable or non-measurable, but radiologically evaluable\n        disease, according to RECIST; ErbB2 (HER2)positive; Age =18 years; ECOG Performance status\n        = 2; Adequate organ function, including adequate hematologic, renal and liver function;\n        Cardiac ejection fraction within institutional range of normal as measured by\n        echocardiogram; Able to swallow and retain oral medications, and/or receive enteral\n        medications via gastrectomy feeding tube; Women and men with potential to have children\n        must be willing to practice acceptable methods of birth control during the study; Prior\n        gastric surgery is permitted if > 3 weeks prior and recovered; Prior chemotherapy for\n        non-gastric malignancy if > than 5 years; Prior neoadjuvant and/or adjuvant chemotherapy\n        for early stage gastric cancer if > 6 months since completion; At least 4 weeks since prior\n        radiotherapy; Prior biologic, hormonal, or immunologic cancer treatment if > 5 years since\n        treatment.\n\n        Exclusion Criteria:\n\n        Pregnant or lactating females; Known history of active CNS disease; Uncontrolled ascites;\n        Concurrent anti-cancer therapy; Gastric carcinoid, epidermoid, sarcomas, or squamous cell\n        carcinoma; Prior palliative chemotherapy for the treatment of gastric cancer; Prior\n        treatment with oxaliplatin < 12 months; Malabsorption syndrome or uncontrolled inflammatory\n        gastrointestinal disease; Known history of uncontrolled or symptomatic angina, arrhythmias,\n        or congestive heart failure; Pre-existing grade = 2 motor or sensory neuropathy;\n        Uncontrolled infection; Concurrent disease or condition that would make the subject\n        inappropriate for study participation or any serious medical condition that would interfere\n        with the subject''s safety; Active hepatic or biliary disease; History of other malignancy\n        except if disease-free for 5 years, a history of completely resected non-melanoma skin\n        cancer, or a successfully treated in situ carcinoma; Unresolved or unstable serious\n        toxicity from prior administration of another investigational drug and/or prior cancer\n        treatment; Dementia, altered mental status, or any psychiatric condition that would\n        prohibit the understanding or rendering of informed consent; Known history of DPD\n        deficiency; Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs\n        chemically related to lapatinib, capecitabine, fluorouracil, platins or their excipients;\n        Use of any investigational drug within 30 days prior randomization; Use of concurrent\n        prohibited medications that would interact with study medications
Inclusion Criteria:\n\n        A woman will be eligible for inclusion in this study if she meets all of the following\n        criteria:\n\n          -  Age >18 to <70 years old.\n\n          -  Has known ER and PR status\n\n          -  Has HER2 nonamplified disease, confirmed by FISH\n\n          -  Has known menopausal status (see Section 7.3 for criteria)\n\n          -  Has operable, histologically confirmed, Stage I, IIA, IIB, or IIIA, IIIB, or IIIC\n             invasive carcinoma of the breast. Bilateral synchronous breast cancer is allowable\n             provided that 1 primary meets the inclusion criteria.\n\n          -  Meets 1 of the 3 following criteria:\n\n               -  T1-3N1-3M0 if ER positive or negative\n\n               -  T2-3N0M0 if ER positive or negative\n\n               -  T1N0M0 if ER and PR negative\n\n          -  Has complete surgical resection of the primary breast tumor: either lumpectomy or\n             mastectomy with sentinel lymph node biopsy or axillary dissection, with clear margins\n             for both invasive and ductal carcinoma in situ (DCIS)\n\n          -  Has had no prior chemotherapy unless >5 years ago\n\n          -  Has an ECOG Performance Status (PS) 0-1\n\n          -  Has laboratory values of: See protocol for specific details\n\n          -  Has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) and alkaline\n             phosphatase (ALP) within the ranges shown below. In determining eligibility the more\n             abnormal of the 2 values (AST or ALT) should be used. See protocol for specific\n             details\n\n          -  Has normal cardiac function as evidenced by a LVEF >50%, but WNL by institutional\n             standard by multiple gated acquisition (MUGA) scan. An echocardiogram (ECHO) may be\n             used if MUGA is not available, but the same modality must be used consistently\n             throughout the study to evaluate LVEF. Ejection fraction as determined by ECHO must be\n             WNL by institutional standard.\n\n          -  Has no evidence of metastatic disease outside of breast by physical examination and\n             chest x-ray. Other scans if done as needed by the patient (eg, bone scan; abdominal,\n             chest CT; PET or PET/CT; ultrasound; or MRI should indicate no evidence of metastatic\n             disease\n\n          -  Has had baseline bilateral mammography\n\n          -  It has been <84 days since the date of definitive surgery (eg, mastectomy or, in the\n             case of a breast-sparing procedure, axillary dissection) with adequate wound healing,\n             as determined by the Treating Physician\n\n          -  Has a negative serum pregnancy test within 7 calendar days prior to registration\n             (female patients of childbearing potential [not surgically sterilized and between\n             menarche and 1 year postmenopause])\n\n          -  If fertile, patient has agreed to use an acceptable method of birth control (barrier\n             contraceptive only) to avoid pregnancy for the duration of the study and for a period\n             of 3 months thereafter\n\n          -  Has adequate tumor specimen available for FISH analysis of TOP2A status (See Appendix\n             VI).\n\n          -  Has signed a Patient Informed Consent Form\n\n          -  Has signed a Patient Authorization Form\n\n        Exclusion Criteria:\n\n        A woman will be excluded from this study if she meets any of the following criteria:\n\n          -  Has any evidence of metastatic disease following surgical resection of the primary\n             tumor including: positive surgical margins, staging work-up, or physical examination\n             suspicious for malignant disease\n\n          -  Has T4 disease (ie, patients with fixed tumors, peau d'orange skin changes, skin\n             ulcerations, or inflammatory changes)\n\n          -  Has Stage IV breast cancer (M1 disease on TNM staging system)\n\n          -  Has a history of severe hypersensitivity reaction to drugs formulated with polysorbate\n             80\n\n          -  Has had neoadjuvant chemotherapy for this breast cancer\n\n          -  Has ever had a myocardial infarction (MI) or has a history of heart failure,\n             uncontrolled angina, severe uncontrolled arrhythmias, pericardial disease, or\n             electrocardiographic evidence of acute ischemic changes\n\n          -  Is receiving concurrent immunotherapy, hormonal therapy (eg, tamoxifen, hormone\n             replacement therapy), or radiation therapy. Must discontinue prior to registering on\n             the study.\n\n          -  Is receiving concurrent investigational therapy or has received such therapy within\n             the past 30 calendar days\n\n          -  Has peripheral neuropathy >Grade 1\n\n          -  Has had a major organ allograft or condition requiring chronic immunosuppression (ie,\n             kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases). Patients\n             who have received corneal transplants or cadaver skin or bone transplants are\n             eligible.\n\n          -  Has a serious uncontrolled intercurrent medical or psychiatric illness, including\n             serious viral (including clinically defined AIDS), bacterial or fungal infection; or\n             history of uncontrolled seizures, or diabetes, or CNS disorders deemed by the Treating\n             Physician to be clinically significant, precluding informed consent\n\n          -  Has active hepatitis B or hepatitis C with abnormal liver function tests (LFTs) or is\n             known to be HIV positive\n\n          -  Has a history of other malignancy within the last 5 years (except cured basal cell\n             carcinoma of skin, carcinoma in situ of uterine cervix, DCIS, which could affect the\n             diagnosis or assessment of any of the study drugs\n\n          -  In an obese patient to whom the Treating Physician would not be comfortable\n             administering full doses of study drugs as calculated by the BSA. Obese patients will\n             be treated based on actual body weight. Obese patients treated with full doses based\n             on actual BSA are eligible.\n\n          -  Is pregnant or breastfeeding\n\n          -  Is deemed unable to comply with requirements of study
Inclusion Criteria:\n\n        Prior to vaccine production -\n\n          1. Diagnosis of advanced cancer (solid tumor) that:\n\n               1. May be receiving or about to start another line of therapy.\n\n               2. If on a line of therapy or about to start a new line of therapy, it is\n                  anticipated that the treatment may provide short-term tumor control.\n\n          2. Available tissue from an archival tissue sample or tissue from a biopsy done during\n             the initial screen, or both. If archival tissue is not available or tissue is not\n             mainly tumor, subjects must be willing to undergo a biopsy or surgery to remove some\n             or all of their tumor for next generation sequencing. New tissue should be obtained\n             prior to starting a new line of therapy, if applicable.\n\n          3. Minimum estimated life expectancy of 6 months.\n\n          4. Age 18 years or older.\n\n          5. Signed written informed consent to allow transfer of tumor tissue and production of\n             vaccine.\n\n          6. Discussion about each patient should occur with the Medical Monitor to confirm\n             eligibility.\n\n        Prior to Treatment -\n\n        Patients who had vaccine manufactured but were treated with an additional line of treatment\n        may start vaccine if they continue to meet the remaining eligibility criteria.:\n\n          1. Diagnosis of advanced cancer (solid tumor) that is refractory to standard therapies.\n\n          2. Signed written informed consent for treatment.\n\n          3. Minimum estimated life expectancy of 3 months.\n\n          4. Eastern Cooperative Oncology Group (ECOG) performance status <2.\n\n          5. Adequate bone marrow function (absolute neutrophil count [ANC] ?1,500/mm^3; absolute\n             lymphocyte count [ALC] ?500/mm^3; platelet count 100,000/mm^3), adequate liver\n             function (serum glutamic oxaloacetic transaminase [SGOT]/aspartate aminotransferase\n             [AST] and alkaline phosphatase <2.5 times the institutional upper limit of normal\n             [IULN], total bilirubin <1.5 mg/dL), and adequate renal function (creatinine <1.5 x\n             IULN).\n\n          6. Adequate cardiac function (New York Heart Association [NYHA] class ?II).\n\n          7. All participants (males and females) must agree to use adequate contraception\n             (hormonal or barrier method of birth control, abstinence) prior to study treatment and\n             for the duration of study participation.\n\n        Female subjects of childbearing potential should have a negative serum pregnancy test at\n        pre-treatment visit and within 72 hours prior to receiving the first dose of study\n        medication.\n\n        Female subjects of childbearing potential must agree to use 2 methods of birth control or\n        be surgically sterile, or abstain from heterosexual activity prior to receiving the first\n        dose of study medication through 30 days after the last dose of study medication.\n\n        Exclusion Criteria:\n\n        Subjects must not meet any of the following exclusion criteria at the time of tumor\n        procurement. All exclusion criteria must be confirmed prior to treatment.\n\n          1. Diagnosis of immunodeficiency or actively receiving systemic steroid therapy or any\n             other form of immunosuppressive therapy within 7 days prior to the first dose of trial\n             treatment.\n\n          2. Corticosteroid dependency.\n\n          3. Requirement for immunosuppressive medication aside from corticosteroids.\n\n          4. Active or history of any autoimmune disease (subjects with diabetes type 1, vitiligo,\n             psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment\n             are eligible) or immunodeficiencies.\n\n          5. History of treated or untreated brain metastases or leptomeningeal spread of disease.\n\n          6. History or current evidence of any condition, therapy, or laboratory abnormality that\n             might confound the results of the trial, interfere with the subject's participation\n             for the full duration of the trial, or is not in the best interest of the subject to\n             participate, in the opinion of the treating investigator.\n\n          7. Known medical, psychiatric or substance abuse disorders that would preclude\n             participation in the study.\n\n          8. Uncontrolled intercurrent illness, including, but not limited to, ongoing or active\n             infection, interstitial lung disease or active, non-infectious pneumonitis,\n             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or\n             psychiatric illness/social situations that would limit compliance with study\n             requirements.\n\n          9. Known to be positive for human immunodeficiency virus (HIV). Testing is not required\n             in the absence of history or high index of suspicion.\n\n         10. Intolerance of prior immunotherapy treatment necessitating cessation of therapy.\n\n         11. History of intolerance or allergic reactions attributed to compounds of similar\n             chemical or biologic composition to AutoSynVax™ vaccine or QS-21.\n\n         12. Women who are pregnant or breastfeeding.\n\n         13. Inability to comply with protocol.\n\n        Prior to Treatment - Subjects must not meet any of the following exclusion criteria prior\n        to treatment in addition to the other exclusion criteria listed above.\n\n          1. Receipt of anticancer medications or investigational drugs within the following\n             intervals before first administration of study drug:\n\n               1. ?14 days for chemotherapy, targeted small molecule therapy, anticancer hormone\n                  therapy or radiation therapy. Subjects must also not have had radiation\n                  pneumonitis as a result of treatment, and cannot participate in the study if they\n                  are on chronic corticosteroids for radiation pneumonitis or other reasons. A\n                  1-week washout is permitted for palliative radiation to non-CNS disease with\n                  sponsor approval.\n\n               2. Note: Bisphosphonates and denosumab are permitted medications. Novel imaging\n                  agents that have Phase 1 safety data and have not demonstrated therapeutic\n                  activity are also permitted.\n\n               3. ?28 days for a prior immunotherapy.\n\n               4. ?28 days for prior monoclonal antibody used for anticancer therapy with the\n                  exception of denosumab.\n\n               5. ?7 days for immunosuppressive-based treatment for any reason. Systemic\n                  corticosteroids are not allowed.\n\n                  Note: Use of inhaled or topical corticosteroid use for radiographic procedures is\n                  permitted.\n\n                  Note: Patients receiving physiologic steroid replacement for adrenal\n                  insufficiency are eligible (i.e. < 10 mg prednisone per day).\n\n                  Note: The use of physiologic corticosteroid replacement therapy may be approved\n                  after consultation with the sponsor.\n\n               6. ?28 days before the first dose for all other investigational study drugs or\n                  devices.\n\n          2. Receipt of other investigational agents or other anticancer therapies during treatment\n             with AutoSynVax™ vaccine.\n\n          3. Receipt of a live vaccine within 30 days prior to the first dose of trial treatment.
Inclusion Criteria:\n\n        Disease-specific inclusion criteria:\n\n          -  Histologically confirmed adenocarcinoma originating from the colon or rectum (Stage 4\n             American Joint Committee on Cancer [AJCC] 7th edition)\n\n          -  Experienced disease progression or was intolerant to at least two systemic\n             chemotherapy regimens for metastatic colorectal cancer that must have included\n             fluroropyrimidines, irinotecan, and oxaliplatin; adjuvant regimen can be considered as\n             one chemotherapy regimen for metastatic disease if the participant had disease\n             recurrence within 6 months of completion; disease progression must have occurred\n             within 3 months of the last systemic therapy administration\n\n        General inclusion criteria:\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          -  Anticipated life expectancy greater than or equal to (>=) 3 months\n\n          -  Adequate hematologic and end organ function\n\n          -  Women of childbearing potential must agree to appropriately use an effective form of\n             contraception (failure rate of less than [<] 1 percent [%] per year) during the\n             treatment period, within 5 months after the last dose of atezolizumab, and within 3\n             months after the last dose of cobimetinib and regorafenib\n\n          -  Men must agree not to donate sperm or have intercourse with a female partner without\n             using appropriate barrier contraception during the treatment period and for 3 months\n             after the last dose of either cobimetinib or regorafenib\n\n          -  Provide an archival or newly obtained tumor tissue sample\n\n        Exclusion Criteria:\n\n          -  After the approximate 5% cap for microsatellite (MSI)-high participants is reached,\n             only MSI-stable participants will be eligible\n\n          -  Once the 50% cap for wild-type RAS has been reached, only extended RAS-mutant\n             participants will be eligible\n\n          -  Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or anticipation of\n             needing such procedure while receiving study treatment\n\n          -  Treatment with any anti-cancer agent within 14 days prior to Cycle 1 Day 1\n\n          -  Uncontrolled tumor-related pain. Participants requiring narcotic pain medication must\n             be on a stable regimen at study entry\n\n          -  Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated\n             drainage more than once every 28 days. Indwelling drainage catheters (e.g., PleurX®)\n             are allowed\n\n          -  Active or untreated central nervous system (CNS) metastases are excluded\n\n          -  Prior therapy with any cancer immunotherapy, MEK inhibitor, or regorafenib\n\n          -  Participants with active malignancy (other than CRC) or a prior malignancy within the\n             past 3 years are excluded. Participants with completely resected cutaneous melanoma\n             (early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical\n             carcinoma in-situ, breast carcinoma in-situ, and localized prostate cancer are\n             eligible\n\n          -  Unstable angina, new onset angina within last 3 months, myocardial infarction within\n             last 6 months and current congestive heart failure New York Heart Association Class II\n             or higher\n\n          -  Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or\n             below 50%, whichever is lower\n\n          -  Poorly controlled hypertension, defined as a blood pressure consistently above 150/90\n             millimeters of Mercury (mmHg) despite optimal medical management\n\n          -  Human immunodeficiency virus (HIV) infection\n\n          -  Active tuberculosis infection\n\n          -  Severe infections within 2 weeks prior to Cycle 1 Day 1\n\n          -  Active or chronic viral hepatitis B or C infection\n\n          -  History of or evidence of retinal pathology on ophthalmologic examination that is\n             considered a risk factor for central serous retinopathy, retinal vein occlusion, or\n             neovascular macular degeneration\n\n          -  Participants will be excluded if they currently have any of the risk factors as\n             defined in the study protocol for retinal vein occlusion\n\n          -  History of autoimmune disease\n\n          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis\n             obliterans, drug-induced pneumonitis, or idiopathic pneumonitis\n\n          -  History of organ transplantation including allogeneic bone marrow transplantation\n\n          -  Inability to swallow medications\n\n          -  Malabsorption condition that would alter the absorption of orally administered\n             medications\n\n          -  Pregnant, lactating, breastfeeding, or intending to become pregnant during the study\n\n          -  Administration of a live, attenuated vaccine within 4 weeks before randomization or\n             anticipation of a live attenuated vaccine will be required during the study
Inclusion Criteria: (All Subjects)\n\n          -  Male or female adult subjects ?18 years of age\n\n          -  Diagnosis of histologically or cytologically confirmed for:\n\n               -  For Schedule 1 and 2: advanced solid tumor malignancy that is refractory to\n                  standard therapy and/or for whom no further standard therapy is available\n\n               -  For Schedule 3: advanced/metastatic tumors for which mFOLFOX6 is appropriate, or\n                  advanced/metastatic tumors that may be sensitive to each component of mFOLFOX6 or\n                  sensitive to topoisomerase 1 inhibitors including pancreatic, colorectal,\n                  esophageal, gastric, bladder or ovarian cancer, triple-negative breast cancer,\n                  small cell lung cancer (SCLC), cholangiocarcinoma, among others\n\n          -  For Schedules 1 and 2: Eastern Cooperative Oncology Group (ECOG) Performance Status of\n             0 to 2, For Schedule 3: ECOG Performance Status of 0 or 1\n\n          -  Life expectancy >12 weeks in the opinion of the Investigator\n\n          -  Subjects with acceptable pre-study* hematology and biochemistry labs ?3 days prior to\n             Week 1 Day 1 (W1D1) defined as:\n\n               -  absolute neutrophil count (ANC) ?1.500 cells / µL (1.5 x 10°/L, without growth\n                  factor support\n\n               -  platelet count ?100,000 cells/µL (100 x 10° cells/L), without growth factor\n                  support\n\n               -  hemoglobin ?9 g/dL (90/g/L)\n\n               -  serum total bilirubin ?1.5 upper limit of normal (ULN), unless Gilbert's disease\n\n               -  alanine transaminase (ALT) or aspartate transaminase (AST) ?2.5 x ULN, (5 x ULN\n                  for subjects with liver metastases)\n\n               -  calculated or measured creatinine clearance ?40 mL/min\n\n                    -  NOTE: If screening hematology and biochemistry labs are performed ?3 days\n                       prior to W1D1, additional pre-study labs do not need to be repeated to\n                       confirm eligibility. However, if screening hematology and biochemistry labs\n                       are performed greater than 3 days prior to W1D1, additional pre-study labs\n                       will need to be performed to confirm continued eligibility to ensure labs\n                       remain acceptable per protocol\n\n          -  Females of childbearing potential must agree to use two effective methods of\n             contraception (or abstain completely from heterosexual intercourse) from the time of\n             informed consent and for 30 days following last dose of study drug\n\n               -  NOTE: Females of childbearing potential are defined as women physically capable\n                  of becoming pregnant unless the female subject cannot have children due to\n                  surgery or other medical reasons (effective tubal ligation, ovaries or the uterus\n                  removed, or are post-menopausal). Fertile males of childbearing potential are\n                  defined as men who are sexually capable to impregnate the female partner even if\n                  surgically sterilized (i.e., vasectomy).\n\n                    -  highly effective methods of contraception include intra-uterine device (IUD)\n                       and hormonal contraception (oral, injectable, patches or implant)\n\n                    -  effective methods of contraception include barrier methods (latex condom,\n                       diaphragm with spermicide, cervical cap, sponge)\n\n                    -  when possible, subjects should be strongly encouraged to include at least\n                       one highly effective method of contraception\n\n          -  Male subjects must agree to use appropriate method of barrier contraception (latex\n             condom with a spermicidal agent) or abstain completely from heterosexual intercourse\n             fro the time of informed consent and for 120 days following last dose of study drug\n             unless female partner absolutely cannot have children because of surgery or for other\n             medical reasons\n\n          -  Negative urine pregnancy test\n\n          -  Ability to understand and willingness to sign a written informed consent form\n\n          -  Able to comply with study visit schedule and assessments\n\n        Exclusion Criteria: (All Subjects)\n\n          -  Subject has received:\n\n               -  chemotherapy or small molecular targeted therapy <2 weeks prior to W1D1\n\n               -  approved antibody therapy <5 half-lives from W1D1 (or 4 weeks since last therapy,\n                  whichever is the shortest)\n\n               -  local palliative radiation <14 days from W1D1\n\n               -  invasive surgery requiring general anesthesia <30 days from W1D1\n\n               -  chemotherapy with nitrosoureas or mitomycin C <45 days from W1D1\n\n          -  Uncontrolled grade 2 or greater toxicity except alopecia related to any prior\n             treatment (i.e., chemotherapy, targeted therapy, radiation or surgery) within 7 days\n             prior to W1D1 unless approved by the Medical Monitor\n\n          -  Prolongation of QT/QTc interval (QTc interval >470) using the Fredericia method of QTc\n             analysis\n\n          -  Women who are pregnant or nursing\n\n          -  Any known human immunodeficiency virus (HIV) infection or acquired immune deficiency\n             syndrome (AIDS) or any concurrent infection requiring IV antibiotics\n\n          -  Any known clinically significant or concurrent acute liver disease, including viral\n             hepatitis\n\n          -  Primary brain malignant tumors\n\n          -  Subjects with uncontrolled symptomatic central nervous system (CNS) involvement\n\n          -  Subjects requiring steroids at stable dose (>4 mg/day dexamethasone or equivalent) for\n             at least 2 weeks\n\n          -  Uncontrolled hypertension >150/100 mmHg\n\n          -  Concurrent participation in any other investigational therapeutic study, unless\n             non-interventional study and approved by Sponsor\n\n          -  History of stroke, deep venous thrombosis (DVT), transient ischemic attack (TIA),\n             unstable angina, or myocardial infarction within 3 months prior to W1D1\n\n          -  Uncontrolled concurrent disease or illness including but not limited to:\n\n               -  symptomatic congestive heart failure (NYHA Class III or IV) per the NYHA\n                  Classification, unstable angina pectoris, clinically significant cardiac\n                  arrhythmia\n\n               -  unstable or untreated cardiac conditions or ejection fraction of <50% as\n                  determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)\n\n               -  diabetes mellitus (i.e., fasting blood glucose >220 despite acceptable chronic\n                  diabetes therapy)\n\n               -  psychiatric illness that would limit compliance with study requirements, as\n                  determined by the Investigator\n\n          -  Other severe, acute, or chronic medical or psychiatric condition or laboratory\n             abnormality that may increase the risk associated with study participation or study\n             drug administration or that may interfere with the interpretation of study results\n             and, in the judgment of the Investigator, would make the subject inappropriate for the\n             study.\n\n          -  Known hypersensitivity to any component of CRLX101 or excipient or documented medical\n             condition that would prohibit adequate pre-medication with antihistamine.\n\n          -  Presence of ?Grade 1 cystitis\n\n        Exclusion Criteria for Subjects Enrolled in Schedule 2 Only\n\n          -  Minor surgical procedure, excluding placement of a vascular access device, within 24\n             hours prior to W1D1.\n\n          -  Cardiovascular disease defined as congestive heart failure (NYHA Class II, III, or IV)\n             per the NYHA Classification, angina pectoris requiring nitrate therapy, or myocardial\n             infarction within the last 6 months prior to therapy\n\n          -  Uncontrolled hypertension (defined as the presence of systolic blood pressure ?150\n             mmHg or diastolic blood pressure ?100 mmHg on two separate occasions. Blood pressure\n             must be controlled to a systolic blood pressure <150 mmHg and/or to diastolic blood\n             pressure <100 mmHg prior to study treatment), or any prior history of hypertensive\n             crisis or hypertensive encephalopathy\n\n          -  Peripheral vascular disease >Grade 1\n\n          -  Known congenital long QT syndrome, history of torsades de pointes or ventricular\n             tachycardia.\n\n          -  Known history of pulmonary hypertension or non-infectious interstitial pneumonitis.\n\n          -  History or evidence of thrombotic or hemorrhagic disorders: including cerebrovascular\n             accident (CVA) / stroke or transient ischemic attack (TIA), intracerebral hemorrhage\n             or sub- arachnoid hemorrhage ? 6 months prior to W1D1\n\n          -  Chronic daily aspirin >325 mg/day or clopidogrel (>75 mg/day)\n\n          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess\n             within 6 months prior to randomization\n\n          -  Any of the following serious, non-healing conditions:wound, ulcer, or bone fracture\n\n          -  Proteinuria at screening as demonstrated by either: urine dipstick ?2+ (subjects\n             discovered to have a ?2+ proteinuria on dipstick urinalysis at baseline should undergo\n             24-hour urine collection and must demonstrate <1g of protein in 24 hours to be\n             eligible): 24-hour urine collection demonstrates >1g of protein in 24 hours\n\n          -  Immunocompromised subjects, including known seropositivity for human immunodeficiency\n             virus (HIV), or current or chronic hepatitis B and/or hepatitis C infection (as\n             detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to\n             hepatitis C virus [anti HCV] with confirmatory testing). [Note: testing is not\n             mandatory to be eligible for the study. However, if a subject is at risk for having\n             undiagnosed hepatitis C virus (HCV) (due to history of injection drug use or due to\n             geographic location for example), testing at screening should be considered]\n\n          -  Chronic treatment with corticosteroids (prednisone >12.5 mg/day or dexamethasone >2\n             mg/day excluding inhaled steroids\n\n        Exclusion Criteria for Subjects Enrolled in Schedule 3 Only\n\n          -  Known hypersensitivity to 5FU, oxaliplatin or other platinum agent, or to their\n             excipients\n\n          -  Known dihydropyridine dehydrogenase (DPD) enzyme deficiency (testing not required)\n\n          -  Baseline peripheral neuropathy grade ? 2\n\n          -  Progressive disease within ? 6 months of completing an oxaliplatin containing adjuvant\n             therapy\n\n          -  Interstitial lung disease with ongoing signs and symptoms at the time of informed\n             consent
Inclusion Criteria: Each patient MUST:\n\n          -  Have histologically confirmed advanced or metastatic pancreatic adenocarcinoma and\n             have failed or did not tolerate first-line therapy.\n\n          -  Have either archival tissue available for immune testing OR if not, a baseline biopsy\n             of a primary or metastatic lesion (including ascites) which is accessible for a biopsy\n             that can be accomplished with reasonable safety.\n\n          -  Be available and agree to; a post-treatment tumor biopsy of either a primary or\n             metastatic lesion (including ascites).\n\n          -  Have measurable disease.\n\n          -  Have no continuing acute toxic effects (except alopecia) of any prior anticancer\n             treatment, i.e., all such effects must have resolved to Common Terminology Criteria\n             for Adverse Events (CTCAE), version 4.02 [2], Grade ?1. Any major surgery (except\n             biopsies) must have occurred at least 28 days prior to study enrolment.\n\n          -  Have an ECOG Performance Score ? 2.\n\n          -  Have baseline laboratory results as follows:\n\n               -  Absolute neutrophil count (ANC) ? 1.5 x 10E9 [SI units 10E9/L].\n\n               -  Platelets ? 100 x10E9 [SI units 10E9/L] (without platelet transfusion)\n\n               -  Serum creatinine ? 1.5 x ULN.\n\n               -  Creatinine clearance (measured over 24 hours) OR calculated creatinine clearance\n                  (Cockcroft-Gault formula) of ? 60 mL/min.\n\n               -  Bilirubin ? 1.5 x ULN.\n\n               -  AST/ALT ? 3 x ULN (? 5 x ULN if patients have liver metastasis).\n\n               -  TSH, T4 and ACTH must be within normal range.\n\n               -  Proteinuria with normal or grade 1 OR Urinary protein < 1 g/24hr.\n\n               -  Negative pregnancy test for females of childbearing potential.\n\n          -  Have signed an informed consent indicating that the patient is aware of the neoplastic\n             nature of their disease and have been informed of the procedures of the protocol, the\n             experimental nature of the therapy, alternatives, potential benefits, side effects,\n             risks, and discomforts.\n\n          -  Be willing and able to comply with scheduled visits, the treatment plan, and\n             laboratory tests.\n\n        Exclusion Criteria: Each patient MUST NOT:\n\n          -  Receive concurrent therapy with any other investigational anticancer agent while on\n             study.\n\n          -  Be on immunosuppressive therapy or have known HIV infection or active hepatitis B or\n             C.\n\n          -  Receive radiotherapy within 28 days prior to receiving study drug.\n\n          -  Be a pregnant or breast-feeding woman. Female patients of childbearing potential must\n             agree to use effective contraception, must be surgically sterile, or must be\n             postmenopausal. Male patients must agree to use effective contraception or be\n             surgically sterile. Barrier methods are a recommended form of contraception.\n\n          -  Have clinically significant cardiac disease (New York Heart Association, Class III or\n             IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial\n             infarction 1 year prior to study entry, or grade 2 or higher compromised left\n             ventricular ejection fraction.\n\n          -  Have dementia or altered mental status that would prohibit informed consent.\n\n          -  Have any other severe, acute, or chronic medical or psychiatric condition or\n             laboratory abnormality that may increase the risk associated with study participation\n             or study drug administration or may interfere with the interpretation of study results\n             and, in the judgment of the Principal Investigator, would make the patient\n             inappropriate for this study.\n\n          -  Have HIGH BURDEN/SYMPTOMATIC brain metastases. LOW VOLUME / ASYMPTOMATIC and\n             pre-treated clinically stable brain metastases ARE allowed.
Inclusion:\n\n          1. Signed and dated written informed consent prior to any mandatory study specific\n             procedures, sampling and analyses.\n\n          2. Signed and dated written informed consent for tumour biopsies. If the tumour is found\n             not to be safely accessible the biopsy will not be taken. Accessible lesions are\n             defined as those which are biopsiable and amenable to repeat biopsy, unless clinically\n             contraindicated. In this case the patient will remain in the study and there will be\n             no penalty or loss of benefit to the patient and they will not be excluded from other\n             aspects of the study.\n\n          3. Postmenopausal women aged ? 18 years\n\n          4. Negative pregnancy test prior to dosing and willing to use a highly effective method\n             of contraception for the duration of the study and for 90 days after the last dose of\n             IP if they are under 50 unless they have medically confirmed irreversible premature\n             ovarian failure, bilateral oophorectomy, bilateral salpinectomy, or complete or\n             partial hysterectomy.\n\n             Highly effective methods of contraception are:\n\n             • Use of oral, injected or implanted hormonal methods of contraception which inhibit\n             ovulation, either estrogen and progestogen containing intravaginal, transdermal) or\n             only progesterone containing (oral, injectable, implantable)\n\n             • Placement of an intrauterine device (IUD or intrauterine system (IUS)\n\n             • True abstinence\n\n             • Bilateral tubal ligation\n\n             • Vasectomised partner\n\n          5. World Health Organisation/Eastern Cooperative Oncology Group (ECOG) performance status\n             of patient is 0-1 with no deterioration over the previous 2 weeks and minimum life\n             expectancy of 12 weeks.\n\n          6. Histologically or cytologically proven diagnosis of breast cancer with evidence of\n             locally advanced or metastatic disease, not amenable to resection or radiation therapy\n             with curative intent.\n\n          7. Documentation of estrogen receptor positive (ER+) breast cancer based on most recent\n             tumour biopsy (unless bone-only disease).\n\n          8. Documented human epidermal growth factor receptor 2 negative (HER2-) tumor on most\n             recent tumor biopsy.\n\n          9. Where regionally permitted, all patients must agree to provide if available a\n             formalin-fixed paraffin embedded (FFPE) tissue biopsy sample taken at the time of\n             presentation with recurrent or metastatic disease.\n\n         10. At least one lesion (measurable and/or non measurable) that can be accurately assessed\n             at baseline with computerised tomography (CT) or magnetic resonance imaging (MRI)\n             which is suitable for accurate repeated measurements.\n\n         11. Meet the following study part specific criteria related to previous therapy for breast\n             cancer:\n\n        For Part A: Postmenopausal patient suitable for fulvestrant. Patient is allowed to have a\n        maximum of 3 prior lines of chemotherapy. Previous treatment with CDK4/6 inhibitors is\n        allowed\n\n        For Part B: Postmenopausal patient with locally advanced or metastatic ER+ve breast cancer\n        and refractory to AIs defined as:\n\n          -  Disease recurrence while on, or within 12 months of end of adjuvant treatment with\n             letrozole, anastrozole, or exemestane, or\n\n          -  Disease progression while on, or within one month of end of letrozole, anastrozole or\n             exemestane treatment for locally advanced or metastatic breast cancer\n\n               -  Letrozole or anastrozole do not have to be the last treatment prior to\n                  randomization.\n\n               -  Patients who received one prior chemotherapy line for advanced/metastatic breast\n                  cancer are allowed.\n\n        Previous treatment with fulvestrant (or letrozole) is allowed. Other prior anticancer\n        therapy (e.g. tamoxifen) are also allowed.\n\n        For Part C: Postmenopausal patient with locally advanced or metastatic ER+ve breast cancer\n        and refractory to AIs defined as:\n\n          -  Disease recurrence while on, or within 12 months of end of adjuvant treatment with\n             letrozole, anastrozole, or exemestane, ot\n\n          -  Disease progression while on, or within one month of end of letrozole, anastrozole or\n             exemestane treatment for locally advanced or metastatic breast cancer\n\n               -  Letrozole or anastrozole do not have to be the last treatment prior to\n                  randomization.\n\n               -  Patients who received one prior chemotherapy line for advanced/metastatic breast\n                  cancer are allowed.\n\n        Previous treatment with CDK4/6 inhibitors is allowed. Other prior anticancer therapy (e.g.\n        tamoxifen) are also allowed.\n\n        For inclusion in the optional research component:\n\n          1. Genetic research: Provision of signed and dated written consent for genetic research\n             sampling and analyses. If a patient declines to participate in genetic component of\n             the study, there will be no penalty or loss of benefit to the patient. The patient\n             will not be excluded from other aspects of the study described in this Clinical Study\n             Protocol, so long as they consent to the main study.\n\n        Exclusion:\n\n          1. Prior chemotherapy, biological therapy, radiation therapy, or immunotherapy,\n             androgens, thalidomide, other anticancer agents, investigational drug or\n             corticosteroids within 14 days. Patients who received prior radiotherapy to >= 25% of\n             bone marrow are not eligible independent of when it was received. Patients is not\n             eligible if there are unresolved toxicities from prior therapy > CTCAE grade 1 at the\n             start of study treatment with the exception of alopecia.\n\n          2. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) or BCRP\n             within stated washout periods.\n\n          3. Exposure to sensitive or narrow therapeutic range substrates of drug transporters\n             OATP1B1, OATP1B3, MATE1 and MATE2K within wash-out period (5 x elimination half-life).\n\n        4 Exposure to proton pump inhibitors within wash-out period (5 x elimination half-life).\n\n        5. Previous AZD2014, AZD8055 or other dual mTORC1/2 inhibitor\n\n          -  In Part B only: Prior treatment with CDK4/6, or everolimus or any PI3K-mTOR pathway\n\n          -  In Part C only: Prior treatment with fulvestrant, or with everolimus, or any agent\n             whose mechanism of action is to inhibit the PI3K-mTOR pathway\n\n             6. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis,\n             or leptomeningeal disease. Patients with a history of CNS metastases or cord\n             compression are eligible if definitively treated and clinically stable and off\n             anticonvulsants and steroids for at least 4 weeks. Patients are not eligible if there\n             is spinal cord compression and/or brain metastases, unless asymptomatic or treated and\n             stable and off steroids for at least 4 weeks.\n\n             7. Evidence of severe or uncontrolled systemic diseases such as:\n\n             • Severe hepatic impairment\n\n               -  Interstitial lung disease (bilateral, diffuse, parenchymal lung disease)\n\n               -  Current unstable or uncompensated respiratory or cardiac conditions\n\n               -  Uncontrolled hypertension\n\n               -  Active bleeding diatheses\n\n               -  Any active infection\n\n                  8. Other malignancy within 3 years, except adequately treated basal cell or\n                  squamous cell skin cancer, or carcinoma in situ of the cervix\n\n                  9. Experienced any of the following currently or in the last 12 months:\n\n               -  Coronary/peripheral artery bypass graft\n\n               -  Angioplasty\n\n               -  Vascular stent\n\n               -  Myocardial infarction\n\n               -  Angina pectoris\n\n               -  Congestive heart failure NYHA Grade ? 2\n\n               -  Ventricular arrhythmias requiring continuous therapy\n\n               -  Supraventricular arrhythmias including atrial fibrillation of any grade\n\n               -  Symptomatic pulmonary embolism\n\n               -  Haemorrhagic or thrombotic stroke\n\n                  10. Abnormal ECHO or MUGA at baseline (LVEF <50%).\n\n                  11. Mean resting QTc >470 msec, family or personal history of long or short QT\n                  syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de\n                  Pointes within 12 months.\n\n                  12. Clinically important abnormalities in rhythm, conduction or morphology of\n                  resting ECG.\n\n                  13. Hepatitis B (HBV), Hepatitis C (HCV) or Human Immunodeficiency virus (HIV).\n\n                  14. Concomitant medications known to predispose to Torsade de Pointes, or factors\n                  that increase the risk of QT prolongation or risk of arrhythmic events such as:\n\n               -  Heart failure\n\n               -  Hypokalaemia\n\n               -  Congenital long QT syndrome\n\n               -  Family history of long QT syndrome\n\n               -  Family history of unexplained sudden death under 40 years-of-age\n\n                  15. Inadequate bone marrow reserve or organ function as demonstrated by:\n\n               -  ANC <1.5 x 10^9/L.\n\n               -  In Part A only - Cohorts of patients with specific baseline ANC range to be\n                  enrolled defined as follows: I) Low ANC patients: between 1.5 x 10^9/L and 3.0 x\n                  10^9/L; ii) High ANC patients > 3.0 x 10^9/L.\n\n               -  Platelets <100 x 10^9/L\n\n               -  Haemoglobin <90 g/L\n\n               -  ALT >2.5 x ULN or > 5 x ULN in the presence of liver mets.\n\n               -  AST >2.5 x ULN or > 5 x ULN in the presence of liver mets.\n\n               -  Total bilirubin >1.5 x ULN. Total bilirubin >3 x ULN in patients with documented\n                  Gilbert's Syndrome.\n\n               -  Serum creatinine >1.5 x ULN concurrent with creatinine clearance ?50 mL/min.\n\n                  16. Pre-existing renal disease including glomerulonephritis, nephritic syndrome,\n                  Fanconi Syndrome or Renal tubular acidosis.\n\n                  17. Refractory nausea/vomiting, chronic GI diseases, inability to swallow the\n                  product or previous significant bowel resection.\n\n                  18. Hypersensitivity to excipients of AZD2014, Palbociclib or Fulvestrant or\n                  drugs with a similar structure.\n\n                  19. Diabetes Type I or uncontrolled Type II, as defined in WHO 2006 (fasting\n                  serum glucose of > 7.0 mmol/L [126 mg/dL]).\n\n                  20. Patient with advanced/metastatic, symptomatic, visceral spread, that are at\n                  risk of life-threatening complications in the short term including patients with\n                  massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary\n                  lymphangitis, and over 50% of liver involvement in metastases.\n\n                  21. Prior hematopoietic stem cell or bone marrow transplant.\n\n                  22. Regular coumadin therapy. Low-molecular-weight heparin therapy or oral Factor\n                  Xa antagonists are allowed.\n\n                  23. Known abnormalities in coagulation, e.g. bleeding diathesis.\n\n                  24. Hematopoietic growth factors (such as erythropoietin, granulocyte colony\n                  stimulating factor [G-CSF], granulocyte macrophage colony stimulating factor\n                  [GM-CSF]) within 2 weeks prior. Primary prophylactic use of G-CSF is not\n                  permitted.\n\n                  25. Other severe acute or chronic psychiatric condition that may increase the\n                  risks associated with study participation.
Major inclusion criteria:\n\n          1. A histologically or cytologically confirmed solid tumor that is locally advanced,\n             recurrent, or metastatic; for which curative resection is not currently possible; and\n             for which systemic treatment with one of the selected anti-cancer agents is a\n             reasonable therapeutic option.\n\n          2. Must be ? 18 years of age\n\n          3. Has disease such that progression or response to therapy can be evaluated objectively\n             while on protocol.\n\n          4. Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          5. Male or female patients of childbearing potential must agree to use contraception or\n             avoidance of pregnancy measures during the study and for 30 days after the last dose.\n\n          6. Females of childbearing potential must have a negative serum pregnancy test.\n\n          7. Must have aspartate transaminase (AST) ? 2.5 × upper limit of normal (ULN) and alanine\n             transaminase (ALT) ? 2.5 × ULN. Patients who do not have hepatocellular carcinoma but\n             who have liver lesions or liver metastases may be eligible if AST ? 3.5 × ULN and AST\n             ? 3.5 × ULN if agreed upon by the investigator and medical monitor for the sponsor.\n\n          8. Hemoglobin (Hgb) ? 9 g/dl\n\n          9. Total bilirubin ? 1.5 × ULN. For patients with liver lesions, total bilirubin ? 2.0 ×\n             ULN may be enrolled if agreed upon by the investigator and medical monitor for the\n             sponsor\n\n         10. Creatinine ? 1.5 × ULN or creatinine clearance ? 60 mL/min/1.73 m^2 for patients with\n             creatinine levels above institutional upper limit of normal (using the Cockcroft-Gault\n             equation).\n\n         11. Absolute neutrophil count ? 1.5 × 10^9/L\n\n         12. Platelets ? 100 × 10^9/L\n\n         13. Life expectancy ? 3 months\n\n        Major exclusion criteria:\n\n          1. Received anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational\n             agents within 7 days of first dose of protocol therapy. Patients may begin protocol\n             therapy on a date determined by the investigator and medical monitor for the sponsor\n             after a minimum of 7 days since last receiving anti-cancer treatment, provided that\n             all adverse events related to that have resolved or have been deemed irreversible.\n\n          2. Major surgery within 4 weeks prior to first dose; major surgery is defined as a\n             procedure requiring any of the following: general anesthesia, intubation and\n             mechanical ventilation, or major incision (e.g., thoracotomy, laparotomy)\n\n          3. Any known, untreated, brain metastases. Patients with treated brain metastases must\n             have no clinical symptoms from the metastases, and must be either off steroids or on a\n             stable dose of steroids ? 10 mg prednisone or equivalent for at least 2 weeks prior to\n             protocol enrollment. Patients with known leptomeningeal metastases are excluded, even\n             if treated.\n\n          4. Pregnant or breastfeeding or expecting to conceive or father children within the\n             projected duration of the study.\n\n          5. Significant gastrointestinal disorder(s), in the opinion of the Principal\n             Investigator, such as active inflammatory bowel disease, extensive gastric or small\n             intestinal resection (which has resulted in short-gut syndrome or the inability to\n             take oral medications).\n\n          6. Unable or unwilling to swallow either BBI503 daily or an oral selected anti-cancer\n             therapeutics; or, unwilling to receive intravenous injection of IV anti-cancer\n             therapeutics.\n\n          7. Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface\n             Antigen [HBsAg] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid\n             (HCV RNA] (qualitative) is detected).\n\n          8. Uncontrolled concurrent illness including, but not limited to: ongoing or active\n             infection requiring therapy, clinically significant non-healing or healing wounds,\n             symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia,\n             significant pulmonary disease (shortness of breath at rest or on mild exertion),\n             uncontrolled infection or psychiatric illness/social situations that would limit\n             compliance with study requirements\n\n          9. Subjects with a history of another primary cancer with the exception of: a) curatively\n             resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ;\n             c) localized prostate cancer not requiring systematic therapy; and d) other primary\n             cancer with no known active disease present, and no treatment administered in the 2\n             years prior to enrollment.\n\n         10. For patients to be treated with a regimen containing capecitabine: a) Known\n             hypersensitivity to capecitabine, b) Known dihydropyrimidine dehydrogenase (DPD)\n             deficiency, c) Significant gastrointestinal disorder(s) that would, in the opinion of\n             the Investigator, prevent absorption of an orally available agent\n\n         11. For patients to be treated with a regimen containing sunitinib: a) Uncontrolled\n             hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg\n             despite optimal medical management), b) Evidence of bleeding diathesis or a clinically\n             significant coagulopathy (? CTCAE Grade 3) within 4 weeks prior to the start of study,\n             c) Recent hypoglycemia, d) Uncontrolled thyroid dysfunction despite optimal medical\n             therapy\n\n         12. For patients to be treated with a regimen containing doxorubicin: a) Known left\n             ventricular ejection fraction < 50%, b) Hypersensitivity to doxorubicin\n\n         13. A patient to be treated with a regimen containing nivolumab or pembrolizumab will be\n             excluded if the patient: a) Has an active autoimmune disease requiring\n             immunosuppression with the exception of subjects with isolated vitiligo, resolved\n             childhood asthma or atopic dermatitis, controlled hypoadrenalism or hypopituitarism,\n             and euthyroid patients with a history of Grave's disease, b) Has had a previous\n             life-threatening (CTCAE grade 4) immune-mediated adverse reaction; or, a previous\n             severe (CTCAE grade 3) immune mediated adverse reaction that required treatment with\n             corticosteroids (more than 10 mg/day prednisone or equivalent dose) for longer than 12\n             weeks, c) Has a transplanted organ, d) Has interstitial lung disease or active,\n             non-infectious pneumonitis, e) Has received a live vaccine within 30 days prior to\n             first dose, f) Previous severe hypersensitivity reaction to another monoclonal\n             antibody (mAb), g) Has been treated with another monoclonal antibody ? 4 weeks before\n             first dose.
Inclusion Criteria:\n\n        Patients must meet the following criteria to be eligible for study participation:\n\n          1. Patients with recurrent squamous carcinoma of the Head and Neck, who in the opinion of\n             their treating physician, cannot be satisfactorily treated with surgery, radiation, or\n             platinum chemotherapy. Diagnosis must be confirmed by biopsy and histopathology.\n\n          2. Patient must have received prior systemic platinum-based chemotherapy for treatment of\n             their head and neck cancer, unless in the opinion of the medical oncologist, the use\n             of platinum-based chemotherapy is contraindicated or not recommended, e.g., renal\n             impairment, allergy to platinum compounds, age, liver disease, myelosuppression,\n             neuropathy, hearing loss, etc.\n\n          3. Patients must have life expectancy > 6 months based on investigator judgment.\n\n          4. Male or female patients at least 18 years old. Female patients must not be pregnant or\n             breast feeding and must be practicing a medically acceptable form of birth control, be\n             sterile, or post-menopausal. Females of childbearing potential (FCBP) is defined as\n             premenopausal women capable of becoming pregnant. This includes women who are\n             post-menopausal for at least 12 months after the last menses. FCBP must agree to use a\n             medically acceptable form of birth control during the study and for at least 6 months\n             after discontinuation of Erbitux® or study medication. Females must agree not to\n             breast feed during the study and for at least two months after discontinuation of\n             Erbitux® or study medication. Male patients should be using a double barrier\n             protection method that is a medically acceptable form of birth control during the\n             study or be sterile.\n\n          5. Patients must have an ECOG score of 0 - 2.\n\n          6. Patient must understand the investigational nature of this study and sign an\n             Independent Ethics Committee/Institutional Review Board approved written informed\n             consent form prior to receiving any study related procedure.\n\n        Exclusion Criteria:\n\n        Patients with any of the following will be excluded from participation in the study:\n\n          1. Patients with a history of significant Erbitux infusion reactions (? Grade 3).\n\n          2. Patients on chemotherapy or Erbitux® therapy or radiation therapy within 4 weeks of\n             enrollment.\n\n          3. Tumor invading a major blood vessel (such as the carotid artery) unless the vessel has\n             been embolized, stented or surgically ligated to prevent hemorrhage.\n\n          4. Tumor is not clearly shown on a CT scan or clinically measurable.\n\n          5. Location and extension of the tumor precludes an effective PIT.\n\n          6. Patients with impaired hepatic function (ALP (hepatic), AST and/or ALT >3 times the\n             upper normal limits, or total serum bilirubin > 2 mg/dL.\n\n          7. Patients with impairment of renal function (serum creatinine >2 mg/dL).\n\n          8. Unwilling or unable to follow protocol requirements.\n\n          9. Any condition which in the Investigator's opinion deems the patient an unsuitable\n             candidate to receive study drug.\n\n         10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac\n             arrhythmia, or psychiatric illness/social situations that would limit compliance with\n             study requirements.\n\n         11. Patient requires examinations or treatments within 4 weeks after study drug\n             administration where they would be exposed to significant light, e.g., eye\n             examinations, surgical procedures, endoscopy, etc.
Inclusion Criteria:\n\n        Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic\n        leukemia) according to WHO classification.\n\n        Performance status (ECOG) of 0-3. Adults with previously untreated AML except for\n        hydroxyurea or corticosteroids. Prior hydroxyurea or lenalidomide treatment for\n        myelodysplastic syndrome (MDS) is allowed.\n\n        Not considered candidates for intensive remission induction chemotherapy at time of\n        enrollment based on EITHER:\n\n          1. ?75 years of age OR\n\n          2. <75 years of age with at least 1 of the following:\n\n        i. Poor performance status (ECOG) score of 2-3.\n\n        ii. Clinically significant heart or lung comorbidities, as reflected by at least 1 of:\n\n          1. Left ventricular ejection fraction (LVEF) ?50%.\n\n          2. Lung diffusing capacity for carbon monoxide (DLCO) ?65% of expected.\n\n          3. Forced expiratory volume in 1 second (FEV1) ?65% of expected.\n\n          4. Chronic stable angina or congestive heart failure controlled with medication.\n\n        iii. Liver transaminases >3 × upper limit of normal (ULN).\n\n        iv. Other contraindication(s) to anthracycline therapy (must be documented).\n\n        v. Other comorbidity the investigator judges incompatible with intensive remission\n        induction chemotherapy, which must be documented and approved by the study medical monitor\n        before randomization.\n\n        Creatinine clearance as estimated by the Cockroft-Gault (C-G) or other medically acceptable\n        formulas ?30 mL/min.\n\n        Exclusion Criteria:\n\n        Candidate for intensive remission induction chemotherapy at the time of enrollment.\n\n        Candidate for best supportive care only, ie, not a candidate for any active therapy with\n        the TC comparators.\n\n        Known extramedullary central nervous system (CNS) AML.\n\n        Second malignancy currently requiring active therapy except breast or prostate cancer\n        stable on or responding to endocrine therapy.\n\n        Prior treatment with decitabine or azacitidine.\n\n        Hypersensitivity to decitabine, SGI-110, or SGI-110 excipients.\n\n        Known active human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C\n        virus (HCV) infection. Inactive hepatitis carrier status or low viral hepatitis titer on\n        antivirals is allowed.\n\n        Known significant mental illness or other condition such as active alcohol or other\n        substance abuse or addiction that, in the opinion of the investigator, predisposes the\n        subject to high risk of noncompliance with the protocol.\n\n        Refractory congestive heart failure unresponsive to medical treatment; active infection\n        resistant to all antibiotics; or advanced pulmonary disease requiring >2 liters per minute\n        (LPM) oxygen.
Inclusion Criteria - Cohort 1:\n\n          -  Received and progressed on ?2 prior chemotherapy regimens for their advanced disease;\n             prior regimen must have included a cisplatin and a fluoropyridine\n\n          -  Human epidermal growth factor receptor 2 (HER-2/neu) negative, or, if HER2/neu\n             positive, must have previously received treatment with trastuzumab\n\n        Inclusion Criteria - Cohort 2 or 3:\n\n          -  HER2/neu negative\n\n          -  Has not received prior systemic anti-cancer therapy for their advanced carcinoma\n             (systemic therapy received in the neoadjuvant and adjuvant setting does not count)\n\n        Inclusion Criteria - All Participants:\n\n          -  Histologically- or cytologically-confirmed recurrent or metastatic gastric or\n             gastroesophageal junction adenocarcinoma that is considered incurable by local\n             therapies\n\n          -  Willing to provide tissue for PD-L1 biomarker analysis from newly-obtained and/or\n             archival tissue\n\n          -  Measurable disease based on Response Evaluation Criteria in Solid Tumors version 1.1\n             (RECIST 1.1)\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days\n             prior to first dose of study drug\n\n          -  Life expectancy of >=3 months\n\n          -  Female participants of childbearing potential should have a negative pregnancy test\n             and be willing to use 2 methods of birth control or be surgically sterile, or abstain\n             from heterosexual activity for the course of the study through 120 days after the last\n             dose of study drug (180 days for participants receiving cisplatin + 5FU)\n\n          -  Male participants should agree to use an adequate method of contraception starting\n             with the first dose through 120 days after the last dose of study drug (180 days for\n             participants receiving cisplatin + 5FU)\n\n          -  Adequate organ function\n\n        Exclusion Criteria - All Participants:\n\n          -  Currently participating and receiving study therapy or participated in a study of an\n             investigational agent and received study therapy or used an investigation device\n             within 4 weeks of the first dose of study drug\n\n          -  Active autoimmune disease that has required systemic treatment in past 2 years\n\n          -  Immunodeficiency or receiving systemic steroid therapy or any other form of\n             immunosuppressive therapy within 7 days prior to the first dose of study drug\n\n          -  Weight loss >10% over 2 months prior to first dose of study drug\n\n          -  Clinical evidence of ascites by physical exam\n\n          -  Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not\n             recovered from AEs due to agents administered more than 4 weeks earlier\n\n          -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2\n             weeks prior to study Day 1 or who has not recovered from AEs due to a previously\n             administered agent\n\n          -  Known additional malignancy that is progressing or requires active treatment excepting\n             basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has\n             undergone potentially curative therapy or in situ cervical cancer\n\n          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis\n\n          -  Known history of, or any evidence of active, non-infectious pneumonitis\n\n          -  Active infection requiring systemic therapy\n\n          -  Psychiatric or substance abuse disorders that would interfere with cooperation with\n             the requirements of the study\n\n          -  Pregnant or breastfeeding, or expecting to conceive or father children within the\n             projected duration of the study, starting with the screening visit through 120 days\n             after the last dose of study drug (180 days for participants receiving cisplatin +\n             5FU)\n\n          -  Prior therapy with an anti-programmed death-1 (PD-1), anti-PD-L1, or anti-PD-L2 agent\n\n          -  Human immunodeficiency virus (HIV)\n\n          -  Hepatitis B or C\n\n          -  Received live vaccine within 30 days of planned start of study drug
Inclusion Criteria:\n\n          -  Histologically or cytologically documented diagnosis of Stage IIIB not amenable to\n             radical treatment or Stage IV NSCLC (pathological characterization must determine the\n             non-squamous or squamous histological subtype as well as adenocarcinoma subtype\n             classification)\n\n          -  HER2 status of IHC 2+ or 3+ as determined by a Sponsor-designated central laboratory\n\n          -  Prior treatment with at least one regimen of platinum-based (cisplatin or carboplatin)\n             chemotherapy in the locally advanced or metastatic setting/recurrent NSCLC with\n             documented disease progression by investigator assessment\n\n          -  Participants with a known anaplastic lymphoma kinase (ALK) fusion oncogene (must be\n             documented in the participant's chart) must have also experienced disease progression\n             or intolerance with a first-line ALK Tyrosine Kinase Inhibitor (TKI) approved for the\n             treatment of ALK fusion oncogene NSCLC (for example, crizotinib). Disease progression\n             or intolerance must be documented\n\n          -  Participants with a known mutation in the epidermal growth factor receptor (EGFR) gene\n             (must be documented in the participant's chart) must have also experienced disease\n             progression or intolerance with an EGFR TKI approved for the treatment of EGFR-mutant\n             NSCLC (for example, gefitinib, erlotinib, afatinib). Disease progression or\n             intolerance must be documented\n\n          -  Measurable disease determined as per the RECIST v1.1\n\n          -  Life expectancy of at least (>/=) 12 weeks\n\n          -  Adequate organ function\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          -  Left ventricular ejection fraction (LVEF) >/= 50 percent (%) by either echocardiogram\n             (ECHO) or multiple-gated acquisition (MUGA) scan\n\n          -  Use of highly effective contraception\n\n        Exclusion Criteria:\n\n        Cancer-Related Criteria:\n\n          -  Any approved anti-cancer therapy less than or equal to (</=) 21 days (including\n             chemotherapy or hormonal therapy) before the first study treatment; the following\n             exceptions are allowed: (1) TKIs approved for the treatment of NSCLC must be\n             discontinued greater than (>) 7 days prior to the first study treatment on D1C1 (The\n             baseline computed tomography [CT] scan must be completed after discontinuation of\n             TKIs); (2) Hormone-replacement therapy or oral contraceptives; (3) Anti-emetics,\n             Granulocyte-colony stimulating factor (GCS-F), and prophylactic antibiotics according\n             to local standards\n\n          -  Investigational therapy participation in another clinical study with therapeutic\n             intent </= 21 days before first study treatment\n\n          -  Previous irradiation is permitted if >/=14 days since the last fraction of\n             radiotherapy have elapsed before the first study treatment on Day 1 as long as a\n             sufficient number of target lesions remain to allow for measurable disease as per\n             RECIST v1.1\n\n          -  Participants who have untreated brain metastases or are symptomatic; participants with\n             treated brain metastases must have discontinued corticosteroid therapy and not have\n             any neurological symptoms\n\n          -  History of intolerance (including Grade 3 or 4 infusion reaction) or hypersensitivity\n             to trastuzumab or murine proteins or any excipient of the product\n\n          -  History of exposure to the following cumulative doses of anthracyclines: Doxorubicin\n             or liposomal doxorubicin > 500 milligram per meter-square (mg/m^2); Epirubicin > 900\n             mg/m^2; Mitoxantrone > 120 mg/m^2. If another anthracycline, or more than one\n             anthracycline, has been used, the cumulative dose must not exceed the equivalent of\n             500 mg/m^2 doxorubicin\n\n          -  Peripheral neuropathy of Grade >/= 3 per the National Cancer Institute Common Toxicity\n             Criteria for Adverse Events Version 4.0 (NCI CTCAE v. 4.0)\n\n          -  History of other malignancy within the last 5 years, except for appropriately treated\n             carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer,\n             or other cancers with a similar outcome as those mentioned above\n\n        Cardiopulmonary Function Criteria:\n\n          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent\n             drainage procedures\n\n          -  Severe dyspnea at rest due to complications of advanced malignancy or requiring\n             current continuous oxygen therapy\n\n          -  Clinical history of active hemoptysis\n\n          -  Evidence of active pneumonitis during screening\n\n          -  Current unstable ventricular arrhythmia requiring treatment\n\n          -  History of symptomatic congestive heart failure (CHF) New York Heart Association\n             (NYHA) classes II-IV\n\n          -  History of myocardial infarction or unstable angina within 6 months of enrollment\n\n          -  History of a decrease in LVEF to <50%\n\n        General Criteria:\n\n          -  Current severe, uncontrolled systemic disease (for example, clinically significant\n             cardiovascular, pulmonary, or metabolic disease)\n\n          -  Major surgical procedure or significant traumatic injury within 28 days before\n             enrollment or anticipation of the need for major surgery during the course of study\n             treatment\n\n          -  Current pregnancy or lactation\n\n          -  Current known active infection with human immunodeficiency virus (HIV), hepatitis B\n             virus (HBV), or hepatitis C virus (HCV)
Inclusion Criteria: 1.Age ? 18 years the time of signing the Informed Consent Form (ICF).\n\n        2. Understand and voluntarily provide written informed consent prior to the conduct of any\n        study related assessments/procedures.\n\n        3. Able to adhere to the study visit schedule and other protocol requirements. 4.\n        Histologically or cytologically confirmed advanced NSCLC who will receive study therapy as\n        second- or third-line of treatment for advanced disease.\n\n        5. No other current active malignancy requiring anticancer therapy. 6. Radiographically\n        documented measurable disease (defined by the presence of ? 1 radiographically documented\n        measurable lesion).\n\n        7. One prior platinum-containing chemotherapy for metastatic or recurrent NSCLC unless\n        patients are ineligible to receive it. Patients may have received no more than one line of\n        chemotherapy; immunotherapy in prior line of treatment (first or second line) is allowed.\n        Absolute neutrophil count (ANC) ? 1500 cells/mm3.\n\n        8. Platelets ? 100,000 cells/mm3. 9. Hemoglobin (Hgb) ? 9 g/dL. 10. Aspartate transaminase\n        (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine transaminase (ALT/serum\n        glutamic pyruvic transaminase [SGPT]) ? 2.5 × upper limit of normal range (ULN) or ? 5.0 ×\n        ULN if liver metastases.\n\n        11. Total bilirubin ? 1.5 ULN (unless there is a known history of Gilberts Syndrome).\n\n        12. Serum creatinine ? 1.5 x ULN, or calculated creatinine clearance ? 60 mL/min (if renal\n        impairment is suspected 24-hour urine collection for measurement is required).\n\n        13. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 14. Eastern\n        Cooperative Oncology Group (ECOG) performance status 0 or 1. 15. Females of childbearing\n        potential [defined as a sexually mature woman who (1) have not undergone hysterectomy (the\n        surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both\n        ovaries) or (2) have not been naturally postmenopausal for at least 24 consecutive months\n        (ie, has had menses at any time during the preceding 24 consecutive months)] must:\n\n          1. Have a negative pregnancy test (ß-hCG) as verified by the study doctor within 72 hours\n             prior to starting study therapy. She must agree to ongoing pregnancy testing during\n             the course of the study, and after end of study therapy. This applies even if the\n             subject practices true abstinence* from heterosexual contact.\n\n          2. Either commit to true abstinence* from heterosexual contact (which must be reviewed on\n             a monthly basis) or agree to use, and be able to comply with, effective contraception\n             without interruption, 28 days prior to starting investigational product (IP), during\n             the study therapy (including dose interruptions), and for 3 months after\n             discontinuation of study therapy.\n\n        Male subjects must:\n\n          1. Practice true abstinence* or agree to use a condom during sexual contact with a\n             pregnant female or a female of childbearing potential while participating in the\n             study, during dose interruptions and for at least 6 months following IP\n             discontinuation, even if he has undergone a successful vasectomy.\n\n          2. Refrain from semen or sperm donation while taking durvalumab and for at least 3 months\n             after the last dose of durvalumab.\n\n             16. Females must abstain from breastfeeding during study participation and 3 months\n             after IP discontinuation.\n\n             Exclusion Criteria:\n\n               -  The presence of any of the following will exclude a subject from enrollment:\n\n                    1. Refractory to prior taxane therapy for advanced disease. Prior taxane used\n                       in the adjuvant setting does not exclude eligibility, provided there is no\n                       disease recurrence within 12 months upon completion of chemotherapy in that\n                       setting.\n\n                    2. Evidence of active brain metastases, including leptomeningeal involvement\n                       (prior evidence of brain metastasis are permitted only if asymptomatic and\n                       clinically stable for at least 8 weeks following completion of therapy). MRI\n                       of the brain (or CT scan w/contrast) is preferred.\n\n                    3. Only evidence of disease is non-measurable at study entry.\n\n                    4. Known activating EGFR mutations (such as exon 19 deletions or L858R).\n\n                    5. Known activating EML4-ALK mutations.\n\n                    6. Preexisting peripheral neuropathy of Grade > 2 (per NCI CTCAE v4.0).\n\n                    7. Any unresolved toxicity NCI CTCAE Grade ? 2 from previous anticancer therapy\n                       with the exception of alopecia, vitiligo, and the laboratory values defined\n                       in the inclusion criteria.\n\n                    8. Venous thromboembolism within 1 month prior to Cycle 1 Day 1.\n\n                    9. Current congestive heart failure (New York Heart Association Class II-IV).\n\n                   10. History of the following within 6 months prior to Cycle 1 Day 1: a\n                       myocardial infarction, severe/unstable angina pectoris, coronary/peripheral\n                       artery bypass graft, New York Heart Association (NYHA) Class III-IV heart\n                       failure, uncontrolled hypertension, clinically significant cardiac\n                       dysrhythmia or clinically significant electrocardiogram (ECG) abnormality,\n                       cerebrovascular accident, transient ischemic attack, or seizure disorder.\n\n                   11. Known hepatitis B or C virus (HBV/HCV) infection, known history of human\n                       immunodeficiency virus (HIV) infection, or receiving immunosuppressive or\n                       myelosuppressive medications that would in the opinion of the investigator,\n                       increase the risk of serious neutropenic complications, history of active\n                       primary immunodeficiency, active tuberculosis (clinical evaluation that\n                       includes clinical history, physical examination and radiographic findings,\n                       and TB testing in line with local practice).\n\n                   12. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring\n                       systemic therapy, defined as ongoing signs/symptoms related to the infection\n                       without improvement despite appropriate antibiotics, antiviral therapy,\n                       and/or other treatment.\n\n                   13. History of interstitial lung disease, history of slowly progressive dyspnea\n                       and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary\n                       fibrosis, or pulmonary hypersensitivity pneumonitis or multiple allergies.\n                       Any lung disease that may interfere with the detection or management of\n                       suspected drug-related pulmonary toxicity.\n\n                   14. Subject has a clinically significant malabsorption syndrome, persistent\n                       diarrhea, or known sub-acute bowel obstruction > NCI CTCAE Grade 2, despite\n                       medical management.\n\n                   15. Treatment with any chemotherapy, investigational product, biologic or\n                       hormonal therapy for cancer treatment within 28 days prior to signing the\n                       ICF. Concurrent use of hormonal therapy for non-cancer-related conditions\n                       (e.g. hormone replacement therapy) is acceptable.\n\n                   16. History of or suspected allergy to any IP or their excipients.\n\n                   17. Major surgical procedure (as defined by the Investigator) within 28 days\n                       prior to the first dose of IP. Note: Local surgery of isolated lesions for\n                       palliative intent is acceptable.\n\n                   18. Currently enrolled in any other clinical protocol or investigational trial\n                       that involves administration of experimental therapy and/or therapeutic\n                       devices.\n\n                   19. Any other clinically significant medical condition, psychiatric illness,\n                       and/or organ dysfunction that will interfere with the administration of the\n                       therapy according to this protocol or which, in the views of investigator,\n                       preclude combination chemotherapy.\n\n                   20. Any other malignancy within 5 years prior to randomization/treatment\n                       assignement, or advanced malignant hepatic tumors, with the exception of\n                       adequately treated squamous cell carcinoma of the skin, in-situ carcinoma of\n                       the cervix, uteri, non-melanomatous skin cancer, carcinoma in situ of the\n                       breast, or incidental histological finding of prostate cancer (TNM\n                       Classification of Malignant Tumours (TNM) stage of T1a or T1b). (All\n                       treatment of which should have been completed 6 months prior to signing\n                       ICF).\n\n                   21. Radiotherapy ? 4 weeks or limited field radiation for palliation ? 2 weeks\n                       prior to starting IP, and/or from whom ? 30% of the bone marrow was\n                       irradiated. Prior radiation therapy to a target lesion is permitted only if\n                       there has been clear progression of the lesion since radiation was\n                       completed.\n\n                   22. Any condition including the presence of laboratory abnormalities, which\n                       places the subject at unacceptable risk if he/she were to participate in the\n                       study.\n\n                   23. Any medical condition that confounds the ability to interpret data from the\n                       study.\n\n                   24. Female patients who are pregnant or breastfeeding or female patients of\n                       reproductive potential who are not willing to employ effective birth control\n                       from screening to 90 days after the last dose of durvalumab.\n\n                   25. Male patients of reproductive potential who are not willing to employ\n                       effective birth control from screenin to 90 days after the last dose of\n                       durvalumab and from screening to 6 months after the last dose of of\n                       nab-paclitaxel.\n\n                   26. History of allogenic organ transplantation.\n\n                   27. Active or prior documented autoimmune or inflammatory disorders (including\n                       inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis\n                       [with the exception of diverticulosis], celiac disease, irritable bowel\n                       disease, or other serious gastrointestinal chronic conditions associated\n                       with diarrhea, systemic lupus erythematosus, sarcoidosis syndrome, or\n                       Wegener's syndrome [granulomatosis with polyangiitis, Graves' disease,\n                       rheumatoid arthritis, hypophysitis, uveitis, etc]) within the past 3 years\n                       prior to the start of treatment. The following are exceptions to this\n                       criterion:\n\n               -  Patients with vitiligo or alopecia\n\n               -  Patients with hypothyroidism (eg, following Hashimoto's syndrome) stable on\n                  hormone replacement\n\n               -  Any chronic skin condition that does not require systemic therapy\n\n               -  Patients without active disease in the last 5 years may be included but only\n                  after consultation with the study physician 28. Current or prior use of\n                  immunosuppressive medication within 14 days before the first dose of durvalumab.\n                  The following are exceptions to this criterion:\n\n               -  Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra\n                  articular injection)\n\n               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of\n                  prednisone or its equivalent\n\n               -  Steroids as premedication for hypersensitivity reactions (eg, CT scan\n                  premedication) 29. Receipt of live attenuated vaccine within 30 days prior to the\n                  first dose of IP. Note: Patients, if enrolled, should not receive live vaccine\n                  during the study and up to 30 days after the last dose of IP.\n\n                  30. Prior enrollment and treatment in a previous durvalumab clinical study. 31.\n                  Patients who have received prior anti-PD-1 or anti PD-L1:\n\n               -  Must not have experienced a toxicity that led to permanent discontinuation of\n                  prior immunotherapy.\n\n               -  All AEs while receiving prior immunotherapy must have completely resolved or\n                  resolved to baseline prior to screening for this study.\n\n               -  Must not have experienced a ? Grade 3 immune related AE or an immune related\n                  neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:\n                  Subjects with endocrine AE of ? Grade 2 are permitted to enroll if they are\n                  stably maintained on appropriate replacement therapy and are asymptomatic.\n\n               -  Must not have required the use of additional immunosuppression other than\n                  corticosteroids for the management of an AE, not have experienced recurrence of\n                  an AE if re-challenged, and not currently require maintenance doses of > 10 mg\n                  prednisone or equivalent per day.
Inclusion Criteria: Provision of signed and dated, written informed consent prior to any\n        mandatory study specific procedures, sampling and analyses. Aged at least 18 years. Any\n        menopausal status. Pre- or peri-menopausal women must have commenced treatment with an LHRH\n        agonist at least 4 weeks prior to starting study treatment and must be willing to continue\n        to receive LHRH agonist therapy for the duration of the trial. Histological or cytological\n        confirmation of adenocarcinoma of the breast. ER-positive according to local laboratory;\n        HER-2 negative. Metastatic disease or locoregionally recurrent disease which is not\n        amenable to treatment with curative intent. Disease progression after at least 6 months of\n        endocrine therapy for ER+ breast cancer. Radiological or objective evidence of progression\n        on or after the last systemic therapy prior to starting study treatment. Receipt of ?2\n        lines of prior chemotherapy for advanced disease. Females of child-bearing potential must\n        agree to use adequate contraceptive measures, must not be breast feeding and must have a\n        negative pregnancy test prior to start of dosing. Eastern Cooperative Oncology Group (ECOG)\n        performance status 0-1 with no deterioration over the previous 2 weeks and minimum life\n        expectancy of 12 weeks.\n\n        Exclusion Criteria: Any cytotoxic chemotherapy, investigational agents or other anti-cancer\n        drugs for the treatment of advanced breast cancer from a previous treatment regimen or\n        clinical study within 14 days of the first dose of study treatment. Any unresolved\n        toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events\n        (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia.\n        Presence of life-threatening metastatic visceral disease, uncontrolled central nervous\n        system metastatic disease or symptomatic pulmonary lymphangitic spread. Any evidence of\n        severe or uncontrolled systemic diseases, including uncontrolled hypertension, active\n        bleeding diatheses, or active infection. Unexplained symptomatic endometrial disorders.\n        Uncontrolled symptomatic thyroid dysfunction. Inadequate bone marrow reserve or organ\n        function
Inclusion Criteria\n\n        a. History of morphologically confirmed AML w/ classification other than WHO Acute\n        Promyelocytic Leukemia (FAB M3), based on bone marrow examination.\n\n        i. not a candidate for allogeneic HSCT or no intention to move to HSCT at time of\n        enrollment.\n\n        ii. Patient's AML could be in morphologic CR or no further cytotoxic chemotherapy is\n        currently being considered.\n\n        iii. Completed consolidation chemotherapy, if available and/or appropriate for patient.\n\n        iv. Can have history of allogeneic HSCT transplant, but must be off immunosuppression for\n        at least 2 wks. before enrollment and w/o GVHD and/or toxicities from HSCT.\n\n        b. Diagnosed in past 5 years w/ smoldering MM at high risk of progressing to symptomatic\n        MM.\n\n        i. Diagnosis defined as: Bone marrow infiltration with plasma cells (PCs) ?10% and presence\n        of a monoclonal component, Ig G ?3 g/dl or IgA ?2 g/dl or Bence-Jones proteinuria >1 g/dl\n        and absence of lytic lesions on skeletal survey, absence of hypercalcemia (corrected\n        calcium <11 mg/dl), absence of renal failure (creatinine ?1.5 x ULN), and absence of anemia\n        (hemoglobin >10 g/dl or not 2 g/dl below LLN).\n\n        ii. Must meet one of following:\n\n          -  ?10% PCs in bone marrow and IgG ?3 g/dl or IgA ?2 g/dl,\n\n          -  ?10% PCs in bone marrow and serum FLC ratio (involved : uninvolved) >100 in blood, or\n\n          -  IgG ?3 g/dl or IgA ?2 g/dl and FLC ratio (involved: uninvolved) >100 in blood. c. MM\n             post-treatment disease that is clinically stable and does not require treatment at\n             least 4 weeks prior to enrollment.\n\n             i. At least one line of treatment and achieved at least PR by IMWG ii. Stable disease\n             or better per IMWG based on 2 subsequent assessments at least one month apart d.\n             history of morphologically confirmed MDS i. previously received at least one treatment\n             for MDS, including but not limited to chemotherapy or hypomethylating agent(s).\n             Subjects may be previously untreated if they refuse treatment with or are not\n             appropriate candidates for chemotherapy or hypomethylating agent(s) in the\n             investigator's opinion.\n\n        ii. intermediate, high, or very high risk MDS by IPSS-r iii. No curative intent option of\n        allogeneic HSCT or refused consideration for allogeneic HSCT iv. Could have history of\n        allogeneic HSCT transplant and relapsed, but must be off immunosuppression for at least 2\n        weeks before enrollment and without GVHD and/or toxicities from HSCT.\n\n        2. Low, moderate, to high levels of OFA expression by IHC analysis of tumor specimens.\n\n        3. HLA-A*02 haplotype.\n\n        4. ECOG performance status 0 to 2.\n\n        5. 18 years or older.\n\n        6. life expectancy ?3 months.\n\n        7. Has following laboratory parameters w/in 28 days:\n\n          -  ANC ?500/mm3\n\n          -  ALC >500/mm3\n\n          -  PLT ?25,000/mm3 and may be transfused\n\n          -  Hgb >8 g/dL (may have been transfused)\n\n          -  Serum creatinine ?1.5 x ULN\n\n          -  Total bilirubin ?2.0 mg/dL, unless elevated bilirubin due to Gilbert's syndrome\n\n          -  ALT and AST less than 5×ULN\n\n             8. If female of child-bearing potential, negative serum pregnancy test result w/in 28\n             of D1 and agree to abstain from heterosexual intercourse or use acceptable method of\n             birth control (hormonal or barrier method) from Screening through 30 days after last\n             dose\n\n             9. If male having sexual contact with a female of child-bearing potential, agrees to\n             use a latex condom dor agrees to ensure partner uses an acceptable method of birth\n             control (hormonal or barrier method)from Screening through 30 days after last dose\n\n             10. Able to provide written informed consent\n\n        Exclusion Criteria\n\n          1. Received chemotherapy, biological therapy, or radiation therapy less than one month\n             before D1\n\n          2. No prior history of active CNS involvement\n\n          3. Grade 2 or higher peripheral neuropathy w/in 28 days\n\n          4. Acute promyelocytic leukemia (FAB M3)\n\n          5. Other active systemic malignancy treated w/ cytotoxic chemotherapy in previous 12 mos.\n\n          6. Monoclonal gammopathy of undetermined significance\n\n          7. For smoldering MM, baseline bone lesions or plasmacytomas\n\n          8. For smoldering MM, lytic lesions on skeletal surveys and hypercalcemia (i.e., ?11\n             mg/dL)\n\n          9. Known HIV or hepatitis virus infection\n\n         10. Active infection requiring antibiotics\n\n         11. History of prior or active autoimmune disease such as Lupus or rheumatoid arthritis\n\n         12. Significant kidney or liver disease, uncontrolled severe cardiovascular or pulmonary\n             disease, other uncontrolled medical condition that would compromise subject's ability\n             to tolerate study treatment\n\n         13. Received any investigational treatment w/in 30 days\n\n         14. Receiving systemic glucocorticosteroid >10 mg daily. Concurrent use after registration\n             on study should be restricted to equivalent of prednisone 10 mg per day. Prior or\n             concurrent topical or localized glucocorticosteroid therapy to treat non-malignant\n             comorbid disorders is permitted. Subject requiring routine use of steroid inhalers are\n             not eligible.\n\n         15. Major surgery w/in 4 wks.\n\n         16. G-CSF w/in 30 days
Inclusion Criteria:\n\n        Histologically confirmed diffuse large B-cell lymphoma that is refractory to prior therapy\n        or relapsed after prior therapy.\n\n        FDG PET-CT (disease) positive baseline scan with measurable disease.\n\n        The patient must have received prior therapy that included:\n\n          -  CD20-targeted therapy (for example, rituximab),\n\n          -  Alkylating agent (for example, cyclophosphomide), and\n\n          -  Steroid, unless the patient is steroid intolerant\n\n        Exposure to at least 1 or 2 (but no more than 3) prior systemic cytotoxic chemotherapeutic\n        regimens.\n\n        Note: Only those subjects who are not eligible for high-dose chemotherapy and autologous\n        stem cell transplant (HD-ASCT), or who refuse HD-ASCT, are eligible with exposure to only 1\n        prior cytotoxic chemotherapeutic regimen.\n\n        ECOG performance status of 0-1.\n\n        The patient must be a stable baseline with CTCAE grade ? 2 regarding any acute or chronic\n        toxicity associated with prior therapy, and have discontinued prior anti-cancer therapy for\n        ? 14 days prior to C1D1; mitomycin-C for at least 6 weeks prior to C1D1; SCT ? 2 months\n        prior to C1D1.\n\n        Note: Palliative steroids for control of disease-related symptoms are allowed and\n        maintenance hormone therapy is allowed.\n\n        Adequate organ function including:\n\n          -  Hematologic: ANC ? 0.5 x 10^9/L. and platelets ? 50 x 10^9/L.\n\n          -  Hepatic: Total Bilirubin ? 2 x ULN (patients with Gilbert's syndrome must have total\n             bilirubin ? 3 x ULN) and serum transaminase levels ? 2.5 x ULN. In the case of known\n             liver metastasis (i.e., radiological or biopsy documented), serum transaminase levels\n             must be ? 5 x ULN.\n\n          -  Renal: Serum creatinine ? 2 x ULN, or creatinine clearance ? 60 mL/min/1.73 m2 for\n             subjects with serum creatinine levels above 2 x ULN.\n\n        Willingness to: 1.) undergo pre-treatment biopsy to obtain adequate tissue for analysis\n        (e.g., core needle, excisional or incisional tumor biopsy) or 2.) provide archived tumor\n        (e.g., FFPE block) for analysis.\n\n        Exclusion Criteria:\n\n        Eligibility for high-dose chemotherapy (HDT) and stem cell transplant (SCT). Note: Subjects\n        who progressed ? 2 months after HDT/SCT are eligible\n\n        Concurrent malignancies requiring treatment.\n\n        Primary mediastinal (thymic) large B-cell lymphoma\n\n        Symptomatic CNS or leptomeningeal involvement of lymphoma.\n\n        Concurrent clinically significant illness, medical condition, surgical history, physical\n        finding, electrocardiogram or laboratory finding that, in the opinion of the investigator,\n        could adversely affect the safety of the patient or impair the assessment of the study\n        results.\n\n        Signs or symptoms of heart failure characterized as greater than NYHA Class II or other\n        significant cardiac abnormalities.\n\n        Pregnant or breast-feeding.\n\n        Prior exposure to PNT2258.\n\n        Life expectancy less than 3 months.
For inclusion in the study patient should fulfil the following criteria:\n\n          1. Male or female, aged at least 18 years.\n\n          2. Histological or cytological confirmation diagnosis of NSCLC.\n\n          3. Radiological documentation of disease progression while on a previous continuous\n             treatment with an EGFR TKI, eg gefitinib, afatinib or erlotinib. In addition, other\n             lines of therapy may have been given. All patients must have documented radiological\n             progression on the last treatment administered prior to enrolling in the study.\n\n          4. Confirmation that the tumour harbours an EGFR mutation known to be associated with\n             EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration\n             over the previous 2 weeks (Appendix G).\n\n          6. Patients must have a life expectancy of ?12 weeks as estimated at the time of\n             screening.\n\n          7. Females should be using adequate contraceptive measures and must have a negative\n             pregnancy test prior to start of dosing if of child-bearing potential, or must have\n             evidence of non-child-bearing potential by fulfilling one of the following criteria at\n             screening: Post-menopausal defined as aged more than 50 years and amenorrhoeic for at\n             least 12 months following cessation of all exogenous hormonal treatments; women under\n             50 years old would be considered post-menopausal if they have been amenorrhoeic for 12\n             months or more following cessation of exogenous hormonal treatments and with LH and\n             FSH levels in the post-menopausal range for the institution; documentation of\n             irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or\n             bilateral salpingectomy, but not tubal ligation.\n\n          8. Male patients should be willing to use barrier contraception, ie, condoms, until 6\n             months after last study drug is taken.\n\n        Exclusion criteria:\n\n          1. Participation in another study with an IP during the last 14 days (or a longer period\n             depending on the defined characteristics of the agents used).\n\n          2. Treatment with any of the following: Treatment with an EGFR TKI (eg, erlotinib or\n             gefitinib) within 8 days or approx. 5 x half-life, whichever is the longer, of the\n             first dose of study treatment; any cytotoxic chemotherapy, investigational agents or\n             other anticancer drugs from a previous treatment regimen or clinical study within 14\n             days of the first dose; major surgery (excluding placement of vascular access) within\n             4 weeks of the first dose of study treatment; radiotherapy with a limited field of\n             radiation for palliation within 1 week of the first dose of study treatment, with the\n             exception of patients receiving radiation to more than 30% of the bone marrow or with\n             a wide field of radiation which must be completed within 4 weeks of the first dose;\n             patients currently receiving (or unable to stop use prior to receiving the first dose\n             of study treatment) medications or herbal supplements known to be potent inhibitors of\n             CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior).\n             All patients must avoid concomitant use of any medications, herbal supplements and/or\n             ingestion of foods with known inducer/inhibitory effects on CYP3A4.\n\n          3. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of\n             starting study treatment with the exception of alopecia and Grade 2, prior\n             platinum-therapy related neuropathy.\n\n          4. Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade,\n             or other products containing grapefruit or Seville oranges within 7 days of the first\n             administration of the IP until the final PK sample collection on Day 32 of Part A.\n\n          5. Spinal cord compression or brain metastases unless asymptomatic, stable and not\n             requiring steroids for at least 4 weeks prior to start of study treatment.\n\n          6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled\n             hypertension and active bleeding diatheses, which in the PI's opinion makes it\n             undesirable for the patient to participate in the study or which would jeopardise\n             compliance with the protocol, or active infection including hepatitis B, hepatitis C,\n             and HIV. Screening for chronic conditions not required.\n\n          7. Inadequate bone marrow reserve or organ function as demonstrated by any of the\n             following laboratory values: ANC <1.5 x 10^9/L; platelet count <100 x 10^9/L;\n             haemoglobin <90 g/L; ALT >2.5 times ULN if no demonstrable liver metastases or >5\n             times ULN in the presence of liver metastases; Aspartate aminotransferase (AST) >2.5\n             times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver\n             metastases; total bilirubin >1.5 times ULN if no liver metastases or >3 times ULN in\n             the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or\n             liver metastases; creatinine >1.5 times ULN concurrent with creatinine clearance <50\n             ml/min (measured or calculated by Cockcroft and Gault equation); confirmation of\n             creatinine clearance is only required when creatinine is >1.5 times ULN.\n\n          8. Any of the following cardiac criteria: mean resting corrected QT interval corrected\n             for heart rate using Fridericia's correction factor (QTcF) >470 msec obtained from 3\n             ECGs; any clinically important abnormalities in rhythm, conduction or morphology of\n             resting ECG eg, complete left bundle branch block, third degree heart block, second\n             degree heart block, PR interval >250 msec; any factors that increase the risk of QTc\n             prolongation or risk of arrhythmic events such as heart failure, hypokalaemia,\n             congenital long QT syndrome, family history of long QT syndrome or unexplained sudden\n             death under age of 40 or any concomitant medication known to prolong the QT interval.\n\n          9. Patients unable to swallow oral medication or patients with GI disorders or\n             significant GI resection likely to interfere with the absorption of AZD9291.\n\n         10. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required\n             steroid treatment, or any evidence of clinically active ILD.\n\n         11. Women who are breastfeeding.\n\n         12. Patients with a known hypersensitivity to AZD9291, simvastatin, or any of the\n             excipients of the products.\n\n         13. Concomitant medication contraindicated for use with simvastatin due to drug\n             interaction associated with increased risk of rhabdomyolysis (including, but not\n             limited to): itraconazole, ketoconazole, posaconazole, erythromycin, clarithromycin,\n             telithromycin, HIV protease inhibitors (eg, nelfinavir), nefazodone, cyclosporine,\n             danazol, gemfibrozil, amiodarone, amlodipine.\n\n         14. 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA)-reductase inhibitors, such as\n             lovastatin and simvastatin.\n\n         15. For optional genetic research: Previous allogenic bone marrow transplant or\n             non-leukocyte depleted whole blood transfusion within 120 days of the date of the\n             genetic sample collection.
Major inclusion criteria:\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of ?2\n\n          -  Pathologically confirmed relapsed/refractory DLBCL\n\n          -  Subjects must have ?1 measurable disease site on CT scan (? 1.5 cm in longest\n             dimension).\n\n          -  Adequate hepatic and renal function:\n\n               -  AST or ALT ?2.5 x ULN\n\n               -  Serum Creatinine ? 2.0 mg/dL and creatinine clearance ?60 mL/min/1.73\n\n               -  Bilirubin ?1.5 x ULN\n\n          -  Adequate hematologic function:\n\n               -  ANC >1,000 cells/mm3\n\n               -  Platelets ?75,000 cells/mm3\n\n               -  Hemoglobin ?8.0 g/dL\n\n               -  Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be\n                  ?1.5 x the upper limit of the normal range (ULN)\n\n          -  Must be registered into the Revlimid REMS™program and be willing to comply with the\n             requirements of Revlimid REMS™.\n\n        Major Exclusion Criteria:\n\n          -  Known central nervous system lymphoma\n\n          -  Any chemotherapy, external beam radiation therapy, or anti-cancer antibodies within 2\n             weeks\n\n          -  Radio- or toxin-immunoconjugates within 10 weeks\n\n          -  Prior allogenetic stem cell (or other organ) transplant within 6 months or any\n             evidence of active graft-versus-host disease or requirement for immunosuppressants\n             within 28 days prior to first dose of study drug
Inclusion Criteria For entire trial:\n\n          -  Adult > or = 18 years old\n\n          -  has signed the Informed Consent Form\n\n          -  has tumor tissue available for the analysis as described in the protocol\n\n          -  has an Eastern Cooperative Oncology Group performance status ?2\n\n          -  has adequate bone marrow and organ function as defined in the protocol\n\n          -  is able to swallow and retain oral medication\n\n          -  has either measurable or non-measurable disease as per RECIST 1.1.\n\n        Inclusion Criteria for the BYL719+ Everolimus combination - escalation phase - all above\n        plus has a histologically/cytologically confirmed metastatic and/or recurrent solid tumors\n        for whom no standard therapy exists.\n\n        Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, renal cell\n        carcinoma cohort - all of above first 7 criteria plus has an histologically/cytologically\n        confirmed Renal Cell Cancer as detailed in the protocol\n\n        Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, pancreatic\n        NeuroEndocrine Tumor cohort\n\n        - all of above first 7 criteria plus has an histologically/cytologically confirmed\n        pancreatic NeuroEndocrine Tumor as detailed in the protocol\n\n        Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, mTOR\n        inhibitor-pretreated patients' cohort - all of above first 7 criteria plus has a\n        histologically and/or cytologically confirmed solid malignancy as described in the protocol\n\n        Inclusion Criteria for the breast cancer cohorts in escalation and expansion phases, - all\n        of above first 7 criteria plus is post-menopausal and has a histologically and/or\n        cytologically confirmed diagnosis of breast cancer as described in the protocol\n\n        Specific Inclusion Criteria at the time of cross-over (breast cancer, expansion phase),\n\n        - Patient randomized to the alpelisib and exemestane combination who has a radiologically\n        documented progressive disease as detailed in the protocol\n\n        Exclusion Criteria:\n\n          -  Patient has received previous treatment with a PI3K and/or AKT and/or mTOR inhibitor\n             (mTOR inhibitor is allowed in expansion cohorts where patients should have areceived a\n             prior mTOR inhibitor)\n\n          -  Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs\n\n          -  Patient with primary central nervous system (CNS) tumor or CNS tumor involvement as\n             detailed in the protocol\n\n          -  Patient with diabetes mellitus, or documented steroid-induced diabetes mellitus\n\n          -  Patient has a history of another malignancy within 2 years prior to starting study\n             treatment as described in the protocol\n\n          -  Patient who has not recovered to grade 1 or better (except alopecia) from related side\n             effects of any prior antineoplastic therapy as detailed in the protocol\n\n          -  Patient who has had systemic therapy within 4 weeks (6 weeks for nitrosoureas or\n             mitomycin C) prior to starting study treatment\n\n          -  Patient who has received radiotherapy ? 4 weeks prior to starting study drugs, with\n             exception of palliative radiotherapy (? 2 weeks prior to starting study drugs), who\n             has not recovered from side effects of such therapy to baseline or Grade ? 1 and/or\n             from whom ? 30% of the bone marrow was irradiated\n\n          -  Patient who has undergone major surgery ? 4 weeks prior to starting study treatment or\n             who has not recovered from side effects of such procedure\n\n          -  Patient has a clinically significant cardiac disease or impaired cardiac function or\n             any severe and/or uncontrolled medical conditions as detailed in the protocol\n\n          -  Patient who is currently receiving medication with a known risk of prolonging the QT\n             interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be\n             discontinued or switched to a different medication prior to starting study drug\n             treatment\n\n          -  Patient who has participated in a prior investigational study within 30 days prior to\n             enrollment as described in the protocol\n\n          -  Patient who is currently receiving treatment with drugs known to be moderate or strong\n             inhibitors or inducers of isoenzymes CYP34A or CYP2C8 as described in the protocol.\n             Switching to a different medication prior to start of treatment is allowed\n\n          -  Patient with impaired gastrointestinal (GI) function or GI disease that may\n             significantly alter the absorption of oral alpelisib, everolimus, exemestane\n\n          -  Patient with known positive serology for human immunodeficiency virus\n\n          -  Patients who have received live attenuated vaccines within 1 week of start of study\n             drug and during the study as specified in the protocol.\n\n          -  Pregnant or nursing (lactating) woman as detailed in the protocol.\n\n          -  Patient who does not apply highly effective contraception during the study and through\n             the duration as defined in the protocol\n\n          -  Patients in the mTOR inhibitor-pretreated cohorts: all of above first 19 criteria plus\n             have discontinued prior mTOR inhibitor therapy due to non-tolerable toxicity
Inclusion Criteria:\n\n        Patients in both treatment groups must meet all of the following criteria to be considered\n        eligible to participate in the study:\n\n          -  Adult men or women, aged 18 years or older, with histologically-confirmed, metastatic\n             adenocarcinoma of the colon or rectum that is resistant to available treatment options\n\n          -  Radiographically documented evidence of disease progression.\n\n          -  Life expectancy of at least 6 weeks, in the investigator's opinion, at the time\n             disease progression is documented.\n\n          -  Considered surgical candidates on the basis of co-morbidity risks, number and sites of\n             metastases, and ability to withstand general anesthesia.\n\n          -  Able to provide written informed consent.\n\n        Patients in Group A must also meet all of the following additional criteria:\n\n          -  ECOG performance status score of 0, 1, or 2.\n\n          -  Adequate hematologic function, defined as follows:\n\n               1. absolute neutrophil count (ANC) ?1500 /mL\n\n               2. hemoglobin ?9 g/dL\n\n               3. platelets ?75,000 /mL\n\n          -  Adequate hepatic function, defined as follows:\n\n               1. bilirubin ?1.5 times the upper limit of normal (x ULN)\n\n               2. aspartate transaminase (AST) ?3 x ULN, or ?5 x ULN if liver metastases are\n                  present\n\n               3. alanine transaminase (ALT) ?3, x ULN, or ?5 x ULN if liver metastases are present\n\n          -  Adequate renal function, defined as creatinine ?2.0 mg/dL.\n\n          -  Adequate coagulation function, defined as follows:\n\n               1. International Normalized Ratio (INR) ?1.5 or between 2 and 3 if the patient is\n                  receiving anticoagulation\n\n               2. partial thromboplastin time (PTT) ?5 seconds above the ULN Note: Patients\n                  receiving full-dose anticoagulation therapy must be receiving a stable dose of\n                  oral anticoagulant therapy or low-molecular-weight heparin.\n\n          -  Clinically significant toxic effects of chemotherapy (excluding alopecia),\n             radiotherapy, hormonal therapy, or prior surgery must have resolved to Grade 1 or\n             better, with the exception of peripheral neuropathy, which must have resolved to Grade\n             2 or better.\n\n          -  Agrees to contraceptive use while on study if sexually active\n\n        Exclusion Criteria:\n\n        Patients in either treatment group who meet any of the following criteria will be excluded\n        from participating in the study:\n\n          -  Hepatic blood flow abnormalities, i.e., portal vein hypertension and thrombosis,\n             and/or a large volume of ascites.\n\n          -  Concurrent cancer of any other type, except skin cancers other than melanoma.\n\n          -  A positive test result for HIV or any hepatitis other than A at screening.\n\n          -  Considered by the investigator to be unsuitable for participation in the study\n\n        Patients in Group A who meet any of the following criteria will be excluded from\n        participating in the study:\n\n          -  Received FDA-approved chemotherapy within 3 weeks of Day 0, or bevacizumab (or similar\n             drugs) within 4 weeks of Day 0, or radiation therapy at any site within 4 weeks of Day\n             0\n\n          -  Investigational anticancer therapy within 4 weeks of Day 0\n\n          -  Positive reaction to the skin test for allergy to mouse antigen\n\n          -  History of hypersensitivity reaction that, in the opinion of the investigator, poses\n             an increased risk of an allergic reaction to the RENCA macrobeads, particularly any\n             known allergy to murine antigens or body tissues.\n\n          -  Ongoing or active infection, symptomatic congestive heart failure, unstable angina\n             pectoris, serious cardiac arrhythmias (with the exception of well controlled atrial\n             fibrillation), active bleeding, or psychiatric illness, or social situations that\n             could interfere with the patient's ability to participate in the study.
Inclusion Criteria:\n\n        Each participant with newly diagnosed multiple myeloma (NDMM) must meet all of the\n        following inclusion criteria to be enrolled in the study:\n\n          1. Adult male or female participants 18 years of age or older with a confirmed diagnosis\n             of symptomatic multiple myeloma (MM) according to standard criteria.\n\n          2. Participants for whom cyclophosphamide and dexamethasone treatment is appropriate and\n             who are considered not eligible for high-dose therapy (HDT)-stem cell transplantation\n             (SCT) for 1 or more of the following reasons:\n\n               -  The participant is 65 years of age or older.\n\n               -  The participant is less than 65 years of age but has significant comorbid\n                  condition(s) that are, in the opinion of the investigator, likely to have a\n                  negative impact on tolerability of HDT-SCT.\n\n        Each participant with relapsed and/or refractory multiple myeloma (RRMM) must meet all of\n        the following inclusion criteria to be enrolled in the study:\n\n          1. Adult male or female participants 18 years or older with a confirmed diagnosis of\n             symptomatic MM either currently or at the time of initial diagnosis, according to\n             standard criteria, and relapsed and/or refractory disease after 1 to 3 lines of prior\n             therapy. A participant is considered to have refractory disease if disease progression\n             occurred during the treatment period or within 60 days of receiving the last dose of a\n             given therapy. A line of therapy is defined as 1 or more cycles of a single-agent or\n             combination therapy or a sequence of planned treatments such as induction therapy\n             followed by autologous stem cell transplantation (ASCT) and then maintenance therapy.\n\n          2. No evidence of graft-versus-host disease for participants who have undergone prior\n             allogeneic stem cell transplantation.\n\n        In addition, all participants (NDMM and RRMM) must meet all of the remaining criteria:\n\n          1. Participants must have measurable disease defined by at least 1 of the following 3\n             measurements:\n\n               -  Serum M-protein ? 1 g/dL (? 10 g/L).\n\n               -  Urine M-protein ? 200 mg/24 hours.\n\n               -  Serum free light chain assay: involved free light chain level ? 10 mg/dL (? 100\n                  mg/L), provided that the serum free light chain ratio is abnormal.\n\n          2. Participants must meet all of the following clinical laboratory criteria:\n\n               -  Absolute neutrophil count (ANC) ? 1000/mm^3 and platelet count ? 75,000/mm^3.\n                  Platelet transfusions to help participants meet eligibility criteria are not\n                  allowed within 3 days prior to administration of the study drug.\n\n               -  Total bilirubin ? 1.5 x the upper limit of the normal range (ULN).\n\n               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 3 x ULN.\n\n               -  Calculated creatinine clearance (CrCL) ? 30 mL/min.\n\n          3. Eastern Cooperative Oncology Group performance status of 0, 1, or 2.\n\n          4. Female participants who:\n\n               -  are postmenopausal for at least 1 year before the screening visit, or\n\n               -  are surgically sterile, or\n\n               -  If they are of childbearing potential, agree to practice 2 effective methods of\n                  contraception, at the same time, from the time of signing the informed consent\n                  through 90 days after the last dose of study drug, or\n\n               -  agree to practice true abstinence over the period previously described, when this\n                  is in line with the preferred and usual lifestyle of the participant. (Periodic\n                  abstinence [ie, calendar, ovulation, symptothermal, postovulation methods] and\n                  withdrawal are not acceptable methods of contraception.), and\n\n               -  adhere to any treatment-specific pregnancy prevention guidelines for\n                  cyclophosphamide and dexamethasone.\n\n          5. Male participants, even if surgically sterilized (ie, status post-vasectomy), who:\n\n               -  agree to practice effective barrier contraception during the entire study\n                  treatment period and through 90 days after the last dose of study drug, or\n\n               -  agree to practice true abstinence over the period previously described, when this\n                  is in line with the preferred and usual lifestyle of the participant. (Periodic\n                  abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the\n                  female partner] and withdrawal are not acceptable methods of contraception.), and\n\n               -  adhere to any treatment-specific pregnancy prevention guidelines for\n                  cyclophosphamide and dexamethasone.\n\n          6. Voluntary written consent must be given before performance of any study-related\n             procedure not part of standard medical care, with the understanding that consent may\n             be withdrawn by the participant at any time without prejudice to future medical care.\n\n          7. Suitable venous access for the study-required blood sampling.\n\n          8. Is willing and able to adhere to the study visit schedule and other protocol\n             requirements.\n\n        Exclusion Criteria:\n\n          1. Prior treatment for multiple myeloma with either standard of care treatment or\n             investigational regimen (for participants with NDMM only).\n\n             NOTE: Prior treatment with corticosteroids (maximum dose of corticosteroids should not\n             exceed the equivalent of 160 mg of dexamethasone over 14 days. Localized radiation is\n             permitted as long as it is below a therapeutic level and administered at least 14 days\n             prior to the first dose of study treatment.\n\n          2. Diagnosis of smoldering MM, Waldenström's macroglobulinemia, POEMS (polyneuropathy,\n             organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome,\n             plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or\n             myeloproliferative syndrome.\n\n          3. Central nervous system involvement.\n\n          4. Diagnosed or treated for another malignancy within 2 years before the first dose or\n             previously diagnosed with another malignancy and have any evidence of residual\n             disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type\n             are not excluded if they have undergone complete resection.\n\n          5. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of\n             any cause on clinical examination during the Screening period.\n\n          6. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral\n             absorption or tolerance of study drug, including difficulty swallowing.\n\n          7. Infection requiring intravenous (IV) antibiotic therapy or other serious infection\n             within 14 days before the first dose of study drug.\n\n          8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active\n             hepatitis B or C infection.\n\n          9. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin,\n             ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin,\n             itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A\n             inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital),\n             or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of\n             study treatment.\n\n         10. Known allergy to any of the study medications, their analogues, or excipients in the\n             various formulations.\n\n         11. Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty\n             or vertebroplasty is not considered major surgery.)\n\n         12. Female participants who are lactating and breastfeeding or have a positive serum\n             pregnancy test during the Screening period.\n\n         13. Any serious medical or psychiatric illness that could, in the investigator's opinion,\n             potentially interfere with the completion of treatment according to this protocol.\n\n         14. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment\n             of the investigator, would make the participant inappropriate for entry into this\n             study or interfere significantly with the proper assessment of safety and toxicity of\n             the prescribed regimens.\n\n         15. Treatment with any investigational products for reasons other than MM within 30 days\n             before the first dose of study drug.
Inclusion Criteria\n\n        Each participant must meet all the following inclusion criteria to be enrolled in the\n        study:\n\n          1. Male or female participants ? 18 years old.\n\n          2. Have a pathologically (histology or cytology) confirmed diagnosis of SCLC.\n\n          3. Have received and progressed after a platinum-based standard chemotherapy regimen for\n             first line treatment of SCLC, either limited stage (LS) or extensive stage (ES).\n\n          4. Have measurable disease within ? 2 weeks before randomization. Clear radiographic\n             evidence of disease progression after initial therapy should have been documented.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (PS 0-1).\n\n          6. Participants with treated brain metastases (surgery, whole or stereotactic brain\n             radiation) are allowed provided the lesions have been stable for at least 2 weeks and\n             the participant is off steroids or is on a stable dose of steroids. Participants\n             should be without neurologic dysfunction that would confound the evaluation of\n             neurological and/or other AEs.\n\n        Exclusion Criteria\n\n        Participants meeting any of the following exclusion criteria are not to be randomized to\n        treatment:\n\n          1. Any prior therapy for second-line treatment of SCLC.\n\n          2. Participants who relapsed ? 180 days after their response to first-line treatment.\n\n          3. Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent,\n             including alisertib, or any other investigational agent.\n\n          4. Prior treatment with paclitaxel or any other taxane agent.\n\n          5. Known hypersensitivity to Cremophor® EL, paclitaxel, or its components.\n\n          6. Any comorbid condition or unresolved toxicity that would preclude administration of\n             alisertib or weekly paclitaxel.\n\n          7. Prior history of ? Grade 2 neurotoxicity that is not resolved to ? Grade 1.\n\n          8. Participants with symptomatic and/or progressive brain metastases or with\n             carcinomatous meningitis.\n\n          9. Treatment with clinically significant enzyme inducers within 14 days prior to the\n             first dose of alisertib and during study conduct. Major prohibited enzyme inducers\n             include: phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine,\n             and St. John's wort.\n\n         10. Inability to swallow alisertib or other orally administered medications.\n\n         11. Requirement for administration of proton pump inhibitor (PPI), H2 antagonist, or\n             pancreatic enzymes.\n\n         12. Diagnosed with or treated for another malignancy within 2 years before the first dose\n             of study drug, or previously diagnosed with another malignancy and have any evidence\n             of residual disease.\n\n         13. Other severe acute or chronic medical or psychiatric condition(s) per protocol.\n\n         14. History of myocardial infarction, unstable symptomatic ischemic heart disease,\n             uncontrolled hypertension despite appropriate medical therapy, any ongoing cardiac\n             arrhythmias of Grade > 2, thromboembolic events (eg, deep vein thrombosis, pulmonary\n             embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg,\n             pericardial effusion or restrictive cardiomyopathy) within 6 months before receiving\n             the first dose of study drug.\n\n         15. Known history of human immunodeficiency virus (HIV) infection, hepatitis B or\n             hepatitis C.\n\n         16. Surgery within 3 weeks (or 2 weeks for a minor surgery) before study enrollment and\n             not fully recovered to baseline or to a stable clinical status.\n\n         17. Participants who are pregnant, lactating, or do not agree to use effective methods of\n             contraception during the study treatment period through 6 months after the last dose\n             of study drug per protocol.
Inclusion Criteria\n\n        Patients must meet the following criteria to be eligible for the study:\n\n          1. Metastatic breast cancer, documented as HER2+ by fluorescence in situ hybridization\n             (FISH) and/or 3+ staining by immunohistochemistry (IHC).\n\n          2. Progressive disease, with a history of prior treatment with both trastuzumab and T-DM1\n             (unless deemed intolerant to or ineligible for T-DM1 by the investigator) for\n             metastatic disease.\n\n          3. ? 18 years at time of consent.\n\n          4. If female and of child-bearing potential, has negative pregnancy test within 14 days\n             prior to treatment.\n\n          5. If a sexually active male or a sexually active female of child-bearing potential,\n             agrees to use dual (two concurrent) forms of medically accepted contraception from the\n             time of consent until 6 months after the last dose of ONT-380, capecitabine, or\n             trastuzumab, whichever is longest.\n\n          6. Signed an informed consent document that has been approved by an institutional review\n             board or independent ethics committee (IRB/IEC).\n\n          7. Must have target or non-target lesions as per Response Evaluation Criteria In Solid\n             Tumors (RECIST) 1.1.\n\n          8. All toxicity related to prior cancer therapies must have resolved to ? Grade 1, with\n             the following exceptions: alopecia; neuropathy, which must have resolved to ? Grade 2;\n             and congestive heart failure (CHF), which must have been ? Grade 1 in severity at the\n             time of occurrence and must have resolved completely.\n\n          9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening.\n\n         10. In the opinion of the Investigator, life expectancy > 6 months.\n\n         11. Adequate hematologic function as defined by:\n\n               1. Hemoglobin ? 9 g/dL\n\n               2. Absolute neutrophil count (ANC) ? 1000 cells/?L\n\n               3. Platelets ? 100,000/?L\n\n         12. Adequate hepatic function as defined by the following:\n\n               1. Total bilirubin ? 1.5 X upper limit of normal (ULN), unless a known history of\n                  Gilbert's disease\n\n               2. Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase\n                  [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase\n                  [ALT/SGPT]) ? 2.5 X ULN (< 5 X ULN if liver metastases are present)\n\n         13. International normalized ratio (INR) and activated partial thromboplastin time (aPTT)\n             ? 1.5 X ULN unless on medication known to alter INR and aPTT.\n\n         14. Creatinine clearance ? 50 mL/min.\n\n         15. Left ventricular ejection fraction (LVEF) must be within institutional limits of\n             normal as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)\n             documented within 4 weeks prior to first dose of study drug.\n\n        Exclusion Criteria\n\n        Patients will be excluded from the study for any of the following reasons:\n\n          1. Medical, social, or psychosocial factors that, in the opinion of the Investigator,\n             could impact safety or compliance with study procedures.\n\n          2. Patient is breastfeeding.\n\n          3. Previous treatment with any experimental agent within 14 days or five half-lives of\n             study treatment, whichever is greater.\n\n          4. Previous treatment with trastuzumab or other antibody-based therapy within three weeks\n             of starting study treatment or with chemotherapy or hormonal cancer therapy within two\n             weeks of starting study treatment.\n\n          5. Previous treatment with cumulative dose of doxorubicin > 360 mg/m2 or previous\n             treatment with another anthracycline with cumulative dose equivalent to > 360 mg/m2\n             doxorubicin.\n\n          6. Previous treatment with:\n\n               1. Capecitabine for metastatic disease at any time, for patients assigned to cohorts\n                  using capecitabine plus ONT-380 (Combination 1) or capecitabine plus trastuzumab\n                  plus ONT-380 (Combination 3). However, patients who have previous treatment with\n                  capecitabine for metastatic disease are eligible for enrollment into cohorts\n                  using trastuzumab plus ONT-380 (Combination 2). Patients who have received\n                  capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to\n                  starting study treatment are eligible to enroll into all cohorts (Combination 1,\n                  2, or 3).\n\n               2. Any small molecule HER2 inhibitors including (but not limited to) lapatinib,\n                  neratinib, or afatinib within the last 4 weeks prior to initiation of study\n                  therapy.\n\n          7. CNS disease:\n\n               1. Patients with leptomeningeal disease are excluded.\n\n               2. Dose escalation and expansion cohorts: Patients with symptomatic CNS metastases\n                  are excluded. Patients with treated CNS metastases or untreated asymptomatic CNS\n                  metastases not requiring immediate local therapy may be eligible. Enrollment of\n                  patients with metastases must be approved by the study medical monitor.\n\n               3. Optional CNS disease expansion cohorts: Patients with untreated asymptomatic CNS\n                  metastases not requiring immediate local therapy or patients with progressive CNS\n                  disease following local therapy may be eligible with medical monitor approval.\n\n          8. History of allergic reactions to compounds of similar chemical or biological\n             composition to capecitabine (for patients assigned to Combination 1 or 3 only),\n             trastuzumab (for patients assigned to Combination 2 or 3 only), or ONT-380, except for\n             a history of Grade 1 or Grade 2 Infusion Related Reaction to trastuzumab, which has\n             been successfully managed.\n\n          9. Patients with uncorrectable electrolyte abnormalities.\n\n         10. Known to be HIV positive. HIV testing is not required for those patients who are not\n             known to be positive.\n\n         11. Known carrier of Hepatitis B and / or Hepatitis C (whether active disease or not).\n\n         12. Known liver disease, autoimmune hepatitis, or sclerosing cholangitis.\n\n         13. Inability to swallow pills or any significant gastrointestinal diseases, which would\n             preclude adequate absorption of oral medications.\n\n         14. Use of a strong CYP3A4 inhibitor or inducer within three elimination half-lives of the\n             inhibitor or inducer prior to the start of study treatment.\n\n         15. Use of a strong CYP2C8 inducer or inhibitor within three elimination half-lives of the\n             inducer or inhibitor prior to the start of study treatment. (See Appendix F).\n\n         16. Radiotherapy within 14 days of first dose of ONT-380; patient must have recovered from\n             acute effects of radiotherapy to baseline.\n\n         17. Known impaired cardiac function or clinically significant cardiac disease such as\n             ventricular arrhythmia requiring therapy, congestive heart failure, and uncontrolled\n             hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood\n             pressure > 100 mmHg on antihypertensive medications).\n\n         18. Myocardial infarction or unstable angina within 6 months prior to the first dose of\n             study drug.\n\n         19. Patient with known dihydropyrimidine dehydrogenase deficiency (for patients assigned\n             to Combination 1 or 3 only).\n\n         20. Patient requiring warfarin therapy with known history of difficulty in management of\n             maintaining INR within therapeutic range. Patients on warfarin may be included if on a\n             stable dose with a therapeutic INR.
Inclusion Criteria:\n\n        All Participants:\n\n          -  At least one bi-dimensionally measurable lesion, defined as greater than (>) 1.5\n             centimeters (cm) in its longest dimension\n\n          -  Life expectancy of at least 24 weeks\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2\n\n          -  Adequate hematologic function (unless inadequate function is due to underlying\n             disease, as established by extensive bone marrow involvement or is due to\n             hypersplenism secondary to the involvement of the spleen by lymphoma per the\n             investigator)\n\n          -  Agreement to use highly effective contraception measures. Women of childbearing\n             potential must agree to remain abstinent or use contraceptive measures that result in\n             a failure rate of <1 percent (%) per year during the treatment period and for at least\n             12 months for R-CHP arm or for at least 18 months for G-CHP arm after the last dose of\n             study drug. Men must agree to remain abstinent or to use a condom plus an additional\n             contraceptive method that together result in a failure rate of <1% per year during the\n             treatment period and for at least 5 months after the last dose of study drug\n\n        Dose-Escalation Portion of the Study:\n\n          -  Histologically confirmed B-cell NHL: Participants with newly diagnosed B-cell NHL or\n             relapsed/refractory B-cell NHL are eligible\n\n          -  No more than one prior systemic treatment regimen for B-cell NHL (single agent\n             anti-cluster of differentiation [CD] 20 monoclonal antibody therapy will not be\n             counted as a prior treatment regimen)\n\n          -  No prior treatment with anthracyclines\n\n        Expansion Portion of the Study:\n\n          -  Previously untreated participants with diffuse large B-cell lymphoma (DLBCL)\n\n          -  International Prognostic Index score of 2-5\n\n        Exclusion Criteria:\n\n        Dose-Escalation Portion of the Study:\n\n          -  Diagnosis of primary mediastinal DLBCL\n\n        Expansion Portion of the Study:\n\n          -  Participants with transformed lymphoma\n\n          -  Prior therapy for NHL\n\n        All Participants:\n\n          -  Prior stem cell transplant\n\n          -  History of severe allergic or anaphylactic reactions to humanized or murine monoclonal\n             antibodies or known sensitivity or allergy to murine products\n\n          -  Contraindication to receive any of the individual components of R-CHP or G-CHP\n\n          -  Current Grade greater than (>) 1 peripheral neuropathy\n\n          -  Ongoing corticosteroid use of >30 milligrams per day (mg/day) of\n             prednisone/prednisolone or equivalent. Participants receiving corticosteroid treatment\n             with less than or equal to (</=) 30 mg/day of prednisone//prednisolone or equivalent\n             must be documented to be on a stable dose of at least 4 weeks' duration before Cycle 1\n             Day 1\n\n          -  Primary central nervous system (CNS) lymphoma\n\n          -  Vaccination with live vaccines within 6 months before Cycle 1 Day 1\n\n          -  History of other malignancy that could affect compliance with the protocol or\n             interpretation of results. Participants with a history of curatively treated basal or\n             squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix are\n             eligible. Participants with a malignancy that has been treated with surgery alone with\n             curative intent will also be excluded unless the malignancy has been in documented\n             remission without treatment for greater than or equal to (</=) 5 years before\n             enrollment\n\n          -  Evidence of significant, uncontrolled concomitant diseases, including renal disease\n             that would preclude chemotherapy administration, or pulmonary disease (including\n             obstructive pulmonary disease and history of bronchospasm)\n\n          -  Significant cardiovascular disease (such as New York Heart Association Class III or IV\n             cardiac disease, congestive heart failure, myocardial infarction within the previous 6\n             months, unstable arrhythmias, or unstable angina) or significant pulmonary disease\n\n          -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection\n             (excluding fungal infections of nail beds) at study enrollment or any major episode of\n             infection requiring treatment with IV antibiotics or hospitalization (relating to the\n             completion of the course of antibiotics) within 4 weeks before Cycle 1 Day 1\n\n          -  Clinically significant history of liver disease, including viral or other hepatitis,\n             current alcohol abuse, or cirrhosis\n\n          -  Positive for hepatitis B or hepatitis C infection\n\n          -  Prior radiotherapy to the mediastinal/pericardial region\n\n          -  Pregnant or lactating women\n\n          -  Recent major surgery within 6 weeks before the start of Cycle 1 Day 1\n\n          -  Abnormal laboratory values
Inclusion Criteria:\n\n          1. Histologically confirmed resected ductal pancreatic adenocarcinoma with macroscopic\n             complete resection (R0 and R1). Subjects with neuroendocrine (and mixed type) tumors\n             are excluded.\n\n          2. Pancreatic cancer surgical staging: T 1-3, N0-1, M0.\n\n          3. Subject should be able to start treatment no later than 12 weeks postsurgery.\n\n          4. ?18 years of age at the time of signing the informed consent form (ICF).\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          6. Acceptable hematology parameters:\n\n               -  Absolute neutrophil count ?1500 cell/mm3\n\n               -  Platelet count ?100,000/mm3\n\n               -  Hemoglobin (Hgb) ?9 g/dL\n\n          7. Acceptable blood chemistry levels:\n\n               -  Aspartate aminotransferase (AST)/ Serum glutamic oxaloacetic transaminase (SGOT)\n                  and Alanine transaminase (ALT)/ Serum glutamic -pyruvic transaminase (SGPT) ?2.5\n                  × upper limit of normal range (ULN)\n\n               -  Total bilirubin ? Upper Limit of Normal (ULN) (subjects with Gilbert's syndrome\n                  can have bilirubin of up to 1.5 x ULN)\n\n               -  Alkaline phosphatase ? 2.5 x ULN\n\n               -  Serum creatinine within upper limits of normal or calculated clearance ?50\n                  mL/min/1.73 m2. If using creatinine clearance, actual body weight should be used\n                  for calculating creatinine clearance (eg, using the Cockroft-Gault formula). For\n                  subjects with a Body Mass Index (BMI) >30 kg/m2, lean body weight should be used\n                  instead\n\n          8. Cancer antigen (CA)19-9 <100 U/mL assessed within 14 days of randomization\n\n          9. Acceptable coagulation studies as demonstrated by Prothrombin Time (PT) and Partial\n             Thromboplastin Time (PTT) within normal limits (±15%)\n\n        Exclusion Criteria:\n\n        A subject will not be eligible for inclusion in this study if any of the following criteria\n        apply:\n\n          1. Prior neo-adjuvant treatment or radiation therapy for pancreatic adenocarcinoma\n\n          2. Presence of or history of metastatic pancreatic adenocarcinoma\n\n          3. Any other malignancy within 5 years prior to randomization, with the exception of\n             adequately treated in-situ carcinoma of the cervix, uteri, or nonmelanomatous skin\n             cancer (all treatment of which should have been completed 6 months prior to\n             randomization)\n\n          4. Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic\n             therapy, defined as ongoing signs/symptoms related to the infection without\n             improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment\n\n          5. Known infection with hepatitis B or C, or history of human immunodeficiency virus\n             (HIV) infection, or subject receiving immunosuppressive or myelosuppressive\n             medications that would in the opinion of the investigator, increase the risk of\n             serious neutropenic complications\n\n          6. History of allergy or hypersensitivity to nab-paclitaxel or gemcitabine or any of\n             their excipients\n\n          7. Serious medical risk factors involving any of the major organ systems, or serious\n             psychiatric disorders, which could compromise the subject's safety or the study data\n             integrity. These include, but are not limited to:\n\n               1. History of connective tissue disorders (eg, lupus, scleroderma, arteritis nodosa)\n\n               2. History of interstitial lung disease, slowly progressive dyspnea and unproductive\n                  cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary\n                  hypersensitivity pneumonitis or multiple allergies\n\n               3. History of the following within 6 months prior to Cycle 1 Day 1: a myocardial\n                  infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass\n                  graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled\n                  hypertension, clinically significant cardiac dysrhythmia or ECG abnormality,\n                  cerebrovascular accident, transient ischemic attack, or seizure disorder
Inclusion Criteria:\n\n        In advanced esophagogastric malignancies:\n\n          -  Participants with histologically confirmed recurrent or metastatic esophageal or\n             gastro-esophageal junction squamous cell or adenocarcinoma or gastric adenocarcinoma\n             with Wnt Signaling Alterations\n\n          -  Participants must be refractory or intolerant to at least one prior therapy(ies) for\n             metastatic or locally advanced disease\n\n               -  If prior therapy consisted of palliative chemoradiation therapy, it will be\n                  considered one line of therapy\n\n               -  Prior treatment with paclitaxel as part of a definitive therapy regimen is\n                  acceptable. Patients who are unable to receive paclitaxel for any reason will be\n                  allowed to receive DKN-01 as a single agent.\n\n               -  Prior treatment anti- programmed death-1 (PD-1)/ anti-PD-ligand 1 (PD-L1)\n                  monoclonal antibody (mAb) is permitted in patients provided the patient's disease\n                  is primary refractory, and the patient is not intolerant of pembrolizumab.\n                  Patients who are not eligible to receive pembrolizumab will be allowed to receive\n                  single agent DKN-01\n\n          -  Tumor tissue for mandatory evaluation\n\n          -  Must have one or more tumors measurable on radiographic imaging as defined by the\n             Response Evaluation Criteria in Solid Tumors (RECIST). Patients with evaluable but not\n             measurable disease per RECIST criteria may be enrolled with the approval of the\n             medical monitor.\n\n          -  Must be ?18 years of age\n\n          -  Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale. A\n             performance status of 2 on the ECOG scale may be entered upon the review and approval\n             of the medical monitor\n\n          -  Disease-free of active second/secondary or prior malignancies for equal to or over 2\n             years with the exception of currently treated basal cell, squamous cell carcinoma of\n             the skin, or carcinoma \in-situ\ of the cervix or breast\n\n          -  Acceptable liver, renal, hematologic and coagulation function\n\n          -  For men and women of child-producing potential, the use of effective contraceptive\n             methods during the study and for 6 months following the last dose of study drug\n\n        Exclusion Criteria:\n\n          -  New York Heart Association Class III or IV, cardiac disease, myocardial infarction\n             within the past 6 months, unstable arrhythmia\n\n          -  Fridericia-corrected QT interval (QTcF) > 470 msec (female) or > 450 (male), or\n             history of congenital long QT syndrome.\n\n          -  Active, uncontrolled bacterial, viral, or fungal infections, within 7 days of study\n             entry requiring systemic therapy\n\n          -  Known to be human immunodeficiency virus (HIV) positive, have hepatitis B surface\n             antigen (HBSAg), or hepatitis C antibodies (HCAb) unless HCV RNA is\n             undetected/negative.\n\n          -  Serious nonmalignant disease\n\n          -  Pregnant or nursing women\n\n          -  History of osteonecrosis of the hip or have evidence of structural bone abnormalities\n             in the proximal femur on MRI scan that are symptomatic and clinically significant.\n\n          -  Systemic central nervous system (CNS) malignancy or metastasis.\n\n          -  Clinically significant peripheral neuropathy at the time of study entry. Patients with\n             pre-existing peripheral neuropathy will be allowed to receive single agent DKN-01\n\n          -  Known osteoblastic bony metastasis\n\n          -  History of known or suspected autoimmune disease with the specific exceptions of\n             vitiligo, atopic dermatitis, or psoriasis not requiring systemic treatment.\n\n          -  Clinically-significant gastrointestinal disorders, such as perforation,\n             gastrointestinal bleeding, or diverticulitis.\n\n          -  Active autoimmune disease that has required systemic treatment in past 2 years (i.e.\n             with use of disease modifying agents, corticosteroids or immunosuppressive drugs).\n             Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement\n             therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of\n             systemic treatment.\n\n          -  Treatment with surgery or chemotherapy within 21 days prior to study entry (42 days\n             for nitrosoureas or mitomycin C)\n\n          -  Treatment with low dose chemotherapy concurrent with radiation within 14 days prior to\n             study entry\n\n          -  Treatment with radiation therapy within 14 days prior to study entry\n\n          -  Treatment with any other investigational agent within 30 days prior to study entry\n\n          -  Previously treated with an anti-DKK-1 therapy\n\n          -  Participants who have a history of hypersensitivity reactions to TAXOL® or other drugs\n             formulated in Cremophor® EL (polyoxyethylated castor oil). Patients who exhibit these\n             hypersensitivities will be eligible to receive single agent DKN-01.\n\n          -  Significant allergy to a pharmaceutical therapy that, in the opinion of the\n             investigator, poses an increased risk to the participant\n\n          -  Treatment with corticosteroids (? 10 mg per day prednisone or equivalent) or other\n             immune suppressive drugs within the 14 days prior to study entry\n\n          -  Active substance abuse\n\n          -  Receipt of any live vaccines within 30 days before the first dose of study treatment\n             and while participating in the study\n\n          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis\n\n          -  History of interstitial lung disease\n\n          -  Intolerance or severe hypersensitivity (?Grade 3) to pembrolizumab and/or of its\n             excipients
Inclusion Criteria: All subjects\n\n          1. Unsuitable for chemoimmunotherapy with FCR in the opinion of the investigator.\n\n          2. Confirmed diagnosis of CD20-positive CLL or SLL.\n\n          3. Binet Stage C disease, or Binet Stage B or A disease requiring treatment.\n\n          4. ECOG performance status of 0, 1 or 2.\n\n          5. Life expectancy ? 6 months.\n\n          6. Adequate bone marrow function.\n\n          7. Adequate renal and hepatic function.\n\n          8. Females of childbearing potential and non-sterile males must agree to use highly\n             effective methods of birth control throughout the course of study\n\n          9. Male patients are eligible if vasectomized or if they agree to use of barrier\n             contraception with other methods described above throughout the course of study.\n\n         10. Written informed consent.\n\n        Exclusion Criteria: All subjects\n\n          1. Previous systemic treatment for CLL/SLL.\n\n          2. Known prolymphocytic leukemia or history of or suspected Richter's transformation.\n\n          3. Clinically significant cardiovascular disease.\n\n          4. Prior malignancy within the past 3 years, except for curatively treated basal or\n             squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the\n             cervix of breast.\n\n          5. Major surgery or significant injury ? 4 weeks prior to start of study treatment.\n\n          6. History of severe bleeding disorder.\n\n          7. History of stroke or intracranial hemorrhage within 6 months before the first dose of\n             study drug.\n\n          8. Severe or debilitating pulmonary disease.\n\n          9. Inability to swallow capsules or disease affecting gastrointestinal function.\n\n         10. Known central nervous system involvement by leukemia or lymphoma.\n\n         11. Active infection requiring systemic treatment.\n\n         12. Known infection with human immunodeficiency virus (HIV) or active hepatitis B or C\n             infection.\n\n         13. Vaccination with live vaccine within 35 days prior to the first dose of study drug.\n\n         14. Known hypersensitivity to BGB-3111, bendamustine, or rituximab or any other\n             ingredients of the study drugs.\n\n         15. Requires ongoing treatment with strong CYP3A inhibitor or inducer.\n\n         16. Pregnant or nursing females.\n\n         17. Concurrent participation in another therapeutic clinical trial.
Inclusion Criteria for Dose Escalation:\n\n          -  Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with\n             evidence of either locally recurrent disease not amenable to resection or radiation\n             therapy with curative intent or with metastatic disease\n\n          -  ER-positive tumor\n\n          -  HER2-negative breast cancer as per local laboratory testing\n\n          -  Measurable disease, or evaluable bone disease; that is, bone lesions that are lytic or\n             mixed (lytic + sclerotic) in the absence of measurable lesion\n\n          -  Required paired pre- and on-treatment tumor biopsies for participants with metastases\n             that are safely accessible as determined by the investigator\n\n          -  Advanced or metastatic ER-positive/HER2-negative breast cancer that has recurred or\n             progressed while being treated with adjuvant endocrine therapy for a duration of at\n             least 24 months and/or endocrine therapy in the incurable, locally advanced, or\n             metastatic setting and derived a clinical benefit from therapy (i.e., tumor response\n             or stable disease for at least 6 months)\n\n          -  No more than 2 prior lines of treatment for advanced or metastatic breast cancer\n\n          -  ? 2 weeks must have elapsed from the use of any other endocrine, targeted therapy or\n             chemotherapy\n\n          -  Cohort B0: No prior treatment with Cyclin-Dependent Kinase (CDK) 4/6 inhibitor\n\n          -  For participants undergoing 18F-fluoroestradiol (FES) positron emission tomography\n             (PET) imaging additional restrictions on prior therapy include: ? 2 months must have\n             elapsed from the use of tamoxifen; ? 6 months must have elapsed from the use of\n             fulvestrant\n\n          -  Postmenopausal status\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status ? 1\n\n          -  Resolution of all acute toxic effects of prior therapy or surgical procedures to\n             baseline or Grade ? 1 (except alopecia or other toxicities not considered to be a\n             safety risk for the patient)\n\n          -  Life expectancy of ? 12 weeks\n\n          -  Adequate organ function\n\n        Inclusion Criteria for Dose Expansion:\n\n        Same as above, except:\n\n          -  No more than one prior line of treatment for advanced or metastatic breast cancer\n\n          -  Advanced or metastatic disease that is either refractory to or intolerant of existing\n             standard therapy or for which no effective standard therapy that confers clinical\n             benefit is available\n\n        And plus:\n\n          -  Cohort B1?2: No prior treatment with CDK4/6 inhibitor\n\n          -  Cohorts A1, A3, and B1 only: Postmenopausal status\n\n          -  Cohorts A2, A4, and B2 only: Participants not defined as post-menopausal\n\n          -  No prior treatment with an oral selective estrogen receptor degrader (SERD)\n\n          -  For women of childbearing potential: agreement to remain abstinent (refrain from\n             heterosexual intercourse) or use non-hormonal contraceptive methods with a failure\n             rate of < 1% per year during the treatment period and for 40 days after the last dose\n             of GDC-9545\n\n        Exclusion Criteria for Dose Escalation:\n\n          -  Known brain metastases that are untreated, symptomatic, or require therapy to control\n             symptoms.\n\n          -  Current treatment with any systemic anti-cancer therapies for advanced disease\n\n          -  Concurrent treatment with warfarin or phenytoin\n\n          -  Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for\n             appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or\n             Stage I uterine cancer\n\n          -  Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major\n             upper GI surgery including gastric resection\n\n          -  Known Human Immunodeficiency Virus (HIV) infection\n\n          -  Known clinically significant history of liver disease consistent with Child-Pugh Class\n             B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C\n             virus), current alcohol abuse, or cirrhosis\n\n          -  Major surgery within 4 weeks prior to enrollment\n\n          -  Radiation therapy within 2 weeks prior to enrollment\n\n        Exclusion Criteria for Dose Expansion:\n\n        Same as above, plus:\n\n          -  Pregnant, lactating, or breastfeeding\n\n          -  Additional exclusion criteria for participants in Cohort B: History of venous\n             thromboembolic event requiring therapeutic anticoagulation
-  INCLUSION CRITERIA:\n\n          -  Patients must have histologically confirmed hairy cell leukemia or hairy cell leukemia\n             variant .with a need for therapy\n\n          -  Patients must be Pseudomonas-immunotoxin naive\n\n          -  Patients must have had at least 2 prior purine analogs, or at least 1 course of purine\n             analog and 1 of either rituximub or BRAF inhibitor.\n\n          -  Men or women age greater than or equal to 18 years.\n\n          -  ECOG performance status less than or equal to 2.\n\n          -  Patients must have adequate organ function\n\n        EXCLUSION CRITERIA\n\n          -  Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks prior\n             to entering the study.\n\n          -  Patients who are receiving any other investigational agents.\n\n          -  Patients with known brain metastases should be excluded from this clinical trial\n\n          -  Patients with clinically significant ophthalmologic findings during screening\n\n          -  Pregnant or breastfeeding females.\n\n          -  Positive for Hepatitis B core antibody surface antigen unless the patient is on\n             Lamivudine or Entecavir and Hepatitis B Viral DNA load is less than 2000 IU/mL.\n\n          -  Lymph nodes greater than 4cm or prior splenectomy\n\n          -  Active second malignancy requiring treatment other than minor resection of indolent\n             cancers like basal cell and squamous skin cancers\n\n          -  HIV-positive patients unless taking appropriate anti-HIV medications with a CD4 count\n             of greater than 200.\n\n          -  History of allogeneic bone marrow transplant.\n\n          -  Patients with history of both thromboembolism and known congenital hypercoagulable\n             conditions.\n\n          -  Uncontrolled pulmonary infection, pulmonary edema.\n\n          -  Aequate oxygen saturation\n\n          -  Radioimmunotherapy within 2 years prior to enrollment in study.\n\n          -  Adequate hematologic function\n\n          -  Adequate lung function\n\n          -  Patients with history of thrombotic microangiopathy or TTP-HUS.\n\n          -  Patients with QTc interval (Federica) elevation > 500 msec based on at least 2\n             separate 12-lead ECGs\n\n          -  Patient on high dose estrogen\n\n          -  Patients with clinical evidence of disseminated intravascular coagulation
Inclusion Criteria: Subjects eligible for enrolment in this study must meet all of the\n        following criteria\n\n          -  Provided written informed consent,\n\n          -  Male or female >=18 years of age and able to swallow and retain orally administered\n             study treatment and does not have any clinically significant gastrointestinal (GI)\n             abnormalities that may alter absorption such as malabsorption syndrome or major\n             resection of the stomach and/or bowels.\n\n          -  Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or\n             metastatic BRAF V600E mutation positive CRC\n\n          -  Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced\n             or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by\n             relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy,\n             defined as patients that derived benefit (disease control based on investigator\n             assessment for >6 months OR partial response [confirmed or unconfirmed] based on\n             RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then\n             subsequently progressed on therapy. The anti-EGFR therapy must have been the most\n             recent therapy and the patient must have progressed based on investigator assessment\n             within 3 months of screening. Acceptable prior anti-EGFR-containing therapies include:\n             a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b.\n             irinotecan/anti-EGFR combo after previously having disease progression (based on\n             investigator assessment) on an irinotecan-containing regimen\n\n          -  Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation\n             positive advanced or metastatic colorectal cancer (CRC who are eligible to receive\n             fluoropyrimidine-containing chemotherapy regimen that have experienced documented\n             radiographic progression on one prior line of fluoropyrimidine-containing chemotherapy\n             (previous anti-EGFR therapy is excluded), Second-line for advanced/metastatic disease,\n             having failed or been intolerant to at least one regimen of\n             fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in the\n             advanced/metastatic setting. Enrollment in Part 3 may only occur following\n             confirmation of KRAS wild-type cancer.\n\n          -  Archival tissue is required; if archival tissue is not available or found to not\n             contain tumor tissue, a fresh biopsy is required.\n\n          -  Measurable disease per RECIST version 1.1.\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.\n\n          -  Men with a female partner of childbearing potential must have either had a prior\n             vasectomy or agree to use one of the contraception methods listed in protocol.\n\n          -  Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal\n             females with a documented tubal ligation or hysterectomy; or post-menopausal female\n             defined as 12 months of spontaneous amenorrhea to be verified with a\n             follicle-stimulating hormone (FSH) level >40 Milli-international units per milliliter\n             (MIU/mL) and estradiol level <40 picogram per milliliter (pg/mL). Child-bearing\n             potential and agrees to use one of the contraceptive methods listed in protocol.\n\n          -  Female subjects must agree to use contraception from 7 days prior to the first dose of\n             study drug(s) until 6 months after the last dose of panitumumab, until 4 months after\n             the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever\n             is longer. Additionally, women of childbearing potential must have had a negative\n             serum pregnancy test within 7 days prior to the first dose of study drug(s).\n\n          -  Adequate organ system function as defined in absolute neutrophil count greater than or\n             equal to 1.2X10^9/Liter (L), hemoglobin greater than or equal to 9 grams per deciliter\n             (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or equal to 75 ×\n             10^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and Partial\n             Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal (ULN);\n             serum magnesium greater than or equal to the lower limit of normal (LLN); albumin\n             greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total bilirubin less\n             than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and Alanine\n             aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than or equal\n             to 1.5XULN or calculated creatinine clearance greater than or equal to 50mL/min; left\n             ventricular ejection fraction (LVEF) greater than or equal to the LLN by\n             echocardiography (ECHO) or multigated acquisition scan (MUGA).\n\n          -  Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible\n             for inclusion in this study only if either affiliated to, or a beneficiary of, a\n             social security category.\n\n        Exclusion Criteria: Subjects meeting any of the following criteria must not be enrolled in\n        the study\n\n          -  History of prior malignancy, other than colorectal cancer.\n\n          -  Any serious and/or unstable pre-existing medical, psychiatric disorder or other\n             conditions that could interfere with subject's safety, obtaining informed consent or\n             compliance to the study procedures.\n\n          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or\n             asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease\n             per investigator's assessment).\n\n          -  History of sensitivity to heparin or heparin-induced thrombocytopenia.\n\n          -  Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or\n             biologic therapy).\n\n          -  Prior exposure to a MEK inhibitor.\n\n          -  Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF\n             inhibitor.\n\n          -  Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of\n             KRAS-mutation based on previous KRAS-testing. Note: Propsective KRAS testing is not\n             required. However, if the results of previous KRAS testing are known, they must be\n             used in assessing eligibility. KRAS testing will be performed retrospectively for all\n             patients.\n\n          -  Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody\n\n          -  Received an investigational or approved anti-cancer drug within 4 weeks, or within 5\n             half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days\n             must have passed between the last dose of prior investigational agent and the first\n             dose of study drug(s).\n\n          -  Part 3: Received more than one prior anti-cancer therapy in the metastatic setting,\n             exclusive of previous adjuvant regimens. Previous investigational anti-cancer therapy\n             in the metastatic setting is prohibited.\n\n          -  Current use of a prohibited medication or requirement to dose with any of these\n             medications during treatment with study drug(s).\n\n          -  Known Hepatitis B, or Hepatitis C infection.\n\n          -  Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first\n             dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of\n             study drug(s).\n\n          -  Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of\n             study drug(s). Chemotherapy regimens given continuously or on a weekly basis with\n             limited potential for delayed toxicity within 2 weeks prior to first dose of study\n             drug(s).\n\n          -  Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria\n             for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer therapy,\n             with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory values that\n             are allowed per inclusion criteria.\n\n          -  History of retinal vein occlusion (RVO).\n\n          -  Presence of active gastrointestinal disease or other condition that will interfere\n             significantly with the absorption, distribution, metabolism or excretion of drugs.\n             Previous colectomy is acceptable.\n\n          -  Subjects with brain metastases are excluded, unless: All known lesions must be\n             previously treated with surgery or stereotactic radio-surgery, and Brain lesion(s), if\n             present, must be confirmed stable (i.e., no increase in lesion size) for >=90 days\n             prior to first dose of study drug(s). This must be documented with two consecutive MRI\n             or CT scans using contrast, and Asymptomatic with no corticosteroids requirement for\n             >=30 days prior to first dose of study drug(s), and No enzyme-inducing anticonvulsants\n             for >=14 days prior to first dose of study drug(s). In addition, for subjects that had\n             brain metastases but currently have no evidence of disease (NED), NED for >=12 weeks\n             is required and must be confirmed by two consecutive MRI or CT scans (using contrast)\n             separated by >=6 weeks, prior to randomization. Enrollment of a subject with brain\n             metastases who meet the above criteria requires approval of a GlaxoSmithKline (GSK)\n             Medical Monitor.\n\n          -  Psychological, familial, sociological or geographical conditions that do not permit\n             compliance with the protocol.\n\n          -  History or evidence of cardiovascular risk including any of the following: LVEF<LLN; A\n             QT interval corrected for heart rate using the Bazett's formula (QTcB;) ? 480\n             milliseconds (msec);.History or evidence of current clinically significant\n             uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for\n             >30 days prior to randomization are eligible. History of acute coronary syndromes\n             (including myocardial infarction and unstable angina), coronary angioplasty, or\n             stenting within 6 months prior to randomization. History or evidence of current >=\n             Class II congestive heart failure as defined by New York Heart Association (NYHA).\n             Treatment refractory hypertension defined as a blood pressure of systolic> 140\n             millimeter of mercury (mm Hg) and/or diastolic > 90 mm Hg which cannot be controlled\n             by anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent\n             pacemakers; Known cardiac metastases\n\n          -  Unstable pulmonary embolism, deep vein thrombosis, or other significant\n             arterial/venous thromboembolic event <=30 days before randomization. If on\n             anticoagulation, subject must be on stable therapeutic dose prior to randomization.\n\n          -  Subjects with a history of pneumonitis or interstitial lung disease (ILD).\n\n          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs\n             chemically related to the study drug(s) or their excipients.\n\n          -  Pregnant or lactating female.\n\n          -  Unwillingness or inability to follow the procedures outlined in the protocol.\n\n          -  Uncontrolled diabetes or other medical condition that may interfere with assessment of\n             toxicity.
Inclusion criteria:\n\n        Male or female patients age 18 years or older. Diagnosis of multiple myeloma and\n        documentation of at least 2 prior therapies (induction therapy, autologous stem cell\n        transplant, consolidation and maintenance therapy is considered one prior therapy); there\n        is no maximum number of prior regimens and prior bone marrow transplant is acceptable.\n\n        Confirmed evidence of disease progression from immediately prior MM therapy or refractory\n        to the immediately prior therapy.\n\n        Patients may have received prior immunomodulatory drugs (IMiDs®) (eg, lenalidomide or\n        thalidomide).\n\n        Patients with measurable disease. Patients with a Karnofsky ?60% performance status.\n        Females of childbearing potential (FCBP). Voluntary written informed consent before\n        performance of any study-related procedure not part of routine medical care with the\n        understanding that consent may be withdrawn by the subject at any time without prejudice to\n        future medical care.\n\n        Ability to understand the purpose and risks of the study and provide signed and dated\n        informed consent and authorization to use protected health information (in accordance with\n        national and local subject privacy regulations).\n\n        Able to take aspirin daily as prophylactic anti-coagulation therapy (patients intolerant to\n        aspirin may use warfarin, low molecular weight heparin or equivalent anti-platelet\n        therapy).\n\n        Adequate organ function.\n\n        Exclusion criteria:\n\n        Diagnosed or treated for another malignancy within 3 years prior to enrollment, with the\n        exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the\n        skin, an in situ malignancy, or low risk prostate cancer after curative therapy.\n\n        Prior anti-cancer therapy (chemotherapy, targeted agents, radiotherapy, and immunotherapy)\n        within 21 days except for alkylating agents (eg, melphalan) where 28 days will be required\n        or participated in another clinical trial during the past 30 days.\n\n        History of significant cardiovascular disease within the past 6 months, unless the disease\n        is well-controlled.\n\n        Prior autologous stem cell transplant within 12 weeks of the first dose of study treatment\n        and/or prior allogeneic transplant within 1 year or has evidence of active\n        graft-versus-host disease (GVHD) requiring >10 mg prednisone daily.\n\n        Daily requirement for corticosteroids (>10 mg prednisone qd for 7 consecutive days) (except\n        for inhalation corticosteroids and patients being treated for adrenal\n        insufficiency/replacement therapy).\n\n        Evidence of mucosal or internal bleeding. Prior radiation therapy or major surgical\n        procedure within 4 weeks of the first dose of study treatment.\n\n        Known active infection requiring parenteral or oral anti-infective treatment. Serious\n        psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse\n        follow-up evaluation.\n\n        Any medical conditions that, in the Investigator's opinion, would impose excessive risk to\n        the patient.\n\n        Hypersensitivity to any of the components of study therapy that is not amenable to\n        premedication with steroids and H2 blockers.\n\n        Known human immunodeficiency virus (HIV) or active hepatitis B or C viral infection.\n\n        Neuropathy ? Grade 3 or painful neuropathy ? Grade 2. Gastro-intestinal abnormalities,\n        including bowel obstruction, inability to take oral medication, requirement for intravenous\n        (IV) alimentation, active peptic ulcer or prior surgical procedures or bowel resection\n        affecting absorption.\n\n        Pregnancy.\n\n        The above information is not intended to contain all considerations relevant to a patient's\n        potential participation in a clinical trial.
Inclusion Criteria:\n\n        Subjects must satisfy the following criteria to be enrolled in the study:\n\n          1. Must be ? 18 years at the time of signing the informed consent form\n\n          2. Must understand and voluntarily sign an informed consent document prior to any\n             study-related assessments/procedures\n\n          3. Must be able to adhere to the study visit schedule and other protocol requirements\n\n          4. Must have documented diagnosis of relapsed or refractory multiple myeloma and have\n             measurable disease (serum M-protein ? 0.5 g/dL or urine M-protein ? 200 mg/24 hours)\n\n          5. Must have had at least 1 prior anti-myeloma regimen\n\n          6. Must have documented progression as per the International Myeloma Working Group\n             uniform response criteria (Durie, 2006) during or after the last anti-myeloma regimen\n\n          7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2\n\n          8. Females of childbearing potential (FCBP) must agree to utilize two reliable forms of\n             contraception simultaneously or practice complete abstinence from heterosexual contact\n             for at least 28 days before starting study drug, while participating in the study\n             (including dose interruptions), and for at least 28 days after study treatment\n             discontinuation, and must agree to regular pregnancy testing during this timeframe\n\n          9. Females must agree to abstain from breastfeeding during study participation and for 28\n             following discontinuation from study treatment\n\n         10. Males must agree to use a latex condom during any sexual contact with FCBP while\n             participating in the study and for 28 days following discontinuation from study\n             treatment, even if he has undergone a successful vasectomy\n\n         11. Males must also agree to refrain from donating semen or sperm while on pomalidomide\n             and for 28 days after discontinuation from study treatment\n\n         12. All subjects must agree to refrain from donating blood while on study drug and for 28\n             days after discontinuation from study treatment\n\n         13. All subjects must agree not to share medication\n\n        Exclusion Criteria:\n\n        The presence of any of the following will exclude a subject from enrollment:\n\n          1. Peripheral neuropathy ? Grade 2\n\n          2. Non-secretory multiple myeloma\n\n          3. Any of the following laboratory abnormalities:\n\n               -  Absolute neutrophil count (ANC) < 1,000/µL\n\n               -  Platelet count < 75,000/µL\n\n               -  Corrected serum calcium > 14 mg/dL (> 3.5 mmol/L)\n\n               -  Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior RBC transfusion or recombinant human\n                  erythropoietin use is permitted)\n\n               -  Serum glutamic oxaloacetic transaminase/aspartate aminotransferase (SGOT/AST) or\n                  serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) > 3.0 x\n                  upper limit of normal (ULN)\n\n               -  Serum total bilirubin > 2.0 mg/dL\n\n          4. Prior history of malignancies, other than the disease being studied, unless the\n             subject has been free of the malignancy for ? 5 years from initiating study treatment,\n             with the following exceptions:\n\n               -  Basal cell carcinoma of the skin\n\n               -  Squamous cell carcinoma of the skin\n\n               -  Carcinoma in situ of the cervix\n\n               -  Carcinoma in situ of the breast\n\n               -  Incidental histologic finding of prostate cancer (T1a or T1b using the TNM\n                  [tumor, nodes, metastasis] clinical staging system).\n\n          5. Previous therapy with Pomalidomide\n\n          6. Hypersensitivity to thalidomide, lenalidomide, or dexamethasone\n\n          7. Rash ? Grade 3 during prior thalidomide or lenalidomide therapy\n\n          8. Incidence of gastrointestinal disease that may significantly alter the absorption of\n             pomalidomide\n\n          9. Subjects with any one of the following:\n\n               -  Congestive heart failure (New York Heart Association Class III or IV)\n\n               -  Myocardial infarction within 12 months prior to starting study treatment\n\n               -  Unstable or poorly controlled angina pectoris, including Prinzmetal variant\n                  angina pectoris\n\n         10. Subjects who received any of the following within the last 14 days of initiation of\n             study treatment:\n\n               -  Plasmapheresis\n\n               -  Major surgery (kyphoplasty is not considered major surgery)\n\n               -  Radiation therapy (with the exception of radiation therapy to a pathological\n                  fracture site to enhance bone healing or to treat post-fracture pain that is\n                  refractory to narcotic analgesics)\n\n               -  Any anti-myeloma drug therapy\n\n         11. Use of any investigational agents within 28 days or 5 half-lives (whichever is longer)\n             of initiating study treatment\n\n         12. Subjects with conditions requiring chronic steroid or immunosuppressive treatment,\n             such as rheumatoid arthritis, multiple sclerosis, and lupus, which likely need\n             additional steroid or immunosuppressive treatments in addition to the study treatment.\n             Includes subjects receiving corticosteroids (> 10 mg/day of prednisone or equivalent)\n             within 3 weeks prior to initiating study treatment\n\n         13. Subjects unable or unwilling to undergo antithrombotic prophylactic treatment will not\n             be eligible to participate in this study\n\n         14. Any condition, including the presence of laboratory abnormalities, which places the\n             subject at unacceptable risk if he/she were to participate in the study\n\n         15. Any serious medical condition, laboratory abnormality, or psychiatric illness that\n             would prevent the subjects from signing the informed consent form\n\n         16. Pregnant or breastfeeding females
Inclusion Criteria:\n\n          1. At least 18 years of age.\n\n          2. Ability to understand the purposes and risks of the study and has signed a written\n             informed consent form approved by the investigator's IRB/Ethics Committee.\n\n          3. Relapsed/refractory multiple myeloma for which no standard therapy options are\n             anticipated to result in a durable remission.\n\n          4. Receipt of at least two prior therapies as indicated by protocol\n\n          5. Subjects with measurable disease\n\n          6. ECOG performance status of less than or equal to 2\n\n          7. Acceptable liver function\n\n          8. Acceptable renal function\n\n          9. Acceptable hematologic status\n\n         10. For Part A, B, C subjects: Women of childbearing potential must have a negative serum\n             pregnancy test and women and men subjects must agree to use effective means of\n             contraception with their partner as indicated by protocol For Part D subjects: a\n             negative serum pregnancy test is required within 10- 14 days prior to initiating with\n             pomalidomide, AND a negative serum pregnancy test within 24 hours of starting\n             pomalidomide and must either commit to continued abstinence from heterosexual\n             intercourse or begin two acceptable methods of birth control at least 28 days before\n             she starts taking pomalidomide.\n\n             Women of childbearing potential must enroll into and follow all requirements of the\n             POMALYST REMS program, which includes adhering to the scheduled pregnancy testing.\n\n             Men must agree to use a latex or synthetic condom during sexual contact with women of\n             child bearing potential even if they have had a vasectomy.\n\n             All subjects must be counseled at a minimum of every 28 days about pregnancy\n             precautions and risks of fetal exposure, or when a female patient misses her period or\n             if there is any abnormality in her menstrual bleeding.\n\n         11. Subjects must adhere to the study visit schedule and other protocol requirements and\n             receive outpatient therapy and laboratory monitoring at the institute that administers\n             the study drug.\n\n        Exclusion Criteria\n\n        Subjects who meet any of the following exclusion criteria are not eligible to be enrolled\n        in this study:\n\n          1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy\n             and skin changes.)\n\n          2. Waldenstrom's macroglobulinemia\n\n          3. Localized radiation therapy to only measurable disease site(s) within 2 weeks of\n             treatment\n\n          4. New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial\n             infarction within 6 months prior to Day 1, or unstable arrhythmia\n\n          5. Significant neuropathy (Grade 3 or 4, or Grade 2 with pain) at the time of enrollment\n             or within 14 days before enrollment\n\n          6. Symptomatic brain metastases (unless previously treated and well controlled for a\n             period of ? 3 months)\n\n          7. Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the\n             investigator any physiological state leading to hypoxemia\n\n          8. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without\n             complete recovery\n\n          9. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic\n             therapy within 14 days prior to the first dose\n\n         10. Previously treated malignancies, except for adequately treated non-melanoma skin\n             cancer (basal cell or squamous cell), in situ cancer, or other cancer from which the\n             subject has been disease-free for at least 5 years\n\n         11. Subjects who participated in an investigational drug or device study within 2 weeks\n             prior to study entry\n\n         12. Known or suspected active infection with HIV, hepatitis A, hepatitis B, or hepatitis C\n\n         13. Subjects who have exhibited allergic reactions to a similar structural compound,\n             biological agent, or formulation similar to TH-302, bortezomib (for subjects enrolled\n             in Part C only), pomalidomide (Part D), dexamethasone or pimonidazole\n\n         14. Females who are pregnant or breast-feeding\n\n         15. Concomitant psychiatric disease or medical condition that could interfere with the\n             conduct of the study, or that would, in the opinion of the investigator, pose an\n             unacceptable risk to the subject in this study\n\n         16. Unwillingness or inability to comply with the study protocol for any reason\n\n         17. Previous cytotoxic therapies for multiple myeloma within 3 weeks prior to study entry\n             (2 weeks for biologic, novel therapy or corticosteroids)\n\n         18. Subjects who have been on hormone replacement less than 2 months (subjects on hormone\n             replacement for at least 2 months will not be excluded provided the HRT regimen\n             remains unchanged during the conduct of the study).\n\n         19. Prior peripheral stem cell transplant within 12 weeks of the start of study\n\n         20. Epilepsy or other convulsive disorder requiring active management\n\n         21. Prior therapy with a pomalidomide-containing regimen\n\n         22. Subjects on strong inducers or strong inhibitors of cytochrome P450 CYP3A4 or CYP1A2\n\n         23. Any other medical condition that in opinion of investigator would place patient at\n             increased risk for toxicity during pomalidomide treatment (i.e. history of recurrent\n             or serious thromboembolic events)
Inclusion Criteria:\n\n          -  All subjects must be ? 18 years at the first screening examination / visit\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1\n\n          -  Life expectancy of at least 12 weeks\n\n          -  Histologically or cytologically documented invasive epithelial ovarian, primary\n             peritoneal, or fallopian tube cancer (tumors with pseudomyxomatous or mucinous\n             histology are excluded) or advanced predominantly epithelioid peritoneal mesothelioma.\n\n             -- Ovarian cancer must have relapsed >0 months and ? 12 months of the prior\n             platinum-based chemotherapy regimen (platinum resistant and partially platinum\n             sensitive).\n\n          -  All patients must provide the tumor tissue sample [Formalin Fixed Paraffin Embedded\n             (FFPE) slides] from archival tissue or fresh biopsy collected any time before the\n             general screening under the separate informed consent.\n\n          -  Mesothelin expression in the tumor tissue from archival or fresh biopsy samples\n             defined as the membrane intensity score of 2+ or 3+ (on the 0-3 scale) expressed on at\n             least 30% of tumor cells.\n\n             -- Mesothelin expression must be determined by the validated Investigational Use Only\n             (IUO) assay for ovarian cancer or the prototype immunohistochemistry (IHC) assay for\n             mesothelioma at Ventana at any time before the general screening in patients who had\n             signed a separate informed consent for tumor tissue analysis for mesothelin\n             expression.\n\n          -  No more than 3 prior lines of systemic cytotoxic therapy for patients with advanced\n             peritoneal or pleural mesothelioma or\n\n          -  No more than 5 prior lines of systemic cytotoxic therapy for patients with ovarian\n             cancer\n\n          -  Possible intraperitoneal administration of cytotoxics during surgery will not count as\n             systemic cytotoxic therapy in either case.\n\n          -  Measurable disease with at least one lesion that can be accurately measured in at\n             least one dimension according to Response Evaluation Criteria In Solid Tumors (RECIST)\n             1.1.\n\n        exclusion Criteria:\n\n          -  More than 3 prior lines of systemic cytotoxic therapy for patients with advanced\n             peritoneal or pleural mesothelioma\n\n          -  More than 5 prior lines of systemic cytotoxic therapy for patients with ovarian cancer\n\n          -  Other systemic anticancer therapies (molecular-targeted, immunotherapy etc.) may be\n             acceptable after the consultation between the Investigator and the Bayer Medical\n             Expert.\n\n          -  Intraperitoneal administration of cytotoxic anticancer agents during tumor surgery\n             will not count as systemic cytotoxic therapy in this context.\n\n          -  Prior local radiotherapy is allowed if it is completed at least 4 weeks prior to the\n             first dose of study drug and the subject has evaluable lesions not previously\n             irradiated.\n\n          -  Anticancer chemotherapy, experimental cancer therapy, or immunotherapy within 2 weeks\n             of start of first dose. Anticancer therapy is defined as any agent or combination of\n             agents with clinically proven anti tumor activity administered by any route with the\n             purpose of affecting the malignancy, either directly or indirectly, including\n             palliative and therapeutic endpoints.\n\n          -  Radiotherapy to the target lesions within 4 weeks prior to the first BAY94-9343\n             infusion, if the subject has evaluable tumor lesions not previously irradiated.\n\n          -  Use of strong inhibitors of P-glycoprotein (transporter) (P-gp) (e.g., ritonavir,\n             cyclosporine, verapamil, and dronedarone) is prohibited from Day -14 and for the\n             duration of the study.\n\n          -  Impaired cardiac function or clinically significant cardiac disease [i.e., congestive\n             heart failure (CHF) New York Heart Association (NYHA) Class III or IV].\n\n          -  Left ventriculat ejection fraction (LVEF) <50 % [as measured at screening by Multiple\n             Gated Acquisition scan (MUGA) or echocardiogram].\n\n          -  Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg and/or\n             diastolic blood pressure > 90 mmHg, despite optimal medical management.\n\n          -  Mild blurry vision, either age-related or due to ocular or systemic disorder (e.g.\n             diabetes, dry eyes, cataracts, uncorrected refraction abnormality) may be allowed at\n             the discretion of the ophthalmologist if deemed as no constituting a predisposition to\n             drug-induced corneal deposits and blurry vision.
INCLUSION CRITERIA:\n\n        Phase 1b\n\n          -  Histologically confirmed diagnosis of a hematologic malignancy, excluding patients\n             with acute leukemia or MDS.\n\n          -  Relapsed after standard therapy for their malignancy and considered to be an\n             appropriate candidate for a Phase 1 clinical study by their treating physician.\n\n        Phase 2\n\n          -  Multiple myeloma with measurable disease\n\n          -  Waldenström macroglobulinemia with symptomatic relapse\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.\n\n        Ethical/Other\n\n          -  Patients must sign a written informed consent form in accordance with federal, local,\n             and institutional guidelines.\n\n          -  Female patients of childbearing potential must have a negative serum or urine\n             pregnancy test and agree to use effective contraception. Male patients must use an\n             effective barrier method of contraception.\n\n        EXCLUSION CRITERIA:\n\n          -  Chemotherapy with approved or investigational anticancer therapeutics, including\n             steroid therapy intended to treat underlying malignancy, within 3 weeks prior to first\n             dose or 6 weeks for antibody therapy.\n\n          -  Radiation therapy within 3 weeks prior to first dose. Radioimmunotherapy within 8\n             weeks prior to first dose. Localized radiation therapy within 1 week prior to first\n             dose.\n\n          -  Immunotherapy within 3 weeks prior to first dose (except for antibody therapy, where 6\n             weeks is required).\n\n          -  Prior stem cell transplant (SCT) therapy (autologous SCT within the prior 8 weeks;\n             allogeneic SCT within the prior 16 weeks). Patients with prior allogeneic SCT should\n             not have evidence of moderate-to-severe graft-vs-host disease (GvHD; as defined in\n             Filipovich 2005).\n\n          -  Evidence of central nervous system (CNS) lymphoma.\n\n          -  Prior treatment with carfilzomib unless in the phase 2.\n\n          -  Major surgery within 3 weeks prior to first dose.\n\n          -  Symptomatic Congestive heart failure, ischemia, conduction abnormalities, or\n             myocardial infarction within 6 months.\n\n          -  Acute active infection requiring systemic antibiotics, antivirals, or antifungals.\n\n          -  Known or suspected human immunodeficiency virus (HIV) infection or patients who are\n             HIV seropositive.\n\n          -  Active hepatitis A, B, or C infection.\n\n          -  Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the\n             first dose.\n\n          -  Patients with pleural effusions requiring routine thoracentesis or ascites requiring\n             routine paracentesis.\n\n          -  History of previous clinically significant GI bleed in the last 6 months prior to\n             first dose.\n\n          -  Female patients who are pregnant or lactating.
Inclusion Criteria:\n\n        Phase I ONLY:\n\n          -  Advanced, metastatic solid tumor that has progressed after standard therapy, or is a\n             tumor type resistant to therapy, and for which bevacizumab is clinically appropriate.\n\n          -  Patient may have measurable disease or non-measureable disease as defined by RECIST\n             v1.1 criteria\n\n        Phase II ONLY:\n\n          -  Progressive GBM after treatment with surgical resection (if possible) and 1st line\n             radiation/chemotherapy.\n\n          -  No previous treatment with a PI3K inhibitor. Previous treatment with bevacizumab as a\n             component of first-line therapy is allowed.\n\n          -  At least one measurable or evaluable lesion definable by MRI scan. Disease must be\n             measurable by RANO criteria.\n\n          -  Archival tumor tissue available for correlative testing.\n\n        ALL PATIENTS:\n\n          -  Patient must be ? 4 weeks from administration of last dose of cancer therapy\n             (including radiation therapy, biologic therapy, hormonal therapy, or chemotherapy).\n             Patients who receive a small molecule targeted therapy as part of their first line\n             treatment regimen must be ? 4 weeks or ? 5 half lives from administration of last\n             dose, whichever is shorter. The patient must have recovered from or come to a new\n             chronic or stable baseline from all treatment-related toxicities.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.\n\n          -  Life expectancy of ? 3 months.\n\n          -  Adequate hematologic, hepatic, and renal function.\n\n        Exclusion Criteria:\n\n          -  Patients with diarrhea ? grade 2.\n\n          -  Patients with uncontrolled type I or type II diabetes mellitus, defined as a fasting\n             plasma glucose ?120 mg/dL.\n\n          -  Patients who have received prior treatment with a P13K inhibitor.\n\n          -  Treatment with therapeutic doses of coumarin-type anticoagulants (maximum daily dose\n             of 1 mg allowed for port line patency permitted).\n\n          -  Patient has active cardiac disease including any of the following:\n\n               -  Left ventricular ejection fraction (LVEF) < 50% as determined by Multiple Grated\n                  acquisition (MUGA) scan or echocardiogram (ECHO)\n\n               -  QTc > 480 msec on screening ECG (using the QTcF formula)\n\n               -  Angina pectoris that requires the use of anti-anginal medication\n\n               -  Ventricular arrhythmias except for benign premature ventricular contractions\n\n               -  Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled\n                  with medication\n\n               -  Conduction abnormality requiring a pacemaker\n\n               -  Valvular disease with documented compromise in cardiac function\n\n               -  Symptomatic pericarditis\n\n          -  Patients who are currently receiving treatment with medication with a known risk to\n             prolong the QT interval or inducing Torsades de Pointes and the treatment cannot\n             either be discontinued or switched to a different medication prior to starting study\n             drug.\n\n          -  Patients with clinical history of hemoptysis or hematemesis (defined as having bright\n             red blood of ½ teaspoon or more per episode) ?1 month prior to study enrollment.\n\n          -  Patients with any history of a bleeding diathesis or coagulopathy (in the absence of\n             therapeutic anticoagulation)\n\n          -  Patients who have received chemotherapy or targeted anticancer therapy ? 4 weeks (6\n             weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must\n             recover to a grade 1 before starting the trial.\n\n          -  Patients who have received any continuous or intermittent small molecule therapeutics\n             (excluding monoclonal antibodies) ? 5 effective half lives prior to starting study\n             drug or who have not recovered from side effects of such therapy.\n\n          -  Patients who have been treated with any hematopoietic colony-stimulating factors (e.g.\n             G-CSF, GM-CSF) ? 2 weeks prior to starting study drug. Erythropoietin or darbepoetin\n             therapy, if initiated at least 2 weeks prior to enrollment may be continued.\n\n          -  Major surgical procedure, open biopsy, intracranial biopsy, ventriculoperitoneal shunt\n             or significant traumatic injury ? 28 days prior to entry.
Inclusion Criteria: Each patient MUST:\n\n          -  Have histologically confirmed cancer of the colon or rectum with radiologically\n             documented and measurable metastases (high CEA alone is insufficient for study entry).\n\n          -  Have received an oxaliplatin-based chemotherapy regimen in the metastatic setting or\n             relapsed within 6 months of completion of adjuvant therapy containing oxaliplatin.\n\n          -  Not have received prior FOLFIRI or irinotecan in the metastatic setting.\n\n          -  Have his/her tumor assessed for KRAS status and found to be mutation positive.\n\n          -  Have NO continuing acute toxic effects (except alopecia) of any prior radiotherapy,\n             chemotherapy, or surgical procedures, i.e., all such effects must have been resolved.\n\n          -  Be at least 18 years of age.\n\n          -  Have an ECOG Performance Score of ? 2.\n\n          -  Have a life expectancy of at least 3 months.\n\n          -  Have baseline laboratory results as follows:\n\n               -  Absolute neutrophil count (ANC) ? 1.5 x 10^9 [SI unit 10^9/L]\n\n               -  Platelets ? 100 x10^9 [SI units 10^9/L] (without platelet transfusion)\n\n               -  Hemoglobin ? 9.0 g/dL [SI units gm/L] (with or without RBC transfusion)\n\n               -  Serum creatinine ? 1.5 x upper limit of normal (ULN)\n\n               -  Bilirubin ? ULN\n\n               -  AST/ALT ? 2.5 x ULN (? 5 x ULN if liver metastases)\n\n               -  Negative pregnancy test for females with childbearing potential.\n\n               -  Proteinuria < grade 2.\n\n          -  Have signed an informed consent indicating that the patient is aware of the neoplastic\n             nature of their disease and have been informed of the procedures of the protocol, the\n             experimental nature of the therapy, alternatives, potential benefits, side effects,\n             risks, and discomforts.\n\n          -  Be willing and able to comply with scheduled visits, the treatment plan, and\n             laboratory tests.\n\n          -  Be medically eligible to receive bevacizumab\n\n        Exclusion Criteria: No patient may:\n\n          -  Receive concurrent therapy with any other investigational anticancer agent while on\n             study.\n\n          -  Have previously received irinotecan or FOLFIRI in the metastatic setting (patient is\n             eligible if he/she had received irinotecan or FOLFIRI as adjuvant therapy more than 6\n             months before entry into the study)\n\n          -  Have brain metastases.\n\n          -  Be on immunosuppressive therapy or have known HIV infection or active hepatitis B or\n             C.\n\n          -  Have received >20 Gy of radiation to the pelvis.\n\n          -  Have received chemotherapy, immunotherapy, hormonal therapy or had major surgery\n             within 28 days; or received radiotherapy within 14 days; or minor surgery within 7\n             days prior to receiving the study drug.\n\n          -  Be a pregnant or breast-feeding woman. Female patients of childbearing potential must\n             agree to use effective contraception, be surgically sterile, or be postmenopausal.\n             Male patients must agree to use effective contraception or be surgically sterile.\n             Barrier methods are a recommended form of contraception.\n\n          -  Have clinically significant cardiac disease (New York Heart Association, Class III or\n             IV) including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial\n             infarction within 1 year prior to study entry, or Grade 2 or higher compromised left\n             ventricular ejection fraction.\n\n          -  Have dementia or altered mental status that would prohibit informed consent.\n\n          -  Have any other acute, or chronic medical or psychiatric condition or laboratory\n             abnormality that may increase the risk associated with study participation or study\n             drug administration or may interfere with the interpretation of study results and, in\n             the judgment of the Principal Investigator, would make the patient inappropriate for\n             this study.\n\n          -  Have uncontrolled hypertension, proteinuria, or recent major surgery (all clinical\n             parameters related to bevacizumab use). Any other clinical parameter considered\n             important should be discussed with the medical monitor.
Inclusion Criteria:\n\n        Participants will be required to meet all of the following criteria to be considered\n        eligible for the study:\n\n          -  Have a confirmed diagnosis of HCC. Biopsy is preferred but is not required.\n\n          -  Male and female participants who are ?18 years of age.\n\n          -  In the opinion of the investigator, the participants have a life expectancy of at\n             least 12 weeks.\n\n          -  Able to take food or nutritional support orally.\n\n          -  On sorafenib for at least 4 weeks prior to randomization. Dose adjustments are allowed\n             prior to randomization.\n\n          -  Have a Karnofsky Performance Score (KPS) equal to or greater than 50.\n\n          -  Have a cirrhotic status of Child-Pugh Class A or B7.\n\n          -  Have the following laboratory parameters:\n\n               -  a. Platelet count ?50 x 10E9/L.\n\n               -  b. Total bilirubin ?1.5 mg/dL (?1.0 mg/dL for primary biliary cirrhosis). If\n                  total bilirubin >1.5 mg/dL but <3.0 mg/dL, a patient could be enrolled after\n                  consultation with the Medical Monitor. If total bilirubin is >3.0 mg/dL, but the\n                  value has been constant for a period of greater than 3 months, a patient could be\n                  enrolled after consultation with the Medical Monitor.\n\n               -  c. Serum creatinine ?1.5 x upper limit of normal (ULN) or creatinine clearance\n                  >60 mL/min calculated using Cockcroft-Gault.\n\n               -  d. Serum albumin ?3.5 g/dL and/or C-reactive protein (CRP) ?3 mg/L\n\n          -  Able to provide written informed consent prior to any study specific screening\n             procedures with the understanding that the patient has the right to withdraw from the\n             study at any time, for any reason without prejudice.\n\n        Exclusion Criteria:\n\n        Participants must not have any of the following criteria to be considered eligible for\n        inclusion in the study:\n\n          -  The patient has a history of another primary cancer, with the exception of: a)\n             curatively resected non-melanomatous skin cancer; b) curatively treated cervical\n             carcinoma in-situ; or c) other primary solid tumor with no known active disease\n             present that in the opinion of the investigator will not affect patient outcome in the\n             setting of current HCC diagnosis.\n\n          -  Contraindication to sorafenib, propranolol, etodolac, or placebo.\n\n          -  Patient currently on beta-blockers for the treatment of portal hypertension or\n             arrhythmia. [Patients on beta blockers for the treatment of hypertension are allowed\n             if they change to a different drug class, e.g. some classes of angiotensin-converting\n             enzyme (ACE) inhibitors, for controlling hypertension at least one week before\n             randomization].\n\n          -  Body mass index (BMI) <17.5 kg/m2.\n\n          -  History or evidence of cardiac disease: congestive heart failure; New York Heart\n             Association class 2 or greater; active coronary artery disease; unstable angina,\n             cardiac arrhythmias requiring anti-arrhythmic therapy, atrioventricular block of\n             second or third degree, or uncontrolled hypertension. Patients with recent (less than\n             6 months) myocardial infarction (MI) or coronary revascularization.\n\n          -  Hypotension at the time of screening (i.e., systolic blood pressure <90 mmHg,\n             diastolic blood pressure <60 mmHg).\n\n          -  Resting heart rate <60 bpm at time of screening.\n\n          -  Participants with a recent diagnosis of bleeding varices that has not been resolved\n             for a minimum period of 4 weeks.\n\n          -  Any uncontrolled intercurrent illness that, in the opinion of the Investigator, may\n             interfere with study evaluation.\n\n          -  On chronotropic drugs (acetylcholine, digoxin, diltiazem, verapamil, atropine,\n             dopamine, dobutamine, epinephrine, isoproterenol).\n\n          -  Active clinically serious infections [>Grade 2 National Cancer Institute (NCI)-Common\n             Terminology Criteria for Adverse Events (CTCAE) version 4.0].\n\n          -  Known history of human immunodeficiency virus (HIV) infection.\n\n          -  Known central nervous system tumors including metastatic brain disease.\n\n          -  Clinically significant gastrointestinal (GI) bleeding within 30 days prior to\n             Screening.\n\n          -  Substance abuse, medical, psychological or social conditions that may, in the in the\n             opinion of the investigator, interfere with the patient's participation in the study\n             or evaluation of the study results.\n\n          -  Known or suspected allergy to the investigational agents or any agent given in\n             association with this trial (hypersensitivity reaction, hives, rash, difficulty\n             breathing swelling of face, lips, tongue, or throat).\n\n          -  Inability to swallow oral medications.\n\n          -  Any condition that is unstable or which in the opinion of the Investigator could\n             jeopardize the safety of the patient and his/her compliance in the study.\n\n          -  Pregnant or breastfeeding participants. Women of childbearing potential\n             (non-childbearing potential is defined as menopausal for at least 2 years,\n             post-bilateral tubal ligation for at least 1 year, post-bilateral oophorectomy or\n             post-hysterectomy) must have a negative urine pregnancy test performed within 10 days\n             prior to the start of study drug. Both men and women enrolled in this trial must use\n             adequate double-barrier birth control measures [2 types of an acceptable form of\n             FDA-approved contraception (e.g., barrier method, Depo-Provera™, Norplant™, Ortho\n             Evra® [birth control patch], oral contraceptives)] during the course of the trial.\n\n          -  Participation in any other investigational trial in which receipt of investigational\n             drug or device occurred within 30 days prior to screening for this study.
Inclusion Criteria\n\n        Subjects eligible for enrollment in the study must meet all of the following criteria:\n\n          1. Signed written informed consent. In Korea and Japan, subjects who are between >=18 and\n             <20 years of age must also have a legal representative sign the written informed\n             consent.\n\n          2. Post-menopausal female subjects >=18 years of age. Post-menopausal as defined by any\n             of the following:\n\n               -  Subjects at least 60 years of age.\n\n               -  Subjects under 60 years of age and amenorrhic for at least 12 consecutive months\n                  AND follicle-stimulating hormone (FSH) and estradiol levels in postmenopausal\n                  range (utilizing ranges from the local laboratory facility).\n\n               -  Prior bilateral oophorectomy.\n\n               -  Prior radiation castration with amenorrhea for at least 6 months\n\n          3. Subjects must have a history of histologically confirmed breast cancer, with a\n             clinically confirmed diagnosis of metastatic disease [confirmed by histology, cytology\n             or other clinical means (e.g. CT, MRI)]. Subjects may have either measurable or\n             non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)\n\n          4. Tumors that are ER+ and/or PgR+ by local laboratory\n\n          5. Documentation of HER2 overexpression or gene amplification, in the invasive component\n             of either the primary tumor or metastatic disease site as defined as:\n\n               -  3+ by Immunohistochemistry (IHC) and/or\n\n               -  HER2/neu gene amplification by fluorescence, chromogenic or silver in situ\n                  hybridization [FISH, CISH or SISH; >6 HER2/neu gene copies per nucleus or a FISH,\n                  CISH or SISH test ratio (HER2 gene copies to chromosome 17 signals) of ?2.0]\n\n          6. Subject must have received at least one prior regimen containing trastuzumab in\n             combination with chemotherapy for breast cancer:.\n\n               -  Subject has ONLY received prior trastuzumab in combination with chemotherapy as\n                  neoadjuvant and/or adjuvant treatment. OR\n\n               -  Subject has received ONE prior trastuzumab-containing regimen for metastatic\n                  disease (and has progressed), and may or may not have received prior trastuzumab\n                  in combination with chemotherapy as neoadjuvant and/or adjuvant treatment.\n\n          7. Subject must have received prior endocrine therapy (such as aromatase inhibitors or\n             selective estrogen receptor modulators). 8. Subjects who have a life expectancy of > 6\n             months as assessed by the treating investigator\n\n        9. Subjects must have baseline Left Ventricular Ejection Fraction (LVEF) ?50% measured by\n        echocardiography (ECHO) or multi-gated acquisition scan (MUGA) 10. Subject must have an\n        ECOG performance status of 0-1 11. All prior treatment related toxicities must be CTCAE\n        (Version 4.0) ? Grade 1 at the time of randomization 12. Completion of screening\n        assessments 13. Adequate baseline organ function. 14. Subjects must meet all of the\n        following criteria:\n\n          -  QTc <450msec or\n\n          -  QTc <480msec for subjects with bundle branch block The QTc is the QT interval\n             corrected for heart rate according to either Bazett's formula (QTcB) or to\n             Fridericia's formula (QTcF), machine or manual over read, for males and females. The\n             specific formula that will be used in a protocol should be determined prior to\n             initiation of the study, and the formula used to determine inclusion and\n             discontinuation should be the same throughout the study. The QTc should be based on\n             single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a\n             brief recording period\n\n        Exclusion criteria:\n\n          1. History of another malignancy. Exception: Subjects who have been disease-free for 5\n             years, or subjects with a history of completely resected non-melanoma skin cancer or\n             successfully treated in situ carcinoma are eligible.\n\n          2. Subjects with extensive symptomatic visceral disease including hepatic involvement and\n             pulmonary lymphangitic spread of tumor, or the disease is considered by the\n             investigator to be rapidly progressing or life threatening (subjects who are intended\n             for chemotherapy)\n\n          3. Serious cardiac illness or medical condition including but not confined to:\n\n               -  Uncontrolled arrhythmias\n\n               -  Uncontrolled or symptomatic angina\n\n               -  History of congestive heart failure (CHF)\n\n               -  Documented myocardial infarction <6 months from study entry\n\n          4. Known history of, or clinical evidence of, central nervous system (CNS) metastases or\n             leptomeningeal carcinomatosis\n\n          5. Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease\n             (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones,\n             liver metastases or stable chronic liver disease per investigator assessment)\n\n          6. Have a concurrent disease or condition that may interfere with study participation, or\n             any serious medical disorder that would interfere with the subject's safety (for\n             example, active or uncontrolled infection or any psychiatric condition prohibiting\n             understanding or rendering of informed consent)\n\n          7. Have any clinically significant gastrointestinal abnormalities that may alter\n             absorption such as malabsorption syndrome or major resection of the stomach or bowels\n\n          8. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs\n             chemically related to any of the study agents or their excipients that, in the opinion\n             of the Investigator or GSK medical monitor, contraindicates their participation\n\n          9. Any prohibited medication.\n\n         10. Administration of an investigational drug within 30 days or 5 half-lives, whichever is\n             longer, preceding the first dose of study treatment.
Inclusion Criteria:\n\n          1. Patients or their legal representatives must be able to provide written informed\n             consent.\n\n          2. Histologically confirmed diagnosis of supratentorial GBM (Grade 4 astrocytoma).\n\n          3. Radiographic evidence of first recurrence or progression of GBM following primary\n             therapy consisting of surgery (biopsy or resection) and chemoradiation; patients may\n             have undergone a second debulking surgery following initial recurrence or progression.\n             Patients whose tumors are O6 methyl guanyl-methyl-transferase (MGMT)\n             methylated-promoter negative need not have received chemotherapy in the past to be\n             eligible.\n\n          4. Human leukocyte antigen type HLA-A*02:01, HLA-A*02:06, or HLA-A*24:02.\n\n          5. Age ?18.\n\n          6. KPS score of ?60.\n\n          7. Serum creatinine value <2X the upper limit of normal (ULN) for the reference\n             laboratory.\n\n          8. Alanine aminotransferase/aspartate aminotransferase <3X the ULN and total bilirubin\n             <2× the ULN for the reference laboratory.\n\n          9. Patients must have recovered from the effect of all prior therapy to Grade 2 or less.\n\n         10. Patients must be at least 28 days from any major surgery, and any surgery incisions or\n             wounds must be completely healed.\n\n         11. Patients must be at least 12 weeks from the completion of prior radiation therapy (RT)\n             in order to discriminate pseudo progression of disease from progression.\n\n         12. Patients must be at least 4 weeks from the completion of prior systemic or\n             intracranial chemotherapy.\n\n         13. For patients who are not receiving therapeutic anticoagulation treatment, an\n             international normalized ratio (INR) and a PTT ? 1.5 × the ULN; patients who are\n             receiving anticoagulation treatment should be on a stable dose.\n\n        Exclusion Criteria:\n\n        Patients with any of the following will be excluded from the study:\n\n          1. Prior therapy with Bev.\n\n          2. Any anti-neoplastic therapy, including RT, for first relapse or recurrence.\n\n          3. Evidence of leptomeningeal spread of tumor or any history, presence, or suspicion of\n             metastatic disease extracranially.\n\n          4. Evidence of impending herniation on imaging.\n\n          5. Patients with infections that have required treatment with systemic antibiotics within\n             7 days of first dose of protocol therapy.\n\n          6. The need for systemic glucocorticoids in doses in excess of 4 mg/day of dexamethasone\n             or in comparable doses with other glucocorticoids.\n\n          7. Treatment with any investigational agents within 5 half-lives of the agent in question\n             or, if the half life is unknown, within 28 days of enrollment.\n\n          8. Pregnant or lactating females.\n\n          9. Prior history of malignancy within 3 years of enrollment other than basal or squamous\n             cell carcinoma of the skin, cervical intra-epithelial neoplasia, in situ carcinoma of\n             the breast, or prostate cancer treated with surgery or RT with a prostate specific\n             antigen of <0.01 ng/mL.\n\n         10. Patients with active autoimmune diseases within 2 years of enrollment into the study\n             including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus,\n             systemic sclerosis, Sjogren's syndrome, Wegener's granulomatosis, ulcerative colitis,\n             Crohn's disease, myasthenia gravis, Graves' disease, or uveitis except for psoriasis\n             not requiring systemic therapy, vitiligo or alopecia areata, or hypothyroidism; if an\n             autoimmune condition has been clinically silent for 12 months or greater, the patient\n             may be eligible for enrollment.\n\n         11. Patients on immunosuppressive therapies; the use of topical, inhalational,\n             ophthalmologic or intra articular glucocorticoids, or the use of physiologic\n             replacement doses of glucocorticoids are permitted.\n\n         12. Patients with primary immunodeficiency diseases.\n\n         13. Patients with significant bleeding in the preceding 6 months or with known\n             coagulopathies.\n\n         14. History of abdominal fistula, intestinal perforation, or intra-abdominal abscess in\n             the preceding 12 months.\n\n         15. Known history of human immunodeficiency virus (HIV) infection, active hepatitis B, or\n             untreated hepatitis C; patients who have completed a course of anti-viral treatment\n             for hepatitis C are eligible.\n\n         16. Significant cardiovascular disease, including New York Hospital Association Class III\n             or IV congestive heart failure, myocardial infarction within 6 months of enrollment,\n             unstable angina, poorly controlled cardiac arrhythmias, or stroke within the preceding\n             6 months.\n\n         17. Any other uncontrolled inter current medical condition, including systemic fungal,\n             bacterial, or viral infection; uncontrolled hypertension; diabetes mellitus; or\n             chronic obstructive pulmonary disease requiring 2 or more hospitalizations in the\n             preceding 12 months.\n\n         18. Known sensitivity to Bev or any of the components of DSP-7888 Dosing Emulsion.
Inclusion Eligibility Criteria\n\n        Age Patients must be ? 1 and ? 21 years of age at the time of enrollment.\n\n        Diagnosis Patients must have a diagnosis of acute lymphoblastic leukemia (ALL) with ? 5%\n        blasts in the bone marrow (M2 or M3), with or without extramedullary disease (excluding\n        active Central Nervous System 3 involvement).\n\n        Subjects with first relapse must have an M3 marrow to be eligible.\n\n        Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for\n        patients ? 16 years of age.\n\n        Prior Therapy\n\n          1. Patients must have recovered from the acute toxic effects (? Grade 2 or baseline) of\n             all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study,\n             unless otherwise specified. Subjects with disease related cytopenias will be eligible.\n\n          2. Patients must have relapsed disease after attaining at least a first remission. They\n             may be in first to third relapse.\n\n          3. Patients with Philadelphia chromosome t(9;22) positive disease must have received at\n             least two prior tyrosine kinase inhibitors.\n\n          4. Patients who have experienced their relapse after a Hematopoietic stem cell\n             transplantation (HSCT) are eligible, provided they have no evidence of\n             graft-versus-host disease (GVHD) and are at least 100 days post-transplant at the time\n             of enrollment.\n\n          5. Prior anthracycline lifetime cumulative exposure: Patients must have less than 320\n             mg/m2 (or 400 mg/m2 if prior cardioprotection) lifetime exposure of anthracycline\n             chemotherapy.\n\n          6. Hematopoietic growth factors: It must have been at least seven days since the\n             completion of therapy with granulocyte colony-stimulating factor (GCSF) or other\n             growth factors at the time of enrollment. It must have been at least 14 days since the\n             completion of therapy with pegfilgrastim (Neulasta®).\n\n          7. Biologic anti-neoplastic agents: At least seven days after the last dose of a biologic\n             agent. For agents that have known adverse events occurring beyond seven days after\n             administration, this period must be extended beyond the time during which adverse\n             events are known to occur. The duration of this interval must be discussed with the\n             study chair or vice chair.\n\n          8. Monoclonal antibodies: At least three half-lives (or 30 days—whichever is longer) of\n             the antibody must have elapsed after the last dose of monoclonal antibody. (e.g.,\n             Rituximab = 66 days, Epratuzumab = 69 days)\n\n          9. Immunotherapy: At least 30 days after the completion of any type of immunotherapy,\n             e.g. tumor vaccines, chimeric antigen receptor T-cells.\n\n         10. Recent prior chemotherapy: At least 14 days after standard vincristine and the\n             completion of any type of chemotherapy induction regimen. At least 3 weeks after\n             radiation therapy. At least 30 days after the completion of any investigational\n             neoplastic agent is also required. An investigational agent is defined as any drug\n             that is not approved and licensed for sale by the FDA for institutions in the United\n             States, by Health Canada for institutions in Canada and by The Therapeutic Goods\n             Administration for institutions in Australia.\n\n        Exceptions:\n\n          1. There is no time restriction in regard to prior intrathecal chemotherapy provided\n             there is complete recovery from any acute toxic effects of such; it is allowable to\n             enroll a patient that has received IT Cytarabine (ARA-C), IT Methotrexate (MTX) or\n             triple IT therapy within 14 days of enrollment as part of their evaluation to diagnose\n             disease relapse. The IT therapy given within 14 days of initiation of protocol\n             specified chemotherapy, will substitute for the day 1 IT.\n\n          2. Subjects with rapidly progressive disease may receive hydroxyurea until they begin\n             study therapy;\n\n          3. Patients who relapse while on maintenance-type ALL therapy or are receiving\n             maintenance therapy for disease stabilization will not require a wash-out period\n             before entry into this study. However, there must be at least 14 days after any dose\n             of standard vincristine.\n\n        Renal and Hepatic Function\n\n          1. Renal function: Patient's serum creatinine must be ? 1.5 x institutional upper limit\n             of normal (ULN) according to age. If the serum creatinine is greater than 1.5 times\n             normal, the patient must have a calculated creatinine clearance or radioisotope\n             glomerular filtration rate (GFR) ? 70milliliter/min/1.73m2. Alternatively, a 24-hour\n             creatinine clearance may also be used.\n\n          2. Hepatic function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST)\n             must be < 3 x institutional upper limit of norm ULN. Total bilirubin must be ? 1.5 x\n             ULN (except in the case of subjects with documented Gilbert's disease ? 5 × ULN).\n\n        Cardiac Function Patients must have a shortening fraction ? 27% or an ejection fraction ?\n        55% by echocardiogram, cardiac MRI or multigated acquisition scan (MUGA).\n\n        Reproductive Function\n\n          1. Female patients must not be pregnant and those of childbearing potential must have a\n             negative urine or serum pregnancy test confirmed within one week prior to enrollment.\n\n          2. Female patients with infants must agree not to breastfeed their infants while on this\n             study.\n\n          3. Male and female patients of childbearing potential must agree to use an effective\n             method of contraception during the study.\n\n        Exclusion Eligibility Criteria\n\n        Patients will be excluded if they have active Central Nervous System (CNS) 3 status.\n\n        Patients will be excluded if they have isolated testicular disease.\n\n        Patients with biphenotypic leukemia will be excluded.\n\n        Patients will be excluded if they have refractory disease or fourth relapse and beyond,\n        defined as any of the following:\n\n          1. Patients with four or more prior induction attempts,\n\n          2. Refractory disease after first or greater relapse and a re-induction attempt,\n\n          3. Failing to go into remission from original diagnosis after two previous induction\n             attempts.\n\n        Patients will be excluded if they have previously received Marqibo®.\n\n        Patients will be excluded if they have a known allergy to any of the drugs used in the\n        study, with the exception that patients with an allergy to PEG-asparaginase who can receive\n        Erwinia are eligible.\n\n        Patients will be excluded if they have active, uncontrolled systemic fungal, bacterial,\n        viral or other infection despite appropriate antibiotics or other treatment.\n\n        Patients who require azole antifungal agents will be excluded. Azoles must be discontinued\n        at least one week prior to the start of Marqibo®.\n\n        Patients will be excluded if there is a plan to administer non-protocol chemotherapy,\n        radiation therapy, another investigational agent or immunotherapy during the study period.\n\n        Patients with pre-existing, persistent grade 2 or greater sensory or motor neuropathy from\n        any cause will be excluded.\n\n        Patients will be excluded if they have Down syndrome, significant concurrent disease,\n        illness, psychiatric disorder or social issue that would compromise patient safety or\n        adherence with the protocol treatment or procedures or interfere with consent, study\n        participation, follow up, or interpretation of study results.\n\n        Patients positive for human immunodeficiency virus (HIV) will be excluded due to the\n        increased risk of complications such as severe infection and unknown interaction of\n        Marqibo® with antiretroviral drugs.\n\n        Active hepatitis B or C infection as defined by seropositive for hepatitis B (hepatitis B\n        surface antigen (HBsAg)) or hepatitis C and elevated liver transaminases (defined as above\n        the ULN per the institution normal ranges).
Inclusion Criteria (Treatment Arm A)\n\n          1. Patients must have histologically-confirmed solid tumors that are advanced or\n             metastatic, and refractory after standard therapy, or for which there is no standard\n             therapy.\n\n          2. Patients must have measurable disease as defined by RECIST version 1.1.\n\n          3. Patients must have received prior anticancer therapy or not be eligible for any\n             established conventional therapy whether surgical or pharmacologic.\n\n          4. Patients must have recovered from all acute adverse effects (excluding alopecia) of\n             prior therapies to baseline or <=grade 1 prior to study entry.\n\n          5. Patients must have a performance status of 0, 1, or 2.\n\n          6. Patients must be men and women >=18 years of age.\n\n          7. Patients must have adequate bone marrow function, defined as an absolute neutrophil\n             count >=1.5 x 10^9/L and a platelet count >= 100 x 10^9/L.\n\n          8. Patients must have adequate renal function, defined as serum creatinine <= 1.2 mg/dL\n             (if > 1.2 mg/dL, a calculated creatinine clearance [by the Cockcroft-Gault method]\n             must be >=60 mL/min/1.73 m^2).\n\n          9. Patients must have adequate hepatic function, defined as plasma total bilirubin <=1.5\n             mg, alanine transaminase (ALT) and aspartate transaminase (AST) <=2.5 X ULN. Patients\n             with Gilbert's disease outside these limits are judged to be ineligible.\n\n         10. Female patients of childbearing potential must have a negative serum or urine\n             pregnancy test result at time of pre-treatment screening.\n\n         11. Patients with reproductive potential must agree to use at least one form of barrier\n             contraception prior to study entry and for up to 30 days beyond the last\n             administration of study drug.\n\n         12. Patients must be judged to be capable by the Investigator of providing informed\n             consent and must be willing to provide written informed consent prior to the start of\n             any study specific procedures.\n\n         13. Patients should have a life expectancy of at least 12 weeks.\n\n        Exclusion Criteria (Treatment Arm A)\n\n          1. Patients may not have had prior chemotherapy, hormonal therapy, radiation therapy, or\n             biologic therapy in the 4 weeks prior to study entry with the exception of mitomycin C\n             or nitrosoureas, for which patients must be 6 weeks from prior treatment. For patients\n             who have been treated with targeted therapy, 5 half-lives of that therapy (or 28 days,\n             whichever is shorter) must have passed prior to enrollment in the study.\n\n          2. Patients may not have any concomitant condition that could compromise the objectives\n             of this study and the patients' compliance and ability to tolerate this therapy and\n             complete at least 2 cycles of therapy, including, but not limited to the following:\n\n               -  Congestive heart failure or uncontrolled angina pectoris, previous history of\n                  myocardial infarction within 1 year from study entry, uncontrolled hypertension,\n                  or dysrhythmias.\n\n               -  Active infection.\n\n               -  Unstable diabetes mellitus\n\n               -  Psychiatric disorder that may interfere with consent and/or protocol compliance.\n\n          3. Pregnant or breastfeeding women.\n\n          4. Patients with another malignancy in the past 3 years except: curatively treated\n             non-melanoma skin cancer; or carcinoma in situ, of either cervix or breast, that does\n             not require further treatment.\n\n          5. Patients with known HIV, HBV, or HCV infection.\n\n          6. Patients with an underlying diagnosis or disease state associated with an increased\n             risk of bleeding.\n\n          7. Patients with central nervous system metastases. Baseline CT or MRI scan of brain is\n             required only in the case of clinical suspicion of central nervous system metastases.\n             Patients with evidence of brain involvement, leptomeningeal disease, or seizure\n             disorder are also excluded.\n\n          8. Patients may not be treated with known CYP3A4 inhibitors or inducers.\n\n        Inclusion and Exclusion Criteria for Combination CTO Plus Temodar® (Treatment Arm B):\n        Inclusion Criteria (Treatment Arm B)\n\n        In addition to the inclusion criteria for adequate organ function as defined for the\n        patients with advanced or metastatic solid tumors, patients enrolled in Arm B (Combination\n        Therapy CTO Plus Temodar-R) must meet the following inclusion criteria:\n\n          1. Patients must have histologically proven malignant glioblastoma or other recurrent\n             malignant gliomas.\n\n          2. Measurable tumor must be present on gadolinium-enhanced MRI.\n\n          3. Patients must have a life expectancy of at least 8 weeks.\n\n          4. Patients must have a Performance Status of 0, 1, or 2 (ECOG scale).\n\n          5. Patients must be men and women >=18 years of age.\n\n          6. Patients must have recovered from all acute adverse effects (excluding alopecia) of\n             prior therapies to baseline or <=grade 1 prior to study entry.\n\n          7. Patients must have shown unequivocal radiographic evidence for tumor progression by\n             MRI scan to be performed within 14 days prior to registration and must be on a steroid\n             dose that has been stable for at least 5 days. If the steroid dose is increased\n             between the date of imaging and registration, a new baseline MRI scan is required.\n\n          8. Patients who have undergone recent resection for recurrent or progressive malignant\n             tumor will be eligible as long as all of the following conditions apply:\n\n               1. They have recovered from the effects of surgery\n\n               2. The extent of residual disease is assessed post-operatively, with an MRI scan\n                  done no later than 96 hours in the immediate post-operative period or at least 4\n                  weeks post-operatively, within 14 days prior to registration. If the 96-hour scan\n                  is more than 14 days before registration, the scan needs to be repeated.\n\n          9. Patients must have had prior radiation therapy with or without chemotherapy and must\n             have progressed following radiation therapy and must have an interval of >=12 weeks\n             from the completion of radiation therapy to registration date to minimize the\n             possibility of pseudo-progression.\n\n         10. Patients under treatment with anti-epileptic drugs which are not known CYP3A4\n             inhibitors or inducers must have been receiving a stable dose for at least 2 weeks\n             with no evidence of seizures at the time of registration.\n\n        Exclusion Criteria (Treatment Arm B)\n\n          1. Patients may not have had prior chemotherapy, hormonal therapy, or biologic therapy in\n             the 4 weeks prior to study entry with the exception of mitomycin C or nitrosoureas,\n             for which patients must be 6 weeks from prior treatment. For patients who have been\n             treated with targeted therapy, 5 half-lives of that therapy (or 28 days, whichever is\n             shorter) must have passed prior to enrollment in the study. Additional exceptions: The\n             following specific drugs are permitted shorter recovery times: 14 days for\n             vincristine, 21 days for procarbazine, and 7 days for non-cytotoxic agents such as\n             interferon, tamoxifen, thalidomide, and cis-retinoic acid.\n\n          2. Patients may not have any concomitant condition that could compromise the objectives\n             of this study and the patients' compliance and ability to tolerate this therapy and\n             complete at least 2 cycles of therapy, including, but not limited to the following:\n\n               -  Congestive heart failure or uncontrolled angina pectoris, previous history of\n                  myocardial infarction within 1 year from study entry, uncontrolled hypertension,\n                  or dysrhythmias.\n\n               -  Active infection.\n\n               -  Unstable diabetes mellitus.\n\n               -  Psychiatric disorder that may interfere with consent and/or protocol compliance.\n\n          3. Pregnant or breastfeeding women.\n\n          4. Patients with another malignancy in the past 3 years except: curatively treated\n             non-melanoma skin cancer; or carcinoma in situ, of either cervix or breast, that does\n             not require further treatment.\n\n          5. Patients with known HIV, HBV, or HCV infection.\n\n          6. Patients with an underlying diagnosis or disease state associated with an increased\n             risk of bleeding.\n\n          7. Uncontrolled seizure activity.\n\n          8. Patients may not be treated with known CYP3A4 inhibitors or inducers.\n\n        Inclusion and Exclusion Criteria for Combination CTO and Temodar® in combination with\n        radiation therapy (Treatment Arm C):\n\n        Inclusion Criteria (Treatment Arm C)\n\n        In addition to the inclusion criteria for adequate organ function as defined for the\n        patients with advanced or metastatic solid tumors, patients enrolled in Arm C (Combination\n        Therapy CTO and Temodar® in combination with radiation therapy) must meet the following\n        inclusion criteria:\n\n          1. Patients must have histologically proven newly diagnosed glioblastoma or other\n             malignant gliomas. Note: Patients with anaplastic oligodendroglioma with 1p/19q\n             deletion or unknown 1p/19q status are not eligible\n\n          2. Patients must have a life expectancy of at least 8 weeks\n\n          3. Patients must have a Performance Status of 0, 1, or 2 (ECOG scale).\n\n          4. Patients must be men and women >=18 years of age.\n\n          5. Patients must have undergone an MRI scan performed within 14 days prior to\n             registration and must be on a steroid dose that has been stable for at least 5 days.\n             If the steroid dose is increased between the date of imaging and registration, a new\n             baseline MRI is required.\n\n          6. Patients under treatment with anti-epileptic drugs which are not known CYP3A4\n             inhibitors or inducers must have been receiving a stable dose for at least 2 weeks\n             with no evidence of seizures at the time of registration.\n\n        Exclusion Criteria (Treatment Arm C)\n\n          1. Patients may not have had any prior chemotherapy, hormonal therapy, or biologic\n             therapy for gliomas.\n\n          2. Patients may not have any concomitant condition that could compromise the objectives\n             of this study and the patients' compliance and ability to tolerate this therapy and\n             complete at least 2 cycles of therapy, including, but not limited to the following:\n\n               -  Congestive heart failure or uncontrolled angina pectoris, previous history of\n                  myocardial infarction within 1 year from study entry, uncontrolled hypertension,\n                  or dysrhythmias.\n\n               -  Active infection.\n\n               -  Unstable diabetes mellitus.\n\n               -  Psychiatric disorder that may interfere with consent and/or protocol compliance.\n\n          3. Pregnant or breastfeeding women.\n\n          4. Patients with another malignancy in the past 3 years except: curatively treated\n             non-melanoma skin cancer; or carcinoma in situ, of either cervix or breast, that does\n             not require further treatment.\n\n          5. Patients with known HIV, HBV, or HCV infection.\n\n          6. Patients with an underlying diagnosis or disease state associated with an increased\n             risk of bleeding.\n\n          7. Uncontrolled seizure activity.\n\n          8. Patients may not be treated with known CYP3A4 inhibitors or inducers.\n\n          9. Patients with anaplastic oligodendroglioma with 1p/19q deletion or unknown 1p/19q\n             status are excluded.
INCLUSION CRITERIA\n\n        PART 1:\n\n          -  confirmed pathologic diagnosis of a solid tumor not curable with available therapies\n             for which neratinib plus capecitabine is a reasonable treatment option.\n\n        PART 2:\n\n          -  confirmed histologically and/or cytologically confirmed diagnosis of breast cancer,\n             metastatic or locally advanced.\n\n          -  erbB-2 gene amplified tumor (FISH or CISH) or erbB-2 overexpression (IHC 3+, or IHC2+\n             with FISH or CISH confirmation), based on local testing, or based on centralized FISH\n             testing prior to day 1.\n\n          -  disease progression on or following at least 1 prior trastuzumab containing treatment\n             regimen (at least 6 weeks) for metastatic or locally advanced disease. (Prior adjuvant\n             trastuzumab is allowed but not required). A 2 week period is required between the last\n             dose of trastuzumab treatment and first dose of the test article.\n\n          -  Prior treatment with a taxane in the neoadjuvant, adjuvant, locally advanced, and/or\n             metastatic disease treatment setting.\n\n        PARTS 1 and 2:\n\n          -  At least 1 measurable lesion as defined by RECIST criteria.\n\n          -  LVEF within institutional range of normal as measured by multi-gated acquisition\n             (MUGA) or echocardiogram (ECHO).\n\n        EXCLUSION CRITERIA\n\n        PART 2:\n\n          -  prior treatment with capecitabine, lapatinib (20 subjects with prior lapatinib\n             exposure will be enrolled) or any erbB-2 targeted agents except trastuzumab. Treatment\n             with erbB-2 targeted therapy must exceed 2 weeks (14 days) in order to be\n             exclusionary.\n\n          -  prior treatment with anthracyclines with a cumulative dose of doxorubicin of greater\n             than 400 mg/m², epirubicin dose of greater than 800 mg/m², or the equivalent dose for\n             other anthracyclines.\n\n        PARTS 1 and 2:\n\n          -  Subjects with bone as the only site of disease.\n\n          -  Active uncontrolled or symptomatic central nervous system (CNS) metastases, as\n             indicated by clinical symptoms, cerebral edema, and/or progressive growth. Subjects\n             with a history of CNS metastases or cord compression are allowable if they have been\n             considered definitively treated and are off anticonvulsants and steroids for at least\n             4 weeks before the first dose of test article.\n\n          -  Any other cancer within 5 years prior to screening with the exception of adequately\n             treated cervical carcinoma in situ, or adequately treated basal or squamous cell\n             carcinoma of the skin.
Inclusion Criteria:\n\n        Patients must fulfill all of the following criteria to be eligible for study participation\n        and have:\n\n          -  Histologically confirmed PTCL not otherwise specified, angioimmunoblastic T-cell\n             lymphoma, extranodal natural killer (NK)/T-cell lymphoma nasal type, enteropathy- type\n             T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous ?? T-cell\n             lymphoma (excludes mycosis fungoides or Sezary syndrome), transformed mycosis\n             fungoides, hepatosplenic T-cell lymphoma, anaplastic large cell lymphoma (ALCL;\n             anaplastic lymphoma kinase [ALK]-1 negative), or patients with ALK 1 expressing ALCL\n             (ALK-1 positive) who have relapsed disease after autologous stem cell transplant\n             (ASCT);\n\n          -  Age ?18 years;\n\n          -  Written informed consent;\n\n          -  Progressive disease following at least one systemic therapy or refractory to at least\n             one prior systemic therapy;\n\n          -  Measurable disease according to the International Workshop Response (IWC) criteria\n             and/or measurable cutaneous disease;\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2;\n\n          -  Serum potassium ?3.8 mmol/L and magnesium ?0.85 mmol/L (electrolyte abnormalities can\n             be corrected with supplementation to meet inclusion criteria);\n\n          -  Negative urine or serum pregnancy test on females of childbearing potential; and\n\n          -  All women of childbearing potential must use an effective barrier method of\n             contraception (either an intrauterine contraceptive device [IUCD] or double barrier\n             method using condoms or a diaphragm plus spermicide) during the treatment period and\n             for at least 1 month thereafter. Male patients should use a barrier method of\n             contraception during the treatment period and for at least 1 month thereafter.\n             Hormonal methods of contraception such as the contraceptive pill or patch\n             (particularly those containing ethinyl-estradiol) should be avoided due to a potential\n             drug interaction.\n\n        Exclusion Criteria:\n\n        Patients are ineligible for entry if any of the following criteria are met:\n\n          -  Known central nervous system (CNS) lymphoma [computed tomography (CT) or magnetic\n             resonance imaging (MRI) scans are required only if brain metastasis is suspected\n             clinically];\n\n          -  Chemotherapy or immunotherapy within 4 weeks of study entry (6 weeks if nitrosoureas\n             given);\n\n          -  Initiation of corticosteroids during study (defined as 7 days prior to Cycle 1 Day\n             1[C1D1] until study drug discontinuation)\n\n               -  Patients treated with a pulse of steroids were to discontinue steroid use 7 days\n                  prior to C1D1 and have a repeat CT scan and disease assessment after\n                  discontinuation of corticosteroids and before starting romidepsin;\n\n          -  Concomitant use of any other anti-cancer therapy;\n\n          -  Concomitant use of any investigational agent;\n\n          -  Use of any investigational agent within 4 weeks of study entry;\n\n          -  Any known cardiac abnormalities such as:\n\n               -  Congenital long QT syndrome;\n\n               -  QTc interval >480 milliseconds (msec);\n\n               -  A myocardial infarction within 6 months of C1D1. Patients with a history of\n                  myocardial infraction between 6 and 12 months prior to C1D1 who are asymptomatic\n                  and have had a negative cardiac risk assessment (treadmill stress test, nuclear\n                  medicine stress test, or stress echocardiogram) since the event may participate;\n\n               -  Other significant electrocardiogram (ECG) abnormalities including 2nd degree\n                  atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia\n                  (ventricular rate less than 50 beats/min).\n\n               -  Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV. In\n                  any patient in whom there is doubt, the patient should be referred to a\n                  cardiologist for evaluation;\n\n               -  An ECG recorded at screening showing significant ST depression (ST depression of\n                  ?2 mm, measured from isoelectric line to the ST segment at a point 60 msec at the\n                  end of the QRS complex). If in any doubt, the patient should have a stress\n                  imaging study and, if abnormal, angiography to define whether or not CAD is\n                  present;\n\n               -  Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class\n                  II to IV definitions and/or ejection fraction <40% by MUGA scan or <50% by\n                  echocardiogram and/or MRI;\n\n               -  A known history of sustained ventricular tachycardia (VT), ventricular\n                  fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently\n                  addressed with an automatic implantable cardioverter defibrillator (AICD);\n\n               -  Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or\n                  other causes (if in doubt, see ejection fraction criteria above);\n\n               -  Uncontrolled hypertension, i.e., blood pressure (BP) of ?160/95; patients who\n                  have a history of hypertension controlled by medication must be on a stable dose\n                  (for at least one month) and meet all other inclusion criteria;\n\n               -  Any cardiac arrhythmia requiring anti-arrhythmic medication;\n\n          -  Serum potassium <3.8 mmol/L or serum magnesium <0.85 mmol/L (electrolyte abnormalities\n             can be corrected with supplementation to meet inclusion criteria);\n\n          -  Concomitant use of drugs that may cause a significant prolongation of the QTc;\n\n          -  Concomitant use of CYP3A4 significant or moderate inhibitors;\n\n          -  Concomitant use of therapeutic warfarin or another anticoagulant due to a potential\n             drug interaction. Use of a small dose of a anticoagulant to maintain patency of venous\n             access port and cannulas is permitted;\n\n          -  Clinically significant active infection;\n\n          -  Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C;\n\n          -  Previous extensive radiotherapy involving ?30% of bone marrow (e.g., whole pelvis,\n             half spine), excluding patients who have had total body irradiation as part of a\n             conditioning regimen for ASCT;\n\n          -  Major surgery within 2 weeks of study entry;\n\n          -  Previous allogeneic stem cell transplant;\n\n          -  Inadequate bone marrow or other organ function as evidenced by:\n\n               -  Hemoglobin <9 g/dL (transfusions and/or erythropoietin are permitted);\n\n               -  Absolute neutrophil count (ANC) ?1.0 × 10^9 cells/L [patients with neutropenia\n                  (ANC 1-1.5 10^9 cells/L) as a function of their disease may be supported with\n                  granulocyte-colony stimulating factor (G-CSF)];\n\n               -  Platelet count <100 × 10^9 cells/L or platelet count <75 × 10^9 cells/L if bone\n                  marrow disease involvement is documented;\n\n               -  Total bilirubin >2.0 × upper limit of normal (ULN) or >3.0 × ULN in the presence\n                  of demonstrable liver metastases;\n\n               -  Aspartate transaminase/serum glutamic oxaloacetic transaminase (AST/SGOT) and\n                  alanine transaminase/serum glutamic pyruvic transaminase (ALT/SGPT) >2.0 × ULN or\n                  >3.0 × ULN in the presence of demonstrable liver metastases; or\n\n               -  Serum creatinine >2.0 × ULN;\n\n          -  Patients who are pregnant or breast-feeding;\n\n          -  Coexistent second malignancy or history of prior solid organ malignancy within\n             previous 3 years (excluding basal or squamous cell carcinoma of the skin, and in situ\n             carcinoma of the cervix (CIN 1) that has been treated curatively);\n\n          -  Any prior history of a hematologic malignancy (other than T-cell lymphoma);\n\n          -  Any significant medical or psychiatric condition that might prevent the patient from\n             complying with all study procedures; or\n\n          -  Prior exposure to romidepsin (other histone deacetylase inhibitors are allowed).
Inclusion Criteria:\n\n        All patients must meet the following inclusion criteria. All tests and eligibility criteria\n        must be completed within four weeks of completion of radiation and chemotherapy, following\n        surgery.\n\n          -  Patients must have sufficient tumor lysate protein that was generated from the\n             surgically obtained tumor material. Patients must also have sufficient DCVax-L product\n             available after manufacturing. These determinations will be made by Cognate\n             BioServices, Inc. (Cognate) and communicated to the clinical site through the Sponsor,\n             or its designee.\n\n          -  Patients with newly diagnosed, unilateral GBM (Grade IV) are eligible for this\n             protocol. An independent neuropathologist will review this diagnosis during the\n             enrollment process.\n\n          -  Subjects ?18 and ?70 years of age at surgery who are capable of informed consent.\n             Patients must be able to understand and sign the informed consent documents indicating\n             that they are aware of the investigational nature of this study.\n\n          -  Patients must have a life expectancy of >8 weeks.\n\n          -  Patients must have a KPS rating of ?70 at the baseline visit (Visit 3).\n\n          -  Primary therapy must consist of surgical resection with the intent for a gross or near\n             total resection of the contrast-enhancing tumor mass, followed by conventional\n             external beam radiation therapy and concurrent Temodar chemotherapy. Patients having a\n             biopsy only will be excluded. These primary treatments must be completed at least two\n             weeks prior to first immunization.\n\n          -  Patients may have received steroid therapy as part of their primary treatment. Steroid\n             treatment must be stopped at least 10 days prior to leukapheresis.\n\n          -  Patients must not have progressive disease at completion of radiation therapy.\n             Patients with suspected pseudoprogression will be enrolled and analyzed separately.\n\n          -  Patients must be willing to forego cytotoxic anti-tumor therapies except temozolomide\n             essentially according to the schedule of the Stupp Protocol (Stupp et al. N Engl J Med\n             352: 987-96, 2005) while being treated with DCVax-L. DCVax-L treatment must be given\n             as described and temozolomide/Temodar treatment schedules must be given essentially\n             according to the Stupp Protocol.\n\n          -  Patients must have adequate bone marrow function (e.g., hemoglobin >10 g/dl, white\n             blood count 3600-11,000mm3, absolute granulocyte count ?1,500/mm3, absolute lymphocyte\n             count ?1,000/mm3, and platelet count ?100K/mm3. Eligibility level of hemoglobin can be\n             reached by transfusion.\n\n          -  Adequate liver function (SGPT, SGOT, and alkaline phosphatase ?1.5 times upper limits\n             of normals (ULN) and total bilirubin ?1.5mg/dl), and adequate renal function (BUN or\n             creatinine ?1.5 times ULN) prior to starting therapy.
Key Inclusion Criteria for Tumor Collection:\n\n          1. Diagnosis or clinical signs of advanced RCC\n\n          2. Scheduled for cytoreductive or partial nephrectomy\n\n        Key Exclusion Criteria for Tumor Collection:\n\n          1. Known inability to undergo sunitinib treatment as currently labeled, due to\n             pre-existing medical conditions\n\n          2. Requirement for systemic chronic immunosuppressive drugs or corticosteroids\n\n          3. Evidence of brain metastases prior to nephrectomy\n\n        Key Inclusion Criteria for Treatment Study:\n\n          1. Advanced disease, histologically assessed as RCC, with predominantly clear cell\n             histology\n\n          2. Metastatic disease (measurable or non-measurable) that can be monitored throughout the\n             course of the study participation per RECIST 1.1\n\n          3. Subjects who are candidates for standard first-line therapy initiating with sunitinib\n\n          4. Time from diagnosis to treatment < 1 year\n\n          5. Karnofsky performance status (KPS) ? 70%\n\n          6. Life expectancy of 6 months or greater\n\n          7. Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to\n             Grade ? 1 according to National Cancer Institute Common Terminology Criteria for\n             Adverse Events Version 4.0\n\n          8. Adequate hematologic, renal, hepatic, and coagulation function\n\n          9. Negative serum pregnancy test for female subjects with reproductive potential, and\n             agreement of all male and female subjects of reproductive potential to use a reliable\n             form of contraception during the study and for 12 weeks after the last dose of study\n             drug\n\n         10. Normal ECG or clinically non-significant finding(s) at Screening\n\n         11. Able to abstain from taking prohibited drugs, either prescription or non-prescription,\n             during the treatment phase of the study\n\n         12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory\n             tests, and other study procedures\n\n        Key Exclusion Criteria for Treatment Study:\n\n          1. Prior systemic therapy (including adjuvant or neoadjuvant) of any kind for RCC,\n             including immunotherapy, chemotherapy, hormonal, or investigational therapy\n\n          2. Prior history of malignancy within the preceding 3 years, except for adequately\n             treated in situ carcinomas or non-melanoma skin cancer, adequately treated early stage\n             breast cancer, superficial bladder cancer, and non-metastatic prostate cancer with a\n             normal PSA\n\n          3. History of or known brain metastases, spinal cord compression, or carcinomatous\n             meningitis, or evidence of brain or leptomeningeal disease\n\n          4. Patients with 4 or more of the following risk factors:\n\n               1. Hgb < LLN\n\n               2. Corrected calcium > 10.0 mg/dL\n\n               3. KPS < 80%\n\n               4. Neutrophils > ULN\n\n               5. Platelets > ULN\n\n          5. Planned or elective surgical treatment post-nephrectomy for the direct management of\n             RCC, within 28 days before Visit 1 (Week 0)\n\n          6. NCI CTCAE Grade 3 hemorrhage < 28 days before Visit 1 (Day 0)\n\n          7. Clinically significant cardiovascular conditions within 3 months prior to\n             Randomization\n\n          8. Significant gastrointestinal abnormalities\n\n          9. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in\n             the normal range with medication\n\n         10. Active autoimmune disease or condition requiring chronic immunosuppressive therapy\n\n         11. Clinically significant infections, including human immunodeficiency virus, syphilis,\n             and active hepatitis B or C\n\n         12. Current treatment with an investigational therapy on another clinical trial\n\n         13. Pregnancy or breastfeeding\n\n         14. Any serious medical condition or illness considered by the investigator to constitute\n             an unwarranted high risk for investigational treatment
Inclusion:\n\n          1. Signed informed consent form (ICF)\n\n          2. Age ? 18 years (Age ? 19 years if required by local regulatory authorities)\n\n          3. ECOG PS of 0-1\n\n          4. Histologically or cytologically-confirmed epithelial ovarian, fallopian tube or\n             primary peritoneal cancer in recurrent stage\n\n          5. prOC (platinum-resistant ovarian cancers) defined as progression within > 1 to < 6\n             months (+ 2 weeks) of completing previous cycle of primary platinum-based therapy, or\n             during or within < 6 months (+ 2 weeks) of starting additional platinum based\n             therapies\n\n          6. Received ? 1 but ? 3 prior platinum-based regimens\n\n          7. Measurable disease according to RECIST 1.1\n\n          8. Left ventricular ejection fraction (LVEF) greater than or equal to at least 45% at\n             baseline assessment if subject is receiving PLD, and/or anthracycline is a concomitant\n             medication\n\n          9. No evidence of active (progressing) brain metastasis. (Treated brain metastasis\n             allowed with a posttreatment magnetic resonance imaging (MRI) or Computed Tomography\n             (CT) of brain showing no active (progressing) brain metastasis). Treatment of brain\n             metastasis may include surgery, radiosurgery (linear accelerator (LINAC), gamma\n             knife), or whole brain irradiation. Surgery for brain metastasis must be > 8 weeks\n             from study entry\n\n         10. Hemoglobin > 9 g/dl. Erythroid growth factors should not have been used in the 2 weeks\n             prior to study entry. Red blood cell transfusions are permitted to maintain the\n             hemoglobin level > 9 g/dl\n\n         11. Adequate bone marrow function in the investigator's opinion\n\n         12. Adequate hepatic function defined by the following:\n\n               -  Total bilirubin < 2 x Upper Limit of Normal (ULN)\n\n               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 X ULN\n                  for the referenced lab (< 5 X ULN for subjects with liver metastases)\n\n         13. Adequate renal function defined by the following:\n\n             - Serum creatinine < 2 X ULN for the referenced lab\n\n         14. Subjects of childbearing potential must have a negative serum pregnancy test prior to\n             study entry and must be practicing a highly effective form of contraception\n\n         15. At least 2 weeks since prior radiotherapy and has recovered from any Grade 3\n             toxicities\n\n         16. Life expectancy ? 12 weeks\n\n        Exclusion:\n\n          1. Subjects who have received prior CA4P therapy\n\n          2. Previously having failed treatment with bevacizumab combined with the intended PCC.\n\n             - For clarity: Investigators should not select a bevacizumab + PCC combination for the\n             FOCUS trial if the patient has previously failed that same regimen, however they may\n             select a new PCC regimen to combine with bevacizumab. For example, a patient who\n             failed bevacizumab + weekly paclitaxel would be allowed to enroll in FOCUS only if\n             they are assigned to bevacizumab + PLD for the study.\n\n          3. Previous treatment with greater than three traditional chemotherapy treatment regimens\n\n          4. Untreated brain metastasis or leptomeningeal brain metastasis\n\n          5. Solid organ or bone marrow transplant\n\n          6. Primary platinum-refractory disease (defined as progression during dosing or within\n             one (1) month of completing the last cycle of patients first platinum-containing\n             regimen)\n\n          7. > Grade 2 peripheral neuropathy\n\n          8. Current thrombotic or hemorrhagic disorder/event or history of prior event within 6\n             months of start of Screening\n\n          9. History of prior cerebrovascular event, (including transient ischemic attack) within 6\n             months of start of Screening\n\n         10. Recent history (within 6 months of start of Screening) of angina pectoris, myocardial\n             infarction (including non-Q wave MI), or NYHA Class III and IV congestive heart\n             failure\n\n         11. History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic\n             sinus bradycardia (<60 bpm), heart block (excluding 1st degree block, benign PR\n             interval prolongation only), congenital long QT syndrome or new ST segment elevation\n             or depression or new Q wave on ECG\n\n         12. Known uncontrolled HIV infection\n\n         13. Uncontrolled, clinically significant active infection\n\n         14. Serious non-healing wound, ulcer or bone fracture\n\n         15. Subjects with known hypersensitivity to any of the components of CA4P, paclitaxel,\n             PLD, or bevacizumab (paclitaxel and PLD dependent on whether PI plans they will be\n             dosed with that PCC)\n\n         16. Subjects who are currently or planning on receiving concurrent investigational therapy\n             or who have received investigational therapy for any indication within 30 days of the\n             first scheduled day of dosing\n\n         17. Subjects with any other intercurrent medical condition, including mental illness or\n             substance abuse, deemed by the Investigator to be likely to interfere with a subject's\n             ability to provide informed consent, cooperate and participate in the study, or to\n             interfere with the interpretation of the study results\n\n         18. Subjects with other invasive malignancies, with the exception of non-melanoma skin\n             cancer, or with previous cancer treatment that contraindicates this protocol therapy\n             within last 3 years\n\n         19. Prior radiation therapy to the pelvis or abdomen within 4 weeks of entry into the\n             study\n\n         20. History of fistula, gastrointestinal (GI) perforation or intra-abdominal abscess, or\n             invasive disease/metastases of the bowel which in the investigators opinion may\n             increase the risk of GI perforation with bevacizumab treatment.\n\n         21. Uncontrolled hypertension (HTN)\n\n             - Sustained BP greater than 150 mmHG SBP / 100 mmHG DBP\n\n         22. Uncontrolled elevated proteinuria levels in the investigator's opinion\n\n         23. Corrected QT interval ([QTc] Fridericia) > 480 ms\n\n         24. Significant vascular disease or recent peripheral arterial thrombosis\n\n         25. Subjects with active bleeding or pathologic conditions that carry high risk of\n             bleeding\n\n         26. Subjects who are pregnant or lactating
Inclusion Criteria - All Phases:\n\n          1. Males and females ?18 years of age;\n\n          2. Eastern Cooperative Oncology Group (ECOG) Performance Status of ?1\n\n          3. Acceptable bone marrow and organ function at screening as described below:\n\n               1. ANC ? 1,500/µL;\n\n               2. Platelet count ? 100,000/µL;\n\n               3. Total bilirubin ? 1.5 × ULN or ? 3.0 × ULN for subjects with hereditary benign\n                  hyperbilirubinemia;\n\n               4. AST (SGOT) ? 3 × ULN (? 5 × ULN if liver metastases are present);\n\n               5. ALT (SGPT) ? 3 × ULN (? 5 × ULN if liver metastases are present);\n\n               6. Serum creatinine ? 1.5 mg/dL or a measured creatinine clearance ³ 60 mL/min\n                  according to Cockcroft-Gault formula\n\n          4. Left ventricular ejection fraction informed (LVEF) ? 55%;\n\n          5. Ability to swallow and retain oral medications;\n\n          6. Negative serum beta-human Chorionic Gonadotropin (?-hCG) test in women of childbearing\n             potential (WOCBP); Note, subject must agree to use dual barrier contraceptive methods;\n             and\n\n          7. Willing and able to provide written informed consent and comply with the requirements\n             of the study;\n\n          8. Phase 1a Dose Escalation only - Histologically confirmed advanced solid tumor for\n             which standard therapy does not exist or is no longer effective\n\n          9. Food Effect Stage - willing and able to ingest a standard meal\n\n         10. Phase 1b All Expansion Cohorts - Evidence of measurable disease per RECIST, v1.1.\n             Measurable disease is defined as a lesion that can be accurately measured in at least\n             1 dimension (longest diameter to be recorded) with a minimum size of 10 mm by computed\n             tomography (CT) scan;\n\n         11. Phase 1b All Expansion Cohorts - Prior treatment with embolization or ablative\n             therapies is allowed if measurable disease remains outside of the treated area or if\n             there is definitive progression in the treated lesions. There is no limit on the\n             number of prior procedures;\n\n         12. Phase 1b Dose Expansion RAS Mutated mCRC Arm only - Histologically confirmed\n             colorectal cancer with a K-RAS or N-RAS mutation in exons 2,3 and 4 that is metastatic\n             or unresectable;\n\n         13. Phase 1b Dose Expansion RAS Mutated mCRC Arm only - At least 2 prior systemic\n             therapies for the treatment of metastatic colorectal cancer. Neo-adjuvant and adjuvant\n             therapies may not be counted as part of the prior therapy requirements. At least 7\n             subjects should be naïve to treatment with regorafenib;\n\n         14. Phase 1b Optional Dose Expansion Advanced RCC Arm only - Histologically confirmed\n             metastatic renal cell carcinoma;\n\n         15. Phase 1b Optional Dose Expansion Advanced RCC Arm only - Must have received 2 prior\n             therapies for metastatic RCC, including a vascular endothelial growth factor receptor\n             (VEGFR) tyrosine kinase inhibitor (TKI) and an immune checkpoint inhibitor (ie\n             anti-PD-1) (if approved and available for commercial use in the local country). At\n             least 7 subjects should be naïve to treatment with prior inhibitors of mammalian\n             target of rapamycin (mTOR) (eg. everolimus);\n\n         16. Phase 1b Optional Dose Expansion pNET Arm only - Histologically confirmed low-grade or\n             intermediate-grade, unresectable or metastatic pNET tumor for which standard therapy\n             does not exist or is no longer effective. Functional and non-functional tumors can be\n             included;\n\n         17. Phase 1b Optional Dose Expansion RAS-MAPK Pathway Mutation Arm only - Histologically\n             confirmed malignancy with a RAS-MAPK pathway mutation that is metastatic or\n             unresectable and for which standard therapy does not exist or is no longer effective.\n             At least 10 subjects with non-small cell lung cancer (NSCLC) are to be enrolled in\n             this arm.\n\n        Exclusion Criteria - All Phases\n\n          1. Any prior treatment (with the exception of somatostatin analogues, which are allowed\n             before and during the study in pNET subjects at the investigator discretion in pNET\n             subjects) such as chemotherapy, immunomodulatory drug therapy, anti-neoplastic\n             hormonal therapy (unless dose has been stable for 3 months prior to Baseline and will\n             remain stable during the study), immunosuppressive therapy, or corticosteroids (unless\n             administered to prevent contrast material reactions during radiographic procedures)\n             received within the past 28 days or 5 half-lives, whichever is shorter;\n\n          2. Presence of an acute or chronic toxicity resulting from prior chemotherapy, with the\n             exception of alopecia, that has not resolved to ? grade 1, as determined by NCI CTCAE\n             v 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/About.html);\n\n          3. Received radiotherapy within the last 21 days (limited palliative radiation is allowed\n             if ? 14 days prior);\n\n          4. Subjects with primary brain tumors or known central nervous system (CNS) metastases;\n\n          5. Major surgery < 28 days from the start of treatment (major surgery is defined as a\n             procedure requiring general anesthesia);\n\n          6. Minor surgery <14 days from the start of treatment (insertion of a vascular access\n             device is not considered major or minor surgery);\n\n          7. Active infection requiring systemic therapy;\n\n          8. Known to be human immunodeficiency virus (HIV) positive or have an acquired\n             immunodeficiency syndrome-related illness;\n\n          9. Uncontrolled congestive heart failure, angina, myocardial infarction, cerebrovascular\n             accident, coronary/peripheral artery bypass graft surgery, transient ischemic attack,\n             or pulmonary embolism within 3 months prior to initiation of study drug;\n\n         10. History of or ongoing cardiac dysrhythmias requiring treatment, atrial fibrillation of\n             any grade, or persistent prolongation of the QTc (Fridericia) interval to > 450 msec\n             for males or > 470 msec for females;\n\n         11. History of esophageal bleeding due to varices;\n\n         12. Gastrointestinal disease that may interfere with the absorption of orally-administered\n             drugs;\n\n         13. History of inflammatory bowel disease or other illness resulting in chronic diarrhea;\n\n         14. Known achlorhydria or history of gastrointestinal surgery that could reduce the\n             acidity of the stomach;\n\n         15. Acute pancreatitis or cholecystitis within 6 months prior to Baseline;\n\n         16. Cirrhosis with severe liver dysfunction (Child-Pugh Class B or C);\n\n         17. Previous or concomitant malignancy, except for basal-cell or squamous cell carcinoma\n             of the skin or carcinoma-in-situ of the uterine cervix. Subjects with other\n             malignancies are eligible if they have remained disease free for at least 2 years\n             prior to study entry;\n\n         18. Any severe, acute, or chronic medical or psychiatric condition, or laboratory\n             abnormality that may increase the risk associated with study participation or study\n             drug administration, may interfere with the informed consent process and/or with\n             compliance with the requirements of the study, or may interfere with the\n             interpretation of the study results and, in the Investigator's opinion, would make the\n             subject inappropriate for entry into this study;\n\n         19. Use of any investigational agents within 28 days or 5 half-lives (whichever is\n             shorter) prior to Baseline;\n\n         20. A condition that is expected to require concomitant use of any medication listed as\n             prohibited while on study;\n\n         21. Pregnant or lactating female;\n\n         22. Women of childbearing potential, or men who partner with a woman of childbearing\n             potential, unless they agree to use dual barrier contraceptive methods which, in the\n             Investigator's opinion, are effective and adequate for that subject's circumstances\n             while on study drug and for 3 months afterward;\n\n         23. Grade 3 or 4 eye disorder at study entry, unless stable and longstanding (>3 months)\n             and unlikely to interfere with protocol-required ophthalmology assessments;\n\n         24. Phase 1b Optional Dose Expansion pNET Arm only - Poorly differentiated pNET;\n\n         25. Phase 1b Optional Dose Expansion RAS-MAPK Pathway Mutation Arm only - Subjects with\n             primary pancreatic cancer or primary RAS mutated colorectal cancer.
Inclusion Criteria (TNBC Cohort Only):\n\n          -  Women ?18 years of age\n\n          -  Pathologically documented diagnosis of TNBC that is metastatic or locally advanced and\n             unresectable\n\n          -  Adequate hepatic function and coagulation profile\n\n          -  Negative HIV, HBV and HCV\n\n        Inclusion Criteria (HCC Cohort Only):\n\n          -  Men or Women ?18 years of age\n\n          -  Histological or cytological confirmed diagnosis of HCC with Barcelona Clinic Liver\n             Cancer Stage B or C who cannot benefit from resection, local ablation, or\n             chemoembolization\n\n          -  ECOG performance status of 0 or 1\n\n          -  Has at least 1 measurable lesion based on irRECIST 1.1.\n\n          -  Negative HIV tests\n\n        Inclusion Criteria (Either Cohort):\n\n          -  subject agrees to undergo a pre-treatment and an on-treatment biopsy of the tumor\n\n          -  Completion of all previous therapy for the treatment of cancer ?3 weeks before the\n             start of study drug\n\n          -  All acute toxic effects of any prior antitumor therapy resolved to Grade ?1 before the\n             start of study drug\n\n          -  Adequate bone marrow and renal function\n\n          -  Life expectancy of ?3 months\n\n        Exclusion Criteria (Either Cohort):\n\n          -  Pregnant or breastfeeding\n\n          -  History of another malignancy except for the following: adequately treated local basal\n             cell or squamous cell carcinoma of the skin; in situ cervical carcinoma; adequately\n             treated, papillary, noninvasive bladder cancer; other adequately treated Stage 1 or 2\n             cancers currently in complete remission; or any other cancer that has been in complete\n             remission for ?2 years.\n\n          -  Gastrointestinal disease that may interfere with drug absorption or with\n             interpretation of GI AEs.\n\n          -  Known symptomatic brain metastases requiring ?10 mg/day of prednisolone (or its\n             equivalent).\n\n          -  Significant cardiovascular disease within 6 months prior to start of study drug\n\n          -  Ongoing risk for bleeding due to active peptic ulcer disease or bleeding diathesis or\n             requirement for systemic anticoagulation with unfractionated heparin,\n             low-molecular-weight heparin or heparin fractions, or oral anticoagulants.\n\n          -  Evidence of an ongoing systemic bacterial, fungal, or viral infection\n\n          -  Has received a live vaccine within 30 days of planned start of study drug\n\n          -  Major surgery within 4 weeks before the start of study drug\n\n          -  Prior solid organ or bone marrow progenitor cell transplantation\n\n          -  Prior therapy with any known inhibitor of MNK1 or MNK2\n\n          -  Prior high dose chemotherapy requiring stem cell rescue\n\n          -  History of or active autoimmune disorders or other conditions that might impair or\n             compromise the immune system\n\n          -  Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids\n\n          -  Use of a strong inhibitor or inducer of cytochrome P450 (CYP)3A4 within 7 days prior\n             to the start of study drug or expected requirement for use of a strong CYP3A4\n             inhibitor or inducer during study participation\n\n          -  Need for proton pump inhibitors and histamine H2 blockers\n\n          -  Previously received investigational product in a clinical trial within 30 days or\n             within 5 elimination half lives (whichever is longer) prior to the start of study\n             drug, or is planning to take part in another clinical trial while participating in\n             this study\n\n          -  HCC Cohort Only: Portal vein invasion at the main portal (Vp4), inferior vena cava, or\n             cardiac involvement of HCC based on imaging.
Inclusion Criteria (Parts A and B):\n\n          1. Male or female aged at least 18 years or older, at the time of signing the informed\n             consent form.\n\n          2. The patient (or their legal representative) has provided written informed consent,\n             which signifies an agreement to enter the study and comply with the restrictions and\n             requirements listed in the informed consent form.\n\n          3. ECOG performance status ? 2\n\n          4. Life expectancy of at least 3 months\n\n          5. Patients must have measurable disease, according to RECIST 1.1 (defined as at least\n             one lesion that can be accurately measured in at least one dimension (longest diameter\n             to be recorded for non-nodal lesions and short axis for nodal lesions) as ? 20 mm (?2\n             cm) with conventional techniques or as ?10 mm (?1 cm) with spiral CT scan), or RANO\n             criteria for Glioma.\n\n          6. Patients must have received at least one prior line of therapy appropriate for their\n             tumor type and stage of disease. For glioma, patient must have received at least one\n             prior treatment with radiotherapy and temozolomide. Prior treatment of any Trk\n             inhibitor(s) is not an exclusion.\n\n          7. Adequate hematologic, hepatic and renal function as defined by the following criteria:\n\n               -  Absolute Neutrophil count ? 1.5x109\n\n               -  Platelet count ? 75,000 / mm3\n\n               -  Hemoglobin level ? 9.0 g/dL\n\n               -  Total Bilirubin level ? 1.5 X ULN\n\n               -  AST and ALT ? 3 X ULN\n\n               -  Creatinine clearance* ?50 mL/min *estimated CLcr by the Cockcroft-Gault equation\n\n          8. Women of:\n\n               1. Childbearing potential must have a negative serum pregnancy test documented\n                  within 14 days prior to enrollment, and must agree to use two adequate methods of\n                  contraception from Day 1 of the study until 3 months after the end of treatment.\n                  Acceptable forms of effective contraception include;\n\n                    -  Established use of oral, injected or implanted hormonal methods of\n                       contraception.\n\n                    -  Placement of an intrauterine device or intrauterine system.\n\n                    -  Barrier methods of contraception: condom or occlusive cap (diaphragm or\n                       cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.\n\n                    -  Male sterilization (with the appropriate post-vasectomy documentation of the\n                       absence of sperm in the ejaculate).\n\n               2. Non-childbearing potential, defined as females with a documented history of a\n                  clinically recognized procedure (e.g. hysterectomy, tubal ligation, bilateral\n                  salpingo-/oophorectomy) ; or postmenopausal defined as 12 months of spontaneous\n                  amenorrhea with follicle-stimulating hormone (FSH) >40 MlU/mL). Females on\n                  hormone replacement therapy (HRT) will be required to use one of the\n                  contraception methods in Inclusion criteria 8a or must discontinue HRT to allow\n                  confirmation of post-menopausal status prior to being enrolled in the study.\n                  Following confirmation of their post-menopausal status, they can resume HRT\n                  during the study and will not be required to use contraception.\n\n          9. A male patient is eligible to participate if he is not trying to father a child and is\n             willing to use one of the relevant contraception methods as in inclusion criterion 8a\n             from Day 1 of the study until 3 months after the end of treatment.\n\n         10. Able to swallow tablets\n\n         11. Patients must be recovered to Grade 1 from the effects (excluding alopecia) of any\n             prior therapy for their malignancies.\n\n             Additional Criterion for Part A only\n\n         12. Patients with histologically/cytologically confirmed advanced solid tumors, and\n             documented tumor progression for whom no further standard anticancer treatment is\n             available.\n\n         13. Patients must be able to comply with the protocol requirements regarding fasting, as\n             determined by the investigator (excluding patients in food assessment cohort(s)).\n\n             Additional Criteria for Part B only\n\n         14. Patients with histologically/cytologically confirmed advanced solid tumors and\n             documented tumor progression for whom no further standard anticancer treatment exists\n             or where, in the opinion of the investigator, the existing standard anticancer\n             treatment options available are not expected to provide a reasonable benefit to the\n             patient.\n\n         15. Patients must have NTRK1, NTRK2 or NTRK3 gene fusion confirmed locally prior to first\n             dose.\n\n        Exclusion Criteria:\n\n          1. Radiotherapy within two weeks prior to study entry\n\n          2. Major surgery (excluding placement of vascular access) within 4 weeks before the first\n             dose of study treatment\n\n          3. Spinal cord compression or brain metastases unless treated and radiologically stable\n             for >6 weeks post treatment and not requiring steroids for at least 4 weeks prior to\n             start of study treatment\n\n          4. As judged by the Investigator, any evidence of severe or uncontrolled psychiatric\n             disease or systemic diseases, including history of suicide attempt or current suicidal\n             ideation or behavior, active infection including hepatitis B, hepatitis C and human\n             immunodeficiency virus (HIV). Screening for chronic conditions is not required.\n\n          5. Concurrent treatment with another investigational agent or participated in another\n             investigational trial within 30 days of study entry\n\n          6. Diagnosed or treated for a malignancy other than the tumor under investigation in the\n             study within 5 years, or who were previously diagnosed with a malignancy other than\n             that required for the study and have any radiographic or biochemical marker evidence\n             of that malignancy. Patients with completely resected basal cell carcinoma, squamous\n             cell carcinoma of the skin, or in situ malignancy are not excluded.\n\n          7. Clinically significant cardiovascular disease, including:\n\n               -  History of myocardial infarction, acute coronary syndromes (including unstable\n                  angina), or coronary angioplasty/stenting/bypass grafting within the past 6\n                  months.\n\n               -  History of Class III or IV heart failure as defined by the New York Heart\n                  Association (NYHA) functional classification system\n\n               -  Severe cardiac arrhythmia requiring medication or other severe conduction\n                  abnormalities (e.g. clinically significant QT prolongation or Torsade de pointes)\n\n               -  Uncontrolled hypertension\n\n               -  Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy,\n                  or cardiomyopathy\n\n          8. QT prolongation defined as a QTcF interval >470 msec or other significant ECG\n             abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia\n             (ventricular rate <50 beats/min) on 12-lead ECG at screening\n\n          9. Serious concurrent medical conditions, including serious active infection, in the\n             opinion of the investigator\n\n         10. Female patients who are pregnant or breast feeding
Key Inclusion Criteria:\n\n          -  Patient newly diagnosed with multiple myeloma, based on following IMWG 2014 definition\n             (Rajkumar et al 2014):\n\n          -  Clonal bone marrow plasma cells ? 10% or biopsy-proven bony or extramedullary\n             plasmacytoma and any one or more of the following myeloma defining events:\n\n          -  Evidence of end organ damage that can be attributed to the underlying plasma cell\n             proliferative disorder\n\n          -  Any one or more of the following biomarkers of malignancy:\n\n               1. Clonal bone marrow plasma cell percentage ? 60%\n\n               2. Involved: uninvolved serum free light chain ratio ? 100\n\n               3. >1 focal lesions on MRI studies\n\n          -  Patient with measurable disease defined by at least 1 of the following conditions\n             present at screening:\n\n          -  Serum M-protein by Protein Electrophoresis (PEP) ? 1.0 g/dL (? 10 g/L).\n\n          -  Urine M-protein by PEP ? 200 mg/24 hours. Involved serum free light chain level ? 10\n             mg/dL (? 100 mg/L), provided that the serum free light chain ratio is abnormal.\n\n          -  Patient eligible for autologous stem cell transplantation based on the investigator's\n             clinical judgment.\n\n          -  Patient with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ? 2\n\n          -  Patient's age ? 18 and <75 years at time of signing the informed consent\n\n          -  Patient provided written informed consent prior to any screening procedures\n\n          -  Women of childbearing potential (WOCBP) with a negative serum pregnancy test at\n             screening and a negative urine pregnancy test at baseline\n\n        Key Exclusion Criteria:\n\n        Patients eligible for this study must not meet any of the following criteria:\n\n          -  Any concomitant anti-cancer therapy (other than bortezomib/lenalidomide/dexamethasone;\n             bisphosphonates are permitted only if commenced prior to the start of screening\n             period)\n\n          -  Unresolved diarrhea ? CTCAE grade 2 or presence of medical condition associated with\n             chronic diarrhea (such as irritable bowel syndrome, inflammatory bowel disease).\n\n          -  Allogeneic stem cell transplant recipient presenting with graft versus host disease\n             either active or requiring immunosuppression\n\n          -  Patient shown intolerance to bortezomib or to dexamethasone or components of these\n             drugs or has any contraindication to one or the other drug, following locally\n             applicable prescribing information\n\n          -  Patient with rade ? 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain\n             on clinical examination at screening\n\n          -  Patient received prior treatment with DAC inhibitors including Panobinostat\n\n          -  Patient needing valproic acid for any medical condition during the study or within 5\n             days prior to first administration of panobinostat/study treatment.\n\n          -  Patient taking any anti-cancer therapy concomitantly (bisphosphonates are permitted\n             only if commenced prior to the start of screening period)\n\n          -  Patient who received:\n\n               1. prior anti-myeloma chemotherapy or medication including Immunomodulator (IMiDs)\n                  and Dex ? 3 weeks prior to start of study.\n\n               2. experimental therapy or biologic immunotherapy including monoclonal antibodies ?\n                  4 weeks prior to start of study.\n\n               3. prior radiation therapy ? 4 weeks or limited field radiotherapy ? 2 weeks prior\n                  start of study.\n\n          -  Patient has not recovered from all therapy-related toxicities associated with above\n             listed treatments to < grade 2 CTCAE.\n\n          -  Patient undergone major surgery ? 2 weeks prior to starting study drug or who have not\n             recovered from side effects of such therapy to < grade 2 CTCAE\n\n          -  Patients with evidence of mucosal or internal bleeding\n\n          -  Clinically significant, uncontrolled heart disease and/or recent cardiac event (within\n             6 month prior to screening)\n\n          -  Inability to determine the Fridericia's Correction Formula (QTc) F interval\n\n          -  Patient with an impairment of gastrointestinal (GI) function or GI disease that may\n             significantly alter the absorption of panobinostat (e.g. ulcerative disease,\n             uncontrolled nausea, vomiting, malabsorption syndrome, obstruction, or stomach and/or\n             small bowel resection)\n\n          -  Sexually active males unless they use a condom during intercourse while taking the\n             drug during treatment, and for 6 months after stopping treatment\n\n          -  Pregnant or nursing (lactating) women.
Inclusion Criteria:\n\n        Part 1 and Part 2\n\n          1. Is male or female aged 18 years or older at the time of consent.\n\n          2. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14\n             days before enrollment.\n\n          3. Has adequate organ and hematologic function as evidenced by the following laboratory\n             values within 14 days before enrollment:\n\n               -  Absolute neutrophil count (ANC) ?1.5x10^9/L.\n\n               -  Platelet count ?100x10^9/L.\n\n               -  Hemoglobin ?9 g/dL (Transfusions are allowed to reach this hemoglobin level).\n\n               -  Serum creatinine ?1.5 times the upper limit of the normal range (ULN) or\n                  creatinine clearance ?50 mL/min either as estimated by the Cockcroft-Gault\n                  equation or based on urine collection (12 or 24 hours).\n\n               -  Total bilirubin ?1.5×ULN.\n\n               -  Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ?2.5×ULN.\n\n          4. Female participants who:\n\n               -  Are postmenopausal for at least 1 year before the screening visit, OR\n\n               -  Are surgically sterile, OR\n\n               -  If they are of childbearing potential, agree to practice 1 highly effective\n                  method and 1 additional effective (barrier) method of contraception at the same\n                  time, from the time of signing the informed consent form through 30 days after\n                  the last dose of study drug (with the exception of those participants assigned to\n                  TAK-659, for whom the duration required is 180 days), or for as long as mandated\n                  by local labeling for docetaxel and paclitaxel, OR\n\n               -  Agree to practice true abstinence, when this is in line with the preferred and\n                  usual lifestyle of the participant, from the time of signing the informed consent\n                  form through 30 days after the last dose of study drug (with the exception of\n                  those participants assigned to TAK-659, for whom the duration required is 180\n                  days), or for as long as mandated by local labeling for docetaxel and paclitaxel.\n                  (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation\n                  methods], withdrawal, spermicides only, and lactational amenorrhea are not\n                  acceptable methods of contraception. Female and male condoms should not be used\n                  together.)\n\n             Male participants, even if surgically sterilized (ie, status postvasectomy), who:\n\n               -  Agree to practice effective barrier contraception during the entire study\n                  treatment period and through 120 days after the last dose of study drug (with the\n                  exception of those participants assigned to TAK-659, for whom the duration\n                  required is 180 days), or for as long as mandated by local labeling for docetaxel\n                  and paclitaxel, OR\n\n               -  Agree to practice true abstinence, when this is in line with the preferred and\n                  usual lifestyle of the participant during the entire study treatment period and\n                  through 120 days after the last dose of study drug (with the exception of those\n                  participants assigned to TAK-659, for whom the duration required is 180 days) or\n                  for as long as mandated by local labeling for docetaxel and paclitaxel. (Periodic\n                  abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the\n                  female partner] and withdrawal are not acceptable methods of contraception.)\n\n          5. Voluntary written consent must be given before performance of any study-related\n             procedure not part of standard medical care, with the understanding that consent may\n             be withdrawn by the participant at any time without prejudice to future medical care.\n\n          6. Has suitable venous access for the study-required blood sampling (ie, pharmacokinetic\n             (PK) sampling, circulating tumor deoxyribonucleic acid [DNA]).\n\n        Part 1 only\n\n          1. Has a histologically confirmed diagnosis of advanced solid tumor, including but not\n             limited to gastric or gastroesophageal junction adenocarcinoma.\n\n          2. Has radiographically or clinically evaluable disease. Measurable disease as defined by\n             Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 is not required.\n\n          3. Is relapsed or refractory with no effective therapeutic options available.\n\n        Part 2 only\n\n          1. Has a histologically confirmed diagnosis of metastatic or locally advanced\n             adenocarcinoma of the stomach or gastroesophageal junction (Stage IIIb or IV according\n             to International Union Against Cancer [UICC] tumor, node, metastases [TNM]\n             classification, 7th edition).\n\n          2. Has at least 1 measurable tumor lesion per RECIST Version 1.1 by radiographic\n             techniques (computed tomography [CT] or magnetic resonance imaging [MRI]).\n\n          3. Has receipt of 1 prior systemic chemotherapy regimen for advanced or metastatic\n             adenocarcinoma of the stomach or gastroesophageal junction with documented progressive\n             disease (PD).\n\n          4. Has archived or fresh tumor biopsy samples obtained during screening sufficient for\n             Epstein-Barr virus (EBV) testing and genotyping.\n\n        Exclusion Criteria:\n\n        Part 1 and Part 2\n\n          1. Has received prior systemic anticancer therapies or other investigational agents\n             within 2 weeks before the first administration of study drug or has failed to recover\n             from the adverse drug effects of prior therapies (to ?Grade 1 or to a level meeting\n             inclusion criteria). For prior therapies with a half-life longer than 3 days, the\n             interval must equal minimally 28 days before the first administration of study drug\n             and the participant must have documented PD.\n\n          2. Has radiotherapy within 14 days before enrollment.\n\n          3. Has fasting glucose ?130 mg/dL. Poorly controlled diabetes mellitus (glycosylated\n             hemoglobin [HbA1c] >7.0%). Participants with a history of transient glucose\n             intolerance due to corticosteroid administration are allowed.\n\n          4. Has received strong cytochrome P-450 (CYP) 3A4 inducers/inhibitors within 7 days\n             before the first administration of study drug or has conditions that require the\n             concomitant use of CYP3A4 inducers/inhibitors during the course of the study.\n\n          5. For TAK-659 (Cohort A) only: Is receiving treatment with medications that are known to\n             be inhibitors or inducers of P-glycoprotein (P-gp). Baseline lipase >ULN. Participants\n             not fulfilling these exclusion criteria can be enrolled in other cohorts (Part 1\n             only).\n\n          6. Has taken proton pump inhibitors within 7 days before the first administration of\n             study drug or has conditions that require the concomitant use of proton pump\n             inhibitors during the course of the study.\n\n          7. Has signs of peripheral neuropathy ? National Cancer Institute Common Terminology\n             Criteria for Adverse Events (NCI CTCAE) Grade 2.\n\n          8. Has symptomatic brain metastases or brain metastases with a stable neurologic status\n             for <2 weeks after completion of the definitive therapy and steroids.\n\n          9. Has systemic infection requiring intravenous (IV) antibiotic therapy or other serious\n             infection within 14 days before the first dose of study drug.\n\n         10. Has known or suspected human immunodeficiency virus (HIV) positive or hepatitis B\n             surface antigen-positive status, or known or suspected active hepatitis C infection.\n             Testing for these agents is not required in the absence of clinical findings or\n             suspicion.\n\n         11. Has known gastrointestinal (GI) disease or GI procedure that could interfere with the\n             oral absorption or tolerability of orally administered study drug, including\n             difficulty swallowing tablets; diarrhea >Grade 1 despite supportive therapy; or prior\n             total gastrectomy.\n\n         12. Has clinically significant comorbidities, such as uncontrolled pulmonary disease,\n             known impaired cardiac function or clinically significant cardiac disease, active\n             central nervous system disease, or any other condition that could compromise the\n             participant's participation in the study.\n\n             • Known impaired cardiac function or clinically significant cardiac disease includes:\n             evidence of currently uncontrolled cardiovascular conditions (including arrhythmias,\n             angina, pulmonary hypertension, acute ischemia or active conduction system\n             abnormalities); current history of New York Heart Association Class III or IV heart\n             failure; acute myocardial infarction within 6 months before starting study drug;\n             baseline QT interval corrected for heart rate (QTc) ?Grade 1 according to NCI CTCAE\n             Version 4.03 criteria; or abnormalities on baseline 12-lead ECG that are considered\n             clinically significant per the investigator.\n\n         13. Female participants who are lactating and breastfeeding or have a positive serum\n             pregnancy test during the screening period or a positive urine pregnancy test on Day 1\n             before the first dose of study drug.\n\n         14. Participants with bilirubin >ULN, or AST and/or ALT >1.5 X ULN concomitant with\n             alkaline phosphatase >2.5 X ULN cannot be allocated to Cohort D (MLN1117+docetaxel) in\n             Part 1 and are not eligible for Part 2 if they are also EBV negative.\n\n        Part 2 only\n\n        1. Has prior treatment with any of the following:\n\n          -  An Aurora A-targeted agent (not eligible for randomization in Cohorts B, C, or D, but\n             eligible for Cohort A if EBV positive).\n\n          -  A docetaxel- or paclitaxel-containing chemotherapy regimen (not eligible for\n             randomization in Cohorts B, C, or D, but eligible for Cohort A if EBV positive).\n\n          -  A spleen tyrosine kinase (SYK) inhibitor (MLN1117+TAK-659 arm only).\n\n          -  A phosphoinositide 3-kinase (PI3K) or serine/threonine kinase, also known as protein\n             kinase B or PKB (AKT) inhibitor.
Inclusion Criteria:\n\n        Phase 1 and 2: Confirmed advanced hematologic malignancies\n\n          -  Confirmed relapsed or refractory AML with a documented FLT3 mutation, or\n\n               -  60 years with newly diagnosed FLT3+ AML and not eligible for standard induction\n                  chemotherapy or FLT3+\n\n          -  high-risk MDS/CMML (defined as ? 10% peripheral blood or marrow blasts and\n             international Prognostic Scoring System [IPSS] score ? 2) and relapsed or refractory\n             to prior therapy\n\n          -  At least 3 weeks beyond the last cancer treatment for the disease under study, major\n             surgery and recovered from all acute toxicities (? Grade 1). Hydroxyurea used to\n             control peripheral blast counts is permitted during the first 2 cycles.\n\n          -  Adequate performance status ECOG ? 2;\n\n          -  Adequate renal and hepatic function:\n\n               -  creatinine ? 1.5 mg/dL OR calculated creatinine clearance ? 45 mL/minute\n\n               -  total bilirubin ? 2 times the upper limit of normal (ULN) unless due to Gilbert's\n                  disease or thought to be due to underlying AML\n\n               -  ALT and AST ? 5 times ULN\n\n          -  Negative serum pregnancy test within 14 days prior to the first dose of study therapy\n             for women of child-bearing potential\n\n          -  Ability to provide written informed consent\n\n        Exclusion Criteria:\n\n          -  History of clinically significant cardiac impairment, congestive heart failure (CHF)\n             New York Heart Association (NYHA) Class III or IV, unstable angina, or myocardial\n             infarction during the previous 6 months, or serious cardiac arrhythmia\n\n          -  QT interval corrected for rate (QTc) ? 450 msec for males and ? 460 msec for females\n             on the ECG obtained at Screening using Fridericia method for QTc calculation (average\n             of 3 readings)\n\n          -  Concomitant medication(s) that may cause QTc prolongation or induce Torsades de\n             Pointes with the exception of anti-microbials used as standard of care to prevent or\n             treat infections and other such drugs that are considered by the investigator to be\n             essential for the care of the patient. However, if such medications are deemed to be\n             necessary during the study, E6201 will be held during the period of their use. of\n             anti-microbials used as standard\n\n          -  Presence of active central nervous system (CNS) leukemia. Subjects adequately treated\n             for CNS leukemia documented by 2 consecutive cerebrospinal fluid samples negative for\n             leukemia cells are eligible. Subjects with no history of CNS leukemia will not be\n             required to undergo cerebrospinal fluid sampling for eligibility.\n\n          -  Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface\n             antigen (HBsAg), or hepatitis C virus HCV)\n\n          -  Active, uncontrolled infection\n\n          -  Known hypersensitivity to any study drug component\n\n          -  History of another malignancy; Exception: Patients disease-free for 2 years or treated\n             in situ carcinoma\n\n          -  Any other medical intervention or other condition which, in the opinion of the\n             Principal Investigator, could compromise adherence to study requirements or confound\n             the interpretation of study results\n\n          -  Pregnancy or lactation
Inclusion Criteria\n\n          -  Histologically and/or cytologically confirmed primary diagnosis of Stage IV NSCLC\n             (according to American Joint Committee on Cancer [AJCC] 7th edition lung cancer\n             staging criteria).\n\n          -  Measurable disease according to RECIST v.1.1.\n\n          -  An EGFR exon 19 deletion and/or an exon 21 (L858R) substitution mutation.\n\n          -  BDX004 Positive Label.\n\n          -  Have received no prior systemic chemotherapy, immunotherapy, targeted therapy, or\n             biologic therapy for metastatic NSCLC. Subjects may have previously been treated with\n             postoperative adjuvant chemotherapy for early stage lung cancer or chemo radiotherapy\n             for locally advanced disease provided this was completed at least 6 months prior to\n             enrollment. No prior EGFR TKI therapy is allowed for any stage of NSCLC.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion\n             Criteria\n\n          -  History of severe allergic or anaphylactic reactions or hypersensitivity to\n             recombinant proteins or excipients in the investigational agent or erlotinib.\n\n          -  History of known brain metastases.\n\n          -  Prior treatment with any other investigational drug or biologic agent within 5 half\n             lives prior to randomization, or any investigational device within 2 weeks prior to\n             randomization.\n\n          -  Any unresolved toxicity from previous radiation therapy.\n\n          -  Significant cardiovascular disease, including:\n\n               -  Echocardiogram (ECHO) or multiple gated acquisition (MUGA) showing left\n                  ventricular ejection fraction of less than 55%.\n\n               -  Cardiac failure New York Heart Association class III or IV.\n\n               -  Myocardial infarction, severe or unstable angina within 6 months prior to\n                  randomization.\n\n               -  History of serious ventricular arrhythmia (ie, ventricular tachycardia or\n                  ventricular fibrillation).\n\n               -  Significant thrombotic or embolic events within 3 months prior to randomization\n                  (significant thrombotic or embolic events include but are not limited to stroke\n                  or transient ischemic attack).\n\n               -  Any uncontrolled or severe cardiovascular disease.\n\n          -  History of prior malignancy within 3 years prior to randomization (except for\n             adequately treated non-melanoma skin cancer, carcinoma in situ of the breast or\n             cervix, superficial bladder cancer, or early stage prostate cancer, without evidence\n             of recurrence).\n\n          -  Radiographic evidence of interstitial lung disease.
Inclusion Criteria:\n\n          1. Male or female patients, > 18 years of age (in Singapore > 21 years or > 18 years with\n             consent of guardian).\n\n          2. Patients with documented (histologically- or cytologically-proven) HCC, with at least\n             1 measureable lesion > 10 mm (excluding bone metastases). If the measurable lesion(s)\n             is in the liver, it either should not have been treated previously with loco-regional\n             therapy, or there must be demonstrated progression of the lesion following previous\n             loco-regional therapy.\n\n          3. Patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC not amenable to\n             surgical intervention due to either medical contraindications or non-resectability of\n             the tumor.\n\n          4. Patients who are either refractory to or intolerant of sorafenib despite dose\n             reduction and best supportive care, or patients who do not have access to sorafenib or\n             other suitable therapy for HCC.\n\n          5. Patients with underlying hepatic cirrhosis must have a current cirrhosis status of\n             Child-Pugh Class A (i.e., score of 5-6) without encephalopathy.\n\n          6. Phase 1b MTD Biopsy Cohort: Patients with primary or metastatic tumor site(s)\n             considered safely accessible for biopsy and consenting to undergo pre- and post-dosing\n             tumor biopsies.\n\n          7. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or\n             1, and an anticipated life expectancy of ? 3 months.\n\n          8. Patients, both male and female, who are either not of childbearing potential or who\n             agree to use a medically effective method of contraception during the study and for 3\n             months after the last dose of study drug.\n\n          9. Patients with the ability to understand and give written informed consent for\n             participation in this trial, including all evaluations and procedures as specified by\n             this protocol.\n\n        Exclusion Criteria (Patients):\n\n          1. Women who are pregnant or lactating; women of child-bearing potential (WOCBP), and\n             fertile men with a WOCBP-partner not using and not willing to use a medically\n             effective method of contraception.\n\n          2. Patients with known central nervous system (CNS) or leptomeningeal metastases not\n             controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS\n             involvement for which treatment is required.\n\n          3. Patients with mixed histology cholangiocarcinoma and HCC, or fibrolamellar variant\n             HCC.\n\n          4. Patients with any of the following hematologic abnormalities at baseline:\n\n               -  Hemoglobin < 8.5 g/dL\n\n               -  Absolute neutrophil count < 1,500 per mm3\n\n               -  Platelet count < 75,000 per mm\n\n          5. Patients with any of the following serum chemistry abnormalities at baseline:\n\n               -  Total bilirubin > 1.5 × the upper limit of normal (ULN) for the institution\n\n               -  AST or ALT > 5 × the ULN for the institution\n\n               -  Serum creatinine > 1.5 × the ULN for the institution\n\n          6. Patients with the following coagulation parameter abnormality at baseline:\n\n               -  INR > 1.7 × ULN for the institution\n\n          7. Patients with:\n\n               -  A history of deep vein thrombosis (DVT) or pulmonary embolism (PE), within 6\n                  months prior to first study drug administration; patients receiving systemic\n                  anti-coagulation for prophylactic or therapeutic reasons\n\n               -  Active uncontrolled bleeding or a known bleeding diathesis\n\n          8. Patients with:\n\n               -  Esophageal or gastric variceal bleeding within 2 months prior to first study drug\n                  administration; patients with a history of variceal bleeding between 2 and 12\n                  months prior to first study drug administration should have undergone adequate\n                  treatment and be considered clinically stable in the opinion of the investigator\n\n               -  A history of symptomatic ascites requiring paracentesis within the past 3 months\n                  or any encephalopathy requiring hospitalization or medication within the past 3\n                  months\n\n               -  Portal-caval shunts\n\n          9. Patients with a significant cardiovascular disease or condition, including:\n\n               -  Congestive heart failure currently requiring therapy\n\n               -  Need for antiarrhythmic medical therapy for a ventricular arrhythmia\n\n               -  Severe conduction disturbance (i.e., 3rd degree heart block)\n\n               -  Angina pectoris requiring therapy\n\n               -  Known left ventricular ejection fraction (LVEF) < 50% by MUGA or echocardiogram\n\n               -  QTc interval > 450 msec in males, or > 470 msec in females\n\n               -  Uncontrolled systemic hypertension (per the Investigator's discretion)\n\n               -  Class III or IV cardiovascular disease according to the New York Heart\n                  Association (NYHA) Functional Criteria\n\n               -  Myocardial infarction within 6 months prior to first study drug administration\n\n         10. Patients with a known or suspected hypersensitivity to any of the components of lipid\n             nanoparticle-formulated DCR-MYC; patients with a known sensitivity to cremophor (found\n             with paclitaxel and other formulations).\n\n         11. Patients with an estimated daily alcohol intake greater than 80 g/day.\n\n         12. Patients having undergone previous organ transplantation (e.g., liver transplantation)\n             requiring immunosuppression; patients on long-term immunosuppressive therapy.\n\n         13. Patients with a known history of human immunodeficiency virus (HIV) seropositivity.\n\n         14. Patients with any other serious/active/uncontrolled infection, with the exception of\n             chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection; any\n             infection requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks\n             prior to first study drug administration.\n\n         15. Patients with inadequate recovery from an acute toxicity associated with any prior\n             antineoplastic therapy.\n\n         16. Patients with inadequate recovery from any previous surgical procedure, or patients\n             having undergone any major surgical procedure within 4 weeks prior to first study drug\n             administration.\n\n         17. Patients with an active second malignancy or history of another malignancy within the\n             last 3 years, with the exception of:\n\n               -  Treated, non-melanoma skin cancers\n\n               -  Treated CIS of the breast or cervix\n\n               -  Controlled, superficial carcinoma of the bladder\n\n               -  T1a or b carcinoma of the prostate treated according to local standard of care,\n                  with prostate specific antigen (PSA) within normal limits (wnl)\n\n         18. Patients with any other life-threatening illness, significant organ system\n             dysfunction, or clinically significant laboratory abnormality, which, in the opinion\n             of the Investigator, would either compromise the patient's safety or interfere with\n             evaluation of the safety of the study drug.\n\n         19. Patients with a psychiatric disorder or altered mental status that would preclude\n             understanding of the informed consent process and/or completion of the necessary\n             study-related evaluations.\n\n         20. Patients with the inability or with foreseeable incapacity, in the opinion of the\n             Investigator, to comply with the protocol requirements, including the ability to\n             attend all visits and undergo all assessments.\n\n        Exclusion Criteria (Treatments):\n\n          1. Phase 1b: Greater than 3 prior systemic anti-cancer chemotherapies or targeted agents\n             for HCC; prior loco-regional treatment, including transcatheter arterial\n             chemo-embolization (TACE), is allowed.\n\n          2. Phase 2: greater than 1 prior systemic anti-cancer chemotherapy or targeted agent for\n             HCC; prior loco-regional treatment, including TACE, is allowed.\n\n          3. Sorafenib therapy within 2 weeks prior to first study drug administration and during\n             study.\n\n          4. Any other antineoplastic agent (standard or experimental) within 4 weeks; monoclonal\n             antibody therapy, nitrosoureas, and nitrogen mustard within 6 weeks prior to first\n             study drug administration and during study.\n\n          5. Loco-regional therapy including TACE or radioembolization within 6 weeks prior to\n             first study drug administration and during study.\n\n          6. Radiotherapy within 4 weeks prior to first study drug administration and during study.\n\n          7. Therapy with sofosbuvir for HCV within 6 weeks prior to first study drug\n             administration and during study.\n\n          8. Herbal preparations, or related non-prescription preparations/supplements containing\n             herbal ingredients, aimed at treating the underlying malignancy within 2 weeks prior\n             to first study drug administration and during study.\n\n          9. Systemic hormonal therapy within 2 weeks prior to first study drug administration and\n             during study.\n\n         10. Any other investigational treatments during study. This includes participation in any\n             medical device or therapeutic intervention clinical trial.\n\n         11. Prophylactic use of hematopoietic growth factors within 1 week prior to first study\n             drug administration and during Cycle 1 of study; thereafter prophylactic use of growth\n             factors is allowed as clinically indicated.
Inclusion Criteria:\n\n        Donors:\n\n          -  Read, understood and provided written informed consent and willing to comply with all\n             study requirements and procedures\n\n          -  6 out of 6 HLA-matched sibling\n\n          -  Negative test for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C\n\n          -  Both male and female patients of childbearing potential enrolled in this trial must\n             use adequate birth control measures\n\n          -  Subjects should be in generally good health and without significant medical\n             conditions, based upon pre-study medical history, physical examination,\n             electrocardiogram (ECG), chest X- ray, and laboratory tests\n\n          -  Meets all criteria to serve as a mobilized blood cell donor in accordance with all\n             applicable individual Transplant Center criteria\n\n        Recipient:\n\n          -  Read, understood and provided written informed consent and willing to comply with all\n             study requirements and procedures\n\n          -  6 out of 6 HLA-matched sibling\n\n          -  Both male and female patients of childbearing potential enrolled in this trial must\n             use adequate birth control measures\n\n        Diagnosis of one of following:\n\n          -  Acute Myelogenous Leukemia (AML) in 1st remission or beyond\n\n          -  Acute Lymphoblastic Leukemia (ALL) in 1st remission or beyond\n\n          -  Chronic Myelogenous Leukemia (CML)\n\n          -  Chronic Lymphoblastic Leukemia (CLL), relapsing after at least one prior regimen\n\n          -  Myelodysplastic Syndrome (MDS), either intermediate 1,2, or high risk by IPI Scoring\n             System or transfusion dependent\n\n          -  Non-Hodgkins Lymphoma (NHL) or Hodgkins Disease (HD) in 2nd or greater complete\n             remission, partial remission, or in relapse\n\n          -  Meets all criteria to serve as a transplant recipient in accordance with all\n             applicable individual Transplant Center criteria\n\n        Exclusion Criteria:\n\n        Donors:\n\n          -  Unwilling or unable to give informed consent, or unable to comply with the protocol\n             including required follow-up and testing\n\n          -  Prior treatment with any rhuFlt3L product\n\n          -  Any vaccination within 4 weeks prior to CDX-301 dosing\n\n          -  Donation of blood within 8 weeks, or donation of plasma within 2 weeks prior to\n             CDX-301 dosing\n\n          -  Any experimental treatment within 4 weeks prior to CDX-301 dosing\n\n          -  Use of systemic immunosuppressive agents (excluding topical steroids) within 12 months\n             prior to CDX-301 dosing.\n\n          -  History of first degree relatives with primary or secondary immunodeficiency to\n             include type 1 diabetes, multiple sclerosis, rheumatoid arthritis, scleroderma or\n             psoriasis\n\n          -  History of tuberculosis infection\n\n          -  Herpes zoster within 3 months prior to starting study drug\n\n          -  Pregnant or nursing\n\n        Recipient:\n\n          -  Unwilling or unable to give informed consent, or unable to comply with the protocol\n             including required follow-up and testing\n\n          -  Prior allogeneic transplant\n\n          -  More than one prior autologous transplant\n\n          -  Prior treatment with any rhuFlt3L product\n\n          -  Any vaccination within 4 weeks prior to transplant\n\n          -  Uncontrolled infection at the time of the transplant conditioning regimen\n\n          -  Pregnant or nursing\n\n          -  Any condition, which, in the opinion of the clinical investigator, would interfere\n             with the evaluation of the study outcome
Inclusion Criteria:\n\n        Male or Female, age ? 18 years Patients with higher risk MDS with a blast count < 20% at\n        the time of screening IPSS Int-2 or High Risk Serum Ferritin ? 300 ng/mL at screening.\n\n        Sexually active women must use an effective method of contraception, or must have undergone\n        clinically documented total hysterectomy and/or oophorectomy, or tubal ligation or be\n        postmenopausal (defined as amenorrhea for at least 12 months)\n\n        Exclusion Criteria:\n\n        Patients currently receiving any therapy other than AZA for MDS (a ? 4 week washout period\n        for any agent (excluding AZA) used to treat MDS prior to first dose of study treatment is\n        required).\n\n        Patients who have received > 2 cycles of AZA or decitabine at the time of randomization.\n        Patients who have received iron chelation therapy within 1 month of screening.\n\n        Patients who have received growth factors within 1 month of screening. Patients who have\n        received Revlimid within 1 month of screening. Patients who have undergone hematopoietic\n        stem cell transplant. ECOG Performance Status > 2 Systemic diseases (cardiovascular, renal,\n        hepatic, etc.) which would prevent study treatment Patients with uncontrolled systemic\n        hypertension Severe cardiac insufficiency (NYHA III or IV), with uncontrolled and/or\n        unstable cardiac or coronary artery disease not controlled by standard medical therapy\n        Patients with a diagnosis of or history of clinically relevant ocular toxicity related to\n        iron chelation Diagnosis of liver cirrhosis (either established diagnosis or diagnosis by\n        liver biopsy or central ultrasound reading) Clinical or laboratory evidence of active\n        Hepatitis B or Hepatitis C (HBsAg in the absence of HBsAb OR HCV Ab positive with HCV RNA\n        positive and ALT above the normal range). History of HIV positive test result (ELISA or\n        Western blot) Presence of a surgical or medical condition which might significantly alter\n        the absorption, distribution, metabolism or excretion of study drug Patients with an active\n        malignancy (currently or within the past two years) with the exception of basal cell skin\n        carcinoma or cervical carcinoma in situ or completely resected colonic polyps carcinoma in\n        situ. History of drug or alcohol abuse within the 12 months prior to enrollment. History of\n        non-compliance to medical regimens or patients who are considered potentially unreliable\n        and/or not cooperative.\n\n        Patients with a known hypersensitivity to azacitidine, mannitol, or deferasirox. Calculated\n        creatinine clearance <40mL/min Serum creatinine greater than 1.5x ULN at screening Urine\n        protein/creatinine ratio> 1 AST or ALT greater than 3x ULN at screening Direct Bilirubin\n        greater than 1.5x ULN at screening. Patients who received treatment with systemic\n        investigational drug within the past 4 weeks or topical investigational drug within the\n        past 7 days or are planning to receive other investigational drugs while participating in\n        the study Patients participating in another therapeutic clinical trial Pregnant or nursing\n        (lactating) women, where pregnancy is defined as the state of a female after conception and\n        until the termination of gestation, confirmed by a positive hCG laboratory test. Women of\n        child-bearing potential, defined as all women physiologically capable of becoming pregnant,\n        unless they are using effective methods of contraception during dosing of study treatment.\n        Sexually active males unless they use a condom during intercourse while taking drug and for\n        3 months after stopping AZA and should not father a child in this period.
Inclusion Criteria:\n\n          1. Male or female patients, > 18 years of age at the time of obtaining informed consent.\n\n          2. Patients with a documented solid tumor malignancy that is locally advanced or\n             metastatic; patients with documented multiple myeloma or non-Hodgkin's lymphoma.\n\n          3. Patients with a malignancy that is either refractory to standard therapy or for which\n             no standard therapy is available.\n\n          4. Patients with a malignancy that is currently not amenable to surgical intervention due\n             to either medical contraindications or non-resectability of the tumor.\n\n          5. Dose escalation portion of study: Patients with measurable or non-measurable disease\n             according to standard response criteria .\n\n          6. MTD Biopsy Cohort ONLY: Patients with measurable disease with primary or metastatic\n             tumor site(s) considered safely accessible for biopsy; patients must consent to\n             undergo 2 tumor biopsies.\n\n          7. MTD PNET Cohort ONLY: Patients with advanced (unresectable or metastatic),\n             histologically-confirmed low or intermediate grade PNET according to the World Health\n             Organization (WHO) 2010 classification. Patients with neuroendocrine tumors (e.g.,\n             gastrinoma, VIPoma) in whom a pancreatic or peripancreatic primary is strongly\n             suspected are also eligible. Patients must also have:\n\n               -  A Ki-67 proliferation index < 20%\n\n               -  Demonstrated radiological evidence of disease progression during or following the\n                  last treatment regimen (based on CT, MRI, or Octreoscan®)\n\n               -  Measurable disease according to RECIST v1.1 (determined by CT or MRI). Any\n                  lesions which have been subjected to percutaneous therapies or radiotherapy\n                  should not be considered measureable, unless the lesion has clearly progressed\n                  (per RECIST v1.1) since the procedure.\n\n               -  Received < 2 prior systemic treatments for PNET, at least one of which must have\n                  been an FDA-approved targeted therapy for PNET (i.e., sunitinib [Sutent®] or\n                  everolimus [Afinitor®]). Treatment with a somatostatin analog (SSA) will not be\n                  considered as a systemic treatment for the purposes of eligibility.\n\n          8. Patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2,\n             and an anticipated life expectancy of ? 3 months.\n\n          9. Patients, both male and female, who are either not of childbearing potential or who\n             agree to use a medically effective method of contraception during the study and for 3\n             months after the last dose of study drug.\n\n         10. Patients with the ability to understand and give written informed consent for\n             participation in this trial, including all evaluations and procedures as specified by\n             this protocol.\n\n        Exclusion Criteria-Patients:\n\n          1. Women who are pregnant or lactating. Women of child-bearing potential (WOCBP), and\n             fertile men with a WOCBP-partner not using and not willing to use a medically\n             effective method of contraception.\n\n          2. Patients with known central nervous system (CNS) or leptomeningeal metastases not\n             controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS\n             involvement for which treatment is required.\n\n          3. Patients with leukemia (any form) or myelodysplastic syndromes.\n\n          4. MTD PNET Cohort ONLY: Patients with poorly differentiated, high grade (grade 3)\n             neuroendocrine carcinoma, as well as patients with adenocarcinoid, goblet cell\n             carcinoid, or small cell carcinoma, or PNET patients with a Ki-67 proliferation index\n             > 20 %.\n\n          5. Patients with any of the following hematologic abnormalities at baseline:\n\n               -  Absolute neutrophil count < 1,500 per mm3\n\n               -  Platelet count < 100,000 per mm3\n\n          6. Patients with any of the following serum chemistry abnormalities at baseline:\n\n               -  Total bilirubin > 1.5 × the ULN for the institution\n\n               -  AST or ALT > 3 × the ULN for the institution (> 5 × if due to hepatic involvement\n                  by tumor)\n\n               -  Creatinine > 1.5 × ULN for the institution\n\n          7. Patients with any of the following coagulation parameter abnormalities at baseline:\n\n               -  PT (INR) > 1.5 × ULN for the institution\n\n               -  PTT > 1.5 × ULN for the institution\n\n          8. Patients with:\n\n               -  Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism,\n                  within 6 months prior to first study drug administration; patients receiving\n                  systemic anti-coagulation for prophylactic or therapeutic reasons\n\n               -  Active uncontrolled bleeding or a known bleeding diathesis\n\n          9. Patients with a significant cardiovascular disease or condition, including:\n\n               -  Congestive heart failure currently requiring therapy\n\n               -  Need for antiarrhythmic medical therapy for a ventricular arrhythmia\n\n               -  Severe conduction disturbance (e.g., 3rd degree heart block)\n\n               -  Angina pectoris requiring therapy\n\n               -  Known left ventricular ejection fraction < 50% by MUGA or echocardiogram\n\n               -  QTc interval > 450 msec in males, or > 470 msec in females\n\n               -  Uncontrolled hypertension (per the Investigator's discretion)\n\n               -  Class III or IV cardiovascular disease according to the New York Heart\n                  Association's Functional Criteria.\n\n               -  Myocardial infarction within 6 months prior to first study drug administration\n\n         10. Patients with a known or suspected hypersensitivity to any of the components of lipid\n             nanoparticle-formulated DCR-MYC.\n\n         11. Patients with a known history of human immunodeficiency virus or active infection with\n             hepatitis B virus or hepatitis C virus.\n\n         12. Patients with any other serious/active/uncontrolled infection, any infection requiring\n             parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to first\n             study drug administration.\n\n         13. Patients with inadequate recovery from an acute toxicity associated with any prior\n             antineoplastic therapy.\n\n         14. Patients with inadequate recovery from any prior surgical procedure, or patients\n             having undergone any major surgical procedure within 4 weeks prior to first study drug\n             administration.\n\n         15. Patients with any other life-threatening illness, significant organ system\n             dysfunction, or clinically significant laboratory abnormality, which, in the opinion\n             of the Investigator, would either compromise the patient's safety or interfere with\n             evaluation of the safety of the study drug.\n\n         16. Patients with a psychiatric disorder or altered mental status that would preclude\n             understanding of the informed consent process and/or completion of the necessary\n             study-related evaluations.\n\n         17. Patients with the inability or with foreseeable incapacity, in the opinion of the\n             Investigator, to comply with the protocol requirements.\n\n        Exclusion Criteria-Treatments:\n\n          1. MTD PNET Cohort ONLY: Greater than 2 prior systemic treatments for the underlying\n             malignancy\n\n          2. Any antineoplastic agent for the primary malignancy (standard or experimental) within\n             4 weeks prior to first study drug administration with the exception of monoclonal\n             antibody therapy, nitrosoureas, and nitrogen mustard for the primary malignancy within\n             6 weeks prior to first study drug administration\n\n          3. Radiotherapy for the primary malignancy within 4 weeks prior to first study drug\n             administration and during study.\n\n          4. Herbal preparations or related over-the-counter preparations/supplements containing\n             herbal ingredients within 2 weeks prior to first study drug administration and during\n             study.\n\n          5. Systemic hormonal therapy within 2 weeks prior to first study drug administration and\n             during study.\n\n          6. Any other investigational treatments during study. This includes participation in any\n             medical device or therapeutic intervention clinical trials.\n\n          7. Prophylactic use of hematopoietic growth factors within 1 week prior to first study\n             drug administration and during Cycle 1 of study; thereafter prophylactic use of growth\n             factors is allowed as clinically indicated.
-  Subjects with Philadelphia negative B-precursor ALL, with any of the following:\n\n               -  refractory to primary induction therapy or refractory to salvage therapy,\n\n               -  in untreated first relapse with first remission duration <12 months\n\n               -  in untreated second or greater relapse\n\n               -  relapse at any time after allogeneic HSCT\n\n          -  Subject has received intensive combination chemotherapy for the treatment of ALL for\n             initial treatment or subsequent salvage therapy.\n\n          -  Greater than 5% blasts in the bone marrow\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status ? 2\n\n        Exclusion Criteria\n\n          -  Malignancy other than ALL within 5 years before blinatumomab treatment, except for\n             adequately treated selected cancers without evidence of disease\n\n          -  Diagnosis of Burkitt's leukemia according to World Health Organization classification,\n             or human immunodeficiency virus (HIV), Hepatitis B or C, or other clinically\n             significant disorder\n\n          -  Current relevant central nervous system (CNS) pathology or known or suspected CNS\n             involvement\n\n          -  Isolated extramedullary disease\n\n          -  Current autoimmune disease or history of autoimmune disease with potential CNS\n             involvement\n\n          -  Autologous HSCT within 6 weeks or allogeneic HSCT within 12 weeks before blinatumomab\n             treatment, or eligibility for allogeneic HSCT at the time of enrollment\n\n          -  Active acute grade 2 to 4 graft versus host disease (GvHD) according to Glucksberg et\n             al (1974) criteria that required systemic treatment to prevent or treat GvHD 2 weeks\n             before blinatumomab treatment\n\n          -  Known exclusion criteria to investigator choice of SOC chemotherapy (per package\n             insert)\n\n          -  Cancer chemotherapy or radiotherapy with 2 weeks, or immunotherapy (included CD19\n             therapy) within 4 weeks of protocol-specified therapy\n\n          -  Abnormal laboratory values (alanine or aspartate transaminase [ALT or AST] or alkaline\n             phosphatase [ALP] ? 5 × upper limit of normal [ULN]; total bilirubin or creatinine ?\n             1.5 × ULN), or calculated creatinine clearance < 60 mL/min.
Inclusion Criteria:\n\n        Registration: Patients having both diffuse and follicular architectural elements will be\n        considered eligible if the histology is predominantly follicular (? 50% of the\n        cross-sectional area), and there is no evidence of transformation to a large cell\n        histology.\n\n          -  Biopsy-proven diagnosis of Grade 1 or 2 follicular non-Hodgkin's lymphoma with no\n             evidence of transformation to large cell histology.\n\n          -  Meet criteria for Low Tumor Burden:\n\n               -  No nodal or extra nodal mass ? 7 centimeter (cm)\n\n               -  <3 nodal masses >3 cm in diameter\n\n               -  No systemic symptoms or B symptoms\n\n               -  No splenomegaly >16 cm by CT scan\n\n               -  No risk of compression of a vital organ.\n\n               -  No leukemic phase with >5000/mm³ circulating lymphocytes.\n\n          -  No cytopenias defined as:\n\n               -  Platelets <100,000/mm³\n\n               -  Hemoglobin (Hgb) <10 g/dL\n\n               -  Absolute Neutrophil Count (ANC) <1500/mm³\n\n          -  Must have Stage III or Stage IV disease.\n\n          -  Baseline measurements/evaluations obtained within 6 weeks of registration. Patient\n             must have at least one objective measurable disease parameter.\n\n          -  Age ? 18 years.\n\n          -  Eastern Oncology Cooperative Group Performance Status 0-1.\n\n          -  Must not have received investigational agents within 30 days of registration.\n\n          -  Signed Institutional Review Board (IRB)-approved informed consent.\n\n          -  Willing to provide blood samples for research purposes.\n\n          -  Women must not be pregnant or breastfeeding.\n\n          -  Women of childbearing potential and sexually active males must use an accepted and\n             effective method of contraception.\n\n          -  No prior chemotherapy, radiotherapy or immunotherapy for lymphoma.\n\n          -  No prior treatment with cytotoxic drugs or rituximab for a previous cancer or another\n             condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody.\n\n          -  No prior use of any monoclonal antibody within 3 months of randomization.\n\n          -  No history of severe allergic/anaphylactic reactions to humanized/murine monoclonal\n             antibodies or known sensitivity/allergy to murine products.\n\n          -  No history of prior malignancy except for adequately treated basal cell or squamous\n             cell skin cancer, in situ cervical cancer, or other cancer for which the patient has\n             been disease-free for at least 2 years and did not require treatment with cytotoxic\n             drugs or rituximab.\n\n          -  No major surgery within 4 weeks prior to randomization, other than for diagnosis.\n\n          -  Must be Human Immunodeficiency Virus (HIV) negative.\n\n          -  Have adequate organ function without growth factor and/or transfusion support within ?\n             2 weeks prior to registration:\n\n               -  ANC ? 1500/mm³\n\n               -  Hgb ? 10 g/dL\n\n               -  Platelets ? 100,000/mm³\n\n               -  Serum Creatinine ? 2x Upper Limit Normal (ULN)\n\n               -  Total Bilirubin ? 2x ULN\n\n               -  AST (aspartate aminotransferase)/ALT (alanine aminotransferase) ? 5x ULN\n\n               -  PTT (Partial Thromboplastin Time) or aPTT (activated Partial Thromboplastin Time)\n                  >1.5x the ULN in the absence of a lupus anticoagulant\n\n               -  INR (International Normalized Ratio) >1.5x the ULN in the absence of therapeutic\n                  anticoagulation\n\n          -  No active, uncontrolled infections (afebrile for ? 48 hours off antibiotics).\n\n          -  Must not receive immunization with attenuated live vaccines within 28 days prior to\n             registration or during the study period.\n\n          -  Must be tested for hepatitis B surface antigen (HBsAg) and total hepatitis B core\n             antibody (anti-HBc) within 2 weeks of registration. Patients who are chronic carriers\n             of HBsAg and anti-HBc are excluded.\n\n          -  Must be tested for hepatitis C antibody within 2 week of registration. If this test is\n             positive, patients are excluded unless a hepatitis C virus ribonucleic acid (HCV RNA)\n             is negative.\n\n          -  No evidence of significant, uncontrolled concomitant diseases that could affect\n             compliance with the protocol or interpretation of results, including significant\n             cardiovascular disease (i.e., severe arrhythmia, myocardial infarction within the\n             previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease.
INCLUSION CRITERIA:\n\n        Pre-Treatment Phase: Tissue Procurement and Establishment of Tumor Cell Line\n\n          1. Histologic diagnosis of invasive melanoma.\n\n          2. Measurable metastatic melanoma with at least one lesion amenable to -resection Stage\n             III: recurrent regional disease, including regional disease with no known primary.\n\n             Stage IV: distant metastatic melanoma.\n\n          3. Age 18 years and older.\n\n          4. Sign the \Tissue Consent\, the pre-Clinical Informed Consent for Melanoma Tissue\n             Procurement and initiation of cell line effort granting Caladrius permission to\n             cryopreserve the tumor and/or to initiate an autologous tumor cell line from excess\n             tissue that has been removed during a medical procedure (e.g., surgically excised).\n\n          5. Initiation of Autologous Tumor Cell Line. Caladrius must have received a viable\n             melanoma tumor tissue specimen that has been obtained and processed according to\n             company SOPs to ensure tissue viability. The cell line can be initiated with either a\n             specimen of fresh tumor or tumor that has been previously cryopreserved.\n\n        Treatment Phase\n\n          1. Successful establishment of an autologous melanoma cell line by Caladrius.\n\n          2. Patients with multiple depots of distant metastatic disease must have previously\n             received at least one or more of the following standard treatments: interleukin 2\n             (IL-2), or ipilimumab, or vemurafenib (if tumor expresses the V600E mutation), or\n             dacarbazine or temozolomide, if not mutated for the V600E mutation, and not felt to be\n             medically appropriate for IL-2 or ipilimumab. These may have been given alone, or in\n             combination with other agents.\n\n          3. Medical fitness to undergo a leukapheresis, including peripheral venous access or\n             access by central vein if necessary.\n\n          4. Medical fitness for participation in a phase III clinical trial.\n\n               -  a. ECOG performance status of 0 or 1.\n\n               -  b. Adequate bone marrow function: absolute neutrophil count (ANC) greater than\n                  1000/mm (3), hematocrit greater than 30%, platelet count greater than 100,000/mm\n                  (3), no ongoing transfusion requirements.\n\n               -  c. Adequate hepatic function: total bilirubin less than 2.0 mg/dL, alanine\n                  aminotransferase (ALT) and aspartate aminotransferase (AST) less than 3 times the\n                  upper limit of normal (ULN), albumin greater than 3 g/dL.\n\n               -  d. Adequate kidney function: creatinine less than or equal to 2.0 mg/dL.\n\n               -  e. Negative pregnancy test for woman of childbearing potential and use of\n                  effective contraception (hormonal or barrier method of birth control) during\n                  therapy (women of childbearing potential and men).\n\n          5. Extent of disease established within 4 weeks of randomization.\n\n               -  a. History and Physical Exam by a licensed practitioner.\n\n               -  b. Fludeoxyglucose(FDG)-based PET/CT or PET scan and CT scan.\n\n               -  c. Brain MRI demonstrating no new untreated or uncontrolled metastases.\n\n          6. Recovery from previous therapies.\n\n               -  a. At least four weeks (28 days) must have elapsed since any prior systemic\n                  therapy at the time of the first dose (six weeks for anti-cytotoxic T\n                  lymphocyte-associated antigen 4 (anti-CTLA-4), and any toxicities experienced\n                  must have recovered to a grade 1 or less (except for alopecia or vitiligo).\n\n               -  b. More than three weeks (at least 22 days) since radiation therapy at the time\n                  of the first dose (7 days for single-dose stereotactic radiotherapy such as gamma\n                  knife) and recovery from acute toxicities. Patients treated with whole brain\n                  radiation must wait at least 22 days after completion of radiation and have\n                  radiographic confirmation of lack of progression before proceeding to\n                  randomization.\n\n        EXCLUSION CRITERIA:\n\n        Pre-Treatment Phase: Tissue Procurement and Establishment of Tumor Cell Line\n\n          1. Eastern Cooperative Oncology Group (ECOG) performance status greater than 2\n\n          2. Lack of a metastatic melanoma lesion that can be resected.\n\n        Treatment Phase\n\n          1. Known positive for hepatitis B or C or HIV.\n\n          2. Pregnant or lactating women.\n\n          3. Underlying cardiac disease associated with known myocardial dysfunction, or active\n             treatment with digoxin or other medications being given to treat heart failure, or\n             unstable angina related to atherosclerotic cardiovascular disease.\n\n          4. Diagnosis of any other invasive cancer that requires ongoing treatment or for which\n             there is evidence of active disease.\n\n          5. Active, unresolved infection and/or receiving concurrent treatment with parenteral\n             antibiotics (patients are eligible after antibiotics have been discontinued for at\n             least 7 days prior to first dose and evidence of infection has resolved).\n\n          6. Other active medical condition that could be imminently life threatening, in the\n             opinion of the investigator, including no active blood clotting or bleeding diathesis.\n\n          7. New or uncontrolled brain metastases or leptomeningeal disease and/or taking\n             pharmacological doses of corticosteroids. Brain metastases treated by gamma knife or\n             stereotactic radiotherapy are considered controlled, unless patient requires\n             pharmacologic doses of corticosteroids. It is recognized that tumor necrosis may be\n             confused with tumor progression in interpretation of Brain MRI.\n\n          8. Known autoimmune disease, immunodeficiency, or disease process that involves the use\n             of immunosuppressive therapy.\n\n          9. Taking other anticancer therapy.\n\n         10. Received another investigational drug within 28 days of the first dose.
Inclusion Criteria:\n\n        Subjects must meet ALL of the following criteria to be eligible for inclusion into the\n        study.\n\n          -  Histological or cytological diagnosis of adenocarcinoma of the prostate\n\n          -  Metastatic disease on chest, abdominal, or pelvic computed tomography (CT) scan and/or\n             bone scan\n\n          -  Currently receiving abiraterone acetate and prednisone and meeting the following\n             criteria:\n\n               -  Any PSA decline within 12 weeks from initiation of abiraterone acetate\n\n               -  Currently tolerating abiraterone acetate (1000 mg oral daily) and prednisone\n                  (10-20 mg oral daily)\n\n               -  PSA progression, defined as an increase in PSA which is ?25% above the nadir and\n                  an absolute value of ?2 ng/mL, which is confirmed by a second value ?2 weeks\n                  later.\n\n               -  No evidence of symptomatic or radiographic progression that would require\n                  alternative therapy (e.g., needing radiation therapy for pain or significant\n                  progression of visceral metastases or >33% increase in daily opioid use within 2\n                  weeks prior to randomization).\n\n          -  All patients who have not had a surgical orchiectomy must continue treatment with a\n             luteinizing hormone-releasing hormone (LHRH) agonist or antagonist to maintain a\n             castrate level of testosterone.\n\n          -  Patient must fulfill \Prior Therapy\ criteria as follows:\n\n               -  Chemotherapy: no more than 1 prior chemotherapy regimen for castrate-resistant\n                  prostate cancer (CRPC) is permitted; a minimum of at least 28 days must have\n                  passed since the last dose of chemotherapy.\n\n               -  Hormone therapy: hormonal androgen ablation therapy prior to abiraterone is\n                  required.\n\n               -  Experimental therapy: prior non-cytotoxic experimental therapy is permitted\n                  provided a minimum of at least 14 days has passed since completing therapy. Prior\n                  treatment with enzalutamide (MDV3100) is allowed.\n\n               -  Radiation: prior external beam radiation is permitted provided a minimum of at\n                  least 14 days have passed since completing radiotherapy (exception for\n                  radiotherapy: at least 7 days since completing a single fraction of ?800 cGy to a\n                  restricted field or limited-field radiotherapy to non-marrow bearing area such as\n                  an extremity or orbit) at the time of randomization\n\n          -  Must be willing to use effective contraception throughout study treatment and for 3\n             months after completion of study treatment if able to father a child.\n\n          -  Must be willing not to change (add or subtract) bone protecting therapy\n             (bisphosphonates and/or denosumab) during the study unless changed for toxicity.\n\n          -  Written informed consent must be obtained prior to any protocol-specific procedures\n             being performed.\n\n        Exclusion Criteria:\n\n        Subjects meeting ANY of the following exclusion criteria will NOT be eligible for inclusion\n        into the study:\n\n          -  Currently receiving abiraterone acetate in combination with any other anti-cancer\n             agent (except prednisone)\n\n          -  Documented brain metastases, or carcinomatous meningitis, treated or untreated (Brain\n             imaging for asymptomatic patients is not required.)\n\n          -  Cord compression requiring surgery or radiation therapy while on abiraterone treatment\n\n          -  Active second malignancy (including lymphoid malignancies such as chronic lymphocytic\n             leukemia or low grade lymphoma) defined, in general, as requiring anticancer therapy\n             or at high risk of recurrence during the study; not including adequately treated non\n             melanomatous skin cancer or other solid tumors curatively treated with no evidence of\n             disease in > 3 years\n\n          -  History of allergic reactions to therapeutic antisense oligonucleotides\n\n          -  Active autoimmune disease requiring treatment\n\n          -  Participated in a prior Phase 3 clinical study evaluating custirsen regardless of\n             study arm assignment (i.e., either control or investigational arm), or prior exposure\n             to OGX-427\n\n          -  Uncontrolled medical conditions such as myocardial infarction, uncontrolled\n             hypertension, stroke or treatment of a major active infection within 3 months of\n             randomization, as well as any significant concurrent medical illness that in the\n             opinion of the Investigator would preclude protocol therapy\n\n          -  Planned concomitant participation in another clinical trial of an experimental agent,\n             vaccine, or device. Concomitant participation in observational studies is acceptable.
Inclusion Criteria:\n\n        3.1.1 Histologically-proven, invasive primary squamous, basaloid, or cloacogenic carcinoma\n        of the anal canal; 3.1.2 AJCC 2009 TN Stage: T1N1-N3, T2(< 4cm)N1-N3, T2(> 4cm)N0,T3N0-3,\n        T4N0-3;based upon the following minimum diagnostic workup: 3.1.2.1 History/physical\n        examination within 14 days prior to registration; 3.1.2.2 Within 42 days prior to\n        registration, the patient must have an anal examination by any of the following:\n        colonoscopy, sigmoidoscopy, or rigid proctoscopy, with documentation of primary anal lesion\n        size, distance from anal verge.\n\n        3.1.3 Groin examination within 42 days prior to registration with documentation of any\n        groin adenopathy and lymphadenopathy (location: right vs. left; medial vs. lateral; mobile\n        vs. fixed; and size); 3.1.4 X-ray (PA and lateral), CT scan, or PET/CT scan of the chest\n        within 42 days prior to registration; 3.1.5 CT scan, MRI, or PET/CT of the abdomen and\n        pelvis within 42 days prior to registration; 3.1.6 Zubrod Performance Status 0-1; 3.1.7 Age\n        ? 18; 3.1.8 Laboratory data obtained ? 14 days prior to registration on study, with\n        adequate bone marrow, hepatic and renal function defined as follows:\n\n          -  Absolute neutrophil count (ANC) ? 1,500 cells/mm3;\n\n          -  Platelets ? 100,000 cells/mm3;\n\n          -  Hemoglobin ? 8.0 g/dl (Note: The use of transfusion or other intervention to achieve\n             Hgb ? 8.0 g/dl is acceptable.);\n\n          -  Serum creatinine ? 1.5 mg/dl;\n\n          -  Bilirubin < 1.4mg/dl;\n\n          -  ALT/AST < 3 x ULN;\n\n          -  Negative serum pregnancy test for women of child-bearing potential; 3.1.9 Women of\n             childbearing potential and male participants must agree to use a 2 forms of medically\n             effective means of birth control (such as a condom and spermicide) throughout their\n             participation in the treatment phase of the study and for 90 days post last dose of\n             study drug.\n\n        3.1.10 Patients must sign a study-specific informed consent prior to study entry.\n\n        3.1.11 Patients with a history of clinically significant pulmonary disease must have PFTs\n        demonstrating a DLCO ? 40%. This testing is considered standard of care prior to mitomycin,\n        5-FU and radiation.\n\n        3.1.12 Patients with a history of clinically significant cardiac disease must have a LVEF ?\n        30% by ECHO. (MUGA scan may also be used to determine LVEF) This testing is considered\n        standard of care prior to mitomycin, 5-FU and radiation.\n\n        3.1.13 Patients must be able to swallow pills.\n\n        Exclusion Criteria:\n\n        3.2.1 Prior invasive malignancy (except non-melanomatous skin cancer), unless disease free\n        for a minimum of 2 years; 3.2.2 Prior systemic chemotherapy for anal cancer; 3.2.3 Prior\n        allergic reaction to the study drugs involved in this protocol. 3.2.4 Prior radiotherapy to\n        the pelvis that would result in overlap of radiation therapy fields; 3.2.5 Severe, active\n        co-morbidity, defined as follows: 3.2.5.1 Patients with uncontrolled intercurrent illness\n        including, but not limited to ongoing or active infection, symptomatic congestive heart\n        failure, unstable angina pectoris and cardiac arrhythmia are ineligible. Furthermore,\n        patients with unstable angina and/or congestive heart failure requiring hospitalization\n        within the past 6 months are ineligible; 3.2.5.2 Patients with active infection requiring\n        systemic therapy (oral or IV) or those currently receiving antibiotics that cannot\n        discontinue prior to dosing are ineligible.\n\n        3.2.5.3 Transmural myocardial infarction within the last 6 months; 3.2.5.4 Acute bacterial\n        or fungal infection requiring intravenous antibiotics at the time of registration; 3.2.5.5\n        Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring\n        hospitalization or precluding study therapy at the time of registration; 3.2.5.6 Hepatic\n        insufficiency resulting in clinical jaundice and/or coagulation defects; 3.2.6 Patients\n        known to be seropositive for HIV and/or active hepatitis, even if liver function studies\n        are in the eligible range.\n\n        3.2.7 Other immunocompromised status (e.g., organ transplant or chronic glucocorticoid\n        use).If patient has diagnosis of immunodeficiency, is dependent on or has received systemic\n        steroids therapy or any form of immunosuppressive therapy within 7 days prior to the first\n        dose of ADXS11-001 they are ineligible. Topical corticosteroid or occasional inhaled\n        corticosteroids are allowed.\n\n        3.2.8 Women who are pregnant or lactating are ineligible because the treatment involved in\n        this study may be significantly teratogenic and there is the potential for transmission of\n        listeria to the infant.\n\n        3.2.9 Patients allergic to or with a sensitivity to penicillin, ampicillin,\n        trimethoprim-sulfa and quinolones (including history of rash or anaphylaxis).\n\n        3.2.10 Patients allergic to naproxen. 3.2.11 Patients receiving oral or IV antibiotics\n        3.2.12 Patients with a prior history of a splenectomy and/or sickle cell trait/disease\n        3.2.13 Patient has implanted medical device(s) that pose a high risk for colonization\n        and/or cannot be easily removed (e.g., prosthetic joints, artificial heart valves,\n        pacemakers, orthopedic screw(s), metal plate(s), bone graft(s), or other exogenous\n        implant(s)). NOTE: More common devices and prosthetics which include arterial and venous\n        stents, dental and breast implants and venous access devices (e.g. Port-a-Cath or Mediport)\n        are permitted. Sponsor must be contacted prior to consenting any subject who has any other\n        device and/or implant. Site is required to submit to BrUOG ALL surgical implants patient\n        has ever had in their medical history and ALL surgeries regardless of link to this cancer\n        diagnosis.\n\n        3.2.14 Patients who are receiving or may receive future treatment with PI3K or TNF?\n        inhibitors. To be confirmed by treating medical oncologist in writing 3.2.15 Has undergone\n        a major surgery, including surgery for a new artificial implant and/or device, within 6\n        weeks prior to the initiation of ADXS11-001 treatment. NOTE: if patient underwent surgery >\n        6 weeks from start of ADSX11-001, all toxicities and/or complications must have recovered\n        to baseline or Grade 1 prior to the initiation of ADXS11-001 study therapy.\n\n        3.2.16 Patient not being willing to have new infusion line placed for each infusion of\n        ADXS11-001 as existing or newly placed central venous catheter or infusion ports are not\n        allowed to be used for ADXS11-001 administration. Must be confirmed as discussed with\n        patient and that they agreed.\n\n        3.2.17 Patient not willing to comply with requirement of central venous catheter or\n        infusion port must not be used for 72 hours following the completion of the ADXS11-001\n        infusion and the patient receives the first post-treatment dose of oral antibiotics. Must\n        be confirmed as discussed with patient and that they agreed.\n\n        3.2.18 Live vaccines within 30 days prior to the first dose of trial treatment and while\n        participating in the trial. Examples of live vaccines include, but are not limited to, the\n        following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid\n        (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus\n        vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live\n        attenuated vaccines and are not allowed. All recent vaccines (within 30 days) to be listed\n        on conmed log 3.2.19 Patient has a history of listeriosis or prior ADXS11-001 therapy.
ENTRY CRITERIA:\n\n        DISEASE CHARATERISTICS:\n\n          -  Confirmed diagnosis of relapsed/refractory multiple myeloma after treatment with at\n             least two different previous regimens.\n\n               -  Refractory disease is defined as progressive disease while on therapy or\n                  progression within 60 days of therapy.\n\n               -  Progressive disease is defined by a 25% increase from the lowest response value\n                  in specified tests.\n\n          -  Measurable disease as defined by at least one of the following:\n\n               -  Serum M-protein ? 1g/dL (for IgG, IgM) or 0.5 g/dL (for IgA)\n\n               -  Urine M-protein ? 200mg/24hours\n\n               -  Serum free light chains ? 10 mg/dL and abnormal kappa/lambda ratio\n\n        PRIOR/CONCURRENT THERAPY:\n\n          -  No anti-myeloma treatments within 28 days before the start of study treatment.\n\n          -  Must have recovered from side effects of prior treatments.\n\n        PATIENT CHARACTERISTICS:\n\n        Age\n\n        • ? 18 years\n\n        Performance Status\n\n        • ECOG 0, 1, or 2\n\n        Bone Marrow Reserve\n\n          -  Absolute neutrophil count (AGC/ANC) ? 1,000/uL\n\n          -  Platelets ? 30,000/uL\n\n          -  Hemoglobin ? 8g/dL\n\n        Renal Function\n\n        • Glomerular Filtration Rate (GFR) > 45mL/min/1.73m^2\n\n        Hepatic Function\n\n          -  Total bilirubin ? 2.0 X ULN\n\n          -  AST, ALT, ALP ? 3.0 X ULN, or ? 5.0 X ULN (if liver metastases exist)\n\n        Cardiovascular\n\n          -  No congestive heart failure < 6 months\n\n          -  No unstable angina pectoris < 6 months\n\n          -  No myocardial infarction < 6 months\n\n          -  No history of ventricular arrhythmias\n\n          -  No history of supraventricular arrhythmias\n\n          -  No NYHA Class > II CHF\n\n          -  Normal Transthoracic Echocardiogram (TTE) is required for patients with history of EKG\n             abnormalities, CHF, coronary artery disease or other cardiac disease, or with a\n             history of having received adriamycin or doxorubicin\n\n          -  Patients with a left ventricular ejection fraction (LVEF) of less than 50% will be\n             excluded from study entry\n\n        Pulmonary\n\n        • Normal clinical assessment of pulmonary function\n\n        Other\n\n          -  Negative serum pregnancy test if female and of childbearing potential\n\n          -  Women who are not pregnant or nursing\n\n          -  Subjects, both females and males, with reproductive potential must agree to use\n             effective contraceptive measures for the duration of the study\n\n          -  No known autoimmune disease other than corrected hypothyroidism\n\n          -  No known prior organ allograft or allogeneic transplantation\n\n          -  Not HIV positive\n\n          -  No history or evidence of uncontrollable CNS disease\n\n          -  No psychiatric illness/social situation\n\n          -  No other illness that in the opinion of the investigator would exclude the subject\n             from participating in the study\n\n          -  Must provide informed consent and HIPPA authorization and agree to comply with all\n             protocol-specified procedures and follow-up evaluations\n\n          -  Active systemic infection requiring parenteral antibiotic therapy.\n\n          -  No ongoing chronic systemic steroid therapy required.
Inclusion Criteria:\n\n        3.1.1 First-line treatment of metastatic colorectal cancer with 3 or more metastases\n        3.1.2At least 10 cycles of combination therapy with an oxaliplatin or irinotecan based\n        regimen per institutional preference (patients may receive 6 cycles, go to surgery, then\n        complete 4 cycles, they may complete all 10 (or more) prior to surgery, or receive any\n        combination as long as they receive at least 10 cycles. ) 3.1.3 Resection or ablation of\n        all metastatic sites that have not achieved complete response with perioperative therapy\n        (regimen). The sequencing of resection, ablation, and 10-12 cycles of combination therapy\n        (regimen) with an oxaliplatin or irinotecan based regimen may be performed according to\n        standard institutional procedure.\n\n        3.1.4 Patients achieving a complete response in a metastatic site by stereotactic body\n        radiation are eligible if the site was not easily accessible by surgery or ablation and a\n        complete response was achieved.\n\n        3.1.5 No severe, uncontrolled concurrent illness that would interfere with protocol\n        therapy.\n\n        3.1.6 No known CNS disease 3.1.7 ECOG Performance Status 0-2 3.1.8 No chemotherapy or\n        radiation therapy within last 3 weeks 3.1.9 For patients who had 3 months of perioperative\n        therapy (regimen), then surgery, then 3 months of therapy (regimen), patients must be off\n        therapy for no more than 8 weeks prior to randomization. For patients who had all their\n        therapy and then surgery, they must be no more than 8 weeks from surgery prior to\n        randomization.\n\n        3.1.10 No concurrent anticancer therapy. 3.1.11 Absolute neutrophil count ? 1,500/uL, Hgb >\n        9.0 g/dl, platelet ? 100,000/uL.\n\n        3.1.12 Total bilirubin ? 1.5x upper limit of normal (ULN) and AST or ALT ? 5x ULN; 3.1.13\n        Creatinine < 1.5 x ULN 3.1.14 Life expectancy of at least 12 weeks. 3.1.15 Age ? 18 years\n        3.1.16 Women of childbearing potential must have a negative pregnancy test. 3.1.17 Men and\n        women of childbearing potential must be willing to consent to using effective contraception\n        while on treatment and for at least 3 months thereafter.\n\n        3.1.18 Voluntary written informed consent.\n\n        Exclusion Criteria:\n\n        3.2.1 Residual metastatic disease after resection/ablation 3.2.2 Clinically significant\n        cardiac disease (e.g., uncontrolled hypertension [blood pressure of >160/90 mmHg on\n        medication], history of myocardial infarction within 6 months,), New York Heart Association\n        (NYHA) Class II or greater congestive heart failure within 6 months, unstable arrhythmia.\n        Patients with an atrial arrhythmia must have this condition well controlled on stable\n        medication. Patients with current or recent (within 6 months) unstable angina are also not\n        eligible. Documentation of cardiac medical history to be provided.\n\n        3.2.3 Significant bleeding diathesis or coagulopathy 3.2.4 History of cerebral aneurysms or\n        cerebral arteriovenous malformations. 3.2.5 Patients with recent (within 12 months)\n        arterial thromboembolic events, including transient ischemic attack (TIA), cerebrovascular\n        accident (CVA), or clinically significant peripheral artery disease should also be\n        excluded.\n\n        3.2.6 Patients with a history of a gastrointestinal fistula or perforation. 3.2.7 Women who\n        are breast-feeding. 3.2.8 Patients who have undergone major surgery, chemotherapy, or\n        radiotherapy within the last 3 weeks.\n\n        3.2.9 Patients on concurrent anticancer therapy.
Inclusion Criteria:\n\n        • Cytomorphologically documented diagnosis of acute myeloid leukemia (AML). Acute\n        promyelocytic leukemia patients will be excluded (FAB M3). FAB classification, cytogenetics\n        and molecular markers (if applicable) must be available at registration.\n\n        Phase I Enrollment:\n\n          -  Must be in first or second complete remission, e.g., no evidence of active disease in\n             blood, bone marrow (<5% blasts), or other tissues.\n\n          -  For each remission, may have received no more than 2 cycles of induction treatment\n             (any type).\n\n          -  May have received no more than one course of consolidation for the current remission\n             prior to enrollment (any type)\n\n        Phase II Enrollment:\n\n          -  Must be in first complete remission, e.g., no evidence of active disease in blood,\n             bone marrow (<5% blasts), or other tissues.\n\n          -  May have received no more than 2 cycles of induction treatment (any type).\n\n        Enrollment in Either Phase:\n\n          -  Remission status must be documented by a bone marrow examination up to 28 days prior\n             to study registration.\n\n          -  Have recovered from induction and first consolidation (if applicable) therapy side\n             effects (or ?grade 1).\n\n          -  ?18 years of age and ?70 years of age.\n\n          -  ECOG performance status 0, 1, 2.\n\n          -  Have not received cytotoxic drug therapy within 21 days of registration.\n\n          -  Have not received hematopoietic colony stimulating growth factors within 14 days of\n             registration.\n\n          -  Have not received packed red blood cells or platelets within 7 days of registration.\n\n          -  Have not received investigational agents within 30 days of registration and will not\n             receive any investigational agents other than eltrombopag/placebo during study.\n\n          -  Signed IRB-approved informed consent.\n\n          -  Willing to provide blood samples for research purposes.\n\n          -  Adequate organ function obtained within 28 days prior to registration:\n\n               -  Absolute neutrophil count >1 x 10?/L\n\n               -  Platelet count >100 x 10?/L\n\n               -  Total direct serum bilirubin ?1.5x upper limit of normal (ULN)\n\n               -  ALT and AST ?3x ULN\n\n               -  BUN and serum creatinine <2x ULN\n\n               -  Albumin ?2.5 g/dL\n\n               -  PT and PTT 80-120% of institutional normal range\n\n          -  Women of childbearing potential must have a negative serum pregnancy test within 14\n             days of registration.\n\n          -  Not pregnant nor breast feeding.\n\n          -  Women of childbearing potential and sexually active males must use an accepted and\n             effective method of contraception.\n\n          -  Patients of known East Asian ancestry (Chinese, Japanese, Taiwanese, and Korean) are\n             excluded from protocol participation for safety and efficacy reasons.\n\n          -  Able to swallow and retain orally administered medication.\n\n          -  No clinically significant gastrointestinal abnormalities such as malabsorption\n             syndrome or major resection of the stomach or bowels.\n\n          -  No clinical evidence of hepatomegaly or splenomegaly.\n\n          -  No known risk for Torsades de Pointes. (Eltrombopag use has not been shown to be\n             associated with Torsades de Pointes.)\n\n          -  No active or unresolved infection and must be off all antibiotics for at least 7 days\n             prior to registration.\n\n          -  No current evidence of invasive fungal infection.\n\n          -  No known Hepatitis B, Hepatitis C active disease.\n\n          -  No known Human Immunodeficiency Virus (HIV) seropositivity. The risk for potential\n             toxicities secondary to HIV (e.g., increased risk for fatal opportunistic infection)\n             may confound the toxicity profile of eltrombopag.\n\n          -  Patients with a history of Central Nervous System (CNS) leukemia are eligible if there\n             is documentation of no current CNS involvement on cerebrospinal fluid (CSF)\n             examination (e.g., negative CSF by lumbar puncture) within 28 days of registration.\n\n          -  No prior or concomitant malignancy in the past 5 years which is currently active and\n             likely to interfere with the patient's treatment for AML or which is likely to\n             increase the patient's morbidity or mortality. No prior chemotherapy or radiation\n             therapy allowed (unless related to AML treatment).\n\n          -  No concurrent organ damage or medical problems that would prohibit therapy.
Inclusion Criteria:\n\n          -  Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without\n             small cell histology. Disease must be either metastatic or locally confined inoperable\n             disease that cannot be treated with definitive intent (no chance for a curative\n             intervention).\n\n          -  Has supplied tumor tissue from a newly obtained biopsy or a biopsy obtained ?12 months\n             prior to study start and an archival specimen, if available, from a site not\n             previously irradiated. Participants in Cohorts 1, 2, and 4 with visceral/measurable\n             lesions must provide a newly obtained biopsy performed after the last line of systemic\n             therapy or a biopsy obtained ?12 months prior to study start and an archival specimen,\n             if available. Participants in Cohorts 3 and 5 must at least provide an archival\n             specimen.\n\n        For Cohorts 1, 2, and 3 only:\n\n          -  Has been treated with:\n\n          -  At least 1 targeted endocrine therapy (defined as second generation antiandrogen\n             therapies that include but are not limited to abiraterone acetate with prednisone,\n             enzalutamide, and next generation targeted agents such as ARN-509).\n\n          -  At least 1 regimen/line of chemotherapy that contained docetaxel.\n\n          -  No more than 2 chemotherapy regimens.\n\n          -  No more than 3 regimens/lines of the aforementioned treatments (having\n             failed/progressed on chemotherapy and targeted endocrine therapy).\n\n        For Cohorts 4 and 5 only:\n\n          -  Failing or showing early signs of failure on current pre-chemotherapy enzalutamide\n             treatment as defined by Prostate Cancer Working Group 3 PCWG3 guidelines. Participants\n             can have failed prior abiraterone treatment before current enzalutamide treatment.\n             Participants must have had a clinically meaningful response to enzalutamide treatment.\n             Enzalutamide must have been initiated no less than 4 weeks prior to the first dose of\n             trial treatment and be continued throughout the study.\n\n        For All Cohorts:\n\n          -  Has documented prostate cancer progression within 6 months prior to screening, as\n             determined by the Investigator, by means of one of the following: 1) PSA progression\n             as defined by a minimum of 3 rising PSA levels with an interval of ?1 week between\n             each assessment where the PSA value at screening should be ?2 ng/mL, OR, 2)\n             Radiographic disease progression in soft tissue or bone with or without PSA\n             progression\n\n          -  Has ongoing androgen deprivation with total serum testosterone <50 ng/dL (<2.0 nM).\n\n          -  Participants receiving bone resorptive therapy (including but not limited to\n             bisphosphonate or Receptor activator of nuclear factor kappa-B ligand [RANK-L\n             inhibitor]) must have been on stable doses for ?4 weeks prior to first dose of study\n             drug.\n\n          -  Has a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG)\n             Performance Scale\n\n          -  Males of reproductive potential must agree to use an adequate method of contraception,\n             starting with the first dose of study drug through 120 days after the last dose of\n             study drug.\n\n          -  Demonstrates adequate organ function.\n\n        Exclusion Criteria:\n\n        For All Cohorts:\n\n          -  Is currently participating and receiving study therapy or has participated in a study\n             of an investigational agent and received study therapy or used an investigation device\n             within 4 weeks of the first dose of study drug.\n\n          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any\n             other form of immunosuppressive therapy within 7 days prior to the first dose of study\n             drug.\n\n          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the\n             first dose of study drug or who has not recovered (i.e., ? Grade 1 or at Baseline)\n             from AEs due to mAbs administered more than 4 weeks earlier.\n\n          -  Has had prior chemotherapy, targeted small molecule therapy, or external beam\n             radiation therapy within 4 weeks prior to the first dose of study drug or who has not\n             recovered (i.e., ? Grade 1 or at Baseline) from AEs due to a previously administered\n             agent.\n\n          -  Has a known additional malignancy that has had progression or has required active\n             treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin and\n             squamous cell carcinoma of the skin that has undergone potentially curative therapy.\n\n          -  Has known active central nervous system (CNS) metastases and/or carcinomatous\n             meningitis.\n\n          -  Has an active autoimmune disease that has required systemic treatment in past 2 years\n             (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive\n             drugs).\n\n          -  Has evidence of interstitial lung disease and/or a history of (non-infectious)\n             pneumonitis that required steroids, or current pneumonitis.\n\n          -  Has an active infection requiring systemic therapy.\n\n          -  Has known psychiatric or substance abuse disorders that would interfere with\n             cooperation with the requirements of the trial.\n\n          -  Has previously participated in any other pembrolizumab (MK-3475) trial, or received\n             prior therapy with an anti-programmed cell death 1 (anti-PD-1, anti-PD ligand 1\n             [anti-PD-L1], and anti-PD-L2 [including ipilimumab or any other antibody or drug\n             specifically targeting T-cell co-stimulation or checkpoint pathways]).\n\n          -  Has a known history of Human Immunodeficiency Virus (HIV).\n\n          -  Has known active Hepatitis B or Hepatitis C.\n\n          -  Has received a live vaccine within 30 days of planned start of study drug.\n\n        For Cohorts 4 and 5 only:\n\n          -  Has received prior chemotherapy (e.g., docetaxel) for mCPRC.\n\n          -  Has any condition (cardiac, neurologic, absorption) other than clinically failing or\n             showing early signs of failure on enzalutamide treatment that would require imminent\n             discontinuation of enzalutamide treatment.
Inclusion Criteria:\n\n        Patients must meet all of the following inclusion criteria to be eligible to enroll in this\n        study.\n\n          1. Written informed consent obtained prior to any screening procedures and in accordance\n             with federal, local, and institutional guidelines.\n\n          2. Age ?18 years.\n\n          3. Patients with advanced solid malignancies or NHL for which all standard therapeutic\n             options considered useful by the investigator have been exhausted.\n\n          4. Patients must have objective evidence of progressive disease on study entry:\n\n               1. Advanced solid malignancies: Measureable disease as defined by RECIST 1.11.\n\n               2. NHL: Measureable disease including target lesion(s) as defined by the Lugano\n                  Classification2 for initial evaluation and staging.\n\n          5. Patients must have a site of disease amenable to biopsy and be a candidate for biopsy\n             according to the treating institution's guidelines.\n\n          6. Eastern Cooperative Oncology Group (ECOG) performance status of ? 1.\n\n          7. Adequate hepatic function:\n\n               1. Total bilirubin < 1.5 times the upper limit of normal (ULN) (except patients with\n                  Gilbert's syndrome [hereditary indirect hyperbilirubinemia] who must have a total\n                  bilirubin of ? 3 times ULN),\n\n               2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2.5 times\n                  ULN (except patients with known liver involvement of their advanced solid\n                  malignancy or NHL who must have their AST and ALT ? 5.0 times ULN).\n\n          8. Adequate renal function: estimated creatinine clearance of ? 60 mL/min, calculated\n             using the formula of Cockroft and Gault (140-Age) • Mass (kg)/(72 • creatinine mg/dL);\n             multiply by 0.85 if female.\n\n          9. Female patients of child-bearing potential must agree to use dual methods of\n             contraception (including one highly effective and one effective method of\n             contraception) and have a negative serum pregnancy test at Screening, and male\n             patients must use an effective barrier method of contraception if sexually active with\n             a female of child-bearing potential. For both male and female patients, effective\n             methods of contraception must be used throughout the study and for 3 months following\n             the last dose.\n\n         10. Adequate hematopoietic function: total white blood cell (WBC) count ? 1500/mm3,\n             absolute neutrophil count (ANC) ? 1000/mm3, hemoglobin (Hb) ? 10.0 g/dL, and platelet\n             count ? 75,000/mm3.\n\n         11. Dose Escalation Phase: Patients will be enrolled according to their NAPRT1 status at a\n             ratio of 2:1 (NAPRT1 negative:NAPRT1 positive). The NAPRT1 status must be determined\n             prior to enrollment based on evaluation of a fresh tumor biopsy or archival tissue\n             taken ? 6 months of screening.\n\n         12. Dose Expansion Phase (KPT-9274 ± niacin ER cohort only): Patient tumors NAPRT1 and\n             IDH1 tumor status must be determined at the central laboratory prior to enrollment.\n\n             a. Confirmation of NAPRT1 expression and IDH1 mutation based on evaluation of a fresh\n             tumor biopsy or archival tumor biopsy taken ? 6 months of screening tests as follows:\n\n             i. NAPRT1 positive for expansion cohort I or III\n\n             ii. NAPRT1 negative for expansion cohort II or III\n\n             iii. IDH1 mutation status for expansion cohort IV\n\n         13. Life expectancy of ? 3 months.\n\n        Exclusion Criteria:\n\n        Patients meeting any of the following exclusion criteria are not eligible to enroll in this\n        study.\n\n          1. Female patients who are pregnant or lactating.\n\n          2. Time since the last prior therapy for treatment of advanced solid malignancies or\n             NHL**:\n\n               1. Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including\n                  investigational anti-cancer therapy ? 2 weeks prior to C1D1.\n\n               2. Palliative steroids for disease related symptoms < 7 days prior to C1D1.\n                  **Patients must have recovered or stabilized (Grade 1 or to their baseline for\n                  non-hematologic toxicities, ? Grade 2 or to their baseline for hematologic\n                  toxicities) from toxicities related to their previous treatment except for\n                  alopecia. In specific cases, patients with Grade 2 non-hematologic toxicities\n                  will be allowed following approval by the Karyopharm medical monitor.\n\n          3. Patients with known central nervous system (CNS) disease or leptomeningeal\n             involvement, regardless of response to prior therapy, are excluded.\n\n          4. Major surgery within four weeks before C1D1.\n\n          5. Impaired cardiac function or clinically significant cardiac diseases, including any of\n             the following:\n\n               1. Unstable angina or acute myocardial infarction ?3 months prior to C1D1;\n\n               2. Clinically significant heart disease (e.g., symptomatic congestive heart failure;\n                  uncontrolled arrhythmia, or hypertension; history of labile hypertension or poor\n                  compliance with an antihypertensive regimen).\n\n          6. Active infection with completion of therapeutic antibiotics, antivirals, or\n             antifungals within one week prior to C1D1. Prophylactic antibiotics, antivirals or\n             antifungals are permitted.\n\n          7. Patients with a known history of Human Immunodeficiency Virus (HIV); HIV testing is\n             not required as part of this study.\n\n          8. Known, active hepatitis A, B, or C infection; or known to be positive for HCV RNA or\n             HBsAg (HBV surface antigen). Testing is not required.\n\n          9. Patients with significantly diseased or obstructed gastrointestinal tract or\n             uncontrolled vomiting or diarrhea that could interfere with the absorption of\n             KPT-9274.\n\n         10. Serious psychiatric or medical conditions that, in the opinion of the Investigator,\n             could interfere with treatment, compliance, or the ability to give consent.\n\n         11. Active peptic ulcer disease or other active gastrointestinal bleeds.
Inclusion Criteria:\n\n        All subjects must meet the following criteria for inclusion:\n\n          -  ? 18 years of age\n\n          -  Life expectancy of ? 3 months\n\n          -  Histological or cytological evidence of advanced and/or metastatic carcinoma or\n             melanoma , excluding sarcoma\n\n          -  At least 1 measurable disease lesion as defined by RECIST 1.1\n\n          -  Serum creatinine clearance ? 60 mL/min and serum creatinine ? 2.0 x the upper limit of\n             normal (ULN) as determined by either of the following: Estimation as calculated by\n             Cockcroft-Gault equation or Direct measurement by 24-hour urine collection\n\n          -  Total bilirubin ? 1.5 x ULN (unless elevated due to Gilbert's syndrome)\n\n          -  Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ? 2.5 x\n             ULN (<5x ULN if liver metastasis)\n\n          -  Adequate hematological function, defined as absolute neutrophil count ?1.5 x 109/L,\n             hemoglobin ? 9.0 g/dL, and platelet count ? 100 x 109/L\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status ? 2 (corresponds to\n             Karnofsky Performance Status (KPS) ? 60%)\n\n        Subjects entering Part A, B, C, or D must also meet the following additional criterion:\n\n        • Failure to respond to standard therapy, or for whom no appropriate therapies are\n        available (based on the judgement of the Investigator)\n\n        Subjects entering Part D, E, F or G must also meet the following additional criterion:\n\n        • Willing to undergo 1 pre-treatment and 1 on-treatment tumor biopsy\n\n        Subjects entering Part E must also meet the following additional criteria:\n\n          -  Histological or cytological evidence of NSCLC, melanoma, , human papillomavirus (HPV)\n             positive or HPV negative SCCHN (oral cavity, pharynx, hypopharynx, larynx,\n             nasopharyngeal [including undifferentiated nasopharyngeal carcinoma]), or another\n             tumor type to be determined\n\n          -  Failure to respond to standard therapy, or for whom no appropriate therapies are\n             available (based on the judgment of the Investigator The most recent treatment prior\n             to study entry must be an anti-PD-1 or anti-PD-L1 antibody given as either monotherapy\n             or in combination\n\n          -  Subjects with NSCLC Tumors that harbor an actionable genetic alteration for which\n             there is a corresponding approved therapy for that specific alteration (including but\n             not limited to alterations in EGFR, ALK, and ROS) must have progressed on, or had\n             intolerance to, the respective therapy\n\n        Subjects entering Part F must also meet the following additional criteria:\n\n          -  Histological or cytological evidence of estrogen-receptor negative (ER-), progesterone\n             receptor negative (PgR-) and human epidermal growth factor-2 receptor negative (HER2-)\n             Breast Cancer by local laboratory testing, based on last available tumor tissue; or\n             another tumor type to be determined\n\n               -  ER/PgR negativity to follow local guidelines\n\n               -  If IHC HER2 2+, a negative FISH test is required\n\n               -  Inflammatory triple negative breast cancer is allowed\n\n          -  Must have received and failed/progressed a cytotoxic chemotherapy as first line\n             therapy per standard of care\n\n          -  No prior anti-PD-1 or anti-PD-L1 therapy\n\n        Subjects entering Part G must also meet the following additional criteria:\n\n          -  Histological or cytological evidence of ACC, mesothelioma, or another tumor type to be\n             determined\n\n               -  Both pleural and peritoneal mesothelioma are allowed\n\n               -  Epithelioid, sarcomatoid, or biphasic mesothelioma subtypes are allowed\n\n          -  Progression after at least first line available therapy\n\n        Exclusion Criteria:\n\n        Subjects are to be excluded from the study if they meet any of the following criteria:\n\n          -  Severe allergic or anaphylactic reaction to any monoclonal antibody therapy, murine\n             protein, or known hypersensitivity to any excipient in the study drugs\n\n          -  Major surgery within 4 weeks prior to Screening\n\n          -  Subjects who have been treated with chemotherapy, biologic therapy, or other\n             investigational agent within < 5 times the half-life of the agent or < 28 days\n             (whichever is shorter) of starting study drug\n\n        NOTE: Subjects whose immediate prior treatment was with nivolumab may start study drug 2\n        weeks after the last dose of nivolumab\n\n          -  Symptomatic or untreated brain metastases\n\n          -  Primary central nervous system (CNS) malignancy\n\n          -  Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C virus\n\n          -  Ongoing treatment with chronic immunosuppressants (eg, cyclosporine) or systemic\n             steroids\n\n          -  Ongoing systemic bacterial, fungal, or viral infections at Screening\n\n        NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically\n        excluded if all other inclusion/exclusion criteria are met\n\n          -  Administration of a live vaccine within 6 weeks of first dose of study drug\n\n          -  Administration of any of the following within 1 week prior to the administration of\n             study drug:\n\n               -  Strong inhibitors or inducers of CYP3A4, including grapefruit products and herbal\n                  supplements\n\n               -  P-glycoprotein (P-gp) inhibitors\n\n               -  Warfarin, phenytoin, or other substrates of CYP2C8 or CYP2C9 with a narrow\n                  therapeutic range\n\n               -  Medications associated with QTc interval prolongation or Torsades de Pointes\n\n          -  Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms (average of\n             triplicate readings) NOTE: criterion does not apply to subjects with a right or left\n             bundle branch block\n\n          -  Parts C, D-Annex, and E only: Subjects with active, known, or suspected autoimmune\n             disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due\n             to autoimmune condition only requiring hormone replacement, psoriasis not requiring\n             systemic treatment, or conditions not expected to recur in the absence of an external\n             trigger are permitted to enroll\n\n          -  Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg,\n             gastric bypass surgery, gastrectomy)\n\n          -  Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of\n             the cervix, or prostate intraepithelial neoplasia\n\n          -  Past medical history of interstitial lung disease, drug-induced interstitial lung\n             disease, radiation pneumonitis which required steroid treatment, or any evidence of\n             clinically active interstitial lung disease\n\n          -  History of peptic ulcer and/or gastrointestinal bleed\n\n          -  History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia\n             requiring medication or mechanical control within the last 6 months prior to Screening\n\n          -  Unstable or severe uncontrolled medical condition (eg, unstable cardiac function,\n             unstable pulmonary condition including pneumonitis and/or interstitial lung disease,\n             uncontrolled diabetes) or any important medical illness or abnormal laboratory finding\n             that would, in the Investigator's judgment, increase the risk to the subject\n             associated with his or her participation in the study.
Inclusion Criteria:\n\n        Phase I part:\n\n        - Patients with advanced/metastatic solid tumors, with measurable or non-measurable disease\n        as determined by RECIST version 1.1 (refer to Appendix 1), who have progressed despite\n        standard therapy or are intolerant of standard therapy, or for whom no standard therapy\n        exists\n\n        Phase II part:\n\n          -  Patients with advanced/metastatic solid tumors, with at least one measurable lesion as\n             determined by RECIST version 1.1, who have had disease progression following their\n             last prior therapy and fit into one of the following groups:\n\n          -  Group 1: NSCLC\n\n          -  Group 2: Melanoma\n\n          -  Group 3: Renal cancer\n\n          -  Group 4: Mesothelioma\n\n          -  Group 5: TNBC\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status ? 1\n\n          -  Patient must have a site of disease amenable to biopsy, and be a candidate for tumor\n             biopsy.\n\n        Exclusion Criteria:\n\n          -  History of severe hypersensitivity reactions to study treatment ingredients or other\n             mAbs\n\n          -  Active, known or suspected autoimmune disease\n\n          -  Active infection requiring systemic antibiotic therapy\n\n          -  HIV infection. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection\n\n          -  Patients receiving chronic treatment with systemic steroid therapy, other than\n             replacement-dose corticosteroids in the setting of adrenal insufficiency\n\n          -  Patients receiving systemic treatment with any immunosuppressive medication\n\n          -  Use of live vaccines against infectious disease within 4 weeks of initiation of study\n             treatment\n\n          -  Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment.\n\n          -  Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that\n             require local CNS-directed therapy or increasing doses of corticosteroids within the\n             prior 2 weeks\n\n          -  History of drug-induced pneumonitis or current pneumonitis.
Inclusion Criteria- Group A:\n\n          -  Age ? 18 years.\n\n          -  Phase 1-Dose Escalation: Patients with histologically confirmed advanced solid tumors\n             who are refractory to, relapsed after, or intolerant to standard therapy or for whom\n             no standard therapy exists.\n\n          -  Phase 2a-RP2D Confirmation (Formulation 2) and Phase 2a-Dose Extension: Patients with\n             a history of histologically confirmed solid tumors with a BRAF mutation.\n\n               -  Phase 2a-Dose Extension—Cohort 1\n\n                    1. Patients with solid tumors driven by a BRAF-V600 mutation\n\n                    2. Patients with no prior exposure to BRAF-directed therapy and for whom no\n                       standard therapy exists.\n\n               -  Phase 2a-Dose Extension—Cohort 2\n\n                    1. Patients with solid tumors driven by BRAF non-V600 mutation.\n\n                    2. Patients with no prior exposure to BRAF-directed therapy and for whom no\n                       standard therapy exists.\n\n          -  Measurable disease by RECIST 1.1.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.\n\n          -  Adequate hematologic, hepatic, and renal function.\n\n          -  Women of child-bearing potential must have a negative pregnancy test and must agree to\n             use an effective form of contraception from the time of the negative pregnancy test up\n             to 3 months after the last dose of study drug. Women of non-child-bearing potential\n             may be included if they are either surgically sterile or have been postmenopausal for\n             ? 1 year.\n\n          -  Fertile men must agree to use an effective method of birth control during the study\n             and for up to 3 months after the last dose of study drug.\n\n          -  Completion of previous anti-cancer therapy at least 2 weeks before study drug\n             initiation.\n\n        Exclusion Criteria- Group A:\n\n          -  Phase 1 and Phase 2a RP2D confirmation-Dose Escalation: Investigational drug use\n             within 28 days (or 5 half-lives, whichever is shorter) of the first dose of PLX8394.\n\n          -  Major surgical procedure, open biopsy (excluding skin cancer resection), or\n             significant traumatic injury within 14 days of initiating study drug or anticipation\n             of the need for major surgery during the study.\n\n          -  Uncontrolled intercurrent illness.\n\n          -  Active secondary malignancy unless the malignancy is not expected to interfere with\n             the evaluation of safety and is approved by the Medical Monitor. Patients with a\n             completely treated prior malignancy and no evidence of disease for ? 2 years are\n             eligible.\n\n          -  Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant\n             bowel resection that would preclude adequate absorption.\n\n          -  Clinically significant cardiac disease.\n\n          -  Known infection with HIV, HBV, or HCV or a known carrier of HBV or HCV.\n\n        Inclusion Criteria — Group B:\n\n          -  Age (all criteria are required):\n\n               -  ?3 and <18 years;\n\n               -  Ability to swallow and retain study drug;\n\n               -  A minimum BSA that allows for adequate dosing with PLX8394.\n\n               -  Patients with a history of activating BRAF mutation, such patients include those\n                  with the following:\n\n                    1. Diagnosis of pediatric brain tumor (e.g., pilocytic astrocytoma, pleomorphic\n                       xanthoastrocytoma, ganglioglioma, astrocytoma, papillary craniopharyngioma,\n                       glioblastoma) with an activating BRAF mutation.\n\n                    2. LCH (Langerhans cell histiocytosis) i.) Patients with either high-risk\n                       disease are eligible. ii) Patients with overlap histiocytic disorders (e.g.,\n                       LCH/juvenile xanthogranuloma, LCH/Erdheim-Chester disease, or\n                       LCH/Rosai-Dorfman disease) are eligible.\n\n                    3. Diagnosis of LCH-associated neurodegenerative disease (LCH-ND).\n\n                    4. Other advanced malignancy with an activating BRAF mutation.\n\n          -  ECOG performance status of 0-2.\n\n          -  Adequate hematologic, hepatic, and renal function.\n\n          -  Females of child-bearing potential must have a negative pregnancy test and must agree\n             to use an effective form of contraception from the time of the negative pregnancy test\n             and for 3 months after the last dose of study drug. Females of non-child-bearing\n             potential may be included if they are either surgically sterile, have been\n             postmenopausal for ?1 year, or are premenopausal.\n\n          -  Fertile male patients must agree to use an effective method of birth control during\n             the study and for 3 months after the last dose of study drug.\n\n          -  Completion of previous anti-cancer therapy at least 2 weeks before study drug\n             initiation.\n\n          -  All patients or their legal guardians (if the patient is <18 years old) must sign an\n             IRB-approved document of informed consent to demonstrate their understanding of the\n             investigational nature and the risks of this study before any protocol-related\n             procedures are performed. When appropriate, pediatric subjects will be included in all\n             discussions.\n\n        Exclusion Criteria — Group B:\n\n          -  Major surgical procedure, open biopsy (excluding skin cancer resection), or\n             significant traumatic injury within 14 days of initiating the study drug or\n             anticipation of the need for major surgery during the study.\n\n          -  Dose Escalation and Dose Extension — Investigational drug use within 28 days (or 5\n             half-lives, whichever is shorter) of the first dose of PLX8394.\n\n          -  Uncontrolled intercurrent illness.\n\n          -  Active secondary malignancy, unless the malignancy is not expected to interfere with\n             the evaluation of safety and is approved by the Medical Monitor.\n\n          -  Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant\n             bowel resection that would preclude adequate absorption.\n\n          -  Clinically significant cardiac disease.\n\n          -  Known infection with HIV, HBV, or HCV or a known carrier of HBV or HCV.
DISEASE CHARACTERISTICS:\n\n          -  Histologically confirmed indolent non-Hodgkin's lymphoma (NHL), including 1 of the\n             following histologic subtypes:\n\n               -  Grade1 or 2 follicular lymphoma\n\n               -  Small lymphocytic lymphoma (SLL)\n\n               -  Marginal zone B-cell lymphoma\n\n          -  CD20-positive disease confirmed by immunohistochemistry or flow cytometry\n\n          -  Bidimensionally measurable disease\n\n               -  At least 1 lesion measuring ? 2.0 cm in a single dimension by CT scan\n\n          -  Less than 25% bone marrow involvement with lymphoma by bilateral iliac crest bone\n             marrow aspiration and biopsy within the past 6 weeks\n\n          -  No clinically significant impaired bone marrow reserve as evidenced by any of the\n             following:\n\n               -  Hypocellular marrow, as evidenced by 1 of the following:\n\n                    -  ? 15% cellularity\n\n                    -  Marked reduction in bone marrow precursors\n\n               -  Platelet count < 100,000/mm^3\n\n               -  Absolute neutrophil count < 1,500/mm^3\n\n               -  History of failed stem cell collection\n\n               -  Prior myeloablative therapy\n\n          -  No greater than 5,000/mm^3 circulating tumor cells in peripheral blood\n\n          -  Requires antilymphoma therapy, as indicated by any of the following:\n\n               -  Systemic symptoms\n\n               -  B symptoms\n\n               -  Cytopenias\n\n               -  Malaise\n\n               -  Organ compromise\n\n               -  Discomfort\n\n               -  Pain\n\n               -  Disfigurement\n\n               -  Rapidly progressive disease\n\n               -  Undue anxiety related to not receiving treatment\n\n          -  No transformation to intermediate or high-grade NHL\n\n          -  No known brain metastases or CNS involvement by lymphoma NOTE: A new classification\n             scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of\n             \indolent\ or \aggressive\ lymphoma will replace the former terminology of \low\,\n             \intermediate\, or \high\ grade lymphoma. However, this protocol uses the former\n             terminology.\n\n        PATIENT CHARACTERISTICS:\n\n        Age\n\n          -  Over 18\n\n        Performance status\n\n          -  ECOG 0-2 OR\n\n          -  WHO 0-2 OR\n\n          -  Karnofsky 70-100%\n\n        Life expectancy\n\n          -  More than 3 months\n\n        Hematopoietic\n\n          -  See Disease Characteristics\n\n          -  WBC ? 3,000/mm^3\n\n          -  Absolute neutrophil count ? 1,500/mm^3\n\n          -  Platelet count ? 100,000/mm^3\n\n          -  Lymphocyte count < 5,000/mm^3 (for patients with SLL )\n\n        Hepatic\n\n          -  Bilirubin ? 2.0 mg/dL\n\n          -  AST and ALT ? 2.5 times upper limit of normal\n\n        Renal\n\n          -  Creatinine ? 2.0 mg/dL OR\n\n          -  Creatinine clearance > 60 mL/min\n\n        Cardiovascular\n\n          -  No symptomatic congestive heart failure\n\n          -  No unstable angina pectoris\n\n          -  No cardiac arrhythmia\n\n        Immunologic\n\n          -  No anti-murine antibody reactivity (in patients with prior exposure to murine\n             antibodies or proteins)\n\n          -  No ongoing or active infection\n\n          -  No history of allergic reaction attributed to compounds of similar chemical or\n             biologic composition to yttrium Y 90 ibritumomab tiuxetan\n\n        Other\n\n          -  Not pregnant or nursing\n\n          -  Negative pregnancy test\n\n          -  Fertile patients must use effective contraception during and for at least 1 year after\n             study treatment\n\n          -  No other active malignancy except non-melanoma skin cancer\n\n          -  No other serious nonmalignant disease that would preclude study participation\n\n          -  No psychiatric illness or social situation that would preclude study compliance\n\n          -  No other uncontrolled illness\n\n        PRIOR CONCURRENT THERAPY:\n\n        Biologic therapy\n\n          -  More than 4 weeks since prior pegfilgrastim\n\n          -  More than 2 weeks since prior filgrastim (G-CSF) or sargramostim (GM-CSF)\n\n        Chemotherapy\n\n          -  No prior chemotherapy\n\n        Endocrine therapy\n\n          -  Not specified\n\n        Radiotherapy\n\n          -  No prior external beam radiotherapy to > 25% of active bone marrow (involved field or\n             regional)\n\n        Surgery\n\n          -  More than 4 weeks since prior major surgery except diagnostic surgery\n\n        Other\n\n          -  No prior systemic antilymphoma therapy\n\n          -  No concurrent combination antiretroviral therapy for HIV-positive patients\n\n          -  No other concurrent anticancer therapy\n\n          -  No other concurrent investigational agents\n\n          -  No other concurrent antilymphoma therapy
Inclusion Criteria:\n\n        General:\n\n          -  Participants with solid tumors must have one or more metastatic tumors evaluable or\n             measurable on radiographic imaging\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (or 2 upon\n             approval by the medical monitor)\n\n          -  Life expectancy of greater than or equal to (>/=) 3 months\n\n          -  Disease-free of active second/secondary or prior malignancies >/= 2 years with the\n             exception of currently treated basal cell, squamous cell carcinoma of the skin, or\n             carcinoma \in-situ\ of the cervix or breast\n\n          -  Adequate hematological, renal, hepatic and coagulation laboratory test results\n\n          -  Women of child bearing potential and men must agree to use adequate contraception\n             during the study and for 4 months after the last dose of study drug\n\n        Advanced Solid Malignancies:\n\n          -  Participants with previously treated, histologically confirmed advanced solid\n             malignancy with progressive disease requiring therapy\n\n          -  Participants must be refractory or intolerant to standard therapy\n\n        NUT-midline carcinoma:\n\n          -  Participants with histologically confirmed newly diagnosed or relapsed/refractory NMC\n             with PD requiring therapy\n\n          -  Diagnosis of one of the following is required:\n\n               1. NUT Midline Carcinoma based on ectopic expression of NUT protein as determined by\n                  Immunohistochemistry (IHC) and/or;\n\n               2. Detection of NUT gene translocation as determined by Fluorescence In-Situ\n                  Hybridization (FISH) Advanced Aggressive DLBCL\n\n          -  Histologically confirmed advanced aggressive B-cell lymphoma with abnormal MYC\n             expression with persistent disease requiring treatment\n\n          -  Participants must have relapsed or progressed after at least 2 lines of prior therapy\n             and not eligible for any curative treatment\n\n          -  Participants must have measurable disease\n\n        Exclusion Criteria:\n\n          -  Participants with hematologic malignancies\n\n          -  New York Heart Association Class III or IV, cardiac disease, myocardial infarction\n             within the past 6 months, unstable arrhythmia\n\n          -  Have Fridericia-corrected QT interval (QTcF) greater than (>) 470 milliseconds (msec)\n             (female) or > 450 (male), or history of congenital long QT syndrome\n\n          -  Active, uncontrolled bacterial, viral, or fungal infections\n\n          -  Known clinically important respiratory impairment\n\n          -  Positive for human immunodeficiency virus (HIV), hepatitis B surface antigen, or\n             hepatitis C antibodies\n\n          -  History of major organ transplant\n\n          -  History of an autologous or allogeneic bone marrow transplant. For DLBCL participants\n             only: DLBCL participants may have had a previous autologous transplant but not within\n             90 days of study entry\n\n          -  Symptomatic central nervous system malignancy or metastasis\n\n          -  Pregnant or nursing\n\n          -  Treatment with surgery or chemotherapy within 28 days prior to study entry\n\n          -  Prior treatment with small molecule (BET) family inhibitor\n\n          -  Radiation for symptomatic lesions within 14 days of study enrollment
Inclusion Criteria:\n\n        Patients must have:\n\n          -  advanced solid tumors and have confirmed cMET dysregulation\n\n          -  at least one measurable lesion as defined by RECIST 1.1.\n\n          -  recovered from all toxicities related to prior anti-cancer therapies\n\n          -  adequate organ function\n\n          -  ECOG performance status (PS) of 0 or 1\n\n        Exclusion Criteria:\n\n        Patients must not have:\n\n          -  known hypersensitivity to any of the excipients of INC280\n\n          -  prior treatment with cMET or HGF-targeting inhibitor\n\n          -  known hypersensitivity to digoxin or rosuvastatin or its excipients\n\n          -  symptomatic central nervous system (CNS) metastases who are neurologically unstable\n\n          -  presence or history of carcinomatous meningitis\n\n          -  history of another primary malignancy that is currently clinically significant or\n             currently requires active intervention\n\n          -  Clinically significant, uncontrolled heart diseases, including QTcF ? 450 msec (male\n             patients), ? 460 msec (female patients) on the screening ECG\n\n          -  Thoracic radiotherapy to lung fields ? 4 weeks prior to starting INC280\n\n          -  Major surgery within 4 weeks prior to starting INC280\n\n          -  Patients receiving unstable or increasing doses of corticosteroids.\n\n          -  Impairment of GI function or GI disease that may significantly alter the absorption of\n             INC280\n\n          -  Patients who have received, or are expected to receive digoxin or rosuvastatin within\n             21 days prior to the beginning of the DDI phase (Day 1) and for the duration of the\n             DDI phase.\n\n        Other protocol-defined inclusion/exclusion criteria may apply
Inclusion Criteria: -\n\n          -  Inclusion Criteria: -\n\n               1. Age ? 70 years at the time of signing the Informed Consent Form.\n\n               2. Understand and voluntarily provide written informed consent prior to the conduct\n                  of any study related assessments/procedures.\n\n               3. Able to adhere to the study visit schedule and other protocol requirements.\n\n               4. Histologically or cytologically confirmed locally advanced or metastatic Non\n                  Small Cell Lung Cancer who are not candidates for curative surgery or radiation\n                  therapy.\n\n               5. No other current active malignancy requiring anticancer therapy.\n\n               6. Radiographically documented measurable disease per RECIST v 1.1\n\n               7. No prior chemotherapy for the treatment of metastatic disease. Adjuvant\n                  chemotherapy is permitted providing that cytotoxic chemotherapy was completed 12\n                  months prior to signing the ICF and without disease recurrence. Patients with\n                  previously known epidermal growth factor receptor mutation or anaplastic lymphoma\n                  kinase gene translocation must have failed or had intolerance to one treatment\n                  with epidermal growth factor receptor tyrosine kinase inhibitor or anaplastic\n                  lymphoma kinase inhibitor therapy, respectively.\n\n               8. Absolute neutrophil count ? 1500 cells/cubic millimetre.\n\n               9. Platelets ? 100,000 cells/cubic millimetre.\n\n              10. Hemoglobin ? 9 grams/decilitre.\n\n              11. Aspartate transaminase/serum glutamic oxaloacetic transaminase/ alanine\n                  transaminase/serum glutamic pyruvic transaminase ? 2.5 × upperlimit of normal\n                  range or ? 5.0 × upper limit of normal range if liver metastases.\n\n              12. Total bilirubin ? 1.5 millilitre/decilitre (unless there is a known history of\n                  Gilberts Syndrome).\n\n              13. Creatinine clearance > 40 millilitre/minute calculated using Cockcroft-Gault\n                  equation (if renal impairment is suspected 24 hour urine collection for\n                  measurement is required).\n\n              14. Eastern Cooperative Oncology Group performance status 0 or 1.\n\n              15. Females who (1) have undergone hysterectomy (the surgical removal of the uterus)\n                  or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have been\n                  naturally postmenopausal for at least 24 consecutive months (ie, has not had\n                  menses at any time during the preceding 24 consecutive months).\n\n              16. Male subjects must: Practice true abstinence or agree to use a condom during\n                  sexual contact with a pregnant female or a female of childbearing potential while\n                  participating in the study, during dose interruptions and for 6 months following\n                  study drug discontinuation, even if he has undergone a successful vasectomy.\n\n                  Exclusion Criteria:\n\n          -  1. Evidence of active brain metastases, including leptomeningeal involvement (prior\n             evidence of brain metastasis are permitted only if treated and stable and off therapy\n             for ? 4 weeks prior to signing Informed consent form. Magnetic Resonance Imaging of\n             the brain (or Computed Tomography scan w/contrast) is preferred for diagnosis.\n\n             2. History of leptomeningeal disease. 3. Only evidence of disease is non measurable.\n             4. Preexisting peripheral neuropathy of Grade 2, 3, or 4 (per Common Terminology\n             Criteria for Adverse Events v4.0).\n\n             5. Subject has received radiotherapy ? 4 weeks or limited field radiation for\n             palliation ? 2 weeks prior to starting investigational product, and/or from whom ? 30%\n             of the bone marrow was irradiated. Prior radiation therapy to a target lesion is\n             permitted only if there has been clear progression of the lesion since radiation was\n             completed.\n\n             6. Venous thromboembolism within 1 month prior to signing Informed consent form.\n\n             7. Current congestive heart failure (New York Heart Association Class II-IV). 8.\n             History of the following within 6 months prior to first administration of a study\n             drug: a myocardial infarction, severe/unstable angina pectoris,coronary/peripheral\n             artery bypass graft, New York Heart Association Class III-IV heart failure,\n             uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically\n             significant Electrocardiogram abnormality, cerebrovascular accident, transient\n             ischemic attack, or seizure disorder. 9. Subject has a known infection with hepatitis\n             B or C, or history of human immunodeficiency virus infection, or subject receiving\n             immunosuppressive or myelosuppressive medications that would in the opinion of the\n             investigator, increase the risk of serious neutropenic complications.\n\n             10. Subject has an active, uncontrolled bacterial, viral, or fungal infection(s)\n             requiring systemic therapy, defined as ongoing signs/symptoms related to the infection\n             without improvement despite appropriate antibiotics, antiviral therapy, and/or other\n             treatment.\n\n             11.History of interstitial lung disease, sarcoidosis, silicosis, idiopathic pulmonary\n             fibrosis, or pulmonary hypersensitivity pneumonitis.\n\n             12. Treatment with any investigational product within 28 days prior to signing the\n             Informed consent form.\n\n             13. History of allergy or hypersensitivity to nab-paclitaxel or carboplatin. 14.\n             Currently enrolled in any other clinical protocol or investigational trial that\n             involves administration of experimental therapy and/or therapeutic devices. 15. Any\n             other clinically significant medical condition, psychiatric illness, and/or organ\n             dysfunction that will interfere with the administration of the therapy according to\n             this protocol or which, in the views of investigator, preclude combination\n             chemotherapy.\n\n             16. Subject has any other malignancy within 5 years prior to randomization. Exceptions\n             include the following: squamous cell carcinoma of the skin, in-situ carcinoma of the\n             cervix, uteri, non-melanomatous skin cancer, carcinoma in situ of the breast, or\n             incidental histological finding of prostate cancer (TNM stage of T1a or T1b). All\n             treatment of which should have been completed 6 months prior to signing Informed\n             consent form.\n\n             17. Any condition including the presence of laboratory abnormalities, which places the\n             subject at unacceptable risk if he/she were to participate in the study.\n\n             18. Any medical condition that confounds the ability to interpret data from the study.\n\n             19. Females who (1) have not undergone hysterectomy (the surgical removal of the\n             uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or (2) have\n             not been naturally postmenopausal for at least 24 consecutive months (ie, has had\n             menses at any time during the preceding 24 consecutive months).
Inclusion Criteria:\n\n        Subjects must meet all of the following major inclusion criteria to be eligible for the\n        study:\n\n          1. 18 years of age or older\n\n          2. Histologically or cytologically documented stage IV ductal adenocarcinoma of the\n             pancreas.\n\n          3. Performance Status (ECOG) 0 or 1\n\n          4. FFPE tumor tissue from metastatic site(s\n\n          5. Adequate organ function\n\n          6. Written consent on an IRB/IEC-approved Informed Consent Form prior to any\n             study-specific evaluation.\n\n          7. For women of child-bearing potential, negative serum pregnancy test at screening and\n             use of physician-approved method of birth control from 30 days prior to the first\n             study drug administration to 30 days following the last study drug administration.\n\n          8. Male subjects must be surgically sterile or must agree to use physician-approved\n             contraception from 30 days prior to the first study drug administration to 30 days\n             following the last study drug administration.\n\n        Exclusion Criteria:\n\n        Subjects who meet any of the following major exclusion criteria will not be eligible for\n        participation in the study:\n\n          1. Neuroendocrine tumors (i.e., carcinoid, islet cell cancer) of the pancreas.\n\n          2. Known brain metastases.\n\n          3. Prior therapy, including systemic therapy, surgical resection or radiation for newly\n             diagnosed stage IV pancreatic cancer.\n\n          4. Presence of any serious or unstable concomitant systemic disorder incompatible with\n             the clinical study (e.g., substance abuse, uncontrolled intercurrent illness including\n             active infection, arterial thrombosis, symptomatic pulmonary embolism).\n\n          5. Any disorder that would significantly compromise protocol compliance.\n\n          6. Prior non-pancreatic malignancy treated with chemotherapy. Prior malignancies treated\n             with surgery and/or radiotherapy alone must be in remission ?3 years. The following\n             prior malignancies are allowable irrespective of when they occurred: in situ carcinoma\n             of the cervix, in situ ductal breast cancer, low-grade local bladder cancer, and\n             nonmelanotic skin cancer.\n\n          7. Known human immunodeficiency virus (HIV) infection.\n\n          8. Females who are pregnant or breastfeeding.
Inclusion Criteria:\n\n        Patients must have:\n\n          -  advanced solid tumors and have confirmed cMET dysregulation\n\n          -  at least one measurable lesion as defined by RECIST 1.1.\n\n          -  recovered from all toxicities related to prior anti-cancer therapies\n\n          -  adequate organ function\n\n          -  ECOG performance status (PS) of 0 or 1\n\n        Exclusion Criteria:\n\n        Patients must not have:\n\n          -  known hypersensitivity to any of the excipients of INC280 or to benzodiazepines or\n             known intolerance and hypersensitivity to caffeine\n\n          -  symptomatic central nervous system (CNS) metastases who are neurologically unstable\n\n          -  presence or history of carcinomatous meningitis\n\n          -  history of another primary malignancy that is currently clinically significant or\n             currently requires active intervention\n\n          -  Clinically significant, uncontrolled heart diseases, including QTcF ? 450 ms (male\n             patients), ? 460 ms (female patients) on the screening ECG\n\n          -  Thoracic radiotherapy to lung fields ? 4 weeks prior to starting INC280\n\n          -  Major surgery within 4 weeks prior to starting INC280\n\n          -  Patients receiving unstable or increasing doses of corticosteroids.\n\n          -  Impairment of GI function or GI disease that may significantly alter the absorption of\n             INC280\n\n          -  Patients who have received or consumed, or are expected to receive or consume\n             midazolam or caffeine-containing products (e.g., tea, coffee, cola), within 2 days\n             prior to Day 1 and during the whole duration of the DDI phase (i.e., from Day -2 to\n             Day 12)\n\n        Other protocol-defined inclusion/exclusion criteria may apply
Inclusion Criteria:\n\n        Patients must be ?18 years of age\n\n        Patients must have documented IDH1 and/or IDH2 gene-mutated disease\n\n        Patients must have an advanced hematologic malignancy with an IDH1 and/or IDH2 mutation\n\n        Patient must be able to understand and willing to sign an informed consent\n\n        Patients must have ECOG PS of 0 to 2\n\n        Patients must have adequate hepatic function as evidenced by serum total bilirubin ?1.5\n        upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic\n        involvement\n\n        Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase\n        (ALP) ?3.0 × ULN, unless considered due to involvement by the neoplasm under consideration\n        for treatment\n\n        Patients must have adequate renal function as evidenced by a serum creatinine ?2.0 × ULN or\n        Creatinine clearance 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)\n        estimation\n\n        Patients must be recovered from any clinically relevant toxic effects of any prior surgery,\n        radiotherapy, or other therapy intended for the treatment of cancer\n\n        Female patients with reproductive potential must have a negative serum pregnancy test\n        within 7 days prior to the start of therapy. Patients with reproductive potential are\n        defined as sexually mature women who have not undergone a hysterectomy, bilateral\n        oophorectomy or tubal occlusion or who have not been naturally postmenopausal (i.e., who\n        have not menstruated at all) for at least 24 consecutive months (i.e., has had menses at\n        any time in the preceding 24 consecutive months)\n\n        Exclusion Criteria:\n\n        Patients who have undergone HSCT within 60 days\n\n        Patients who received systemic anticancer therapy or radiotherapy <14 days prior to their\n        first day of study drug administration\n\n        Patients who received an investigational agent <14 days prior\n\n        Patients who are pregnant or breast feeding\n\n        Patients with an active severe infection who require anti-infective therapy or with an\n        unexplained fever >38.5°C during Screening visits or on their first day of study drug\n        administration (at the discretion of the Investigator, patients with tumor fever may be\n        enrolled)\n\n        Patients with New York Heart Association (NYHA) Class III or IV congestive heart failure or\n        LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within\n        approximately 28 days of C1D1\n\n        Patients with a history of myocardial infarction within the last 6 months\n\n        Patients with known unstable or uncontrolled angina pectoris\n\n        Patients with a known history of severe and/or uncontrolled ventricular arrhythmias\n\n        Patients with QTc interval ?450 msec or with other factors that increase the risk of QT\n        prolongation or arrhythmic events\n\n        Patients taking medications that are known to prolong the QT interval\n\n        Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B\n        or C\n\n        Patients with clinical symptoms suggesting active central nervous system (CNS) leukemia or\n        known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a\n        clinical suspicion of CNS involvement by leukemia during Screening\n\n        Patients with immediately life-threatening, severe complications of hematologic\n        malignancies such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or\n        disseminated intravascular coagulation
Key inclusion criteria:\n\n          -  Histologically confirmed aggressive diffuse large B-cell lymphoma (DLBCL), including\n             follicular lymphoma (FL) transforming to DLBCL, transformed indolent lymphoma, mantle\n             cell lymphoma (MCL), or Grade 3B FL for dose-escalation cohorts. Only participants\n             with DLBCL will be enrolled in the dose-expansion cohort.\n\n          -  Willing to provide a fresh tumor sample\n\n          -  Evaluable/measurable disease with measurable disease defined as greater than or equal\n             to (>= 1) lesion less than or equal to (<=) 20 mm in one dimension or ? 15 mm in 2\n             dimensions as measured by conventional or high-resolution (spiral) computed tomography\n             (CT). Disease evaluable by the International Working Group criteria (Cheson et al,\n             2007). (NOTE: Irradiated lesions will not be evaluable.)\n\n          -  Baseline fludeoxyglucose positron emission tomography (FDG-PET) or FDG-PET/CT scans\n             must show positive lesions compatible with CT-defined anatomical tumor sites.\n\n          -  Relapsed from or refractory to >= 2 prior chemotherapy regimens with >= 1 regimen\n             containing rituximab or failed 1 prior rituximab-containing regimen and unable to\n             tolerate additional multiagent chemotherapy. NOTE: Subjects enrolled in the\n             dose-escalation portion of the study must have exhausted all available standard\n             therapy.\n\n          -  At least 100 days past autologous stem cell transplant (ASCT).\n\n          -  At least 1 year past allogeneic stem-cell transplant (SCT) and off immunosuppression\n             therapy, with no evidence of graft-versus-host disease.\n\n          -  Eastern Cooperative Oncology Group performance status 0-2.\n\n          -  Adequate hematological function\n\n          -  Adequate organ function\n\n          -  Females of childbearing potential who are sexually active with a nonsterilized male\n             partner must use a highly effective method of contraception for 30 days prior to the\n             first dose of investigational product, and must agree to continue using such\n             precautions for 180 days after the final dose of investigational product.\n\n          -  Nonsterilized males who are sexually active with a female partner of childbearing\n             potential must use a highly effective method of contraception from Day 1through 90\n             days after receipt of the final dose of investigational product.\n\n        Key exclusion criteria:\n\n          -  Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic or hormonal therapy\n             for treatment of cancer.\n\n          -  Receipt of any experimental therapy, mAb, cancer vaccine, chemotherapy or small\n             molecule within 28 days prior to Cycle 1 Day 1 or 5 half-lives of that therapy,\n             whichever is shorter.\n\n          -  Previous therapy directed against cluster of differentiation 19 (CD19)\n\n          -  Prior exposure to immunotherapy such as but not limited to other anti-cytotoxic\n             T-lymphocyte-associated antigen-4 (CTLA-4), anti-PD 1, or anti-PD-L1 antibodies\n             excluding cancer vaccines.\n\n          -  Vaccination with a live virus within 28 days prior to receiving the first dose of\n             study drug\n\n          -  History of other invasive malignancy within 2 years except for cervical carcinoma in\n             situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast\n             that has been surgically cured.\n\n          -  Evidence of significant active infection requiring antimicrobial, antifungal,\n             antiparasitic, or antiviral therapy or for which other supportive care is given unless\n             the subject is clinically stable.\n\n          -  Human immunodeficiency virus (HIV) positive serology or acquired immunodeficiency\n             syndrome (AIDS).\n\n          -  Active hepatitis B\n\n          -  Ongoing >= Grade 2 toxicities from previous cancer therapies or any unresolved > Grade\n             1 immune-related adverse event (irAE) event unless specifically allowed in the\n             inclusion/exclusion criteria.\n\n          -  No immunosuppressive therapy within 14 days of Cycle 1 Day 1 of MEDI0680 (AMP-514)\n             dosing.\n\n          -  Active or prior documented autoimmune or inflammatory disease except vitiligo.\n\n          -  History of primary immunodeficiency.\n\n          -  Major surgical procedures (as defined by the principal investigator) within 28 days of\n             Cycle 1 Day 1 or still recovering from prior surgery.\n\n          -  History of tuberculosis, including those who may have completed prophylactic isoniazid\n             (INH) therapy.\n\n          -  Documented current central nervous system (CNS) involvement, leptomeningeal disease,\n             or spinal cord compression.\n\n          -  Pregnancy or lactation.\n\n          -  Clinically significant abnormality on electrocardiogram (ECG).\n\n          -  Uncontrolled inter-current illness including, but not limited to, ongoing or active\n             infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled\n             hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease,\n             or psychiatric illness/social situations that would limit compliance with study\n             requirement, substantially increase risk of incurring AEs from MEDI-551 or MEDI0680\n             (AMP-514), or compromise the ability of the subject to give written informed consent.
General eligibility criteria:\n\n          -  ECOG performance status 0 or 1.Patients with multiple myeloma who have an ECOG\n             performance status of 2 based on peripheral neuropathy from prior therapies are\n             eligible.\n\n          -  Ability to understand and the willingness to sign a written informed consent document.\n\n          -  Pathological confirmation of AML, MDS-RAEB or Multiple myeloma.\n\n          -  Agree to use adequate contraception prior to the study, for the duration of study\n             participation, and 4 months after completion of CM-CS1 CART-cell administration.\n\n          -  Ability to adhere with the study visit schedule and other protocol procedures.\n\n          -  Willingness to remain within a 50 mile radius of Brigham Women's Hospital during the\n             initial 10 days following CM-CS1 infusion\n\n        Disease specific eligibility criteria for patients with AML, MDS-RAEB:\n\n          -  Pathological confirmation of AML, MDS-RAEB according to WHO classification (CMML is\n             excluded) that is not in remission (defined as >5% blasts in bone marrow or peripheral\n             blood) and for which there are no reasonable standard treatment options.\n\n          -  No known or suspected CNS disease. A neurologic exam is required and signs or symptoms\n             suggestive of potential CNS disease require CNS imaging.\n\n          -  Disease status deemed not to require additional therapy for at least 4 weeks from\n             enrollment.\n\n          -  Life expectancy of greater than 4 weeks.\n\n          -  Participants must have satisfactory organ function as defined below:\n\n               1. Total bilirubin ?2.0 × institutional upper limit of normal (Except for subjects\n                  with known Gilbert's syndrome)\n\n               2. AST(SGOT)/ALT(SGPT) ?3 × institutional upper limit of normal\n\n               3. Creatinine ? 2.0 mg/dL\n\n        Disease specific eligibility criteria for patients with multiple myeloma:\n\n          -  Diagnosis of active multiple myeloma according to the International Myeloma Working\n             Group diagnostic criteria.\n\n          -  Relapsed or relapsed/refractory multiple myeloma with progressive disease\n\n          -  Presence of measurable disease as defined as one or more of the following:\n\n               1. Serum M-protein >0.5g/dl\n\n               2. Urine M-protein > 200mg/24hr\n\n               3. Serum FLC assay: involved FLC level > 10mg/dl with abnormal serum FLC ratio\n\n               4. Measurable plasmocytoma in non-secretory patients.\n\n          -  Previous treatment with both an immunomodulator and a proteosome inhibitor therapy\n\n          -  Life expectancy of greater than 12 weeks\n\n          -  No known or suspected CNS involvement. A neurologic exam is required and signs or\n             symptoms of potential CNS involvement require CNS imaging. Peripheral neuropathy is\n             acceptable.\n\n          -  Participants must have satisfactory organ and marrow function as defined below:\n\n               1. Absolute neutrophil count > 500/mcL. Screening ANC should be independent of G-CSF\n                  and GM-CSF support for at least 1 week and of pegylated G-CSF for at least 2\n                  weeks\n\n               2. Platelets >20,000/mcL. Subjects may receive platelet transfusions, if clinically\n                  indicated, in accordance with institutional guidelines.\n\n               3. Total bilirubin ?2.0 × institutional upper limit of normal. (Except patients with\n                  known Gilbert's syndrome)\n\n               4. AST(SGOT)/ALT(SGPT) ?3 × institutional upper limit of normal\n\n               5. Creatinine ? 2.0 mg/dL\n\n        Exclusion Criteria:\n\n          -  Participants who have received chemotherapy or radiotherapy within 3 weeks prior to\n             entering the study or those who have not recovered from adverse events due to agents\n             administered more than 3 weeks earlier.\n\n          -  Concurrent systemic steroid or other immunosuppressive therapy.\n\n          -  Participants who are concurrently receiving any other investigational agents, or have\n             received another investigational agent within 3 weeks before enrollment.\n\n          -  Participants who have received prior allogeneic stem cell transplantation, gene\n             therapy, or adoptive T-cell therapy.\n\n          -  Active infections necessitating use of treatment antibiotics/antivirals during the\n             screening period (prophylaxis is acceptable) or evidence of an active communicable\n             infectious disease.\n\n          -  Participants who underwent major surgery within 4 weeks before day 0 of planned CM-CS1\n             T-cell infusion (this does not include placement of vascular access device or tumor\n             biopsies).\n\n          -  Participants with any known history of primary immunodeficiency.\n\n          -  History of allergic reactions or hypersensitivity attributed to Human serum albumin or\n             Plasma-lyte A.\n\n          -  Uncontrolled intercurrent illness or serious uncontrolled medical disorder\n\n          -  Pregnancy or breastfeeding\n\n          -  Known HIV-positive participants are ineligible because the effect of transducing\n             HIV-infected lymphocytes with the chimeric NKG2D- transgene on the disease course is\n             unknown.\n\n          -  Clinically relevant active infection including active hepatitis B or C or any other\n             concurrent disease which in the judgment of the Investigator would make the subject\n             inappropriate for enrollment on this study.\n\n          -  Active autoimmune disease\n\n          -  History of a malignancy other than one of the malignancies in this study with\n             exception of the following circumstances:\n\n               1. Patients with a history of malignancy who have been adequately treated and have\n                  been disease-free for at least 2 years are not excluded.\n\n               2. Patients with adequately treated active non-invasive cancers (such as\n                  non-melanomatous skin cancer or in-situ bladder, cervical and breast cancers) are\n                  not excluded.\n\n          -  Unwillingness to use an effective contraceptive method during the study and at least 4\n             months after administration of CM-CS1 T-cells unless subject is naturally infertile.
Inclusion Criteria:\n\n          -  Must have histologically-confirmed diagnosis of cholangiocarcinoma Stage II, III, or\n             IV CCA (intra-hepatic, extra-hepatic and perihilar) that is not eligible for curative\n             resection, transplantation, or ablative therapies. Tumors of mixed histology are not\n             allowed.\n\n          -  Must have radiographically measurable disease in at least one site not previously\n             treated with radiation, chemoembolization, radioembolization, or other local ablative\n             procedures; a new area of tumor progression within or adjacent to a previously-treated\n             lesion, if clearly measurable by a Radiologist, is acceptable.\n\n          -  May have received prior radiation, chemoembolization, radioembolization, or other\n             local ablative therapies, or hepatic resection if completed ? 4 weeks prior to\n             registration AND if patient has recovered to ? grade 1 toxicity. NOTE: Measurable\n             disease (as required above) must still be present.\n\n          -  May have received prior radiation for bone or brain metastases if patient is now\n             asymptomatic and has completed all radiation and steroid therapy (if applicable) ? 2\n             weeks prior to registration.\n\n          -  Age ? 18 years.\n\n          -  Child-Pugh score of A or B with ? 7 points.\n\n          -  Eastern Cooperative Oncology Group performance status of 0-1.\n\n          -  Willing to provide archived tissue, if available, from a previous diagnostic biopsy.\n\n          -  Must be able to tolerate CT and/or MRI with contrast.\n\n          -  Adequate organ function obtained ? 2 weeks prior to registration:\n\n               -  Absolute Neutrophil Count ? 1500/mm³\n\n               -  Hemoglobin ?9.0 g/dL\n\n               -  Platelets ?100,000/mm³\n\n               -  Serum Creatinine ? 1.5x Upper Limit Normal (ULN)\n\n               -  Creatinine Clearance ? 50 mL/min\n\n               -  Albumin ? 2.8 g/dL\n\n               -  Total Bilirubin ? 1.5 mg/dL or ? 1.5x ULN\n\n               -  Aspartate Aminotransaminase (AST)/Alanine Aminotransaminase (ALT) ? 2.5x ULN (?\n                  5x ULN in patients with liver metastases)\n\n               -  International Normalized Ratio (INR) <1.5x the ULN [INR ? 1.5 is allowed if\n                  anticoagulation is used.]\n\n          -  Women must not be pregnant or breastfeeding since nab-paclitaxel and/or gemcitabine\n             may harm the fetus or child.\n\n          -  Must not have received prior systemic cytotoxic chemotherapy or targeted therapy for\n             this cancer.\n\n          -  Must not be receiving treatment with other investigational agents.\n\n          -  Must not have a pre-existing >grade 2 peripheral neuropathy.\n\n          -  Must not be receiving immunosuppressive medications, including systemic\n             corticosteroids, aside from the following exceptions: used for adrenal replacement,\n             appetite stimulation, therapy for asthma, bronchitis exacerbation (? 2 weeks),\n             anti-emesis, or pre-medication for procedures (i.e. CT scan).\n\n          -  No known Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV)\n             seropositivity.\n\n          -  Must not have undergone liver transplantation.\n\n          -  Must not have serious non-healing wound, ulcer, bone fracture, or abscess.\n\n          -  Must not have undergone a major surgical procedure <4 weeks prior to registration.\n\n          -  Must not have possible histories of pneumonitis or pneumonitis risk factors.\n\n          -  Must not have an active second malignancy other than non-melanoma skin cancer or\n             cervical carcinoma in situ.\n\n          -  Must have no ongoing or active, uncontrolled infections.\n\n          -  Must have no evidence of significant, uncontrolled concomitant diseases including, but\n             not limited to: symptomatic congestive heart failure, unstable angina pectoris,\n             uncontrolled cardiac arrhythmia, myocardial infarction within preceding 12 months,\n             uncontrolled peripheral vascular disease, cerebrovascular accident within preceding 12\n             months, pulmonary disease impairing functional status or requiring oxygen, connective\n             tissue disease including lupus.\n\n          -  Must not have any history of allergic reaction(s) attributed to compounds of similar\n             composition to nab-paclitaxel or gemcitabine.
Inclusion Criteria:\n\n        Patient has a confirmed diagnosis of a select solid tumor (except with a primary diagnosis\n        of Urothelial cell carcinoma, Cholangiocarcinoma, Endometrial cancer, and Glioblastoma\n        multiforme) or hematologic malignancies and is in need of treatment because of progression\n        or relapse.\n\n        Patient's tumor has been evaluated and pre-identified as having a tumor with a FGFR genetic\n        alteration. The qualifying alteration must be assessed and reported by a CLIA-certified\n        laboratory.\n\n        Patient must have received at least one prior treatment for recurrent, metastatic and /or\n        locally advanced disease and for whom no standard therapy options are anticipated to result\n        in a durable remission.\n\n        Patient must have progressive and measurable disease per RECIST 1.1. or other appropriate\n        hematological response criteria.\n\n        Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ? 1\n\n        Exclusion Criteria:\n\n        Patient has received prior treatment with BGJ398\n\n        Patients with Central Nervous System (CNS) metastasis or leptomeningeal carcinomatosis\n\n        Patient has received chemotherapy or other anticancer therapy ? 4 weeks (6 weeks for\n        nitrosourea, antibodies or mitomycin-C) prior to starting study drug.\n\n        Patients with acute or chronic pancreatitis\n\n        Patients with impaired cardiac function or clinically significant cardiac diseases\n\n        History and/or current evidence of extensive tissue calcification\n\n        Use of medications that increase serum levels of phosphorus and/or calcium\n\n        Current evidence of corneal or retinal disorder/keratopathy\n\n        History and/or current evidence of renal or endocrine alterations of calcium/phosphate\n        homeostasis\n\n        Patients with another primary malignancy within 3 years prior to starting study treatment,\n        with the exception of adequately treated basal cell carcinoma, squamous cell carcinoma or\n        other non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix
Inclusion Criteria\n\n        Subjects must meet the following criteria to be eligible for study participation:\n\n          1. At least 18 years at the time of signing the informed consent form.\n\n          2. Able to understand and voluntarily sign an informed consent form prior to any\n             study-related assessments/procedures.\n\n          3. Able to adhere to the study visit schedule and other protocol requirements.\n\n          4. Documented diagnosis of multiple myeloma and measurable disease by serum or urine\n             protein electrophoresis (SPEP or UPEP): SPEP ?0.5 g/dL, UPEP ?200 mg/24 hours, or\n             involved serum free light chain (FLC) level ?10 mg/dL provided the serum FLC ratio is\n             abnormal.\n\n          5. Previously received 1 or more lines of anti-myeloma therapy that must have included\n             both lenalidomide and bortezomib (either separately or in combination).\n\n          6. Documented disease progression during or within 60 days after their most recent line\n             of anti myeloma therapy.\n\n          7. Eastern Cooperative Oncology Group (ECOG) performance status score ?2.\n\n          8. All study participants in the USA must be registered into the mandatory POMALYST REMS™\n             (Risk Evaluation & Mitigation Strategy) program, and be willing and able to comply\n             with the requirements of the POMALYST REMS™ program.\n\n          9. All study participants in the USA who are females of child-bearing potential (FCBP)\n             must adhere to the scheduled pregnancy testing as required in the POMALYST REMS™\n             program.\n\n         10. All study participants outside the USA must agree to comply with the POMALYST® PPRMP\n             requirements.\n\n         11. All subjects must be able and agree to take aspirin (81 or 325 mg) daily as\n             prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low\n             molecular weight heparin).\n\n         12. For females of child bearing potential (FCBP): Agree to use 2 reliable forms of\n             contraception simultaneously or practice complete abstinence from heterosexual contact\n             for at least 28 days before starting study treatment, while participating in the study\n             (including dose interruptions), and for at least 28 days after study treatment\n             discontinuation; must follow pregnancy testing requirements as outlined in the\n             POMALYST REMS™ program or the PPRMP.\n\n         13. For all females: Agree to abstain from breastfeeding during study participation and\n             for at least 28 days after study treatment discontinuation.\n\n         14. For all males: Agree to use a latex or synthetic condom during any sexual contact with\n             FCBP while participating in the study and for at least 28 days following\n             discontinuation from study treatment, even if he has undergone a successful vasectomy.\n\n         15. For all males: Agree to refrain from donating semen or sperm while on study and for at\n             least 28 days after discontinuation from study treatment.\n\n         16. Refrain from donating blood while on study treatment and for at least 28 days after\n             discontinuation from study treatment.\n\n         17. Agree not to share medication.\n\n        Exclusion Criteria\n\n        Subjects with any of the following will be excluded from participation in the study:\n\n          1. Peripheral neuropathy Grade ?2.\n\n          2. Non-secretory multiple myeloma.\n\n          3. Any of the following laboratory abnormalities:\n\n               -  ANC <1,000/µL;\n\n               -  Platelet count <50,000/µL for subjects in whom <50% of bone marrow nucleated\n                  cells are plasma cells; or a platelet count <30,000/µL for subjects in whom ?50%\n                  of bone marrow nucleated cells are plasma cells;\n\n               -  Creatinine clearance (CrCL) <45 mL/min as measured directly or as calculated\n                  according to Cockcroft Gault formula;\n\n               -  Corrected serum calcium >13.5 mg/dL (>3.4 mmol/L);\n\n               -  Hemoglobin <8 g/dL (<4.9 mmol/L; prior red blood cell [RBC] transfusion or\n                  recombinant human erythropoietin use is permitted before study entry);\n\n               -  Serum aspartate aminotransferase (AST) >3.0 x upper limit of normal (ULN);\n\n               -  Serum alanine aminotransferase (ALT) >3.0 x ULN;\n\n               -  Serum total bilirubin >1.5 x ULN (>3.0 x ULN for subjects with known Gilbert's\n                  disease).\n\n          4. Prior history of malignancies, other than MM, unless the subject has been free of the\n             disease for ?5 years. Subjects may be entered earlier than 5 years if they have\n             received curative treatment for the following:\n\n               -  Basal cell carcinoma of the skin;\n\n               -  Squamous cell carcinoma of the skin;\n\n               -  Carcinoma in situ of the cervix;\n\n               -  Carcinoma in situ of the breast;\n\n             Or if they have:\n\n             o Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor,\n             nodes, metastasis] clinical staging system) or non metastatic prostate cancer that is\n             in complete remission or does not require treatment.\n\n          5. Previous therapy with POM and/or MRZ.\n\n          6. History of allergic reaction or hypersensitivity to thalidomide, lenalidomide,\n             bortezomib, carfilzomib, boron, mannitol, or DEX.\n\n          7. Grade ?3 rash during prior thalidomide or lenalidomide therapy.\n\n          8. Gastrointestinal disease that may significantly alter the absorption of POM.\n\n          9. History of the following:\n\n               -  Congestive heart failure of Class III or IV of the New York Heart Association\n                  (NYHA) classification;\n\n               -  Myocardial infarction within 12 months prior to starting study treatment;\n\n               -  Unstable or poorly controlled angina pectoris, including Prinzmetal variant\n                  angina pectoris.\n\n         10. Any of the following within 14 days prior to initiation of study treatment:\n\n               -  Plasmapheresis;\n\n               -  Major surgery (kyphoplasty is not considered major surgery);\n\n               -  Radiation therapy;\n\n               -  Anti-myeloma drug therapy.\n\n         11. Received any investigational agents within 28 days or 5 half-lives (whichever is\n             longer) prior to initiation of study treatment.\n\n         12. Conditions requiring chronic steroid or immunosuppressive treatment (eg, rheumatoid\n             arthritis, multiple sclerosis, or lupus), which likely need additional steroid or\n             immunosuppressive treatments in addition to the study treatment.\n\n         13. Subjects may not receive corticosteroids (>10 mg/day of prednisone or equivalent)\n             within 3 weeks prior to enrollment (use of steroidal inhalation aerosol for asthma is\n             permitted).\n\n         14. Unable or unwilling to undergo antithrombotic prophylactic treatment.\n\n         15. Any condition, including the presence of laboratory abnormalities, which places the\n             subject at unacceptable risk if he/she were to participate in the study, as determined\n             by the Investigator.\n\n         16. Pregnant and/or breastfeeding females.\n\n         17. Known seropositive for or active viral infection with human immunodeficiency virus\n             (HIV).\n\n         18. Known seropositive for or active viral infection with hepatitis B virus (HBV), with\n             the following exceptions:\n\n               -  negative are eligible.\n\n               -  Subjects who had hepatitis B but have received an antiviral treatment and show\n                  non-detectable viral DNA for 6 months are eligible.\n\n               -  Subjects who are seropositive because of hepatitis B virus vaccine are eligible.\n\n         19. Known seropositive for or active viral infection with hepatitis C virus (HCV), with\n             the following exception: Subjects who had hepatitis C but have received an antiviral\n             treatment and show no detectable viral ribonucleic acid (RNA) for 6 months are\n             eligible.
Inclusion Criteria:\n\n        Cohort 0 and Arm A\n\n          -  Patient must have histologically or cytologically confirmed advanced cancer for which\n             standard cures or relieving measures either do not exist, are ineffective or are not\n             acceptable to the patient.\n\n          -  Measureable disease according to RECIST criteria version 1.1.\n\n          -  ECOG performance status of 0 to 1.\n\n          -  Adequate bone marrow function.\n\n        Arm B\n\n          -  Patients with documented acute myeloid leukemia (AML), except for acute promyelocytic\n             leukemia.\n\n          -  Patients with relapsed/refractory AML or patients who have not received prior therapy\n             who are high risk according to European LeukemiaNet (ELN) criteria.\n\n          -  ECOG performance status of 0 to 2.\n\n        For Cohort 0, Arms A and B\n\n          -  Life expectancy of >/= 12 weeks.\n\n          -  Age >/= 18 years or older.\n\n          -  All patients must be willing to use effective methods of contraception until 10 days\n             after the last dose; women must not be pregnant or breast-feeding.\n\n          -  Adequate renal and hepatic function.\n\n          -  Patients with stable central nervous system (CNS) tumors are eligible.\n\n          -  There are no requirements or limitations on the amount or type of prior\n             anti-tumor/anti-leukemia therapy.\n\n        Exclusion Criteria:\n\n        Cohort 0 and Arm A\n\n          -  Patients with a history of any form of leukemia except for Stage 0 and 1 chronic\n             lymphocytic leukemia (CLL) not requiring treatment.\n\n          -  Patients receiving any cancer treatment within 21 days of start of study medication.\n             Patients must also have recovered from severe side effects due to prior treatment\n             before study start.\n\n          -  Patients with known bone marrow disorders that may interfere with bone marrow\n             recovery, or patients with delayed recovery from prior chemoradiotherapy.\n\n          -  Patients with known bleeding or clotting disorders or non-drug-induced low platelet\n             count.\n\n        Arm B\n\n        - Patients receiving any cancer treatment within 14 days of start of study medication.\n        Hydroxyurea may be taken until first administration of the study drug. Patients must also\n        have recovered from severe side effects due to prior treatment before study start.\n\n        For Cohort 0, Arms A and B\n\n          -  Patients receiving any other test drugs within 30 days of start of study medication\n\n          -  Patients receiving the cytochrome P450 inhibitors, substrates or inducers specified in\n             the protocol.\n\n          -  Anticoagulation or antiplatelet treatment must be discontinued 7 days prior to start\n             of study medication.\n\n          -  Patients who have received hormonal therapy (except for prostate cancer treatment and\n             hormone replacement therapy) within the 2 weeks prior to start of study medication.\n\n          -  Patients with evidence of electrolyte imbalance, which may be treated to meet\n             eligibility.\n\n          -  Serum albumin < 2.8 g/dL.\n\n          -  HIV-positive patients who are currently receiving combination antiretroviral therapy.\n\n          -  Patients who have any severe and/or uncontrolled medical conditions or other\n             conditions that could affect their participation in the study.
Inclusion Criteria:\n\n        Patient must be at least 1 year of age.\n\n        Patient or the patient's legally authorized guardian must be fully informed about their\n        illness and the investigational nature of the study protocol (including foreseeable risks\n        and possible side effects), and must sign an informed consent in accordance with the\n        institutional policies approved by the U.S. Department of Health and Human Services.\n\n        Patients should have been off other investigational therapy for one month prior to entry in\n        this study.\n\n        Patient must have adequate organ function as below:\n\n        Adequate renal function defined as:\n\n          -  Serum creatinine <2.0 x normal, or\n\n          -  Creatinine clearance or radioisotope GFR > 40 ml/min/m2 or >60 ml/min/1.73 m2 or an\n             equivalent GFR as determined by the institutional normal range\n\n        Adequate liver function defined as:\n\n          -  Total bilirubin <2.0 x normal; and\n\n          -  SGOT (AST) or SGPT (ALT) <5.0 x normal\n\n        Adequate pulmonary function defined as:\n\n        - Pulse oximetry >94% in room air. Lansky (< 16yr) or Karnofsky (> 16 yrs) performance\n        status ? 50% Life expenctancy ? 6 weeks. Women of child bearing age require a negative\n        urine pregnancy test. Clinical status at enrollment to allow tapering of steroids to less\n        than 0.5mg/kg/day prednisone at time of treatment.\n\n        4.5 Disease Status (Eligibility) 4.5.1 Any patient, with one or more of the following\n        EBV-positive type II latency or associated disorders, regardless of the histological\n        subtype: Hodgkin lymphoma Non-Hodgkin lymphoma Lymphoproliferative disorder Severe chronic\n        active EBV infection syndrome (SCAEBV), defined as high EBV viral load in plasma or PBMC (>\n        4000 genomes per ?g PBMC DNA) and/or biopsy tissue positive for EBV\n\n        The disease needs to be in one of the following stages:\n\n        At diagnosis who would be unable to receive conventional chemotherapy or in first relapse\n        AND the patient is not a candidate for HSCT Partial response after conventional therapy.\n        Refractory to conventional therapy for his/her condition. In second or subsequent relapse.\n        Residual disease after autologous, syngeneic or allogeneic HSCT.\n\n        All patients entered into the study ideally will have tumor tissue from the original\n        diagnostic specimen and/or relapse reviewed centrally for confirmation of EBV positive\n        disease. If no specimen is available, local pathology report documenting EBV positivity is\n        acceptable. Appropriate immunophenotyping to confirm the diagnosis will be performed. In\n        addition, in situ hybridization for EBV (LMP1, and/or EBER positivity) will be performed.\n        All central morphologic analysis and immunohistochemical/insitu hybridization staining will\n        be performed in the laboratory of Sherrie Perkins and Rodney Miles at the University of\n        Utah.\n\n        Donor Eligibility for LMP-CTL Third Party Banking (Aim 2.1.2)\n\n          -  Donor must be HIV negative.\n\n          -  Donors must have adequate hematopoietic function defined as absolute neutrophil count\n             > 1000/mm3, hemoglobin > 10 g/dl, and platelet count >50,000/mm3 and be EBV IgG\n             seropositive.\n\n          -  Donors will have peripheral blood collected for LMP specific CTL production. A minimum\n             of 60 cc of peripheral blood x 2 for a total maximum amount of blood of 120cc, will be\n             collected from the donor (subjects must be at least 12 kg or 24 pounds). (See Appendix\n             B) For donors <18 years a maximum of 3cc/kg blood will be taken in an 8 week period.\n\n          -  For donors that are to undergo stem cell collection, the peripheral blood for LMP\n             specific CTL production will be collected prior to the stem cell collection and\n             without a specific day specification.\n\n          -  Donor eligibility must meet criteria as per 21 CFR 1271.\n\n        Exclusion Criteria:\n\n        Currently receiving any investigational agents or have received any tumor vaccines within\n        previous 4 weeks.\n\n        Active acute grade III-IV graft-versus-host disease. Severe refractory intercurrent\n        infection other than EBV. Received alemtuzumab or other anti-Tcell antibody within 28 days.\n        HIV seropositivity. Pregnancy (due to unknown effects of this therapy on a fetus) or\n        lactation. Patients with PTLD post solid organ transplantation eligible for the COG PTLD\n        LMP/CTL protocol.
Inclusion Criteria\n\n        Each patient must meet all of the following inclusion criteria to be enrolled in the study:\n\n          1. Male or female patients 18 years or older.\n\n          2. Patients must have a histologically confirmed diagnosis of an advanced, metastatic\n             malignant solid tumor and must have failed or exhausted standard therapies or for\n             which no standard therapy is available.\n\n          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          4. Patients with adequate hematologic and organ function\n\n          5. All patients must have radiographically detectable tumors; however, measurable disease\n             as defined by RECIST (version 1.1) is not required for participation in the dose\n             escalation part of this study.\n\n          6. Patients undergoing a biopsy procedure must have accessible lesions which are safe to\n             biopsy.\n\n          7. Recovered (ie, ? Grade 1 toxicity) from the reversible effects of prior antineoplastic\n             therapy, except alopecia.\n\n          8. Female patients who are postmenopausal for at least 1 year before the screening visit,\n             surgically sterile, or agree to practice 2 effective methods of contraception, at the\n             same time, from the time of signing the informed consent form through 4 months after\n             the last dose of study drug, or agree to practice true abstinence.\n\n             Male patients who agree to practice effective barrier contraception during the entire\n             study treatment period through 4 months after the last dose of study drug or agree to\n             practice true abstinence.\n\n          9. Suitable venous access for the study-required blood sampling including PK sampling.\n\n        Exclusion Criteria\n\n        Patients meeting any of the following exclusion criteria are not to be enrolled in the\n        study:\n\n          1. Patients with clinically significant pre-existing cardiac impairment.\n\n          2. Patients with known active CNS lesions are excluded. Systemic antineoplastic therapy\n             or investigational agents within 21 days before the first dose of study drug.\n\n          3. Radiotherapy within 14 days before the first dose of study drug is not allowed except\n             for limited field radiotherapy for palliative bone pain.\n\n          4. For patients where tumor biopsies are required or requested:\n\n               -  Any known coagulation abnormalities that would contraindicate the tumor biopsy\n                  procedure.\n\n               -  Ongoing therapy with any anticoagulant or antiplatelet agents (eg, aspirin,\n                  clopidogrel [Plavix®], heparin, or warfarin).\n\n          5. Major surgery within 28 days before the first dose of MLN7243.\n\n          6. Life-threatening illness unrelated to cancer.\n\n          7. Any evidence of active infection or antibiotic therapy within 14 days before the first\n             dose of MLN7243.\n\n          8. Known human immunodeficiency virus (HIV) positivity or AIDS-related illness, hepatitis\n             B virus, and hepatitis C virus.\n\n          9. Patients whose weight is <40 kg.\n\n         10. History of uncontrolled sleep apnea syndrome and other conditions that could result in\n             excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.\n\n         11. Female patients who are lactating and breastfeeding or have a positive serum pregnancy\n             test during the Screening period or a positive urine pregnancy test on Day 1 before\n             first dose of study drug.\n\n        For the exhaustive list, please contact the study central contact.
Inclusion Criteria:\n\n        Diagnosis of intermediate- or high-risk (IPSS criteria) myelodysplastic syndrome.\n\n        Cohort 1: Any prior treatment, enrollment complete. Cohort 2: Limited or no prior treatment\n        for MDS. Prior treatment should not include hypomethylating agents such as azacitidine or\n        decitabine, or HDAC inhibitors.\n\n        ECOG Performance Status 0 or 1.\n\n        Exclusion Criteria:\n\n        Current or history of small, moderate or large pericardial effusion, tamponade and/or\n        pericarditis.\n\n        Significant cardiac abnormalities such as recent myocardial infarction, congestive heart\n        failure ? Class 3, or symptomatic, uncontrolled atrial fibrillation, atrial flutter or\n        sinus tachycardia.\n\n        Prolonged QT/QTc interval.\n\n        Other active cancer excluding basal cell carcinoma or cervical intraepithelial neoplasia.
Inclusion Criteria: Clinical diagnosis of metastatic uveal melanoma; Written consent from\n        female or male patients aged 18 years and over. Histological or cytological confirmation of\n        melanoma who are suitable for treatment with dacarbazine chemotherapy.\n\n          -  At least one lesion that can be accurately measured at baseline as>/=10mm in the\n             longest diameter. (except lymph nodes which must have short axis ?15 mm) with CT or\n             MRI and which is suitable for accurate repeated measurements\n\n          -  ECOG performance status 0-1\n\n          -  life expectancy >12 weeks\n\n          -  Normal organ and marrow function\n\n          -  Evidence of post-menopausal status, or negative urinary or serum pregnancy test for\n             female pre-menopausal patients\n\n          -  Patients should be able to swallow selumetinib/placebo capsules\n\n        Exclusion Criteria:-Involvement in the planning and/or conduct of the study (applies to\n        both AstraZeneca staff and/or staff at the study site)\n\n          -  Previous randomisation in the present study\n\n          -  Patients cannot have previously been treated with a systemic anti-cancer therapy.\n             Patients can have prior intra-hepatic or non-systemic therapy. -Having received any of\n             the following within the specified timeframe:\n\n        Any prior systemic anti-cancer therapy for the treatment of this current diagnosis, An\n        investigational drug within 30 days of starting treatment or within five half-lives of the\n        compound (whichever is the most appropriate is at the discretion of the Investigator), or\n        have not recovered from side effects of an investigational drug Any non-systemic\n        anti-cancer therapy which has not been cleared from the body by the time of starting study\n        treatment Radiation therapy within 4 weeks prior to starting study treatment, or limited\n        field of radiation for palliation within 7 days of the first dose of study treatment Major\n        surgery within 4 weeks prior to entry into the study (excluding the placement of vascular\n        access) which would prevent administration of study treatment, Any prior investigational\n        therapy comprising inhibitors of RAS, RAF or MEK at any time, Previous treatment with\n        dacarbazine. Any unresolved toxicity >CTCAE grade 2 from previous anti-cancer therapy,\n        excluding alopecia -History of allergic reactions attributed to compounds of similar\n        chemical or biologic composition to selumetinib or dacarbazine\n\n        --Symptomatic brain metastases or spinal cord compression (patients must be treated and\n        stable off steroids and anti-convulsants for at least 1 month prior to entry into the\n        study)\n\n        Cardiac conditions as follows:\n\n          -  Uncontrolled hypertension (BP ?150/95 mmHg despite medical therapy)\n\n          -  Acute coronary syndrome within 6 months prior to starting treatment\n\n          -  Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical\n             therapy - Symptomatic heart failure (New York Heart Association [NYHA] Class II-IV,-\n             Prior or current cardiomyopathy\n\n          -  Baseline LVEF <55% measured by echocardiography or MUGA. Appropriate correction to be\n             used if a MUGA is performed\n\n          -  Severe valvular heart disease\n\n          -  Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest\n\n          -  QTcF >450 ms or other factors that increase the risk of QTc prolongation\n\n          -  Any evidence of severe or uncontrolled systemic disease, active infection, active\n             bleeding diatheses or renal transplant, including any patient known to have hepatitis\n             B, hepatitis C or human immunodeficiency virus (HIV)\n\n          -  Refractory nausea and vomiting, chronic gastrointestinal diseases (eg inflammatory\n             bowel disease), or significant bowel resection that would preclude adequate absorption\n\n          -  History of another primary malignancy within 5 years prior to starting study\n             treatment, except for adequately treated basal or squamous cell carcinoma of the skin\n             or cancer of the cervix in situ and the disease under study\n\n          -  Ophthalmologic conditions:\n\n          -  Current or past history of central serous retinopathy\n\n          -  Current or past history of retinal vein occlusion\n\n          -  IOP >21 mmHg or uncontrolled glaucoma (irrespective of IOP)\n\n          -  Female patients who are breast-feeding a child and male or female patients of\n             reproductive potential who are not employing an effective method of birth control\n\n          -  Clinical judgement by the Investigator that the patient should not participate in the\n             study.
Inclusion Criteria: A subject will be eligible for inclusion in this study only if all of\n        the following criteria are met:\n\n          1. Female subjects, age ? 18 years at the time informed consent is signed\n\n          2. Pathologically confirmed adenocarcinoma of the breast\n\n          3. Pathologically confirmed as triple negative, source documented, defined as both of the\n             following\n\n               1. Estrogen Receptor (ER) and Progesterone Receptor (PgR) negative: < 1% of tumor\n                  cell nuclei are immunoreactive in the presence of evidence that the sample can\n                  express ER or PgR (positive intrinsic controls)\n\n               2. Human Epidermal Growth Factor Receptor 2 (HER2) negative as per American Society\n                  of Clinical Oncology - College of American Pathologists (ASCO/CAP) guidelines i.\n                  Immunohistochemistry (IHC) 0 or 1 Fluorescence In Situ Hybridization (FISH)\n                  negative (or equivalent negative test). Subjects with IHC 2 must have a negative\n                  by Fluorescence In Situ Hybridization (FISH),, (or equivalent negative test).\n\n          4. Subjects with prior breast cancer history of different phenotypes (ie, ER/PgR/HER2\n             positive) must have pathologic confirmation of triple negative disease in at least one\n             of the current sites of metastasis\n\n          5. Subjects must have received prior adjuvant or neoadjuvant anthracycline therapy;\n             unless (a) anthracycline treatment was not indicated or was not the best treatment\n             option for the subject in the opinion of the treating physician; and (b) anthracycline\n             treatment remains not indicated or, in the opinion of the treating physician, is not\n             the best treatment option for the subject's metastatic disease.\n\n             a. Newly diagnosed subjects presenting with TNMBC are eligible for the study if\n             anthracycline treatment is not indicated or is not the best treatment option for the\n             subject in the opinion of the treating physician.\n\n          6. Subjects with measurable metastatic disease, defined by Response Evaluation Criteria\n             in Solid Tumors 1.1 (RECIST 1.1) guidelines\n\n          7. Life expectancy ? 16 weeks from randomization\n\n          8. No prior cytotoxic chemotherapy for metastatic breast cancer. Prior immunotherapy\n             and/or monoclonal antibody therapy are acceptable. Prior treatments must have been\n             discontinued at least 30 days prior to start of study treatment and all related\n             toxicities must have resolved to Grade 1 or less.\n\n          9. Prior neoadjuvant or adjuvant chemotherapy, if given, must have been completed at\n             least 6 months before randomization with all related toxicities resolved, and\n             documented evidence of disease progression per RECIST 1.1 guidelines is required.\n\n             a. If prior neoadjuvant or adjuvant chemotherapy contained taxane, gemcitabine, or\n             platinum agents, the treatment must have completed at least 12 months before\n             randomization\n\n         10. Prior radiotherapy must have completed before randomization, with full recovery from\n             acute radiation side effects. At least one measurable lesion must be completely\n             outside the radiation portal or there must be unequivocal radiologic or clinical exam\n             proof of progressive disease within the radiation portal, in accordance with RECIST\n             1.1 guidelines\n\n         11. At least 30 days from major surgery before randomization, with full recovery\n\n         12. Eastern Cooperative Oncology Group (ECOG) performance status 0-1\n\n         13. Subject has the following blood counts at screening:\n\n               -  Absolute Neutrophil Count (ANC) ? 1500/mm^2 ;\n\n               -  Platelets ? 100,000/mm^2 ;\n\n               -  Hemoglobin (Hgb) ? 9 g/dL\n\n         14. Subject has the following blood chemistry levels at screening:\n\n               -  Aspartate aminotransferase (AST) Serum glutamic-oxaloacetic transaminase (SGOT),\n                  Alanine Aminotransferase (ALT ) Serum Glutamic Pyruvate Transaminase (SGPT) ? 2.5\n                  x upper limit of normal range (ULN); if hepatic metastases present ? 5.0 x ULN\n\n               -  Total serum bilirubin ? ULN; or total bilirubin ? 3.0 × ULN with direct bilirubin\n                  within normal range in subjects with documented Gilbert's Syndrome\n\n               -  Creatinine clearance > 60 mL/min (by Cockcroft-Gault)\n\n         15. Females of child-bearing potential [defined as a sexually mature women who (1) have\n             not undergone hysterectomy (the surgical removal of the uterus) or bilateral\n             oophorectomy (the surgical removal of both ovaries) or (2) have not been naturally\n             postmenopausal for at least 24 consecutive months (i.e., has had menses at any time\n             during the preceding 24 consecutive months)] must:\n\n               -  Demonstrate a negative serum pregnancy test result at screening (performed by\n                  central lab) confirmed by local negative urine pregnancy dipstick within 72 hours\n                  prior to the first dose of IP); pregnancy test with sensitivity of at least 25\n                  mIU/mL; and\n\n               -  Either commit to true abstinence* from heterosexual contact (which must be\n                  reviewed on a monthly basis) or agree to use, and be able to comply with, two\n                  physician approved effective contraception methods (oral, injectable, or\n                  implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier\n                  contraceptive with spermicide; or vasectomized partner) without interruption for\n                  28 days or longer as required by local guidelines, prior to starting study drug,\n                  during the study therapy (including dose interruptions), and for 28 days after\n                  discontinuation of the study or longer as required by local guidelines\n\n         16. Females must abstain from breastfeeding starting at randomization, during study\n             participation and for 28 days or longer as required by local guidelines, after IP\n             discontinuation\n\n         17. Understand and voluntarily sign an informed consent document prior to any study\n             related assessments/procedures are conducted\n\n         18. Able to adhere to the study visit schedule and other protocol requirements\n\n        Exclusion Criteria:\n\n        A subject will not be eligible for inclusion in this study if any of the following criteria\n        apply:\n\n          1. Male subjects\n\n          2. Concurrent chemotherapy or any other anti tumor therapy for breast cancer. Prior\n             immunotherapy & monoclonal antibody therapy are acceptable.\n\n          3. Subjects who received prior cytotoxic chemotherapy after incomplete resection of\n             locoregional recurrent disease\n\n          4. History of, or known current evidence of brain metastasis, including leptomeningeal\n             involvement.\n\n          5. Subjects with bone as the only site of metastatic disease\n\n          6. Subjects with regional lymph node as the only site of metastatic disease\n\n          7. Serious intercurrent medical or psychiatric illness, including serious active\n             infection\n\n          8. History of class II-IV congestive heart failure or myocardial infarction within 6\n             months of randomization\n\n          9. History of other primary malignancy in the last 5 years prior to randomization.\n             Subjects with prior breast cancer history are eligible, however, the most recently\n             obtained biopsy must demonstrate triple negative disease (source documented). Subjects\n             with prior history of in situ cancer or basal or localized squamous cell skin cancer\n             are eligible.\n\n         10. Subjects with a history of interstitial lung disease, history of slowly progressive\n             dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis,\n             pulmonary hypersensitivity pneumonitis or multiple uncontrolled or unstable allergies\n             which, in the opinion of the investigator, may lead to serious complications\n\n         11. Peripheral neuropathy Grade ? 2 by National Cancer Institute Common Terminology\n             Criteria for Adverse Events (NCI CTCAE) v4.0\n\n         12. Subjects who have received an investigational product within the previous 4 weeks\n             prior to randomization\n\n         13. Subject is currently enrolled, or will enroll in a different clinical study in which\n             investigational therapeutic procedures are performed or investigational therapies are\n             administered while participating in this study\n\n         14. Pregnant or nursing women\n\n         15. Subjects with prior hypersensitivity to nab-paclitaxel, gemcitabine, carboplatin or\n             any other platin, or nucleoside analogue agents\n\n         16. Any significant medical condition, laboratory abnormality, or psychiatric illness that\n             would prevent the subject from participating in the study\n\n         17. Any condition including the presence of laboratory abnormalities, which places the\n             subject at unacceptable risk if she were to participate in the study\n\n         18. Any condition that confounds the ability to interpret data from the study\n\n         19. History of seropositive human immunodeficiency virus (HIV)\n\n         20. Subjects who are receiving immunosuppressive or myelosuppressive medications that\n             would, in the opinion of the investigator, increase the risk of serious neutropenic\n             complications
Inclusion Criteria:\n\n        Subjects must meet all of the following criteria to be eligible for the study:\n\n          1. Histologically or cytologically documented extensive stage small cell lung cancer.\n\n          2. Adults of 18 years of age or older.\n\n          3. Performance Status (ECOG) of 0 or 1.\n\n          4. FFPE tumor tissue.\n\n          5. Adequate organ function:\n\n               1. Adequate hematologic function (absolute neutrophil count [ANC] ? 1,500 cells/?L;\n                  hemoglobin ? 9 g/dL, platelets ? 100,000/?L).\n\n               2. Adequate renal function (serum creatinine ? 1.5 mg/dL or calculated creatinine\n                  clearance ? 60 mL/min using Cockcroft-Gault formula).\n\n               3. Adequate hepatic function (alanine aminotransferase [ALT] ? 3 x upper limit of\n                  normal [ULN], ALT may be ? 5 x ULN if due to liver metastases but cannot be\n                  associated with concurrent elevated bilirubin >1.5xULN unless it is approved by\n                  the Sponsor's Medical Monitor).\n\n               4. Prothrombin Time (PT)/International Normalized Ration (INR) ?1.5 × ULN, activated\n                  partial thromboplastin time (aPTT) ?1.5 × ULN.\n\n          6. Written consent on an IRB/IEC-approved Informed Consent Form prior to any\n             study-specific evaluation.\n\n          7. For women of child-bearing potential, negative serum pregnancy test at screening and\n             use of physician-approved method of birth control from 30 days prior to the first\n             study drug administration to 30 days following the last study drug administration or\n             the last EP in the study, whichever is discontinued last.\n\n          8. Male subjects must be surgically sterile or must agree to use physician-approved\n             contraception during the study and for 30 days following the last study drug\n             administration or the last EP in the study, whichever is discontinued last.\n\n        Exclusion Criteria:\n\n        Subjects who meet any of the following criteria will not be eligible for participation in\n        the study:\n\n          1. Limited stage small cell lung cancer appropriate for radical treatment with\n             chemoradiation.\n\n          2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed\n             extensive stage small cell lung cancer.\n\n          3. Presence of any serious or uncontrolled illness including, but not limited to: ongoing\n             or active infection, symptomatic congestive heart failure unstable angina pectoris,\n             uncontrolled cardiac arrhythmia, uncontrolled arterial thrombosis, symptomatic\n             pulmonary embolism, and psychiatric illness that would limit compliance with study\n             requirement.\n\n          4. History of myocardial infarction, acute coronary syndromes (including unstable\n             angina), coronary angioplasty and/or stenting within 6 months prior to the first\n             administration of study drug.\n\n          5. A history of malignancy with the exception of:\n\n               1. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or\n                  in situ cervical cancer\n\n               2. Adequately treated stage I cancer from which the subject is currently in\n                  remission, or\n\n               3. Any other cancer from which the subject has been disease-free for ? 3 years\n\n          6. Known human immunodeficiency virus (HIV) infection.\n\n          7. Females who are pregnant or breastfeeding.\n\n          8. Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg\n             daily for port catheter is allowed)
Inclusion Criteria:\n\n        Subjects must meet all of the following criteria to be eligible for the study:\n\n          1. Age >18 years\n\n          2. ECOG performance status <2 (see Appendix B)\n\n          3. Solid tumor malignancy for which there is no remaining standard therapy or either\n             refuse or are not considered to be candidates for any remaining standard therapy.\n\n          4. Must have a tumor that is measurable or evaluable per RECIST v1.1 in the dose\n             escalation phase. In the expansion cohort(s), subjects must have measurable disease.\n\n          5. Subjects must have Formalin-Fixed, Paraffin-Embedded (FFPE) tissue available either\n             archived or fresh core or punch needle biopsied at study entry (two fresh\n             cores/punches preferred whenever possible) for determination of Notch1 pathway\n             activation status.\n\n          6. Must have received their last chemotherapy, biologic, radiotherapy, or investigational\n             therapy at least 4 weeks prior to enrollment; 6 weeks if the last regimen included\n             BCNU or mitomycin C.\n\n          7. Subjects must have normal organ and marrow function as defined below:\n\n               -  Absolute neutrophil count >1500/mL without growth factor support in the past 7\n                  days\n\n               -  Platelets >100,000/mL without transfusions in the past 7 days\n\n               -  Total bilirubin <1.5 X institutional upper limit of normal (ULN) (<2X ULN for\n                  subjects with Gilbert's syndrome)\n\n               -  AST (SGOT) and ALT (SGPT) <3 X institutional ULN (for subjects with hepatic\n                  involvement <5 X institutional ULN but cannot be associated with elevated\n                  bilirubin)\n\n               -  PT/INR and aPTT within 1.5 X institutional ULN\n\n               -  Creatinine <1.5 X institutional ULN OR\n\n               -  Creatinine clearance >60 mL/min/1.73 m2 for subjects with creatinine levels above\n                  institutional normal\n\n               -  Normal Ejection Fraction (>50%) on ECHO scan or MUGA\n\n          8. Women of childbearing potential must have had a prior hysterectomy or have a negative\n             serum pregnancy test and be using adequate contraception prior to study entry and must\n             agree to use adequate contraception from study entry through at least 6 months after\n             discontinuation of study drug. Men must also agree to use adequate contraception\n             (hormonal or barrier method of birth control; abstinence) prior to study entry and\n             from study entry through at least 6 months after discontinuation of study drug. Should\n             a woman enrolled in the study or a female partner of a man enrolled in the study\n             become pregnant or suspect she is pregnant while participating in this study or within\n             6 months after discontinuation of study, she should inform the Investigator\n             immediately.\n\n          9. Ability to understand and the willingness to sign a written informed consent document\n\n        Exclusion Criteria:\n\n        Subjects who meet any of the following criteria will not be eligible for participation in\n        the study:\n\n          1. Currently receiving any therapeutic treatment for their malignancy including other\n             investigational agents\n\n          2. Prior treatment with gamma secretase inhibitors or other Notch 1 inhibitors\n\n          3. Uncontrolled seizure disorder, active neurologic disease, or active CNS involvement\n             except for individuals who have previously-treated CNS metastases, are asymptomatic,\n             and have no requirement for higher doses of corticosteroids (> prednisone 10mg orally\n             per day) or anti-seizure medication for at least 4 weeks prior to first dose of study\n             drug.\n\n          4. History of a Grade 4 allergic reaction attributed to humanized or human monoclonal\n             antibody therapy\n\n          5. Significant intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac\n             arrhythmia, or psychiatric illness/social situations that would limit compliance with\n             study requirements\n\n          6. Pregnant women or nursing women\n\n          7. Ongoing malignancies or malignancies in remission <3 years other than the malignancies\n             included in this trial. Patients with history of known squamous cell skin cancers\n             within the past 3 years will not be included in this trial. The following prior\n             malignancies are allowable irrespective of when they occurred: in situ carcinoma of\n             the cervix, in situ ductal breast cancer, and low-grade local bladder cancer.\n\n          8. Subjects with known HIV infection\n\n          9. Known bleeding disorder or coagulopathy\n\n         10. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.\n\n         11. Hemoptysis in excess of 2.5 mL(or one-half teaspoon) within 8 weeks of first dose of\n             study drug.\n\n         12. Subjects receiving heparin, warfarin, or other similar anticoagulants, except for\n             subjects on low molecular weight heparin for DVT/PE prophylaxis. Note: Subjects may be\n             receiving low-dose aspirin and/or non-steroidal anti-inflammatory agents.\n\n         13. New York Heart Association Classification II, III, or IV (see Appendix D)\n\n         14. Subjects with poorly controlled blood pressure (defined as systolic blood pressure\n             ?140 mmHg or diastolic blood pressure ?90 mmHg) that is not responsive to medical\n             therapy. Subjects taking antihypertensive medications must be taking ?2 medications to\n             obtain this level of blood pressure control.\n\n             NOTE: Initiation or adjustment of antihypertensive medication(s) is permitted prior to\n             study entry.\n\n         15. Subjects with ECG evidence of ischemia or ?Grade 2 ventricular arrhythmia, subjects\n             who have a history of acute myocardial infarction within 6 months, or subjects with\n             unstable angina.\n\n         16. Subjects with known clinically significant gastrointestinal disease including, but not\n             limited to:\n\n               -  inflammatory bowel disease\n\n               -  active peptic ulcer disease\n\n               -  known intraluminal metastatic lesion(s) with risk of bleeding\n\n               -  history of abdominal fistula, GI perforation, or intra-abdominal abscess within\n                  28 days prior to beginning study treatment\n\n         17. Subjects with diarrhea at time of enrollment or have an ongoing requirement for anti\n             diarrheal therapy
Inclusion Criteria:\n\n          1. Lymphoid malignancy that has relapsed or is refractory after two or more treatments\n             that are FDA approved or are commonly used clinically.\n\n          2. Subjects must have progressive disease requiring therapy. Subjects who are candidates\n             for observation only are not eligible.\n\n          3. Subjects are either not currently considered to be candidates or refuse potentially\n             curative therapies including peripheral stem cell or bone marrow transplant\n\n          4. Subjects must have measurable disease as per disease specific criteria\n\n          5. Must have received their last chemotherapy, biologic, radiotherapy, or investigational\n             therapy at least 4 weeks prior to enrollment; 12 weeks from their last\n             radioimmunotherapy; 3 months if the last therapy was bone marrow/ peripheral stem cell\n             transplant.\n\n          6. Age >18 years\n\n          7. ECOG performance status <2\n\n          8. Normal Ejection Fraction on ECHO scan\n\n          9. Subjects must have normal organ and marrow function as defined below:\n\n             Absolute neutrophil count >1000/mL Platelets >75,000/mL For subjects with known marrow\n             infiltration, ANC ?500 and platelets ?30,000 Total bilirubin <1.5 X institutional\n             upper limit of normal (ULN) (<2X ULN for subjects with Gilbert's syndrome) AST (SGOT)\n             and ALT (SGPT) <3 X institutional ULN (for subjects with hepatic involvement <5 X\n             institutional ULN) PT/INR and aPTT within 1.5 X institutional ULN Creatinine <1.5 X\n             institutional ULN OR Creatinine clearance >60 mL/min/1.73 m2 for subjects with\n             creatinine levels above institutional normal\n\n         10. Women of childbearing potential must have had a prior hysterectomy or have a negative\n             serum pregnancy test and be using adequate contraception prior to study entry and must\n             agree to use adequate contraception from study entry through at least 6 months after\n             discontinuation of study drug. Men must also agree to use adequate contraception\n             (hormonal or barrier method of birth control; abstinence) prior to study entry and\n             from study entry through at least 6 months after discontinuation of study drug. Should\n             a woman enrolled in the study or a female partner of a man enrolled in the study\n             become pregnant or suspect she is pregnant while participating in this study or within\n             6 months after discontinuation of study, she should inform the Investigator\n             immediately.\n\n         11. Ability to understand and the willingness to sign a written informed consent document\n\n        Exclusion Criteria:\n\n        Subjects who meet any of the following criteria will not be eligible for participation in\n        the study:\n\n          1. Currently receiving any therapeutic treatment for lymphoid malignancies including\n             other investigational agents\n\n          2. Prior treatment with gamma secretase inhibitors or other Notch 1 inhibitors\n\n          3. Active CNS involvement, uncontrolled seizure disorder, or active neurologic disease\n\n          4. History of a Grade 4 allergic reaction attributed to humanized or human monoclonal\n             antibody therapy\n\n          5. Significant intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac\n             arrhythmia, or psychiatric illness/social situations that would limit compliance with\n             study requirements\n\n          6. Pregnant women or nursing women\n\n          7. Ongoing malignancies or malignancies in remission <3 years other than the lymphoid\n             malignancies included in this trial. Patients with history of known skin cancers\n             including non-melanotic skin cancers within the past 3 years will not be included in\n             this trial. The following prior malignancies are allowable irrespective of when they\n             occurred: in situ carcinoma of the cervix, in situ ductal breast cancer, and low-grade\n             local bladder cancer.\n\n          8. Subjects with known HIV infection\n\n          9. Known bleeding disorder or coagulopathy\n\n         10. Subjects receiving heparin, warfarin, or other similar anticoagulants, except for\n             subjects on low molecular weight heparin for DVT/PE prophylaxis. Note: Subjects may be\n             receiving low-dose aspirin and/or non-steroidal anti-inflammatory agents.\n\n         11. New York Heart Association Classification II, III, or IV\n\n         12. Subjects with a blood pressure of >140/90 mmHg that is not responsive to medical\n             therapy. Subjects taking antihypertensive medications must be taking ?2 medications to\n             obtain this level of blood pressure control.\n\n         13. Subjects with EKG evidence of ischemia or ?Grade 2 ventricular arrhythmia, subjects\n             who have a history of acute myocardial infarction within 6 months, or subjects with\n             unstable angina.\n\n         14. Subjects with known clinically significant gastrointestinal disease including, but not\n             limited to, inflammatory bowel disease\n\n         15. Subjects with diarrhea at time of enrollment or have an ongoing requirement for anti\n             diarrheal therapy
Inclusion criteria:\n\n        Part A only:\n\n          1. Patients with histologically confirmed advanced solid tumours that are metastatic or\n             unresectable and for which standard curative or palliative measures do not exist or\n             are no longer effective. Patients who refuse standard therapy are also eligible.\n\n             Part B only:\n\n          2. Pathologically confirmed diagnosis of Stage IV (M1a or b) non-small cell lung cancer\n\n          3. Documented Epidermal Growth Factor Receptor (EGFR) T790M mutation\n\n          4. Progression of disease on a reversible tyrosine kinase inhibitor within 30 days of\n             starting study drug. Loss of exposure to prior EGFR TKI should not be >30 days; any\n             procedural delay in confirmation of progression is to be discussed with the BI\n             Clinical Monitor.\n\n             Parts A and B:\n\n          5. Evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1\n\n          6. Age >/= to 18 years\n\n          7. Eastern Cooperative Group (ECOG) performance status 0-1\n\n          8. Adequate organ function\n\n          9. Recovered from any previous therapy-related toxicity to </= to Grade 1 at study entry\n             (except for stable sensory neuropathy </= Grade 2 and alopecia)\n\n         10. Written informed consent\n\n         11. Ability to take oral medication\n\n        Exclusion criteria:\n\n        Parts A and B:\n\n          1. Chemotherapy, biological therapy, or investigational agents (except erlotinib or\n             gefitinib) within 4 weeks prior to the start of study treatment\n\n          2. Hormonal treatment within 2 weeks prior to the start of study treatment (continued use\n             of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer is\n             permitted)\n\n          3. Radiotherapy within two weeks prior to the start of study treatment (except palliative\n             radiotherapy given for symptom control)\n\n          4. Less than 3 days from prior treatment with gefitinib or erlotinib. Patients with\n             adverse events related to gefitinib or erlotinib must recover to Grade 1 or less to be\n             eligible.\n\n          5. Major surgery within 4 weeks before starting study treatment or scheduled for surgery\n             during the projected course of the study\n\n          6. Known hypersensitivity to afatinib or the excipients of any of the trial drugs\n\n          7. History or presence of clinically relevant cardiovascular abnormalities such as\n             uncontrolled hypertension, congestive heart failure New York Heart Association\n             classification of 3, unstable angina or poorly controlled arrhythmia as determined by\n             the investigator. Myocardial infarction within 6 months prior to starting study\n             treatment\n\n          8. Women of childbearing potential and men who are able to father a child, unwilling to\n             be abstinent or use adequate contraception prior to study entry, for the duration of\n             study participation and for at least 2 months after treatment has ended.\n\n          9. Female patients of childbearing potential who are nursing; are pregnant; are not using\n             an acceptable method of birth control, or do not plan to continue using this method\n             throughout the study; and do not agree to submit to pregnancy testing required by this\n             protocol\n\n         10. Any history of or concomitant condition that, in the opinion of the investigator,\n             would compromise the patient's ability to comply with the study or interfere with the\n             evaluation of the efficacy and safety of the test drug\n\n         11. Previous or concomitant malignancies at other sites, except effectively treated\n             non-melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ\n             or effectively treated malignancy that has been in remission for more than 3 years and\n             is considered to be cured\n\n         12. Required treatment with any of the prohibited medications listed in this protocol that\n             cannot be stopped for the duration of trial participation\n\n         13. Known pre-existing Interstitial Lung Disease\n\n         14. Any history or presence of poorly controlled gastrointestinal disorders that could\n             affect the absorption of the study drug (for example, Crohn's disease, ulcerative\n             colitis, chronic diarrhea, malabsorption) in the opinion of the investigator\n\n         15. Active hepatitis B infection (defined as the presence of Hepatitis B DNA), active\n             hepatitis C infection (defined as the presence of Hepatitis C RNA) and/or known Human\n             Immunodeficiency Virus carrier\n\n         16. Prior participation in a blinded afatinib clinical study, unless permission to unblind\n             was granted in consultation with the Clinical Monitor of the blinded study\n\n         17. Meningeal carcinomatosis\n\n         18. Patients with brain or subdural metastases are not eligible, unless they have\n             completed local therapy and have discontinued use of corticosteroids or have been on\n             stable doses of corticosteroids for at least 4 weeks before starting study treatment.\n             Any symptoms attributed to brain metastases must be stable for at least 4 weeks before\n             starting study treatment\n\n         19. QTc interval > 0.47 seconds as measured during screening procedures
Inclusion Criteria for Both Stages:\n\n          -  Measureable disease per RECIST v1.1 with tumor accessible for biopsy\n\n          -  Adequate hematologic and end organ function\n\n        Inclusion Criteria for Stage 1:\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1\n\n          -  Metastatic or inoperable, locally advanced, histologically or cytologically confirmed\n             invasive HR-positive HER2-negative breast cancer\n\n          -  Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study\n             entry\n\n          -  Recurrence or progression following most recent systemic breast cancer therapy\n\n          -  Disease progression during or after CDK4/6 inhibitor treatment for metastatic disease\n\n          -  Postmenopausal according to protocol-defined criteria\n\n          -  Life expectancy >3 years\n\n          -  Available tumor specimen for determination of PD-L1 status\n\n        Inclusion Criteria for Stage 2:\n\n          -  ECOG performance status of 0-2\n\n          -  Ability to initiate treatment within 3 months after disease progression or\n             unacceptable toxicity on a Stage 1 regimen\n\n        Exclusion Criteria for Both Stages:\n\n          -  Significant or uncontrolled comorbid disease as specified in the protocol\n\n          -  Uncontrolled tumor-related pain\n\n          -  Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes\n             mellitus, or certain dermatologic conditions\n\n          -  Positive human immunodeficiency virus or hepatitis B or C\n\n          -  Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study\n             treatment\n\n          -  Prior allogeneic stem cell or solid organ transplantation\n\n          -  History of malignancy other than breast cancer within 2 years prior to screening\n             except those with negligible risk of metastasis/death\n\n          -  History of or known hypersensitivity to study drug or excipients\n\n        Exclusion Criteria for Stage 1:\n\n          -  HER2-positive breast cancer\n\n          -  Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain\n             other agents as specified in the protocol\n\n          -  Unresolved AEs from prior anti-cancer therapy\n\n        Exclusion Criteria for Stage 2:\n\n          -  Unacceptable toxicity with atezolizumab during Stage 1\n\n          -  Uncontrolled cardiovascular disease or coagulation disorder, including use of\n             anticoagulants as specified in the protocol\n\n          -  Significant abdominal or intestinal manifestations within 6 months prior to treatment\n\n          -  Proteinuria
Inclusion Criteria:\n\n        To be eligible for participation in the study, patients must meet the following criteria.\n        Patients who are HRG negative do not need to complete screening procedures beyond HRG\n        assessment.\n\n          1. Patients must have histologically or cytologically confirmed ER+ and/or PR+ (with\n             staining of >1% cells) breast cancer.\n\n          2. Patients with confirmed postmenopausal status due to either surgical/natural menopause\n             or ovarian suppression.\n\n          3. Patients must be HER2 negative.\n\n          4. Patient must have at least one lesion amenable to either core needle biopsy or fine\n             needle aspiration.\n\n          5. Patient must have a positive in-situ hybridization (ISH) test for heregulin, as\n             determined by centralized testing of unstained tumor tissue.\n\n          6. Patients that have progressed following at least one but no more than two prior\n             systemic therapies in the locally advanced or metastatic disease setting.\n\n          7. Patients with documented progression of locally advanced or metastatic disease as\n             defined by RECISTv1.1 (Exception: patients with bone-only metastatic disease are\n             eligible if they have at least 2 lytic lesions visible on a CT or MRI and have\n             documented disease progression on prior therapy based on the appearance of new\n             lesions).\n\n          8. Patients with bone-only lesions who have received radiation to those lesions must have\n             documented progression following radiation therapy.\n\n          9. ECOG Performance Score (PS) of 0 or 1.\n\n         10. Patients with adequate bone marrow reserves.\n\n         11. Adequate hepatic function.\n\n         12. Adequate renal function.\n\n         13. Patient has recovered from clinically significant effects of any prior, surgery,\n             radiosurgery, or other antineoplastic therapy.\n\n         14. Patients who have experienced a venous thromboembolic event within 60 days of signing\n             the main consent form should have been treated with anti-coagulants for at least 7\n             days prior to beginning treatment and for the duration of treatment on this study.\n\n        Exclusion Criteria:\n\n        Patients must meet all the inclusion criteria listed above and none of the following\n        exclusion criteria.\n\n          1. Prior treatment with an anti-ErbB3 antibody.\n\n          2. Prior treatment with a chemotherapy in the locally advanced or metastatic disease\n             setting.\n\n          3. Patients cannot have received prior treatment with fulvestrant or other SERDs in the\n             locally advanced or metastatic setting.\n\n          4. Uncontrolled CNS disease or presence of leptomeningeal disease.\n\n          5. Inflammatory breast cancer.\n\n          6. History of another active malignancy that required systemic therapy in the last 2\n             years. Patients with prior history of in-situ cancer, basal, or squamous cell skin\n             cancer are eligible.\n\n          7. Patients with an active infection, or unexplained fever > 38.5 C during screening\n             visits or on the first scheduled day of dosing, which in the investigator's opinion\n             might compromise the patients participation in the trial or affect the study outcome.\n             At the discretion of the investigator, patients with tumor fever may be enrolled.\n\n          8. Known hypersensitivity to any of the components of seribantumab, fulvestrant, or who\n             have had hypersensitivity reactions to fully human monoclonal antibodies.\n\n          9. NYHA Class III or IV congestive heart failure.\n\n         10. Patients with a significant history of cardiac disease (i.e. uncontrolled blood\n             pressure, unstable angina, myocardial infarction within 1 year or ventricular\n             arrhythmias requiring medication) are also excluded.\n\n         11. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; or active\n             human immunodeficiency virus (HIV) infection, active hepatitis B infection or active\n             hepatitis C infection.
Inclusion Criteria:\n\n        Among other criteria, patients must meet the following conditions to be eligible for the\n        study:\n\n          1. 18 years of age or older.\n\n          2. Body Weight ? 120 kg.\n\n          3. Histologic diagnosis of either a B-cell or T-cell hematologic malignancy known to\n             express CD27 or one of the following solid tumors: metastatic melanoma, renal (clear)\n             cell carcinoma, hormone-refractory prostate adenocarcinoma, ovarian cancer, colorectal\n             adenocarcinoma or non-small cell lung cancer. For the solid tumor expansion cohorts,\n             enrollment is limited to the following solid tumors: melanoma and renal cell\n             carcinoma.\n\n          4. Tumor must be recurrent or treatment refractory with no remaining alternative,\n             approved therapy options, with the following exception: melanoma patients enrolled in\n             the expansion phase must have previously received ipilimumab and, for patients with\n             the BRAF V600E mutation, vemurafenib, or have been offered such therapies and refused,\n             and patients must have progressive disease subsequent to previous therapies.\n\n          5. Measurable or evaluable disease.\n\n          6. Have adequate blood, bone marrow, liver and kidney function as determined by\n             laboratory tests.\n\n          7. If of childbearing potential (male or female), agree to practice an effective form of\n             contraception during study treatment.\n\n          8. Have little or no side effects remaining from prior cancer therapies.\n\n          9. Provide written informed consent.\n\n        Exclusion Criteria:\n\n        Among other criteria, patients who meet the following conditions are NOT eligible for the\n        study:\n\n          1. Known prior primary or metastatic brain or meningeal tumors.\n\n          2. Receiving treatment with immunosuppressive agents, including any systemic steroids.\n\n          3. Active infection requiring systemic therapy, known HIV infection, or positive test for\n             hepatitis B surface antigen or hepatitis C.\n\n          4. Is being treated for anti-coagulation (i.e. warfarin) for reasons other than catheter\n             patency.\n\n          5. Women who are pregnant or lactating.\n\n          6. Prior allogeneic bone marrow transplant.\n\n          7. Autologous bone marrow transplant within 100 days of first dosing.\n\n          8. Recent chemotherapy or other anti-cancer therapy (within 2 - 14 weeks depending on\n             treatment type).\n\n          9. Systemic radiation therapy within 4 weeks or prior focal radiotherapy within 2 weeks\n             prior to first dosing.
Inclusion Criteria:\n\n        Pre-screening Parts 1, 2, and 3\n\n          -  Male or female at least 18 years of age at the time of signing the informed consent\n             form and capable of giving written informed consent, which includes compliance with\n             the requirements and restrictions listed in the consent form.\n\n          -  Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group\n             (ECOG) scale.\n\n          -  Able to swallow and retain orally administered medication.\n\n          -  Sufficient archival tumor biopsy specimen is available for PTEN IHC analysis, or\n             subject is willing to undergo a fresh tumor biopsy for PTEN IHC analysis.\n\n        Pre-screening Parts 1 and 2 only\n\n          -  Histologically or cytologically confirmed diagnosis of one of the following solid\n             tumor malignancies that is not responsive to standard therapies or for which there is\n             no approved or curative therapy or for subjects that refuse standard therapy:\n             Endometrial cancer (endometriod), Prostate cancer, Ovarian cancer, Non-small cell lung\n             cancer, Breast cancer (ER, PR, and HER2 negative), Gastric adenocarcinoma, Colorectal\n             cancer, Head/neck squamous cell carcinoma, Melanoma, or Glioblastoma multiformae at\n             first or second recurrence (more specific disease history is detailed in the study\n             protocol).\n\n        Pre-screening Part 3 only\n\n          -  Must have tumor amenable to biopsy Pre-screening Part 3 CRPC cohort only: prostate\n             adenocarcinoma, surgically castrated or continuously medically castrated (for greater\n             than or equal to 8 weeks prior to pre-screening), and\n\n          -  persistent disease with evidence of disease progression following standard\n             therapy(ies) including prior treatment with docetaxel and androgen/androgen receptor\n             directed therapy, including enzalutamide and/or abiraterone\n\n          -  serum testosterone level <1.7 nmol/L or <50 ng/dL\n\n          -  PSA level of greater than or equal to 2.0 ng/mL For CRC cohort: CRC with persistent\n             disease with evidence of disease progression following standard therapy(ies) that\n             included multi-agent chemotherapy regimen(s) with exposure to oxaliplatin and\n             irinotecan.\n\n        For Signal-finding Expansion Cohort: one of the specified tumor types that is not\n        responsive to standard therapies, or for which there is no approved or curative therapy, or\n        for which subjects have refused standard therapy, including:\n\n          -  Triple negative breast cancer (ER, PR, and HER2 negative), Endometriod, Gastric,\n             Glioblastoma multiformae, Head/neck squamous cell carcinoma, Melanoma, Non-small cell\n             lung cancer, Ovarian Screening Parts 1, 2 includes Pre-screening criteria (above) and\n\n          -  For Parts 1 and 2, histologically or cytologically confirmed diagnosis of one of the\n             following solid tumor malignancies that is not responsive to standard therapies or for\n             which there is no approved or curative therapy or for subjects that refuse standard\n             therapy: Endometrial cancer (endometriod), Prostate cancer, Ovarian cancer, Non-small\n             cell lung cancer, Breast cancer (ER, PR, and HER2 negative), Gastric adenocarcinoma,\n             Colorectal cancer, Head/neck squamous cell carcinoma, Melanoma, or Glioblastoma\n             multiformae at first or second recurrence (more specific disease history is detailed\n             in the study protocol). For Part 3, histologically or cytologically confirmed\n             diagnosis of one of the following solid tumor malignancies that is not responsive to\n             standard therapies or for which there is no approved or curative therapy or for\n             subjects that refuse standard therapy: Endometrial cancer (endometriod), Prostate\n             cancer, or Gastric adenocarcinoma.\n\n          -  All prior treatment-related toxicities must be National Cancer Institute (NCI) Common\n             Terminology Criteria for Adverse Events (CTCAE), Version 4.0, <=Grade 1 (except\n             alopecia) at the time of treatment allocation with the exception of peripheral\n             neuropathy, which must be <=Grade 2.\n\n          -  Adequate organ system function defined as ANC greater than or equal to 1X10^9/L\n             without growth factor in the past 7 days, hemoglobin greater than or equal to 9g/dL\n             without transfusion in the past 7 days, platelets greater than or equal to 75X10^9/L\n             without transfusion in the past 7 days, PT/INR and PTT less than or equal to 1.5XULN,\n             total bilirubin less than or equal to 1.5XULN (isolated bilirubin >1.5XULN is\n             acceptable if bilirubin is fractionated and direct bilirubin <35%), AST and ALT less\n             than or equal to 2.5XULN (AST/ALT can be up to 4XULN in the presence of liver\n             metastasis, but cannot be associated with elevated bilirubin), calculated creatinine\n             clearance or 24-hour urine creatinine clearance greater than or equal to 50mL/min,\n             cardiac ejection fraction greater than or equal to LLN by echocardiography.\n\n          -  Women of childbearing potential and men with reproductive potential must be willing to\n             practice acceptable methods of birth control prior to and after the start of dosing.\n             Additionally, women of childbearing potential must have a negative serum pregnancy\n             test within 14 days prior to the first dose of study medication.\n\n          -  Subjects must have tumors with a documented PTEN deficiency using an analytically\n             validated IHC assay or other correlative assay (e.g., FISH). Determination of PTEN\n             deficiency using archival tumor is acceptable. Where archival tissue is not available\n             or does not confirm PTEN deficiency, a fresh tumor sample will be acceptable for\n             screening, and those with PTEN deficiency will be eligible.\n\n          -  Subjects enrolled as part of PD expansion group (Part 2) must agree to undergo pre-\n             and on-treatment tumor biopsies.\n\n        Screening Part 3 includes Pre-screening criteria (above) and\n\n          -  UPC <0.2\n\n          -  Must continue to have tumor amenable to biopsy\n\n          -  Must agree to undergo both pre-treatment and on-treatment tumor biopsies\n\n          -  Male Subjects of Reproductive Potential: Subjects must agree to use effective\n             contraception throughout the treatment period and for five days after the last dose of\n             study treatment.\n\n        Exclusion Criteria:\n\n        Pre-screening Parts 1, 2, and 3\n\n          -  Presence of any clinically significant GI abnormalities or other condition that may\n             alter absorption such as malabsorption syndrome or major resection of the stomach or\n             bowels.\n\n          -  History of congenital platelet function defect (e.g., Bernard-Soulier syndrome,\n             Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect)\n\n          -  Any serious or unstable pre-existing medical, psychiatric, or other condition\n             (including laboratory abnormalities) that could interfere with subject's safety or\n             providing informed consent.\n\n        Screening Parts 1, 2 includes Pre-screening criteria (above) and\n\n          -  Subject has had chemotherapy, radiotherapy, immunotherapy, or other anti-cancer\n             therapy including investigational drugs within 14 days prior to the first dose of the\n             investigational drug described in this study. Hormonal (e.g., anti-androgen) therapies\n             for prostate cancer must be stopped 4 to 6 weeks prior to enrolment. NOTE: Subjects\n             with prostate cancer may remain on LHRH agonists. Subjects with prostate cancer may\n             remain on low-dose prednisone or prednisolone (up to 10 mg per day) and still be\n             eligible for this study.\n\n          -  Current use of prohibited medication during treatment with GSK2636771. Current use of\n             aspirin, clopidogrel, ticlopidine, prasugrel, or ticagrelor is prohibited.\n             Anticoagulants are permitted only if the subject meets PTT and INR entry criteria.\n             Their use must be monitored in accordance with local institutional practice.\n\n          -  Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra\n             abdominal abscess within 28 days prior to beginning study treatment.\n\n          -  Any major surgery within the last four weeks.\n\n          -  Poorly controlled hypertension (defined as systolic blood pressure of >=150 mmHg or\n             diastolic blood pressure of >100 mmHg based on a mean of 3 measurements at\n             approximately 2-minute intervals). NOTE: Initiation or adjustment of antihypertensive\n             medication(s) is permitted prior to study entry.\n\n          -  Known active infection requiring parenteral or oral anti-infective treatment.\n\n          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated\n             respiratory, hepatic, renal or cardiac disease).\n\n          -  Subjects with brain metastases of non-central nervous system (CNS) primary tumors are\n             excluded if their brain metastases are:\n\n               -  Symptomatic\n\n               -  Treated (surgery, radiation therapy) but not clinically and radiographically\n                  stable one month after local therapy (as assessed by contrast enhanced magnetic\n                  resonance imaging [MRI] or computed tomography [CT]), OR\n\n               -  Asymptomatic and untreated but >1 cm in the longest dimension\n\n               -  Subjects with small (<=1 cm in the longest dimension), asymptomatic brain\n                  metastases that do not need immediate local therapy can be enrolled.\n\n               -  NOTE: Subjects on a stable (i.e., unchanged) dose of corticosteroids for more\n                  than one month, or those who have been off corticosteroids for at least 2 weeks\n                  can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for\n                  more than 4 weeks\n\n          -  QTcF interval >=470 msecs. If a screening QTcF is >=470 msecs, it should be repeated 2\n             additional times at least 5 minutes apart and the average of the 3 readings should be\n             used to determine eligibility.\n\n          -  Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd\n             degree atrioventricular block.\n\n          -  History of myocardial infarction, acute coronary syndromes (including unstable\n             angina), coronary angioplasty, or stenting or bypass grafting within the past 6\n             months.\n\n          -  Class III or IV heart failure as defined by the New York Heart Association functional\n             classification system.\n\n          -  Baseline cardiac troponin (cT-n) >10% coefficient of variance (CV).\n\n          -  Known hypersensitivity to any of the components of the study treatment.\n\n          -  Pregnant or lactating female.\n\n          -  Any malignancy related to human immunodeficiency virus (HIV) or solid organ\n             transplant; history of known HIV, history of known Hepatitis B virus (HBV) surface\n             antigen positivity (subjects with documented laboratory evidence of HBV clearance may\n             be enrolled) or positive Hepatitis C virus antibody confirmed by recombinant\n             immunoblot assay.\n\n        Screening Part 3 includes Pre-screening criteria (above) and\n\n          -  Prior treatment with: Anti-cancer therapy (e.g., chemotherapy with delayed\n             toxicity,immunotherapy, biologic therapy or chemoradiation) within 21 days (or within\n             42 days if prior nitrosourea or mitomycin C containing therapy)prior to enrollment\n             and/or daily or weekly chemotherapy without the potential for delayed toxicity within\n             14 days prior to enrollment • Investigational drug(s) within 30 days or five\n             half-lives, whichever is longer, prior to enrollment\n\n          -  Current use of prohibited medication(s) or requirement for prohibited medication(s)\n             during study treatment NOTE: Current use of anticoagulants is permitted if the subject\n             meets the PTT and INR entry criteria (see Table 6) and monitored in accordance with\n             local institutional practice. NOTE: Subjects who are currently on an aspirin regimen\n             or using aspirin containing product(s) at the time of screening MUST agree to\n             discontinue aspirin or aspirin-containing product(s) at least 10 days prior to first\n             dose of study treatment. After study Day 22 and completion of all assessments to be\n             performed during this period, including tumor biopsies, the aspirin regimen or use of\n             aspirin-containing product(s) may be resumed CRPC cohort only: subjects may remain on\n             LHRH agonists (i.e., leuprolide, goserelin, triptorelin or histrelin), low dose\n             prednisone or prednisolone (up to 10 mg/day), or bisphosphonates (if on stable dose\n             for at least four weeks) without interruption and remain eligible for this study.\n\n          -  Any unresolved greater than or equal to Grade 2 (per CTCAE, v 4.0) toxicity from\n             previous anti-cancer therapy, except alopecia or Grade 2 anemia (if hemoglobin is\n             greater than or equal to 9.0 g/dL)\n\n          -  Any greater than or equal to Grade 3 (per CTCAE, v 4.0) electrolyte abnormality\n\n          -  Any greater than or equal to Grade 2 (per CTCAE, v 4.0) hypocalcemia (except where\n             ionized calcium is less than or equal to Grade 1), hypokalemia, hyponatremia,\n             hypomagnesemia, or symptomatic hypophosphatemia\n\n          -  Active peptic ulcer disease or history of abdominal fistula, GI perforation, or\n             intraabdominal abscess within 28 days prior to enrollment\n\n          -  Previous major surgery within 28 days prior to enrollment\n\n          -  Poorly controlled hypertension (defined as systolic blood pressure of ?150 mmHg or\n             diastolic blood pressure of >100 mmHg based on a mean of three measurements at\n             approximately 2-minute intervals) NOTE: Initiation or adjustment of antihypertensive\n             medication(s) is permitted within 30 days prior to enrollment.\n\n          -  Known active infection requiring IV or oral anti-infective treatment\n\n          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated\n             respiratory, hepatic, renal or cardiac disease)\n\n          -  Subject
DISEASE CHARACTERISTICS:\n\n          -  Histologically or cytologically confirmed\n\n          -  Locally advanced or metastatic non-hematologic malignancies\n\n          -  Measureable\n\n          -  Refractory to standard therapies or single agent gemcitabine is indicated as a\n             standard treatment option\n\n        PRIOR/CONCURRENT THERAPY:\n\n          -  No concurrent radiotherapy, chemotherapy, immunotherapy or other investigational\n             agents\n\n          -  Must have recovered from side effects of prior therapies\n\n        PATIENT CHARACTERISTICS:\n\n        Life expectancy\n\n          -  > 12 weeks\n\n        Performance Status\n\n          -  ECOG 0 or 1\n\n        Bone Marrow Reserve\n\n          -  Absolute Neutrophil count (AGC/ANC) ? 1,500/uL\n\n          -  Platelets ? 100,000/uL\n\n          -  Hemoglobin > 9 g/dL\n\n        Renal Function\n\n          -  Calculated Glomerular filtration rate (GFR) > 59mL/min/1.73M^2\n\n        Hepatic Function\n\n          -  Total bilirubin ? 1.5 X ULN\n\n          -  AST, ALT, and ALP ? 3 X ULN or ? 5.0 x ULN, if liver metastasis exists\n\n          -  PT INR ? 1.5 X ULN\n\n        Cardiovascular\n\n          -  No history of clinically significant vascular disease\n\n          -  No New York Heart Association (NYHA) Class > II heart failure\n\n        Hematologic\n\n          -  No history of bleeding disorders\n\n          -  No evidence of bleeding diathesis or coagulopathy\n\n          -  No presence of clinically significant hemoptysis or hematuria, presence of serious\n             non-healing wound or ulceration, or signs of other bleeding\n\n          -  No evidence of a tumor invasion of any major blood vessel\n\n          -  No trauma with increased risk of life-threatening bleeding or history of severe head\n             trauma or intracranial surgery within two months of study entry\n\n        Surgery/Procedures\n\n          -  No major surgery or open biopsy within 28 days before drug infusion or evidence of\n             active bleeding postoperatively\n\n          -  No plan for any major surgery during treatment period\n\n          -  No presence or requirement of an epidural catheter or lumbar puncture within 48 hours\n             prior to each dose of study treatment\n\n          -  No anticipation of receiving an epidural catheter or a lumbar puncture within 48 hours\n             after each dose of study treatment\n\n        Excluded Medications or Treatment Regimens\n\n          -  Unfractionated heparin of > 15,000 units/day within 8 hours prior to each dose of\n             study treatment\n\n          -  Low-molecular weight heparin at a higher dose than recommended for prophylactic used\n             or required within 20 hours prior to each dose of study treatment\n\n          -  Warfarin used or required within 48 hours prior to each dose of study treatment and\n             the prothrombin time (INR) exceeded the upper limit of normal range\n\n          -  Direct thrombin inhibitors or Xa inhibitors\n\n          -  Acetylsalicylic acid used or required within 72 hours prior to each dose of study\n             treatment\n\n          -  Clopidogrel bisulfate used or required within 48 hours prior to each dose of study\n             treatment\n\n          -  Anticipated requirement for anti-platelet or anti-coagulant agents excluding\n             non-aspirin NSAID within 48 hours following study treatment infusion\n\n        Other\n\n          -  No active systemic infection requiring parenteral antibiotic therapy\n\n          -  No history of or presence of a CNS disease\n\n          -  No history of allergic reactions to compounds of similar chemical or biologic\n             composition\n\n          -  Not HIV positive\n\n          -  No women who are pregnant or nursing\n\n          -  A negative serum pregnancy test if female\n\n          -  Patients, both females and males, with reproductive potential must agree to use\n             effective contraceptive measures for the duration of the study\n\n          -  No history of significant renal, endocrinologic, metabolic, immunologic or hepatic\n             disease\n\n          -  No evidence of psychiatric illness/social situations\n\n          -  Other illness that in the opinion of the investigator would exclude the patient from\n             participating\n\n          -  Must provide informed consent and HIPAA authorization and comply with\n             protocol-specified procedures and follow-up evaluations
Inclusion Criteria include:\n\n          -  Male and female patients, 7 to 16 years of age, inclusive, with malignant and/or\n             nonmalignant moderate to severe pain requiring or anticipated to require continuous,\n             around-the-clock, opioid treatment for at least 2 weeks (based on the investigator's\n             judgment);\n\n          -  Patients must have written informed consent provided by the parent or legal guardian\n             and assent provided by the patient, when appropriate;\n\n          -  Patients on incoming opioids must be taking ? 80 mg/day morphine or equivalent if aged\n             12 to 16 years or ? 40 mg/day morphine or equivalent if aged 7 to 11 years prior to\n             the screening visit;\n\n          -  Patients and patient's parent/caregiver must be compliant with the protocol, ie, must\n             be able to perform study assessments and understand and complete the age-appropriate\n             scale to rate pain intensity. Patients must not have a cognitive developmental delay\n             or any other condition that would preclude them from completing the age-appropriate\n             pain scale.\n\n        Exclusion Criteria include:\n\n          -  Patients who are allergic to buprenorphine or have a history of allergies to other\n             opioids (this criterion does not include patients who have experienced common opioid\n             side effects [eg, nausea, constipation]) or who have allergies or other\n             contraindications to transdermal delivery systems or patch adhesives;\n\n          -  Patients with a dermatological disorder, including burn and skin graft sites, at any\n             relevant patch application site that would preclude proper placement and/or rotation\n             of BTDS patches;\n\n          -  Patients with evidence of impaired renal function;\n\n          -  Patients with hepatic impairment;\n\n          -  Patients with history of seizures;\n\n          -  Patients with intracranial pressure;\n\n          -  Patients who have a history of sleep apnea within the past year;\n\n          -  Patients who require mechanical ventilation during study treatment period, are\n             cyanotic, or who have unstable respiratory disease;\n\n          -  Patients with clinically significant structural heart disease or a pacemaker;\n\n          -  Patients with clinically unstable cardiac disease;\n\n          -  Patients who receive or anticipate to receive investigational medication/therapy\n             during study drug treatment period.\n\n        Other protocol-specific inclusion/exclusion criteria may apply.
Inclusion Criteria:\n\n          -  Must have evidence of c-MET dysregulation from either local data or the results of\n             molecular pre-screening evaluations.\n\n          -  Confirmed diagnosis of a solid tumor.\n\n          -  Measureable lesion.\n\n          -  Refractory to currently available treatment or no therapies available.\n\n          -  18 years or older.\n\n          -  ECOG performance status of 0, 1, or 2.\n\n          -  Obtained written informed consent.\n\n        Additional inclusion criteria for NSCLC patients EGFRwt with high c-MET expression:\n\n          -  Written documentation of EGFRwt NSCLC.\n\n          -  Written documentation of c-MET positivity.\n\n          -  Patients should not have received more than three prior lines of antineoplastic\n             therapy for NSCLC.\n\n          -  Presence of at least one measurable lesion as determined by modified RECIST version\n             1.1\n\n        Exclusion Criteria:\n\n        HCC with liver dysfunction greater than Child-Pugh A. Previous treatment with a c-MET\n        inhibitor or HGF-targeting therapy. Symptomatic CNS metastases that are neurologically\n        unstable or requiring increasing doses of steroids to control their CNS disease.\n\n        Any CNS deficits. For patients with GBM, CNS symptoms grade 2 or greater. Subjects with\n        significant or uncontrolled cardiovascular disease (eg, uncontrolled hypertension,\n        peripheral vascular disease, congestive heart failure, cardiac arrhythmia, or acute\n        coronary syndrome) within 6 months of starting study treatment or heart attack within 12\n        months of starting study treatment.\n\n        Receiving anti-epileptic drugs that are known to be strong inducers of CYP3A4. Prior or\n        current anti-angiogenic therapy for patients with GBM. Radiation therapy within ? 4 weeks\n        (< 12 for GBM) prior to the first dose of study drug or limited field radiotherapy within ?\n        2 weeks (< 12 weeks GBM) prior to the start of study treatment. Any persistent side effect\n        of prior radiotherapy must be resolved to ? Grade 1 prior to the first dose of study drug.\n\n        Additional exclusion criteria for NSCLC patients EGFRwt with high c-MET expression:\n\n          -  Patients who have received more than three prior lines of antineoplastic therapies\n\n          -  Any unresolved toxicity (CTCAE grade > 1) from previous anti-cancer therapy or\n             radiotherapy, except alopecia\n\n          -  Patients have received anti-cancer therapies within the following time frames prior to\n             the first dose of study treatment:\n\n               -  Conventional cytotoxic chemotherapy: ?4 weeks (?6 weeks for nitrosoureas and\n                  mitomycin-C)\n\n               -  Biologic therapy (e.g., antibodies): ?4 weeks\n\n               -  Non-cytotoxic small molecule therapeutics: ?5 half-lives or ?2 weeks (whichever\n                  is longer)\n\n               -  Other investigational agents: ?4 weeks\n\n               -  Radiation therapy (palliative setting is allowed.): ?4 weeks\n\n               -  Major surgery: ?2 weeks\n\n        Other protocol-defined inclusion/exclusion criteria may apply.
Key Inclusion Criteria (Part 1 and Part 2):\n\n          -  Confirmed relapsed or refractory MM (measurable disease) or PCL.\n\n          -  Prior treatment regimens for Part 1: Patients should have received at least 2 prior\n             treatment regimens. Prior treatment must have included at least one full cycle of a\n             proteasome inhibitor (e.g., bortezomib or carfilzomib) and at least one full cycle of\n             an IMiD (e.g., thalidomide, lenalidomide or pomalidomide).\n\n          -  Prior treatment regimens for Part 2: Patients should have received 1 to 3 prior\n             treatment regimens. Prior treatment could have included bortezomib only if the disease\n             was not refractory to treatment with bortezomib (refractory defined as documented\n             progression on therapy or within 60 days of completing treatment with bortezomib).\n\n          -  The disease should have progressed per IMWG criteria during or after the last prior\n             treatment regimen.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.\n\n          -  Adequate hematology laboratory values without transfusion support and without\n             hematological growth factor support within 2 weeks of screening.\n\n          -  Adequate liver and renal function.\n\n          -  Additional criteria exist.\n\n        Key Exclusion Criteria (Part 1 and Part 2):\n\n          -  Primary amyloidosis.\n\n          -  Peripheral neuropathy ? Grade 2 or neuropathy with pain, regardless of grade.\n\n          -  Concomitant malignancies or previous malignancies with less than a 3-year disease free\n             interval at the time of enrollment (patients with adequately resected basal or\n             squamous cell carcinoma of the skin, carcinoma in situ of the cervix or Stage A low\n             grade prostate cancer may enroll irrespective of the time of diagnosis).\n\n          -  Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to\n             first dose of study drug.\n\n          -  Treatment with an investigational medicinal product or device within 28 days prior to\n             first dose of study drug.\n\n          -  Cytotoxic therapy or monoclonal antibodies within 21 days prior to first dose of study\n             drug.\n\n          -  Radiotherapy within 21 days prior to first dose of study drug (if the radiation portal\n             covered ? 5% of the bone marrow reserve, the patient may be enrolled irrespective of\n             the end date of radiotherapy).\n\n          -  Major surgery within 14 days and minor surgery within 7 days prior to first dose of\n             study drug.\n\n          -  Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to\n             first dose of study drug.\n\n          -  Known positive serology for the human immunodeficiency virus (HIV), hepatitis B and/or\n             active hepatitis C.\n\n          -  Additional criteria exist.
Inclusion Criteria - Phase 1 (Cohort A):\n\n          -  Female patient ? 18 years\n\n          -  Patient must be postmenopausal, verified by 1 of the following:\n\n               -  Bilateral surgical oophorectomy\n\n               -  No spontaneous menses > 1 year\n\n               -  No menses for < 1 year with FSH and estradiol levels in postmenopausal range\n\n          -  Postmenopausal women with primary invasive breast cancer, histologically confirmed by\n             core needle (or incisional biopsy), whose tumors are estrogen (ER) and/or progesterone\n             (PgR) positive. Estrogen- and/or progesterone-receptor positive disease based on 10%\n             or more nuclear staining of the invasive component of the tumor\n\n          -  Stage IV disease (as defined by the AJCC Staging Manual, 6th Edition, 2002); or\n             locally relapsed, unresectable disease\n\n          -  Measurable or evaluable disease according to RECIST criteria (see appendix VII)\n\n          -  Both HER2-positive and HER2-negative disease (as defined by IHC or by fluorescence in\n             situ hybridization [FISH]). HER2+ must have had prior treatment with trastuzumab\n             and/or lapatinib.\n\n          -  ECOG performance status 0-2 (see appendix VI)\n\n          -  Patients are suitable candidates for treatment with anastrozole (patients may have had\n             any prior endocrine therapy or prior chemotherapy for treatment of their disease,\n             either as adjuvant therapy, or as treatment for advanced disease). There is no\n             restriction on the number of prior regimens in the phase I cohort A.\n\n          -  Patient is accessible and willing to comply with treatment and follow-up\n\n          -  Patient is willing to provide written informed consent prior to the performance of any\n             study-related procedures\n\n          -  Required laboratory values\n\n               -  Absolute neutrophil count ? to 1.5 x 10^9/L\n\n               -  Hemoglobin ? to 9.0 g/dL\n\n               -  Platelet count ? to 100 x 10^9/L\n\n               -  Creatinine ? 1.5 mg/dL\n\n               -  Total bilirubin ? 1.0 x upper limit of normal (ULN)\n\n               -  Alkaline phosphatase and AST/ALT within protocol parameters. In determining\n                  eligibility, the more abnormal of the two values (AST or ALT) should be used.\n\n        Inclusion Criteria - Phase 2 (Cohort B):\n\n          -  Female patient ? 18 years\n\n          -  Patient must be postmenopausal, verified by 1 of the following:\n\n               -  Bilateral surgical oophorectomy\n\n               -  No spontaneous menses ? 1 year\n\n               -  No menses for < 1 year with FSH and estradiol levels in postmenopausal range\n\n          -  Postmenopausal women with primary invasive breast cancer, histologically confirmed by\n             core needle (or incisional biopsy), whose tumors are estrogen (ER) and/or progesterone\n             (PgR) positive. Estrogen- and/or progesterone-receptor positive disease based on 10%\n             or more nuclear staining of the invasive component of the tumor. Patients may have\n             bilateral or multifocal invasive breast cancers. The patient may have concurrent DCIS\n             in either breast but the DCIS will not be measured as part of the study endpoints.\n\n          -  Tumor size ? 2 cm\n\n          -  Tumor measurable either by clinical examination, mammography, MRI, or ultrasound\n\n          -  HER2-negative disease (as defined by fluorescence in situ hybridization [FISH] or by\n             IHC)\n\n          -  ECOG performance status 0-1 (see Appendix VI)\n\n          -  Patient is accessible and willing to comply with treatment and follow-up\n\n          -  Patient is willing to provide written informed consent prior to the performance of any\n             study-related procedures\n\n          -  Required laboratory values\n\n               -  Absolute neutrophil count ? 1.5 x 10^9/L\n\n               -  Hemoglobin ? 9.0 g/dL\n\n               -  Platelet count ? 70 x 10^9/L\n\n               -  Creatinine ? 1.5 mg/dL\n\n          -  Total bilirubin ? 1.5 x upper limit of normal (ULN)\n\n          -  Alkaline phosphatase and AST/ALT ? 1.5 x upper limit of normal (ULN)\n\n        Exclusion Criteria - Phase 1 (Cohort A):\n\n          -  Concurrent therapy with any other non-protocol anti-cancer therapy\n\n               -  Any agent with estrogenic or putatively estrogenic properties, including herbal\n                  preparations, must be stopped at least one week prior to registration.\n\n               -  Ongoing, chronic administration of bisphosphonate therapy is allowed so long as\n                  such treatment was ongoing at the time of study entry.\n\n          -  Current therapy with hormone replacement therapy, or any hormonal agent such as\n             raloxifene, tamoxifen, or other selective estrogen receptor modulators (agents must be\n             stopped prior to randomization)\n\n          -  Presence of neuropathy ? grade 2 (NCI-CTC version 3.0) at baseline\n\n          -  History of any other malignancy within the past 5 years, with the exception of\n             non-melanoma skin cancer or carcinoma-in-situ of the cervix\n\n          -  Clinically significant cardiovascular disease (e.g., hypertension [BP > 150/100],\n             history of myocardial infarction or stroke within 6 months, unstable angina), New York\n             Heart Association (NYHA) Grade II or greater congestive heart failure, or serious\n             cardiac arrhythmia requiring medication\n\n          -  Active, uncontrolled infection requiring parenteral antimicrobials\n\n          -  A history of a severe hypersensitivity reaction to anastrozole, or AZD0530 or their\n             excipients\n\n          -  Evidence of bleeding diathesis or coagulopathy.\n\n          -  Resting EKG with measurable QTc interval of >480msec at 2 or more time points within a\n             24 hr period.\n\n          -  Since AZD0530 is a substrate and inhibitor of CYP3A4, patients requiring medication\n             with drugs listed in Appendix XI should be excluded from study.\n\n          -  Any evidence of severe or uncontrolled systemic medical or psychiatric conditions\n             (e.g. Severe hepatic impairment, interstitial lung disease [bilateral, diffuse,\n             parenchymal lung disease]) or current unstable or uncompensated respiratory or cardiac\n             conditions which make it undesirable for the patient to participate in the study or\n             which could jeopardize compliance with the protocol\n\n          -  Evidence of underlying pulmonary dysfunction as evidenced by oxygen saturation <90% by\n             pulse oximetry, interstitial pulmonary infiltrates on high resolution CT scan prior to\n             study entry and/or symptomatic pulmonary (pleural or parenchymal) metastasis.\n\n        Exclusion Criteria - Phase 2 (Cohort B):\n\n          -  Prior chemotherapy, endocrine therapy or radiotherapy for the presenting breast\n             cancer. Prior incidence and treatment of contralateral invasive or non-invasive breast\n             cancer is not an exclusion criterion.\n\n          -  Inflammatory breast cancer, clinically defined as the presence of erythema or\n             induration involving one-third or more of the breast, or pathologically defined as\n             dermal lymphatic invasion\n\n          -  Prior excisional biopsy or complete resection of the primary invasive tumor (prior\n             sentinel node biopsy allowed)\n\n          -  Prior ipsilateral radiation therapy for invasive or non-invasive breast cancer\n\n          -  Distant metastasis is an exclusion criterion - Isolated ipsilateral supraclavicular\n             node involvement and/or direct invasion of the primary tumor into skin is allowed\n\n          -  Concurrent therapy with any other non-protocol anti-cancer therapy\n\n          -  Any agent with estrogenic or putatively estrogenic properties, including herbal\n             preparations, must be stopped at least one week prior to registration\n\n          -  Current therapy with hormone replacement therapy, or any hormonal agent such as\n             raloxifene, tamoxifen, or other selective estrogen receptor modulators (agents must be\n             stopped for one week prior to randomization)\n\n          -  Presence of neuropathy ? grade 2 (NCI-CTC AE version 3.0) at baseline\n\n          -  History of any other malignancy within the past 5 years, with the exception of\n             non-melanoma skin cancer or carcinoma-in-situ of the cervix\n\n          -  Clinically significant cardiovascular disease (e.g. history of myocardial infarction\n             or stroke within 6 months, unstable angina), New York Heart Association (NYHA) Grade\n             II or greater congestive heart failure, or serious cardiac arrhythmia requiring\n             medication\n\n          -  Active, uncontrolled infection requiring parenteral antimicrobials\n\n          -  A history of a severe hypersensitivity reaction to anastrozole, or AZD0530 or their\n             excipients\n\n          -  Evidence of bleeding diathesis or coagulopathy\n\n          -  Resting EKG with measurable QTc interval of >480msec at 2 or more time points within a\n             24 hr period.\n\n          -  AZD0530 is a substrate and inhibitor of CYP3A4. Since concurrent administration of\n             AZD0530 with other CYP3A4 substrates has been shown to be well tolerated, continuation\n             or initiation of medically indicated drugs that are substrates of CYP3A4 is permitted\n             at MD discretion. Drugs listed in Appendix XI that are known to strongly induce or\n             inhibit CYP3A4 activity should be discontinued prior to study entry and should not be\n             initiated during protocol treatment.\n\n          -  Any evidence of severe or uncontrolled systemic psychiatric or medical conditions (eg.\n             Severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal\n             lung disease]) or current unstable or uncompensated respiratory or cardiac conditions\n             which make it undesirable for the patient to participate in the study or which could\n             jeopardize compliance with the protocol\n\n          -  Evidence of underlying pulmonary dysfunction as evidenced by oxygen saturation <90% by\n             pulse oximetry prior to study entry and/or symptomatic pulmonary (pleural or\n             parenchymal) disease.\n\n          -  Subjects unwilling or unable to undergo breast MRI as required by protocol will be\n             excluded from study
Inclusion Criteria:\n\n          1. Pathologically documented Stage IV malignant melanoma or unresectable Stage III\n             melanoma for which no standard effective therapy exists or for which an appropriate\n             window exists between alternative therapeutic options. Patients for whom early\n             treatment with vemurafenib is indicated e.g. rapidly progressing or symptomatic\n             disease, are excluded from this trial.\n\n          2. Previous surgery (other than resection of skin metastases), radiotherapy,\n             chemotherapy, immunotherapy or experimental therapy completed >4 weeks before and all\n             adverse events resolved to ? grade 1. In cases where localised radiotherapy has been\n             applied, treatment with IMCgp100 can be commenced after a two week period.\n\n          3. HLA A2 positive.\n\n          4. ? 18 years old.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status ?1.\n\n          6. Measurable disease according to RECIST 1.1 criteria. Patients participating in the\n             dose escalation part of Arm 2 only require assessable disease.\n\n          7. Life expectancy >3 months.\n\n          8. Blood tests within the following parameters:\n\n               1. Platelet count ?100 x10?/L\n\n               2. Haemoglobin ?9g/dL (blood transfusion to achieve this level is permitted)\n\n               3. Calculated creatinine clearance ?50 mL/min using the modified Cockroft-Gault\n                  equation\n\n               4. Neutrophil count ?1x10?/L\n\n               5. Lymphocyte count ?0.5x10?/L\n\n          9. Female patients of childbearing potential must use maximally effective birth control\n             during the period of therapy, must be willing to use contraception for 6 months\n             following the last study drug infusion and must have a negative urine or serum\n             pregnancy test upon entry into this study. Otherwise, female patients must be\n             postmenopausal (no menstrual period for a minimum of 12 months) or surgically sterile.\n\n         10. Male patients must be surgically sterile or willing to use a double barrier\n             contraception method upon enrolment, during the course of the study, and for 6 months\n             following the last study drug infusion.\n\n         11. Patients with a history of adrenal insufficiency, maintained on stable replacement\n             dose corticosteroid (<10 mg/d prednisone or the equivalent) are eligible for treatment\n             with IMCgp100, unless there is a past history of adrenal crisis. Eligible patients\n             with a history of adrenal insufficiency receiving replacement dose corticosteroid must\n             receive prophylactic stress dose corticosteroid prior to dosing during the first four\n             doses of IMCgp100 treatment, regardless of weekly or daily dosing regimen.\n\n         12. Able to give informed consent.\n\n        Exclusion Criteria:\n\n        Patients meeting any of the following criteria will be excluded from the study:\n\n          1. Symptomatic brain metastases that are unstable, require steroids, or that have\n             required radiation within the last 28 days.\n\n          2. Other active malignancy in the past 5 years except carcinoma in situ, completely\n             excised nonmelanomatous skin cancer or any other malignancy that in the opinion of the\n             investigator is considered to be cured.\n\n          3. Comorbid medical condition that would increase the risk of toxicity in the opinion of\n             the investigator or sponsor. Symptomatic on-going infection must be resolved before\n             the patient can be treated in the study.\n\n          4. Uveitis\n\n          5. Had myocardial infarction within 1 year before enrolment, symptomatic congestive heart\n             failure (New York Heart Association >Class II), unstable angina or unstable cardiac\n             arrhythmia requiring medication.\n\n          6. Has an ejection fraction <50%.\n\n          7. Clinically significant electrocardiogram (ECG) changes that obscure the ability to\n             assess the RR, PR and QT intervals. Patients with QTc calculated by Bazetts or locally\n             preferred formula which is greater than 500ms.\n\n          8. Has hepatic function as follows:\n\n               1. Aspartate aminotransferase >2.5 x upper limit of normal (ULN)\n\n               2. Alanine aminotransferase >2.5 x ULN\n\n               3. Bilirubin >2.0 x ULN\n\n               4. Prothrombin time or partial thromboplastin time >1.5 x ULN\n\n          9. Bleeding diathesis.\n\n         10. Immunosuppressive condition or treatment including previous transplantation,\n             splenectomy or known HIV infection.\n\n         11. Has a history of adult seizures.\n\n         12. Patients with evidence of a raised intracranial pressure in Arm 2 of the study who\n             will have a CSF sample taken.\n\n         13. Patients receiving chronic corticosteroid treatment (longer than 8 weeks duration) for\n             management of pre-existing adverse events at any dose, or patients with a history of\n             chronic corticosteroid treatment longer than 8 weeks duration for adverse events\n             within 6 months.
INCLUSION CRITERIA:\n\n          -  Age: >/= 18\n\n          -  Diagnosis:\n\n               -  Histologically confirmed recurrent, locally advanced unresectable or metastatic\n                  adenocarcinoma of the pancreas who have progressed after front line chemotherapy,\n                  OR\n\n               -  Histologically confirmed metastatic colorectal adenocarcinoma who have progressed\n                  after at least 2 standard chemotherapy regimens.\n\n          -  Tumor sections must stain >/= 20% positive for NPC-1C antibody/antigen target\n\n          -  Measurable disease (by RECIST)\n\n          -  Karnofsky performance status of >/= 50%\n\n          -  Laboratory Function (within 21 days of receiving first dose of study drug):\n\n               -  Hemoglobin > 8.5 g/dL, or on stable doses (hematocrit stable within 1 gram and\n                  dose stable for one month) of erythropoietin or similar medication.\n\n               -  Absolute neutrophil count (ANC) >/= 1,500/mm3\n\n               -  Platelets >/= 50,000/mm3\n\n               -  Total bilirubin </= 2.0 mg/dL\n\n               -  ALT and AST </= 2.5 times the ULN, or, if the patient has liver metastases, </= 5\n                  times the ULN\n\n               -  Creatinine </= ULN\n\n          -  Voluntary written informed consent before performance of any study-related procedure\n             that is not part of normal medical care.\n\n          -  Expected to be able to remain on a study protocol for at least 8 weeks.\n\n          -  Is post-menopausal, surgically sterilized, or willing to use acceptable methods of\n             birth control for the duration of the study. Male subject agrees to use an acceptable\n             barrier method for contraception during the study.\n\n        EXCLUSION CRITERIA:\n\n          -  Has history of disseminated or uncontrolled brain metastases or central nervous system\n             disease.\n\n          -  Ascites with abdominal distention.\n\n          -  Mechanical, non-reversible reason for not being able to eat, or have a likelihood of\n             developing malignant bowel obstruction during the course of the induction phase of\n             treatment; subjects with uncomplicated J-tubes will not be excluded.\n\n          -  Any major surgery within four weeks of enrollment.\n\n          -  Uncontrolled concomitant illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac\n             arrhythmia.\n\n          -  Has another serious medical illness, including a second malignancy, or psychiatric\n             illness that could, in the Investigator's opinion, potentially interfere with the\n             completion of treatment according to this protocol.\n\n          -  Pregnant or breast-feeding.\n\n          -  Any chemotherapeutic agents or corticosteroids within 2 weeks of study entry or\n             biologic treatment within 4 weeks of study entry.\n\n          -  Use of any high risk medications that prolong the QT/QTc interval.\n\n          -  History of allergic reaction to Erbitux greater than grade 1.\n\n          -  Uncontrolled diabetes.\n\n          -  Prior history of a documented hemolytic event.\n\n          -  Receiving warfarin.
Inclusion criteria:\n\n        Phase I Part:\n\n          1. Histologically-confirmed WHO Grade III or IV malignant glioma that is recurrent after\n             prior chemoradiotherapy. Patients with prior low-grade glioma are eligible if\n             histologic assessment demonstrates transformation to WHO Grade III or IV malignant\n             glioma.\n\n          2. Age at least 18 years at entry\n\n          3. KPS at least 60%\n\n          4. Patients must have recovered from previous surgery and chemotherapy.\n\n          5. Written informed consent that is consistent with local law and ICH-GCP guidelines.\n\n        Phase II Part:\n\n          1. Histologically-confirmed WHO Grade IV malignant glioma at first episode of recurrence\n             after prior combined chemoradiotherapy. Patients with prior low-grade glioma are\n             eligible if histologic assessment demonstrates transformation to WHO Grade IV\n             malignant glioma and if prior treatment included temozolomide chemotherapy and\n             radiotherapy.\n\n          2. Bi-dimensionally measurable disease with a minimum measurement of 1 cm (10 mm) in one\n             diameter on Gd MRI performed within 14 days prior to first treatment (Day 1).\n\n          3. Age at least 18 years at entry\n\n          4. KPS at least 70%\n\n          5. Patients must have recovered from previous surgery and chemotherapy.\n\n          6. Written informed consent that is consistent with local law and ICH-GCP guidelines.\n\n          7. Patients receiving corticosteroids have to receive a stable or decreasing dose for at\n             least 14 days before start of study treatment.\n\n        Exclusion criteria:\n\n        Phase I and Phase II Parts:\n\n          1. Less than 12 weeks between radiotherapy and start of study treatment, unless new\n             enhancing lesion outside of radiation field or radiologically progressive on two\n             consecutive MRI scans at least four weeks apart or biopsy-proven recurrence.\n\n          2. Less than two weeks from surgical resection (one week from prior stereotactic biopsy)\n             or major surgical procedure.\n\n          3. Less than two weeks after previous chemotherapy (6 weeks from nitrosureas).\n\n          4. Treatment with other investigational drugs; participation in another clinical study\n             within the past 2 weeks before start of therapy or concomitantly with this study.\n\n          5. Progressive disease or toxicity =CTCAEv3 Grade 3 to protracted temozolomide dosing\n             (defined as temozolomide administered more than 5 days/28 day cycle).\n\n          6. Active infectious disease requiring intravenous therapy.\n\n          7. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.\n\n          8. Gastrointestinal disorders that may interfere with the absorption of the study drug or\n             chronic diarrhea.\n\n          9. Serious illness or concomitant non-oncological disease considered by the investigator\n             to be incompatible with the protocol.\n\n         10. Patient is <3 years free of another primary malignancy except: if the other primary\n             malignancy is either not currently clinically significant or does not require active\n             intervention (such as a basal cell skin cancer or a cervical carcinoma in situ).\n             Existence of any other malignant disease is not allowed.\n\n         11. Cardiac left ventricular function with resting ejection fraction <50%.\n\n         12. Absolute neutrophil count (ANC) less than 1500/mm3.\n\n         13. Platelet count less than 100,000/mm3.\n\n         14. Bilirubin greater than 1.5 x upper limit of institutional norm.\n\n         15. Aspartate amino transferase (AST) greater than 3 x upper limit of institutional norm.\n\n         16. Serum creatinine greater than 1.5 x upper limit of institutional norm.\n\n         17. Patients who are sexually active and unwilling to use a medically acceptable method of\n             contraception.\n\n         18. Pregnancy or breast-feeding.\n\n         19. Patients unable to comply with the protocol.\n\n         20. Known pre-existing interstitial lung disease (ILD).\n\n        Phase I part only:\n\n        1. Less than four weeks from prior treatment with bevacizumab.\n\n        Phase II Part only:\n\n          1. Prior EGFR-directed therapy.\n\n          2. Prior bevacizumab therapy.\n\n          3. Patients presenting with second or higher number of episodes of recurrence.\n\n          4. Requirement of treatment with any of the prohibited concomitant medications listed in\n             Section 4.2.2 (Restrictions regarding concomitant treatment).
Inclusion Criteria:\n\n        A subject will be eligible for inclusion in this study only if all of the following\n        criteria apply:\n\n          -  Subjects must have histologically confirmed invasive breast cancer with Stage IV\n             disease at primary diagnosis or at relapse after curative-intent surgery. Where the\n             disease is restricted to a solitary lesion, the neoplastic nature of the lesion should\n             be confirmed by cytology or histology.\n\n          -  Documented amplification of ErbB2 3+ by immunohistochemistry or a positive score\n             (>2.2) by FISH using a local laboratory result (which will be considered sufficient in\n             this study with no further verification by a central laboratory).\n\n          -  Subjects must have received no more than one prior chemotherapeutic regimen in the\n             metastatic setting.\n\n          -  If a taxane had been administered in the neoadjuvant, adjuvant or metastatic setting,\n             progression must have occurred ?12 months after completion of this treatment.\n\n          -  Prior therapy with radiation for this breast cancer population is permitted if it was\n             administered in the neoadjuvant or adjuvant non metastatic setting. Radiotherapy given\n             in the metastatic setting, prior to initiation of study medication, is allowed to a\n             limited area (e.g., palliative therapy and involving less than 25% of bone marrow), if\n             it is not the sole site of disease. Subjects must have completed radiation treatment\n             and recovered from all acute radiation treatment related toxicities (e.g., bone marrow\n             suppression) prior to commencement of combination treatment.\n\n          -  The subject must have received all prior chemotherapy treatment at least 4 weeks prior\n             to enrollment in this study and must have recovered from all related toxicities.\n             Subjects who have received weekly dose of prior chemotherapy e.g. gemcitabine or\n             capecitabine may enroll 2 to 3 weeks after cessation of treatment provided that they\n             have recovered from all related toxicities.\n\n          -  Prior therapy with trastuzumab in the neoadjuvant, adjuvant or metastatic setting is\n             permitted. The subject must have received all prior trastuzumab treatment at least 4\n             weeks prior to enrollment in this study and must have recovered from all related\n             toxicities.\n\n          -  Prior endocrine therapy is permitted in the neoadjuvant or adjuvant or metastatic\n             setting. The subject must have received all prior endocrine treatment at least 1 week\n             prior to enrollment in this study and must have recovered from all related toxicities.\n\n          -  Prior diagnosis of cancer is allowed as long as the subject is free of disease for 5\n             years. Subjects with completely resected basal or squamous cell skin cancer, thyroid\n             cancer or successfully treated cervical carcinoma in-situ will be allowed if it has\n             been 1 year or greater since definitive surgery.\n\n          -  Subjects must have measurable disease, according to Response Evaluation Criteria in\n             Solid Tumors (RECIST) guidelines; defined as at least 1 lesion that can be accurately\n             measured in at least 1 dimension (longest diameter [LD] to be recorded) by mammogram,\n             ultrasound or physical exam [Therasse, 2000].\n\n          -  Subjects with liver metastases or stable chronic liver disease are permitted into the\n             study.\n\n          -  Women ?18 years of age:\n\n          -  Non-child-bearing potential (i.e., women with functioning ovaries who have a current\n             documented tubal ligation or hysterectomy, or women who are postmenopausal); or\n\n          -  Child-bearing potential (i.e., women with functioning ovaries and no documented\n             impairment of oviductal or uterine function that would cause sterility). This category\n             includes women with oligomenorrhoea (severe), women who are perimenopausal and young\n             women who have begun to menstruate. These subjects must provide a negative serum\n             pregnancy test at Screening and agree to 1 of the following:\n\n          -  Complete abstinence from intercourse from 2 weeks prior to administration of the first\n             dose of study medication until 5 days after the final dose of study medication; or\n\n          -  Consistent and correct use of 1 of the following acceptable methods of birth control:\n\n          -  Male partner who is sterile prior to the female subject's entry into the study and is\n             the sole sexual partner for that female subject.\n\n          -  Implants of levonorgestrel.\n\n          -  Injectable progestogen.\n\n          -  Any intrauterine device with a documented failure rate of less than 1% per year.\n\n          -  Oral contraceptives (either combined or progestogen only).\n\n          -  Barrier methods, including diaphragm or condom with a spermicide.\n\n          -  Considered by the Investigator to have a life expectancy of ?6 months.\n\n          -  ECOG Performance Status (PS) of 0 or 1 (Karnofsky ?80%) [Oken, 1982].\n\n          -  Subjects must have normal organ and marrow function as defined in Table 3:\n\n        CONFIDENTIAL UM2007/00382/01 LPT111111 28\n\n          -  Table 3 Baseline Laboratory Values for Adequate Organ Function\n\n          -  Hematologic\n\n          -  Absolute neutrophil count ?1.5 × 10^9/L\n\n          -  Hemoglobin ?9 g/dL\n\n          -  Platelets ?100 × 10^9/L\n\n          -  Hepatic\n\n          -  Serum bilirubin ? upper limit of normal (ULN)\n\n          -  Aspartate aminotransferase and alanine aminotransferase\n\n          -  ?3 × ULN without liver metastases\n\n          -  ?5 × ULN if documented liver metastases\n\n          -  Renal\n\n          -  Serum creatinine ?1.5 mg/dL\n\n          -  OR -\n\n          -  Calculated creatinine clearance ?40 mL/min\n\n          -  Subjects must have a cardiac ejection fraction of >50% as measured by echocardiogram\n             (ECHO) or multigated acquisition scan (MUGA) and within the institutional range of\n             normal.\n\n          -  Subjects with stable central nervous system metastases (stable for at least 3 months)\n             as confirmed by computerized tomography (CT)/magnetic resonance imaging (MRI) or\n             evidence of leptomeningeal involvement are eligible only if they are not taking\n             steroids or enzyme-inducing anticonvulsants.\n\n          -  Subject must be free of gastrointestinal diseases that impede swallowing and retaining\n             of oral medications.\n\n          -  Signed, informed consent prior to registration.\n\n          -  Bisphosphonate therapy for bone metastases is allowed; however, treatment must be\n             initiated prior to the first dose of study medication. Prophylactic use of\n             bisphosphonates in subjects without bone disease, except for the treatment of\n             osteoporosis, is not permitted.\n\n          -  Subjects whose disease is estrogen receptor + and/or progesterone receptor + or\n             unknown status will only be included in the study if they meet the following criteria:\n\n          -  They have symptomatic visceral disease that requires chemotherapy.\n\n          -  Significant visceral organ tumor burden\n\n          -  The disease is considered by the Investigator to be progressing rapidly or is life\n             threatening.\n\n          -  Subjects who have received prior endocrine therapy and who are no longer benefiting\n             from this therapy.\n\n        Exclusion Criteria:\n\n        A subject will not be eligible for inclusion in this study if any of the following criteria\n        apply:\n\n          -  Subjects who have received more than one prior chemotherapeutic regimen in the\n             metastatic setting\n\n          -  Subjects taking treatment with medications provided in the list of restricted\n             medications and substances in the drug information section for lapatinib are not\n             eligible for the study (Section 5.11.2). This includes human immunodeficiency\n             virus-positive subjects receiving combination anti-retroviral therapy because of\n             possible pharmacokinetic interactions with lapatinib.\n\n          -  Prior treatment with lapatinib.\n\n          -  Concurrent anticancer or concomitant radiotherapy treatment;\n\n          -  Concurrent treatment with prohibited medications (Section 5.11.2);\n\n          -  Use of an investigational drug within 30 days or 5 half-lives, whichever is longer,\n             preceding the first dose of investigational treatment, or, concurrent treatment with\n             an investigational agent or participation in another clinical trial involving\n             investigational agents.\n\n          -  Known history of allergic reactions attributed to compounds of similar chemical or\n             biologic composition to lapatinib or nab-paclitaxel or excipients;\n\n          -  Known history of uncontrolled inter-current illness including, but not limited to,\n             ongoing or active infection, symptomatic congestive heart failure, unstable angina\n             pectoris, clinically significant cardiac arrhythmia, or psychiatric illness/social\n             situations that would limit compliance with study requirements.\n\n          -  Have current active hepatic or biliary disease (with exception of patients with\n             Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver\n             disease per investigator assessment)\n\n          -  Concurrent disease or condition that would make the subject inappropriate for study\n             participation or any serious medical disorder that would interfere with the subject's\n             safety.\n\n          -  Pregnant or lactating females at any time during the study (due to the potential\n             teratogenic or abortifacient effects of lapatinib and breastfeeding).\n\n          -  Subjects with diseases affecting gastrointestinal function resulting in an inability\n             to take oral medication, including; malabsorption syndrome, a requirement for iv\n             alimentation, prior surgical procedures affecting absorption e.g. gastric resection\n             and uncontrolled inflammatory bowel disease (e.g., Crohn's, ulcerative colitis).\n\n          -  Peripheral neuropathy of Grade 2 or greater.\n\n          -  Unresolved or unstable, serious toxicity from prior administration of another\n             investigational drug and/or of prior cancer treatment.\n\n          -  History of prior malignancy. However, subjects who have been disease-free for 5 years,\n             or subjects with completely resected basal or squamous cell skin cancer, thyroid\n             cancer or successfully treated cervical carcinoma in situ will be eligible if it has\n             been at least 1 year since definitive surgery.\n\n          -  or rendering of informed consent.\n\n        Other Eligibility Criteria Considerations:\n\n          -  To assess any potential impact on subject eligibility with regard to safety, the\n             Investigator must refer to the following document(s) for detailed information\n             regarding warnings, precautions, contraindications, AEs, and other significant data\n             pertaining to the investigational product(s) being used in this study: Clinical\n             Investigator's Brochure (IB), SPM, and the nab-paclitaxel Product Label.
DISEASE CHARACTERISTICS:\n\n          -  Histologically confirmed metastatic melanoma, meeting any of the following criteria:\n\n               -  Progressive disease after chemotherapy, radiotherapy, surgery, or immunotherapy\n\n               -  No longer responding to standard therapy OR have refused standard therapy\n\n          -  Unresectable disease\n\n          -  Measurable or evaluable disease\n\n          -  No clinical ascites\n\n          -  No symptomatic pleural effusion\n\n        PATIENT CHARACTERISTICS:\n\n          -  Life expectancy ? 12 weeks\n\n          -  Karnofsky performance status 70-100%\n\n          -  Bilirubin ? 3.0 mg/dL\n\n          -  Albumin ? 3.0 g/dL\n\n          -  Alkaline phosphatase < 5 times upper limit of normal (ULN)\n\n          -  Serum glucose > 60 mg/dL\n\n          -  Amylase < 1.5 times ULN\n\n          -  Absolute neutrophil count > 1,500/mm³\n\n          -  Platelet count > 100,000/mm³\n\n          -  No New York Heart Association class III-IV heart failure\n\n          -  No serious infection requiring treatment with antibiotics\n\n          -  No known allergy to E. coli drug products (e.g., sargramostim [GM-CSF])\n\n          -  Not pregnant or nursing\n\n          -  Negative pregnancy test\n\n          -  Fertile patients must use 2 forms of effective contraception\n\n        PRIOR CONCURRENT THERAPY:\n\n          -  See Disease Characteristics\n\n          -  At least 4 weeks since prior anticancer therapy\n\n          -  At least 4 weeks since prior surgery and recovered\n\n          -  No concurrent participation in another investigational drug study
DISEASE CHARACTERISTICS:\n\n          -  Histologically confirmed colorectal cancer\n\n          -  Stage IV disease (i.e., any T, any N, M1 disease)\n\n          -  Relapsed or refractory disease\n\n               -  Disease progressed after ? 2 different fluorouracil-containing chemotherapy\n                  regimens (e.g., irinotecan hydrochloride or oxaliplatin with or without\n                  bevacizumab)\n\n          -  Bidimensionally measurable disease\n\n          -  Must have tumor amenable to biopsy and be willing to undergo fine-needle aspiration\n\n          -  No CNS metastases\n\n        PATIENT CHARACTERISTICS:\n\n          -  ECOG performance status 0-2\n\n          -  Life expectancy > 2 months\n\n          -  Platelet count > 100,000/mm^3\n\n          -  WBC ? 3,000/mm^3\n\n          -  Creatinine ? 1.5 times upper limit of normal\n\n          -  Bilirubin ? 2 times normal\n\n          -  SGOT ? 5 times normal\n\n          -  Not pregnant or nursing\n\n          -  Negative pregnancy test\n\n          -  Fertile patients must use effective contraception during and for at least 4 months\n             after completion of study treatment\n\n          -  No preexisting peripheral neuropathy ? grade 2\n\n          -  Ejection fraction ? 30%\n\n          -  Baseline QT interval < 500 msec\n\n          -  No serious underlying medical illness or active infection\n\n          -  No underlying medical condition that could be aggravated by the treatment\n\n          -  No life-threatening disease unrelated to colorectal cancer\n\n          -  No other malignancy within the past 5 years unless currently disease-free and all\n             therapy for the malignancy has been completed\n\n          -  No preexisting neurological disorder (i.e., seizure disorder) ? grade 3\n\n          -  No cardiac disease, including any of the following:\n\n               -  Recurrent supraventricular arrhythmia\n\n               -  Any type of sustained ventricular arrhythmia or conduction block (e.g., grade II\n                  or III atrioventricular block or left bundle branch block)\n\n               -  Uncontrolled ischemic heart disease\n\n               -  History of nonsustained ventricular tachycardia\n\n               -  Prolonged PR intervals (i.e., 1st degree heart block)\n\n          -  No known hypersensitivity to arsenic trioxide or fluorouracil\n\n          -  No history of allergic reactions attributed to compounds of similar biologic\n             composition to arsenic trioxide or fluorouracil\n\n        PRIOR CONCURRENT THERAPY:\n\n          -  See Disease Characteristics\n\n          -  Recovered from all treatment-related toxicity\n\n          -  At least 4 weeks since prior chemotherapy or radiotherapy and recovered\n\n          -  More than 4 weeks since prior investigational drug\n\n          -  No other concurrent investigational or commercial anticancer agent or therapy\n\n          -  Concurrent local radiotherapy allowed for symptom relief (e.g., significant onset of\n             pain after enrollment, but before beginning study therapy)
Tissue Procurement Inclusion Criteria:\n\n        Patients will be eligible for tissue procurement for the Vigil™ manufacturing process, if\n        they meet all of the following criteria:\n\n          1. Histologically or cytologically confirmed diagnosis of NSCLC.\n\n          2. Age ? 18 years.\n\n          3. Locally advanced or metastatic disease that is progressive after one prior\n             platinum-based systemic chemotherapy regimen\n\n               1. Adjuvant therapy will count as a line of therapy if administered within 6 months\n                  of relapse).\n\n               2. Subjects with EGFR or ALK mutations should also have received appropriate\n                  targeted therapy.\n\n          4. No systemic therapy, immunologic therapy or investigational therapy within 3 weeks and\n             no radiation therapy within 1 week prior to tumor procurement for vaccine manufacture.\n\n          5. Planned standard of care surgical procedure (e.g., tumor biopsy or palliative\n             resection or thoracentesis) and expected availability of a cumulative mass of ~10-30\n             grams tissue (\golf-ball\ size) or pleural fluid estimated volume ? 500mL (must be\n             primary tap) for immunotherapy manufacture.\n\n          6. At least one area of cancer, not intended for vaccine manufacture, that is measureable\n             by RECIST 1.1 criteria.\n\n          7. At least one tumor, not intended for vaccine manufacture, that is considered\n             appropriate for on-treatment biopsy. The same tumor may suffice for both on-treatment\n             biopsy and RECIST 1.1 measurement so long as imaging occurs prior to biopsy.\n\n          8. ECOG Performance Status ? 1\n\n          9. Estimated survival ? 6 months.\n\n         10. Ability to understand and the willingness to sign a written informed consent document\n             for tissue harvest.\n\n        Tissue Procurement Exclusion Criteria:\n\n        Patients meeting any of the following criteria are not eligible for tissue procurement for\n        the Vigil™ manufacturing:\n\n          1. Any localized anticancer therapy (e.g., radiation, radiofrequency ablation,\n             cryotherapy) to tumor intended for vaccine manufacture unless unequivocal evidence of\n             post-treatment disease progression of the target tumor.\n\n          2. Medical condition requiring any form of chronic systemic immunosuppressive therapy\n             (steroid or other) except physiologic replacement doses of hydrocortisone or\n             equivalent (no more than 30 mg hydrocortisone or 10 mg prednisone equivalent daily for\n             < 30 days duration\n\n          3. Known history of other malignancy unless having undergone curative intent therapy\n             without evidence of that disease for ? 3 years except cutaneous squamous cell and\n             basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other\n             in situ cancers are allowed if definitively resected.\n\n          4. Brain metastases unless treated with curative intent (gamma knife or surgical\n             resection) and without evidence of progression for ? 4 months.\n\n          5. Any documented history of autoimmune disease with exception of Type 1 diabetes on\n             stable insulin regimen, hypothyroidism on stable dose of replacement thyroid\n             medication, vitiligo, or asthma not requiring systemic steroids.\n\n          6. Known history of allergies or sensitivities to gentamicin.\n\n          7. History of or current evidence of any condition (including medical, psychiatric or\n             substance abuse disorder), therapy, or laboratory abnormality that might confound the\n             results of the study, interfere with the patient's participation for the full duration\n             of the study, or is not in the best interest of the patient to participate, in the\n             opinion of the treating Investigator.\n\n          8. Known HIV or chronic Hepatitis B or C infection.\n\n          9. History of pneumonitis or interstitial lung disease.\n\n        Study Enrollment Inclusion Criteria:\n\n        Patients will be eligible for registration into the trial if they meet all of the following\n        inclusion criteria:\n\n          1. Successful manufacturing of at least 4 vials of Vigil™.\n\n          2. ECOG Performance Status ? 1\n\n          3. Estimated survival ? 4 months.\n\n          4. Disease that is measurable by RECIST 1.1 criteria.\n\n          5. Adequate organ function as defined by the following laboratory values:\n\n             Absolute granulocyte count ? 1,500/mm3 Absolute lymphocyte count ? 500/mm3 Platelets ?\n             75,000/mm3 Hemoglobin ? 9 g/dL Creatinine ? 1.5x institutional upper limit of normal\n             Total bilirubin ? 1.5x institutional upper limit of normal AST(SGOT) and ALT(SGPT) ?2x\n             institutional upper limit of normal or\n\n             ?5x institutional upper limit of normal if liver metastases INR / PT and aPTT ? 1.5 x\n             ULN (if not using anticoagulants) Immunological Thyroid Stimulating Hormone within\n             institutional limits\n\n          6. Subject has recovered to CTCAE Grade 1 or better from all adverse events associated\n             with prior therapy or surgery. Pre-existing motor or sensory neurologic pathology or\n             symptoms must be recovered to CTCAE Grade 2 or better.\n\n          7. If female of childbearing potential, has a negative urine or serum pregnancy test. If\n             the urine test is positive or cannot be confirmed as negative, a negative serum test\n             will be required for study entry.\n\n          8. Investigator deems the patient to have a tumor appropriate for on-treatment biopsy and\n             patient agrees to provide tissue biopsy at Cycle 5 (Week 9) for correlative studies.\n\n          9. Ability to understand and the willingness to sign a written informed protocol specific\n             consent.\n\n        Study Enrollment Exclusion Criteria:\n\n        In addition to the procurement exclusion criteria, patients will NOT be eligible for study\n        registration and enrollment if meeting any of the following criteria:\n\n          1. Any anti-neoplastic therapy between tissue procurement for vaccine manufacture and\n             start of study therapy.\n\n          2. Live vaccine used for the prevention of infectious disease administered < 30 days\n             prior to the start of study therapy.\n\n          3. Post-surgery complication that in the opinion of the treating investigator would\n             interfere with the patient's study participation or make it not in the best interest\n             of the patient to participate.
The target population for this study is patients who have participated in any REGN2810\n        clinical study.\n\n        Inclusion Criteria for Patients Receiving Re-treatment:\n\n          1. Tolerated prior treatment with REGN2810 with no unacceptable toxicity (except select\n             reversible irAEs) requiring discontinuation of REGN2810\n\n          2. Developed documented progressive disease after first demonstrating clinical benefit\n             from their initial treatment\n\n          3. Eastern Cooperative Oncology Group (ECOG) performance status ? 1\n\n          4. ?18 years old\n\n          5. Hepatic function:\n\n               -  Total bilirubin ? 1.5 x upper limit of normal (ULN; if liver metastases ? 3 x\n                  ULN)\n\n               -  Transaminases ? 3 x ULN (or ? 5.0 x ULN, if liver metastases)\n\n               -  Alkaline phosphatase (ALP) ? 2.5 x ULN (or ? 5.0 x ULN, if liver metastases)\n\n               -  For patients with hepatic metastases or hepatic malignancies, exclude patients\n                  with concomitant 3 x ULN ? aspartate aminotransferase (AST) and/or alanine\n                  aminotransferase (ALT) ? 5 x ULN and 1.5 x ULN ? total bilirubin ? 3 x ULN\n\n          6. Renal function: Serum creatinine ? 1.5 x ULN\n\n          7. Bone marrow function:\n\n               -  Hemoglobin ? 9.0 g/dL\n\n               -  Absolute neutrophil count (ANC) ? 1.5 x 10^9/L\n\n               -  Platelet count ? 75 x 10^9/L\n\n        Inclusion Criteria for Patients who Will not Receive Re-treatment:\n\n        Patients must have completed participation in any REGN2810 clinical study.\n\n        Exclusion Criteria:\n\n        A patient who meets any of the following criteria will be excluded from receiving\n        re-treatment with REGN2810:\n\n          1. Ongoing or recent (within 5 years) evidence of significant autoimmune disease that\n             required treatment with systemic immunosuppressive treatments, which may suggest risk\n             for irAEs.\n\n          2. Patients who experienced an irAE in while participating in another REGN2810 protocol\n             who were unable to have their corticosteroid dose reduced to <10 mg per day prednisone\n             equivalent within 12 weeks of toxicity.\n\n          3. Patients who developed ? Grade 2 uveitis in a prior REGN2810 protocol\n\n          4. Immunosuppressive corticosteroid doses (> 10 mg prednisone daily or equivalent) within\n             4 weeks prior to the first dose of REGN2810\n\n          5. Active infection requiring therapy, including known infection with human\n             immunodeficiency virus, or active infection with hepatitis B or hepatitis C virus.\n\n          6. History of pneumonitis within the last 5 years.\n\n          7. Any investigational or antitumor treatment within 30 days prior to the initial\n             administration of REGN2810.\n\n          8. History of documented allergic reactions or acute hypersensitivity reaction attributed\n             of Grade ? 3 severity during or directly following an REGN2810 infusion\n\n          9. Known allergy to doxycycline or tetracycline. (precaution due to presence of trace\n             components in REGN2810)\n\n         10. Breast-feeding\n\n         11. Positive serum pregnancy test\n\n         12. History within the last 5 years of an invasive malignancy other than the one treated\n             in this study, with the exception of resected/ablated basal or squamous-cell carcinoma\n             of the skin or carcinoma in situ of the cervix, or other local tumors considered cured\n             by local treatment.\n\n         13. Acute or chronic psychiatric problems that, under the evaluation of the investigator,\n             make the patient ineligible for participation\n\n         14. Unwilling to practice adequate contraception during the study until 6 months after the\n             last dose of study drug
Inclusion Criteria:\n\n        For inclusion in the study, patients should fulfill the following criteria:\n\n          1. Aged at least 18 years.\n\n          2. Histologically or cytologically documented Stage IV NSCLC.\n\n          3. Confirmed tumor PD-L1 status prior to randomization.\n\n          4. Patients must have tumors that lack activating EGFR mutations and ALK fusions.\n\n          5. No prior chemotherapy or any other systemic therapy for metastatic NSCLC.\n\n          6. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance\n             status of 0 or 1.\n\n          7. No prior exposure to immunemediated therapy, excluding therapeutic anticancer\n             vaccines.\n\n        Exclusion Criteria:\n\n        Patients should not enter the study if any of the following exclusion criteria are\n        fulfilled:\n\n          1. Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant.\n\n          2. Active or prior documented autoimmune or inflammatory disorders.\n\n          3. Brain metastases or spinal cord compression unless the patient's condition is stable\n             and off steroids.\n\n          4. Active infection including tuberculosis, hepatitis B, hepatitis C, or human\n             immunodeficiency virus.
-  Must be greater than 18 years of age at the time of consent.\n\n          -  Must have persistent, recurrent or metastatic HNSCC; histologic documentation of the\n             primary tumor is required via the pathology report.\n\n          -  Must have had at least 1 prior systemic chemotherapeutic regimen for management of\n             persistent, recurrent or metastatic HNSCC. Patients must not have any curative therapy\n             options, or be intolerant of, or decline standard of care therapy for persistent,\n             recurrent or metastatic disease.\n\n          -  Any prior therapy directed at the malignant tumor, including radiation therapy,\n             chemotherapy, biologic/targeted agents and immunologic agents must be discontinued at\n             least 28 days prior to lymphodepletion\n\n          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          -  Patients must be seronegative for the HIV antibody,\n\n          -  Female patients of childbearing potential must be willing to practice an approved\n             method of birth control starting at the time of informed consent and for 1 year after\n             the completion of the lymphodepletion regimen.\n\n        Exclusion Criteria:\n\n          -  Patients who have received prior cell therapy, except for prior LN-145.\n\n          -  Patients who are on a systemic steroid therapy (greater than 10 mg of prednisone or\n             equivalent).\n\n          -  Patients who currently have prior therapy-related toxicities greater than Grade 1\n             according to Common Toxicity Criteria for Adverse Events (CTCAE) v4.03; (see Appendix\n             Section 16.4), except for alopecia or vitiligo prior to enrollment.\n\n          -  Patients with documented Grade 2 or greater diarrhea or colitis as a result of\n             previous immunotherapy within six months from screening.\n\n          -  History of severe immediate hypersensitivity reaction to cyclophosphamide,\n             fludarabine, IL-2., or aminoglycosides.\n\n          -  Patients with active systemic infections, coagulation disorders or other active major\n             medical illnesses of the cardiovascular, respiratory or immune system.\n\n          -  Patients with symptomatic and/or untreated brain metastases.\n\n          -  Have any form of primary immunodeficiency, such as severe combined immunodeficiency\n             disease or acquired immune deficiency syndrome (AIDS).\n\n          -  Diagnosis of end-stage renal disorder requiring hemodialysis.\n\n          -  Patients who have a left ventricular ejection fraction (LVEF) < 45%.\n\n          -  Patients who have a FEV1 (forced expiratory volume in one second) of less than or\n             equal to 60 % of normal or walk a distance less than 80% predicted in a 6-min walk\n             test or demonstrate evidence of hypoxia during that test.
INCLUSION CRITERIA:\n\n          1. Subjects must be ? 18 years old and have a life expectancy ? 12 weeks\n\n          2. Histologically proven, primary (de novo) GB that has recurred or progressed (first or\n             second recurrence, including this recurrence)\n\n          3. Confirmation that archived tissue is available from first diagnosis of GB for\n             biomarker analysis\n\n          4. Recurrent tumor must be supratentorial, contrast-enhancing GB no smaller than 1 cm x 1\n             cm (largest perpendicular dimensions) and no larger than 4 cm maximum in a single\n             direction based on MRI taken within 14 days prior to catheter placement\n\n          5. Karnofsky Performance Score (KPS) ? 70\n\n          6. Subjects must be able and willing to undergo multiple brain MRI examinations\n\n          7. Subjects must be able and willing to comply with all study procedures\n\n          8. Any related toxicities following discontinuation of prior GB therapies must have\n             resolved to CTCAE Grade 1 or lower prior to inclusion in this study\n\n        EXCLUSION CRITERIA:\n\n          1. Prior treatment with cytotoxic chemotherapy\n\n               1. Temozolomide (standard induction and / or maintenance dosing) within the past 4\n                  weeks prior to planned infusion\n\n               2. \Metronomic\ Temozolomide (low-dose, continuous administration) within the past 7\n                  days prior to planned infusion\n\n               3. Nitrosoureas within the past 6 weeks prior to planned infusion\n\n               4. Treatment with any other cytotoxic agent within the past 4 weeks prior to planned\n                  infusion\n\n          2. Prior investigational treatment within the past 4 weeks or prior immunotherapy or\n             antibody therapy within the past 4 weeks prior to planned infusion\n\n          3. Prior treatment with bevacizumab (Avastin) or other vascular-endothelial growth factor\n             (VEGF) inhibitors or VEGF-receptor signaling inhibitors within the past 4 weeks prior\n             to planned infusion\n\n          4. Prior therapy that included interstitial brachytherapy or Gliadel® Wafers (carmustine\n             implants) within the past 12 weeks prior to planned infusion\n\n          5. Prior surgery (including stereotactic radiosurgery and biopsy procedures) within the\n             past 4 weeks prior to planned infusion\n\n          6. Ongoing Optune© therapy within 5 days of planned infusion\n\n          7. Secondary GB (i.e., GB that progressed from low-grade diffuse astrocytoma or AA)\n\n          8. Known mutation in either the isocitrate dehydrogenase 1 (IDH1) or the IDH2 gene.\n\n          9. Tumor in the brainstem (not including fluid-attenuated inversion recovery [FLAIR]\n             changes), an infratentorial tumor, diagnosis of gliomatosis cerebri (highly\n             infiltrative T2 hyperintense tumor with ill-defined margins encompassing at least\n             three lobes of the brain.\n\n         10. Tumor with a mass effect (e.g. 1-2 cm midline shift)\n\n         11. Subjects with tumors for which the preponderance of tissue is not of the type in which\n             convection would be possible (e.g. preponderance of cystic component)\n\n         12. Tumor with geometric features that make them difficult to adequately cover the tumor\n             volume with infusate by using CED catheters\n\n         13. Clinical symptoms that are thought by the Investigator to be caused by uncontrolled\n             increased intracranial pressure, hemorrhage, or edema of the brain\n\n         14. Any condition that precludes the administration of anesthesia\n\n         15. Known to be human immunodeficiency virus positive\n\n         16. Concurrent or a history of any significant medical illnesses that in the\n             Investigator's opinion cannot be adequately controlled with appropriate therapy or\n             would compromise the subject's ability to tolerate the study drug therapy and/or put\n             the subject at additional risk or interfere with the interpretation of the results of\n             this trial\n\n         17. Known history of allergy to gadolinium contrast agents\n\n         18. Presence of another type of malignancy requiring treatment within < 3 years prior to\n             the screening visit, except for adequately treated carcinoma in-situ of the cervix,\n             prostate cancer not actively treated, and basal or squamous cell carcinoma of the skin
Inclusion Criteria (All):\n\n          -  Written informed consent must\n\n          -  Patient has histologically and/or cytologically confirmed malignancies:\n\n        Phase I:\n\n        • Patients with advanced or metastatic solid tumors who have failed at least one prior line\n        of systemic antineoplastic therapy in the advanced setting without a standard of care\n        treatment option available;\n\n        Phase II:\n\n          -  Advanced or metastatic pancreatic adenocarcinoma who have failed at least one prior\n             systemic antineoplastic therapies in the advanced setting\n\n          -  Advanced or metastatic KRAS-mutant CRC who have failed at least two prior systemic\n             antineoplastic therapies in the advanced setting without a standard of care treatment\n             option available. Testing for KRAS mutation in patients with CRC using locally\n             approved diagnostic kit will be used for eligibility.\n\n          -  Phase II only: patient must have measurable disease\n\n          -  Patient has an ECOG performance status 0 or 1.\n\n          -  Patient has adequate bone marrow and organ function\n\n          -  Patient must have specified laboratory values within normal limits or corrected to\n             within normal limits with supplements before the first dose of study medication on\n             Cycle 1 Day 1:\n\n          -  Standard 12-lead ECG values defined\n\n        Exclusion Criteria:\n\n        Phase II only:\n\n        • Patient has received prior treatment with a MEK inhibitor or a CDK4/6 inhibitor.\n\n        Phase I and Phase II:\n\n          -  Patient with a known hypersensitivity to the study drugs or any of the excipients of\n             ribociclib or trametinib.\n\n          -  Patient is concurrently using other anti-cancer therapy.\n\n          -  Patient has received radiotherapy ? 4 weeks or limited field radiation for palliation\n             ? 2 weeks prior to Cycle 1 Day 1\n\n          -  Patient has received local therapy to liver ? 3 months of C1D1\n\n          -  History of liver disease as follow:\n\n          -  Cirrhosis\n\n          -  Autoimmune hepatitis\n\n          -  Portal hypertension\n\n          -  Drug induced liver steatosis\n\n          -  Prior systemic anti-cancer treatment within 28 days prior to Cycle 1 Day 1\n\n          -  Prior therapy with anthracyclines at cumulative doses of 450 mg/ m2 or more for\n             doxorubicin or 900 mg/m2 or more for epirubicin.\n\n          -  Patient is currently receiving warfarin or other coumadin derived anti-coagulant\n\n          -  Patient has a history of deep venin thrombosis or pulmonary embolism within 6 months\n             of screening.\n\n          -  Patient has a concurrent malignancy or malignancy within 3 years prior to Cycle 1 Day\n             1, with the exception of adequately treated basal or squamous cell carcinoma or\n             curatively resected cervical cancer.\n\n          -  Patients with central nervous system (CNS) involvement\n\n          -  Patient has impairment of GI function or GI disease that may significantly alter the\n             absorption of the study drugs\n\n          -  History of interstitial lung disease or pneumonitis.\n\n          -  Clinically significant, uncontrolled heart disease and/or cardiac repolarization\n             abnormality\n\n          -  Patient is currently receiving any strong inducers or inhibitors of CYP3A4/5 and/or\n             Substances that have a narrow therapeutic window and are predominantly metabolized\n             through CYP3A4/5 and cannot be discontinued 7 days prior to Cycle 1 Day 1:\n\n          -  Patient is currently receiving or has received systemic corticosteroids ? 2 weeks\n             prior to starting study drug, or who have not fully recovered from side effects of\n             such treatment.\n\n          -  History of retinal vein occlusion (RVO)\n\n        Other protocol-defined inclusion/exclusion criteria may apply.
Inclusion Criteria:\n\n        Inclusion Criteria for Enrollment Phase\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          -  Histological or cytological diagnosis of Stage IB (tumors greater than or equal to\n             [>/=] 4 centimeters [cm])-IIIA (T2-3 N0, T1-3 N1, T1-3 N2, T4 N0-1) NSCLC (per the\n             Union Internationale Contre le Cancer staging system (UICC)/American Joint Committee\n             on Cancer staging system (AJCC) staging system, 7th edition; Detterbeck et al. 2009)\n\n          -  Participants must have had complete resection of NSCLC 4-12 weeks (>/=28 days and less\n             than or equal to [</=] 84 days) prior to enrollment and must be adequately recovered\n             from surgery\n\n          -  If mediastinoscopy was not performed preoperatively, it is required that, at a\n             minimum, mediastinal lymph node systematic sampling will have occurred. Systematic\n             sampling is defined as removal of at least one representative lymph node at specified\n             levels. MLND entails resection of all lymph nodes at those same levels. For a right\n             thoracotomy, sampling or MLND is required at levels 4 and 7 and for a left\n             thoracotomy, levels 5 and/or 6 and 7. Exceptions will be granted if there is clear\n             documentation in the operative report or in a separately submitted addendum by the\n             surgeon of exploration of the required lymph node areas, the participant will be\n             considered eligible if no lymph nodes are found in those areas; if participants have\n             documented N2 disease in one level (per the UICC/AJCC staging system, 7th edition;\n             Detterbeck et al. 2009), not all levels need to be sampled; if the preoperative\n             staging imaging results (contrast computed tomography [CT] and positron emission\n             tomography [PET] scans) do not suggest evidence of disease in the mediastinum, the\n             participant will be considered eligible if N2 nodal sampling is not performed per\n             surgeon's decision\n\n          -  Eligible to receive a cisplatin-based chemotherapy regimen\n\n          -  Adequate hematologic and end-organ function\n\n          -  Women who are not postmenopausal (>/=12 months of non-therapy-induced amenorrhea) or\n             surgically sterile must have a negative serum pregnancy test result within 14 days\n             prior to initiation of cisplatin-based chemotherapy\n\n        Inclusion Criteria for Randomized Phase - Women who are not postmenopausal (>/=12 months of\n        non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy\n        test result within 14 days prior to initiation of atezolizumab or BSC\n\n        Exclusion Criteria:\n\n        Exclusion Criteria for Enrollment Phase\n\n          -  Illness or condition that may interfere with a participant's capacity to understand,\n             follow, and/or comply with study procedures\n\n          -  Pregnant and lactating women\n\n          -  Treatment with prior systemic chemotherapy: Chemotherapy for early stage of malignancy\n             with curative intent, provided that the last dose received was more than 5 years prior\n             to enrollment and low-dose chemotherapy for non-malignant conditions may be allowed\n             upon approval by the Medical Monitor\n\n          -  Hormonal cancer therapy or radiation therapy as prior cancer treatment within 5 years\n             before enrollment\n\n          -  Treatment with any other investigational agent with therapeutic intent within 28 days\n             prior to enrollment\n\n          -  Participants with hearing impairment\n\n          -  Known sensitivity to any component of the chemotherapy regimen the participant will be\n             assigned to, or to mannitol\n\n          -  Prior treatment with cluster of differentiation (CD) 137 (CD137) agonists or immune\n             checkpoint blockade therapies, anti-programmed death-1 (PD-1), and anti programmed\n             death ligand 1 (PD-L1) therapeutic antibodies\n\n          -  Malignancies other than NSCLC within 5 years prior to randomization, with the\n             exception of those with a negligible risk of metastasis or death (e.g., expected\n             5-year OS greater than [>] 90 percent [%]) treated with expected curative outcome\n             (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell\n             skin cancer, localized prostate cancer treated surgically with curative intent, ductal\n             carcinoma in situ treated surgically with curative intent)\n\n          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to\n             chimeric or humanized antibodies or fusion proteins\n\n          -  Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells\n             or any component of the atezolizumab formulation\n\n          -  History of autoimmune disease, including but not limited to myasthenia gravis,\n             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,\n             inflammatory bowel disease, vascular thrombosis associated with antiphospholipid\n             syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome,\n             multiple sclerosis, vasculitis, or glomerulonephritis\n\n          -  Positive test for human immunodeficiency virus (HIV)\n\n          -  Participants with active hepatitis B (chronic or acute; defined as having a positive\n             hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C\n\n          -  Active tuberculosis\n\n          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease\n             (Class II or greater), myocardial infarction, or cerebrovascular accident within the\n             previous 3 months, unstable arrhythmias, or unstable angina\n\n          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis\n             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active\n             pneumonitis on screening chest CT scan\n\n          -  Prior allogeneic bone marrow transplantation or solid organ transplant\n\n          -  Any other diseases, metabolic dysfunction, physical examination finding, or clinical\n             laboratory finding giving reasonable suspicion of a disease or condition that\n             contraindicates the use of an investigational drug or that may affect the\n             interpretation of the results or render the participant at high risk from treatment\n             complications\n\n          -  Known tumor PD-L1 expression status as determined by an immunohistochemistry (IHC)\n             assay from other clinical studies (e.g., participants whose PD-L1 expression status\n             was determined during screening for entry into a study with anti-PD-1 or anti-PD-L1\n             antibodies but were not eligible are excluded)\n\n        Specific Exclusions for Pemetrexed Treatment\n\n        - Participants with squamous cell histology\n\n        Exclusion Criteria for Randomized Phase\n\n          -  Signs or symptoms of infection within 14 days prior to randomization (severe infection\n             within 28 days prior to randomization), including but not limited to hospitalization\n             for complications of infection, bacteremia, or severe pneumonia\n\n          -  Received therapeutic oral or intravenous (IV) antibiotics within 14 days prior to\n             randomization\n\n          -  Major surgical procedure within 28 days prior to randomization or anticipation of need\n             for a major surgical procedure during the course of the study\n\n          -  Administration of a live, attenuated vaccine within 28 days prior to randomization or\n             anticipation that such a live attenuated vaccine will be required during the study\n\n          -  Treatment with systemic immunostimulatory agents (including but not limited to\n             interferons or interleukin-2) within 4 weeks or 5 half-lives of the drug, whichever is\n             longer, prior to randomization: Prior treatment with cancer vaccines is allowed\n\n          -  Treatment with systemic corticosteroids or other immunosuppressive medications\n             (including but not limited to prednisone, dexamethasone, cyclophosphamide,\n             azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF]\n             agents) within 14 days prior to randomization
Inclusion Criteria:\n\n          -  Be willing and able to provide written informed consent for the trial.\n\n          -  Over 18 years of age on day of signing informed consent.\n\n          -  Have histologically confirmed muscle invasive disease of the urinary bladder, renal\n             pelvis, or ureters.\n\n          -  Histology must be urothelial carcinoma (transitional cell carcinoma) or urothelial\n             carcinoma with mixed histology/features.\n\n          -  Clinical stage cT2-4aN0M0. Please see exclusion criteria for acceptable N0\n             determination/lymph node size.\n\n          -  Have a surgical evaluation that documents the plan for multimodality therapy with a\n             consolidative radical cystectomy or nephroureterectomy.\n\n        NOTE on surgical intent: Criteria for acceptable surgical risk are not defined and per\n        treating urologist. Minimum guidance on surgical intent includes subjects who do not have\n        significant cardiovascular disease such as NHYA class III or IV heart failure, unstable\n        arrhythmias or angina, active CAD, and/or EF<25%. Specific diagnostic testing to determine\n        surgical intent is not required and per treating urologist or oncologist discretion.\n\n          -  Have an archived tumor block available to submit unstained slides for PD-L1\n             expression, basal and luminal subtype analysis; MANDATORY. If slides are not\n             available, a biopsy is strongly encouraged to obtain tissue for submission\n\n          -  Subjects on full dose anticoagulants must be on a stable regimen of warfarin or low\n             molecular weight heparin (LMWH) for at least two weeks.\n\n          -  Female subjects of childbearing potential must have a negative urine or serum\n             pregnancy test within 72 hours prior to study registration. If the urine test is\n             positive or cannot be confirmed as negative, a serum pregnancy test is required.\n\n          -  Female subjects of childbearing potential must be willing to use 2 methods of birth\n             control, be surgically sterile, or abstain from heterosexual intercourse for the\n             course of the study and through 120 days after the last dose of study medication.\n             NOTE: Subjects of childbearing potential are those who have not been surgically\n             sterilized or have not been free from menses for > 1 year.\n\n          -  Male subjects must agree to use a barrier method of male contraception starting with\n             the first dose of study therapy and through 120 days after the last dose of study\n             therapy.\n\n        COHORT I - CISPLATIN-ELIGIBLE:\n\n        In addition to the inclusion criteria listed above, Cohort I subjects must satisfy all of\n        the following criteria:\n\n          -  Glomerular filtration rate (GFR) or creatinine clearance (Ccr) ? 50 mL/min. (24 hour\n             urine preferred). The cisplatin dose will be split over two days for values between\n             50-59 mL/min\n\n          -  ECOG PS 0, 1 (and not 2)\n\n          -  Hearing impaired ? grade 1 (may or may not be enrolled in a monitoring program)\n\n          -  Peripheral neuropathy ?grade 1\n\n        COHORT II - CISPLATIN-INELIGIBLE:\n\n        In addition to the inclusion criteria listed above, Cohort II subjects must also meet any\n        ONE of the following criteria:\n\n          -  GFR or Ccr: 30-49 (24 hour urine preferred).\n\n          -  ECOG PS 2\n\n          -  Hearing impaired ?grade 2 as assessed by treating physician (may or may not be\n             enrolled in a monitoring program).\n\n          -  Peripheral neuropathy of Grade 2-4\n\n        Exclusion Criteria:\n\n        Subjects may not have any of the following:\n\n          -  A non-surgical approach recommended by the treating urologist due to any reason.\n             Criteria for surgical intent are not defined and, rather, suitability is determined\n             and documented by the subject's treating urologist. Minimum guidance on surgical\n             intent includes subjects who do not have significant cardiovascular disease such as\n             NHYA class III or IV heart failure, unstable arrhythmias or angina, active CAD, and/or\n             EF<25%. Specific cardiopulmonary diagnostic testing to determine surgical intent is\n             not required and per treating urologist or oncologist discretion.\n\n          -  Has abdomino-pelvic short axis lymph node of ?15mm without biopsy. NOTE: A subject\n             with a staging biopsy proving a non-neoplastic process/N0 will meet inclusion.\n\n          -  Is currently participating in or has participated in a study of an investigational\n             agent or using an investigational device within 28 days prior to study registration.\n\n          -  Has a diagnosis of immunodeficiency or received systemic steroid therapy or any other\n             form of immunosuppressive therapy within 7 days prior to study registration. Subjects\n             on steroids for physiologic replacement due to a non-cancer related cause would not be\n             excluded.\n\n          -  Has had a prior monoclonal antibody ? 28 days prior to study registration or who has\n             not recovered (i.e., ? Grade 1 or at baseline) from adverse events due to agents\n             administered more than 28 days earlier.\n\n          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy for\n             urothelial carcinoma.\n\n          -  Has a known additional malignancy that is progressing or required treatment ? 48\n             months of study registration. Exceptions include basal cell carcinoma of the skin,\n             squamous cell carcinoma of the skin, in situ cervical cancer that has undergone\n             potentially curative therapy, stable (as defined by PSA change, checked within 30\n             days) and untreated very low-risk or low-risk prostate cancer defined by current NCCN\n             guidelines.\n\n          -  Has known active central nervous system (CNS) metastases and/or carcinomatous\n             meningitis. Brain imaging is not required and per discretion of treating physician.\n\n          -  Has an active autoimmune disease requiring systemic treatment within the past 3 months\n             or a documented history of clinically severe autoimmune disease, or a syndrome that\n             requires systemic steroids or immunosuppressive agents. NOTE: Subjects with vitiligo\n             or resolved childhood asthma/atopy would be an exception. Subjects that require\n             intermittent use of bronchodilators or local steroid injections would not be excluded\n             from the study. Subjects with hypothyroidism stable on hormone replacement or\n             Sjogren's syndrome will not be excluded from the study.\n\n          -  Has known evidence of interstitial lung disease or active, non-infectious pneumonitis.\n\n          -  Has an active infection requiring systemic therapy.\n\n          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality\n             that might confound the results of the trial, interfere with the subject's\n             participation for the full duration of the trial, or is not in the best interest of\n             the subject to participate, in the opinion of the treating investigator.\n\n          -  Has known psychiatric or substance abuse disorders that would interfere with\n             cooperation with the requirements of the trial.\n\n          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the\n             projected duration of the trial, starting with the pre-screening or screening visit\n             through 120 days after the last dose of trial treatment.\n\n          -  Has received therapy with hematopoietic growth factor such as G-CSF or GM-CSF in the\n             14 days prior to registration.\n\n          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or\n             anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including\n             ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation\n             or checkpoint pathways).\n\n          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).\n\n          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA\n             [qualitative] is detected).\n\n          -  Has received a live vaccine within 30 days prior to the first dose of trial treatment.\n             NOTE: Examples of live vaccines include, but are not limited to, the following:\n             measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral)\n             vaccines. Seasonal influenza vaccines for injection are generally killed virus\n             vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are\n             live attenuated vaccines, and are not allowed.
Inclusion Criteria:\n\n        Diagnosis of locally advanced or metastatic cancer that has progressed despite standard\n        therapy or for which no effective standard therapy exists and histological confirmation of\n        one of the following diseases indicated below:\n\n        Single Agent Dose escalation part:documented B-RAF mutant colorectal cancer or pancreatic\n        adenocarcinoma. In addition, tumors of any histological origin with documented genetic\n        alterations upstream in the Wnt signaling pathway are eligible with prior agreement with\n        Novartis.\n\n        Single Agent Dose expansion part: documented B-RAF mutant colorectal cancer with documented\n        RNF43 mutation and/or RSPO fusion or pancreatic adenocarcinoma with documented RNF43\n        mutation. In addition, patients with tumors of any histological origin with documented\n        genetic alterations upstream in the Wnt signaling pathway (e.g. RNF43 or RSPO fusion) are\n        eligible with prior agreement with Novartis\n\n        LGK974 with PDR001: Dose escalation: patients with the following cancers that were\n        previously treated with anti-PD-1 therapy and whose best response on that therapy was\n        progressive disease (i.e. primary refractory): melanoma, lung SCC, HNSCC. Patients with\n        esophageal SCC, cervical SCC or TNBC who are either naïve or primary refractory to prior\n        anti-PD-1 therapy.\n\n        LGK974 with PDR001: Dose expansion: patients with pancreatic cancer, or TNBC, or melanoma,\n        or head and neck cancer.\n\n        Exclusion Criteria:\n\n          -  Impaired cardiac function\n\n          -  Impairment of gastrointestinal function or gastrointestinal disease that may\n             significantly alter the absorption of oral LGK974 (e.g., ulcerative diseases,\n             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel\n             resection)\n\n          -  Brain metastases that have not been adequately treated\n\n          -  Malignant disease other than that being treated in this study\n\n          -  Laboratory abnormalities as specified in the protocol\n\n          -  Osteoporosis, severe or untreated osteopenia\n\n          -  Bone fractures within the past year\n\n          -  Pathologic bone fracture\n\n          -  Active, known or suspected autoimmune disease or severe hypersensitivity reactions to\n             other monoclonal antibodies\n\n        Other protocol-defined inclusion/exclusion criteria may apply
Inclusion Criteria:\n\n        Patients must be treated by nephrectomy and patients must meet all of the following\n        inclusion criteria to be eligible for enrollment into the trial:\n\n          1. Patients must have no evidence of macroscopic residual disease or metastatic disease.\n\n          2. Male or female, age >=18 years (age >=20 years in Japan, Korea and Taiwan).\n\n          3. Patients must be diagnosed with one of the following based on American Joint Committee\n             on Cancer (AJCC) TNM staging version 2010, Eastern Collaborative Oncology Group (ECOG)\n             performance status (PS):\n\n               -  pT2, pN0 or pNx, M0 and ECOG PS 0-1\n\n               -  pT3, pN0 or pNx, M0 and ECOG PS 0-1\n\n               -  pT4, pN0 or pNx, M0 and ECOG PS 0-1\n\n               -  Any pT, pN1, M0 and ECOG PS 0-1\n\n          4. Patients must have histologically confirmed preponderant, defined as >50%, clear cell\n             RCC.\n\n          5. Patients must not have received any previous systemic (includes chemotherapeutic,\n             hormonal, or immunotherapeutic) treatment for RCC.\n\n          6. Patients must not have received any previous anti angiogenic treatment.\n\n          7. Patients must have adequate organ function.\n\n        Exclusion Criteria\n\n          1. Histologically undifferentiated carcinomas, sarcomas, collecting duct carcinoma,\n             lymphoma, or patients with any metastatic renal sites.\n\n          2. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)\n             Grade 3 hemorrhage <4 weeks of date of randomization.\n\n          3. Diagnosis of any non-RCC malignancy within the 5 years from date of randomization,\n             except basal cell carcinoma, squamous cell skin cancer, or in situ carcinoma of the\n             cervix uteri that has been adequately treated with no evidence of recurrent disease\n             for 12 months.\n\n          4. Any of the following within the 12 months prior to study drug administration:\n             myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft,\n             symptomatic congestive heart failure, cerebrovascular accident or transient ischemic\n             attack and 6 months for deep vein thrombosis or pulmonary embolism.\n\n          5. Gastrointestinal abnormalities
Inclusion Criteria:\n\n        Male or female patients with either:\n\n        Newly diagnosed non small cell lung cancer (NSCLC) (Group A) who meet the following\n        criteria:\n\n          -  Previously untreated, histologically or cytologically confirmed stage IIB, IIIA or\n             IIIB disease, without evidence of distant metastases\n\n          -  A measurable primary tumor with at least one diameter > 2 cm or primary tumor\n             extending to one or more lymph nodes which cannot be distinctively delineated as\n             confirmed by a diagnostic quality chest CT performed within 4 weeks prior to\n             initiation of the concurrent CRT.\n\n          -  Planned to receive concurrent chemoradiotherapy as definitive treatment. The radiation\n             dose should not exceed 70 Gy.\n\n          -  Undergone the following minimum workup to confirm disease staging within 4 weeks prior\n             to initiation of the concurrent CRT:\n\n               -  GBCA-enhanced Brain MRI or contrast enhanced CT if there are signs or symptoms\n                  suggesting brain metastases within the past 2 months.\n\n               -  If necessary to confirm stage of disease, an upper abdomen CT scan will be\n                  performed.\n\n               -  whole-body FDG PET/CT; OR\n\n          -  Newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) (Group B) who\n             meet the following criteria:\n\n               -  Previously untreated, histologically or cytologically confirmed (from the primary\n                  tumor and/or lymph nodes) stage III-IV disease without evidence of distant\n                  metastases.\n\n               -  A measurable (i) primary tumor with at least one diameter ?2 cm and (ii) lymph\n                  node with at least one diameter ? 2 cm as confirmed by a diagnostic quality neck\n                  CT performed within 4 weeks prior to initiation of the concurrent CRT.\n\n               -  Planned to receive concurrent chemoradiotherapy as definitive treatment. The\n                  radiation dose should not exceed 70 Gy.\n\n               -  Have undergone the following minimum workup to confirm disease staging within 4\n                  weeks prior to initiation of the concurrent CRT:\n\n          -  Whole-body FDG PET/CT.\n\n          -  Patients ? 18 years of age.\n\n          -  Able to comply with lying still during the PET/CT imaging session which may last for\n             up to 3 hrs with intermediate breaks.\n\n          -  ECOG performance status of 0, 1 or 2.\n\n          -  Adequate renal function and adequate hepatic function, as assessed by standard\n             laboratory criteria and defined as:\n\n          -  Serum creatinine ? 1.2 times the Upper Limit of Normal (ULN).\n\n          -  Total bilirubin ? 1.5 times the ULN.\n\n          -  Asparagine aminotransferase (AST) and/or alanineaminotransferase (ALT) ? 2.5 times the\n             ULN (grade 1 according to the NCI-CTCAE v.3).\n\n          -  Women of child-bearing potential must have a negative blood pregnancy test at\n             screening and use an adequate and medically acceptable contraceptive method.\n\n          -  Willing and able to comply with the protocol requirements.\n\n          -  Able to provide written informed consent.\n\n        Exclusion Criteria:\n\n        Exclusion criteria specific to patients with NSCLC (Group A):\n\n          -  Predominant small cell carcinoma histology.\n\n          -  Pure bronchioalveolar cell carcinoma histology.\n\n          -  Treatment planned with chemotherapy other than a platinum-based doublet regimen.\n\n          -  Malignant pleural or pericardial effusions.\n\n          -  Any contraindication to perform CT with IV contrast agent.\n\n        Exclusion criteria specific to patients with SCCHN (Group B):\n\n          -  Histology other than squamous cell carcinoma.\n\n          -  Treatment planned with chemotherapy other than a platinum-based regimen.\n\n          -  Treatment planned with cetuximab.\n\n          -  Treatment with induction chemotherapy.\n\n          -  Any contraindication to CT with IV contrast agent.\n\n          -  Evidence of distant metastases.\n\n          -  Patients who, based on the investigator's judgment, have other unstable medical\n             conditions that may preclude safe and complete study participation.\n\n          -  Treatment with any investigational drug, device or biologic agent within 30 days prior\n             to administration of [18F]-ML-10.\n\n          -  Pregnancy or lactation.
Inclusion Criteria:\n\n          -  In order to be eligible for participation in this trial, the subject must meet all the\n             following:\n\n               1. Pathologically documented unresectable melanoma, AJCC Stage III or IV. Subjects\n                  must have histological or cytological confirmed diagnosis of unresectable\n                  melanoma with progressive locally advanced or metastatic disease.\n\n               2. Subjects must be refractory to anti-PD-1 monoclonal antibodies (pembrolizumab or\n                  nivolumab either as monotherapy or in combination with other approved checkpoint\n                  inhibitors or targeted therapies according to their approved label) and subjects\n                  must meet all of the following criteria:\n\n                    1. Received at least 4 doses of anti-PD1 mAb (minimum dose of 2 mg/kg or fixed\n                       dose of 200 mg given Q3W for pembrolizumab; minimum dose of 240 mg given Q2W\n                       for nivolumab in monotherapy; minimum dose of 1 mg/kg given Q3W for\n                       nivolumab in combination with ipilimumab)\n\n                    2. Progressive disease after anti-PD1 mAb will be defined according to RECIST\n                       v1.1.\n\n                    3. Documented disease progression within 24 weeks of the last dose of anti-PD1\n                       mAb.\n\n               3. Resolution/improvement of anti-PD1 mAb-related AEs\n\n                    1. No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs\n                       from anti-PD1 mAb.\n\n                    2. No history of CTCAE Grade 3 requiring steroid treatment (>10 mg/day\n                       prednisone or equivalent dose) for >12 weeks or CTCAE Grade 2 pneumonitis\n                       regardless of steroid treatment.\n\n                    3. Minimum of 4 weeks (washout period) from the last dose of anti PD1 mAb.\n\n               4. Prior treatment with an approved BRAF inhibitor if BRAF V600 mutation-positive.\n\n               5. Age ? 18 years of age on day of signing informed consent.\n\n               6. Has a performance status of 0 or 1 on the ECOG Performance Scale.\n\n               7. Have measurable disease based on RECIST v1.1, with at least one anatomically\n                  distinct lesion. Lesion or lesions must meet all the following baseline criteria:\n\n                    1. Accessible for electroporation,\n\n                    2. Must be accurately measured in at least one dimension (longest diameter in\n                       the plane of measurement is to be recorded)\n\n               8. Demonstrate adequate organ function as defined below. All screening laboratories\n                  should be performed within 10 days of treatment initiation.\n\n                  System Laboratory Value Hematological Absolute neutrophil count (ANC) ?1.5 ×\n                  109/L Platelets ?100 × 109/L Hemoglobin ?9 g/dL or ?5.6 mmol/L* Renal Creatinine\n                  OR ?1.5 × the upper limit of normal (ULN) OR Measured or calculated** creatinine\n                  clearance (CrCl) Glomerular filtration rate (GFR) can also be used instead of\n                  creatinine or CrCl ? 30 mL/min for patient with creatinine levels >1.5 ×\n                  institutional ULN Hepatic Total bilirubin ?1.5 × ULN OR direct bilirubin ?ULN for\n                  patients with total bilirubin levels > 1.5× ULN Aspartate aminotransferase (AST)\n                  and alanine aminotransferase (ALT) ?2.5 × ULN OR ?5 × ULN for patients with liver\n                  metastases Coagulation International Normalized Ratio (INR) or Prothrombin Time\n                  (PT) ?1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT\n                  or PTT is within therapeutic range of intended use of anticoagulants Activated\n                  Partial Thromboplastin Time (aPTT)\n\n                  * Criteria must be met without erythropoietin dependency and without packed red\n                  blood cell (pRBC) transfusion within last 2 weeks\n\n                  ** Creatinine clearance should be calculated per institutional standard.\n\n               9. Women of childbearing potential must have negative serum or urine pregnancy test\n                  within 72 hours prior to receiving the first study drug administration.\n\n              10. For women of childbearing potential, must be willing to use an adequate method of\n                  contraception from 30 days prior to the first study drug administration and 120\n                  days following last day study drug administration. Spermicide alone is not\n                  considered sufficient in Canada and will not be accepted.\n\n              11. Male patients must be surgically sterile, or must agree to use adequate method of\n                  contraception during the study and at least 120 days following the last day of\n                  study drug administration.\n\n              12. Able and willing to provide written informed consent and to follow study\n                  instructions.\n\n        Exclusion Criteria:\n\n        The subject must be excluded from participating in the trial if meet any of the following:\n\n          1. Subject has disease that is suitable for local therapy administered with curative\n             intent.\n\n          2. Subject with a diagnosis of uveal melanoma.\n\n          3. Subject has a known additional malignancy that is progressing or requires active\n             treatment within the past 3 years. Exceptions include basal cell carcinoma of the\n             skin, squamous cell carcinoma of the skin that has undergone potentially curative\n             therapy or in situ cervical cancer.\n\n          4. Clinically active CNS metastases or non-measurable bone-only metastases. Subjects with\n             previously treated brain metastases may participate provided they are radiologically\n             stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging,\n             clinically stable and without requirement of steroid treatment for at least 14 days\n             prior to first dose of study drug.\n\n          5. Greater than 3 visceral sites of metastases. Liver lesions must meet RECIST v1.1\n             criteria for SD for at least 1 month prior to enrolment.\n\n          6. Subjects with electronic pacemakers or defibrillators.\n\n          7. Subjects who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2\n             antibodies).\n\n          8. Subjects who have known active Hepatitis B (defined as HBsAg reactive) or Hepatitis C\n             virus infection (defined as HCV RNA [qualitative] is detected)\n\n          9. Subject has a diagnosis of immunodeficiency or is receiving chronic systemic steroid\n             therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form\n             of immunosuppressive therapy within 7 days prior to the first dose of study drug. The\n             use of physiologic doses of corticosteroids may be approved after consultation with\n             the Sponsor.\n\n         10. Subjects who have received a live-virus vaccination within 30 days of the first dose\n             of treatment. Seasonal flu vaccines that do not contain live virus are permitted.\n\n         11. Subject has severe hypersensitivity (?Grade 3) to pembrolizumab and/or any of its\n             excipients.\n\n         12. Subject who have received transfusion of blood products (including platelets or red\n             blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF\n             or recombinant erythropoietin) within 4 weeks prior to study Cycle 1, Day 1\n             (baseline).\n\n         13. Subject has a history of (non-infectious) pneumonitis that required steroids or\n             current pneumonitis.\n\n         14. Subject has a history of interstitial lung disease.\n\n         15. Subject has an active infection requiring systemic therapy.\n\n         16. Subject has a history or current evidence of any condition, therapy, or laboratory\n             abnormality that might confound the results of the trial, interfere with the subject's\n             participation for the full duration of the study, or is not in the best interest of\n             the subject to participate, in the opinion of the treating Investigator.\n\n         17. Subject has not recovered (i.e., ? Grade 1 or at baseline) from adverse events due to\n             a previously administered agent.\n\n         18. Participation in another clinical study of an investigational agent or has used an\n             investigational device within 30 days of screening.\n\n         19. Subjects who have had any targeted small molecule therapy or any immunotherapy after\n             their confirmed progression on anti-PD-1 therapy.\n\n         20. Subject has known psychiatric or substance abuse disorders that would interfere with\n             cooperation with the requirements of the study.\n\n         21. Subjects who are pregnant or breastfeeding, or expecting to conceive or father\n             children within the projected duration of the study, starting with the screening visit\n             through 120 days after the last dose of studytreatment.
-  Patient must have a histologically confirmed (biopsy-proven) diagnosis of follicular\n             B-cell non-Hodgkin lymphoma (WHO classification: follicular center grades 1, 2, and 3a\n             [3b patients are not eligible]), with no evidence of transformation to large cell\n             histology.\n\n          -  Patient must meet criteria for High Tumor Burden (higher risk) as defined by either\n             the Groupe D'Etude des Lymphomes Follicularies (GELF) criteria [at least one\n             criterion] OR the follicular lymphoma international prognostic index (FLIPI) [score of\n             3, 4, or 5].\n\n          -  Patient must have Stage II, III or IV disease.\n\n          -  Baseline measurements and evaluations (PET/ CT) must be obtained within 10 weeks of\n             randomization to the study. Patient must have at least one objective measurable\n             disease parameter.\n\n          -  Age ? 18 years.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.\n\n          -  Ability to understand and willingness to sign Institutional Review Board\n             (IRB)-approved informed consent.\n\n          -  Willing to provide mandatory tissue samples (if sufficient tissue available) for\n             research purposes.\n\n          -  Adequate organ function as measured by the following criteria:\n\n               -  Absolute Neutrophil Count (ANC) ? 1000/mm³\n\n               -  Hemoglobin ? 8 g/dL\n\n               -  Platelets ?75,000/mm³\n\n               -  Creatinine clearance ? 50 mL/min, calculated with the use of 24-hour creatinine\n                  clearance or by Cockcroft-Gault formula\n\n               -  Total Bilirubin ? 1.5x Upper Limit of Normal (ULN) or ? 3x ULN for patients with\n                  documented Gilbert's syndrome\n\n               -  Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ? 2.5x ULN\n\n               -  Alkaline Phosphatase <5x ULN\n\n          -  All females of childbearing potential (not surgically sterilized and between menarche\n             and 1 year post menopause) must have a blood or urine test to rule out pregnancy\n             within 2 weeks prior to registration.\n\n          -  Women must not be pregnant or breastfeeding.\n\n          -  Patient must have had no prior chemotherapy, radiotherapy or immunotherapy for\n             lymphoma. For purposes of this trial, prednisone or other corticosteroids used for\n             non-lymphomatous conditions will not be considered as prior chemotherapy. In addition,\n             a prior/recent short course (<2 weeks) of steroids for symptom relief of\n             lymphoma-related symptoms will not make a patient ineligible.\n\n          -  Patient must have no recent history of malignancy except for adequately treated basal\n             cell or squamous cell skin cancer, Stage I melanoma of the skin, or in situ cervical\n             cancer. Individuals in documented remission without treatment for ? 2 years prior to\n             enrollment may be included at the discretion of the investigator.\n\n          -  Patient must have no active, uncontrolled infections.\n\n          -  Patients must be tested for hepatitis B virus (HBV), hepatitis B surface antigen\n             (HBsAg+) and hepatitis C (HCV) antibody within 6 weeks of registration. Patients who\n             are chronic carriers of HBV with positive HBsAg+ and positive HCV serology are\n             excluded, as chemotherapy and B-cell depleting therapy have been associated with virus\n             reactivation and fulminant hepatitis. NOTE: Patients with a past or resolved HBV\n             infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence\n             of HBsAg) may be included if HBV DNA is undetectable. If enrolled, patients must be\n             willing to undergo monthly HBV DNA testing. Patients with positive HCV antibody must\n             be negative for HCV by polymerase chain reaction (PCR) to be eligible for study\n             participation.\n\n          -  HIV positive patients are not excluded, but to enroll, must meet all of the below\n             criteria:\n\n               -  HIV is sensitive to antiretroviral therapy.\n\n               -  Must be willing to take effective antiretroviral therapy if indicated.\n\n               -  No history of CD4 prior to or at the time of lymphoma diagnosis <300 cells/mm³.\n\n               -  No history of AIDS-defining conditions.\n\n               -  If on antiretroviral therapy, must not be taking zidovudine or stavudine.\n\n               -  Must be willing to take prophylaxis for Pneumocystis jiroveci pneumonia during\n                  therapy and until at least 2 months following the completion of therapy or until\n                  the CD4 cells recover to over 250 cells/mm³, whichever occurs later.\n\n          -  Evidence of significant, uncontrolled concomitant diseases that could affect\n             compliance with the protocol or interpretation of results or that could increase risk\n             to the patient.\n\n          -  No major surgery within 2 weeks prior to cycle 1, other than for diagnosis.\n\n          -  A condition that precludes oral route of administration (venetoclax).\n\n          -  No known allergies to both xanthine oxidase inhibitors and rasburicase.\n\n          -  Patient must not require the use of warfarin (because of potential drug-drug\n             interactions that may potentially increase the exposure of warfarin). Blood thinners\n             of other classes are permitted.\n\n          -  Patient may not receive the following agents within 7 days prior to the first dose of\n             venetoclax:\n\n               -  Strong and moderate CYP3A inhibitors\n\n               -  Strong and moderate CYP3A inducers\n\n               -  Consumed grapefruit, grapefruit products, Seville oranges (including marmalade\n                  containing Seville oranges), or star fruit within 3 days prior to the first dose\n                  of venetoclax.\n\n          -  Patient must not have serious medical or psychiatric illness likely to interfere with\n             participation in this clinical study.
Inclusion Criteria:\n\n        Subjects will be eligible for the study if they:\n\n          1. Are of or older than the legal age in the respective countries at the time when\n             written informed consent is obtained\n\n          2. Have histologically or cytologically confirmed advanced (unresectable) or metastatic\n             biliary tract cancer, including intrahepatic or extrahepatic cholangiocarcinoma (CCA),\n             gallbladder cancer and carcinoma of Ampulla of Vater. This includes clinical diagnosis\n             of biliary tract cancer with histological confirmation of adenocarcinoma.\n\n          3. Have received and failed one and only one prior line of systemic treatment for\n             advanced or metastatic disease with radiologic evidence of disease progression. This\n             prior line of systemic treatment must also contain gemcitabine\n\n          4. Have received at least 6 doses of gemcitabine containing treatment in first line\n             (Adjuvant therapy is not regarded as 1st line therapy)\n\n          5. Have radiographically measurable disease based on Response Evaluation Criteria in\n             Solid Tumours (RECIST) v1.1 as assessed by Independent Central Review (ICR) (For Part\n             1)\n\n          6. Have no evidence of biliary duct obstruction, unless obstruction is controlled by\n             local treatment or, in whom the biliary tree can be decompressed by endoscopic or\n             percutaneous stenting with subsequent reduction in bilirubin to below or equal to 1.5\n             × upper level of normal (ULN)\n\n          7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1\n\n          8. Are able to understand and willing to sign the informed consent form\n\n          9. Have adequate organ and hematological function:\n\n               1. Hematological function, as follows:\n\n                    -  Absolute neutrophil count (ANC) ? 1.5 × 109/L\n\n                    -  Platelet count ? 100 × 109/L\n\n               2. Renal functions, as follows:\n\n                  • Estimated glomerular filtration rate or creatinine clearance > 50 mL/min/1.73m2\n\n               3. Hepatic function, as follows:\n\n                    -  Albumin ? 3 g/dL\n\n                    -  Total bilirubin ? 1.5 × ULN\n\n                    -  Aspartate aminotransferase and alanine aminotransferase ? 5 × ULN\n\n        Exclusion Criteria:\n\n        Subjects will be ineligible for the study if they:\n\n          1. Are currently on or have received anti-cancer therapy within the past 3 weeks before\n             receiving the first dose of study medication\n\n          2. Are currently on or have received radiation or local treatment within the past 3 weeks\n             for the target lesion(s) before receiving the first dose of study medication\n\n          3. Have evidence of multiple (? 2) peritoneal metastases or ascites at baseline as\n             assessed by ICR (For Part 1). (Ascites which can be attributed by non-malignant causes\n             is not excluded.)\n\n          4. Have had major surgical procedures within 14 days prior to first dose of study\n             medication\n\n          5. Have a known metastatic brain lesion(s), including asymptomatic and well controlled\n             lesion(s)\n\n          6. Have malabsorption syndrome, diseases significantly affecting gastrointestinal\n             function, resection of the stomach or small bowel, or difficulty in swallowing and\n             retaining oral medications which in the opinion of the Investigator could jeopardize\n             the validity of the study results\n\n          7. Have uncontrolled intercurrent illness including, but not limited to, ongoing or\n             active infection, unstable angina pectoris, cardiac arrhythmia, diabetes,\n             hypertension, or psychiatric illness/social situations that would limit compliance\n             with study requirements\n\n          8. Have any history of other malignancy unless in remission for more than 1 year\n             (non-melanoma skin carcinoma and carcinoma-in-site of uterine cervix treated with\n             curative intent is not exclusionary)\n\n          9. Are female patients who are pregnant or breast feeding\n\n         10. Have been previously treated with varlitinib or have been previously treated with\n             capecitabine as first line therapy for advanced or metastatic disease. For patients\n             who have previously received capecitabine as a radiosensitizer or as part of their\n             adjuvant therapy and their disease has relapsed for more than 6 months after their\n             last dose of capecitabine adjuvant therapy, their capecitabine therapy will not be\n             considered as a line of systemic chemotherapy for metastatic/advanced disease, and\n             thus they can participate in the study\n\n         11. Have received any investigational drug (or have used an investigational device) within\n             the last 14 days before receiving the first dose of study medication\n\n         12. Have unresolved or unstable serious toxicity (? common terminology criteria for\n             adverse events [CTCAE] 4.03 Grade 2), with the exception of anemia, asthenia, and\n             alopecia, from prior administration of another investigational drug and/or prior\n             cancer treatment\n\n         13. Have a known positive test for human immunodeficiency virus, hepatitis C (treatment\n             naïve or after treatment without sustained virologic response), or hepatitis B\n             infection with hepatitis B virus deoxyribonucleic acid exceeding 2000 IU/mL\n\n         14. Have a known history of drug addiction within last 1 year which, in the opinion of the\n             Investigator, could increase the risk of non-compliance to investigational product\n\n         15. Need continuous treatment with proton pump inhibitors during the study period\n\n         16. Have a history of (non-infectious) pneumonitis that required steroids or current\n             pneumonitis, or have a history of interstitial lung disease or current interstitial\n             lung disease\n\n         17. Have any history or presence of clinically significant cardiovascular, respiratory,\n             hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic,\n             neurologic or psychiatric disease or any other condition which in the opinion of the\n             Investigator could jeopardize the safety of the patient or the validity of the study\n             results\n\n         18. Have a baseline corrected QT interval (Fridericia's formula) (QTcF) > 450 ms or\n             patients with known long QT syndrome; torsade de pointes; symptomatic ventricular\n             tachycardia; an unstable cardiac syndrome in the past 3 months before screening visit;\n             > class 2 New York Heart Association heart failure; or > class 2 angina pectoris; or\n             receiving quinidine, procainamide, disopyramide, amiodarone, dronedarone, arsenic,\n             dofetilide, sotalol, or methadone. Please also see prohibited medication/therapy\n             (Section 5.4.10.1)
Inclusion Criteria (Key factors listed):\n\n          -  Eastern Cooperative Oncology Group Performance Status of ?2.\n\n          -  Confirmed malignancy with relapsed/refractory disease after ?2 lines of standard\n             systemic therapy including prior BTK inhibitor therapy having CLL, LPL/WM or MCL and\n             for DLBCL-ABC and FL, after ?2 lines of standard systemic therapy.\n\n          -  Presence of measurable disease through various assessments depending on specific\n             cancer type.\n\n          -  Current medical need for therapy of the B-lymphoid malignancy due to disease-related\n             symptoms, lymphadenopathy, organomegaly, extranodal organ involvement, or PD.\n\n        Exclusion Criteria (Key factors listed):\n\n          -  Known central nervous system malignancy.\n\n          -  History of other malignancies except for some which have been adequately treated\n             (e.g., local cancers of the skin, cervix or breast cancers, non-invasive bladder\n             cancer, prostate or other cancers of stages 1 or 2 in complete remission).\n\n          -  Significant cardiovascular disease or electrocardiogram (ECG) abnormalities\n\n          -  Ongoing risk for bleeding due to bleeding diathesis, platelet function disorder,\n             uncontrolled peptic ulcer disease, oral anticoagulation medications.\n\n          -  Evidence of uncontrolled systemic bacterial, fungal or viral infections at the start\n             of drug therapy.\n\n          -  Demonstrated intolerance to BTK inhibitor as shown by discontinuation due to adverse\n             effects.\n\n          -  Use of a moderate or strong inhibitor or inducer of CYP3A4 within 7 days prior to\n             start of study therapy (e.g., some antibiotics, antifungals, anticonvulsants,\n             grapefruit).
Inclusion Criteria:\n\n        All Patients\n\n          -  Histologically or cytologically confirmed MM; CLL/SLL, LPL, MZL; or MCL OR\n             histologically proven, de novo, DLBCL\n\n          -  ECOG performance status of 0 to 2\n\n          -  18 years of age or older\n\n          -  Life expectancy of at least 6 months\n\n          -  Platelets ? 100,000/µL (if full-dose anticoagulation therapy is used, platelets ?\n             150,000/µL are required)\n\n          -  WBC count ? 3000/µL\n\n          -  Absolute neutrophil count ? 1500/µL\n\n          -  Hemoglobin ? 9 g/dL (last transfusion, if any, must be at least 1 week prior to study\n             registration, and no transfusions are allowed between registration and dosing)\n\n          -  Estimated glomerular filtration rate ? 30 mL/min/1.73 m2\n\n          -  Alanine aminotransferase < 3 × upper limit of normal (ULN)\n\n          -  Bilirubin < 1.5 × ULN\n\n          -  International normalized ratio (INR) < 2.5\n\n          -  If patient is on full-dose anticoagulation therapy, the anticoagulation therapy must\n             be reversible and reversal of the anticoagulation therapy must not be\n             life-threatening, as judged by the Investigator\n\n          -  Patients who have undergone stem cell transplant must be at least 100 days from\n             transplant\n\n          -  Patient is judged by the Investigator to have the initiative and means to be compliant\n             with the protocol and be within geographical proximity to make the required study\n             visits\n\n          -  Patient or his or her legal representative has the ability to read, understand, and\n             provide written informed consent for the initiation of any study-related procedures\n\n          -  Female patients of childbearing potential must have a negative pregnancy test within\n             24 hours of dosing\n\n          -  Women of childbearing potential and men who are able to father a child must agree to\n             use an effective method of contraception (eg, oral contraceptives, double-barrier\n             methods such as a condom and a diaphragm, intrauterine device, Norplant, Depo-Provera)\n             during the study and for 12 months following administration of the study drug\n\n        Patients with Multiple Myeloma\n\n          -  At least 2 prior regimens, which must include at least 1 approved proteasome inhibitor\n             (bortezomib, carfilzomib, or ixazomib) and at least 1 approved immunomodulatory agent\n             (thalidomide, lenalidomide, or pomalidomide), with or without maintenance therapy,\n             unless patients are ineligible to receive such agents.\n\n          -  Bone marrow biopsy within 28 days of CLR 131 infusion demonstrating at least 5% plasma\n             cell involvement\n\n          -  Progressive disease defined by any of the following:\n\n               -  25% increase in serum M-protein from the lowest response value during (or after)\n                  last therapy and/or absolute increase in serum M-protein of ? 0.5 g/dL\n\n               -  25% increase in urine M-protein from the lowest response value during (or after)\n                  last therapy and/or absolute increase in urine M-protein of ? 200 mg/24 h\n\n               -  25% increase in bone marrow plasma cell percentage from the lowest response value\n                  during (or after) last therapy. Absolute bone marrow plasma cell percentage must\n                  be ? 10% unless prior CR when absolute bone marrow plasma cell percentage must be\n                  ? 5%.\n\n               -  25% increase in serum FLC level from the lowest response value during (or after)\n                  last therapy; the absolute increase must be > 10 mg/dL\n\n               -  New onset hypercalcemia > 11.5 mg/dL\n\n          -  Measurable disease defined by any of the following:\n\n               -  Serum M-protein > 0.5 g/dL\n\n               -  Urine M-protein > 200 mg/24 h\n\n               -  Serum FLC assay: Involved FLC level ? 10 mg/dL provided serum FLC ratio is\n                  abnormal.\n\n               -  Measurable plasmacytoma\n\n          -  Patients who are non-secretors will be considered for accrual on a case-by-case basis\n             by the Sponsor and will require an Investigator plan to define PD prior to enrollment\n             and to assess clinical benefit after treatment.\n\n        Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Lymphoplasmacytic\n        Lymphoma, or Marginal Zone Lymphoma\n\n          -  Prior treatment with at least 2 prior regimens, which may include chemotherapy, an\n             approved anti-CD20 antibody with or without maintenance therapy, and an approved\n             targeted agent, unless patients are ineligible to receive such agents\n\n          -  Patients with Helicobacter pylori+ mucosa-associated lymphoid tissue lymphoma must\n             have received 1 prior antibiotic regimen for H pylori\n\n          -  At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable\n             extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm\n\n        Patients with Mantle Cell Lymphoma\n\n          -  Prior treatment with at least 1 prior regimen\n\n          -  At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable\n             extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm\n\n        Patients with Diffuse Large B-Cell Lymphoma\n\n          -  Relapsed or refractory to combination chemotherapy for DLBCL that contains rituximab\n             and an anthracycline. Relapsed disease is defined as either recurrence of disease\n             after a CR or PD after achieving a partial response (PR) or SD. Refractory disease is\n             defined as failure to achieve at least SD with any 1 line of therapy or with PD ? 3\n             months of the most recent chemotherapy regimen.\n\n          -  At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable\n             extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm\n\n        Exclusion Criteria:\n\n          -  Ongoing Grade 2 or greater toxicities due to previous therapies. Stable, tolerable\n             Grade 2 AEs (eg, neuropathy) may be allowed.\n\n          -  Prior external-beam RT resulting in greater than 20% of total bone marrow receiving\n             greater than 20 Gy.\n\n          -  Prior total body or hemi-body irradiation\n\n          -  Extradural tumor in contact with the spinal cord or tumor located where swelling in\n             response to therapy may impinge upon the spinal cord\n\n          -  Central nervous system involvement unless previously treated with surgery or\n             radiotherapy with the patient neurologically stable and off corticosteroids\n\n          -  For patients with CLL/SLL, LPL, or MZL, transformation to a more aggressive form of\n             NHL\n\n          -  Ongoing chronic immunosuppressive therapy\n\n          -  Clinically significant bleeding event within prior 6 months\n\n          -  Ongoing anti-platelet therapy (except low-dose aspirin [eg, 81 mg daily] for\n             cardioprotection)\n\n          -  PTT > 1.3 × ULN\n\n          -  INR > 2.5\n\n          -  Radiation therapy, chemotherapy, immunotherapy, or investigational therapy within 2\n             weeks of eligibility-defining bone marrow biopsy.\n\n          -  History of hypersensitivity to iodine\n\n          -  Any other concomitant serious illness or organ system dysfunction that in the opinion\n             of the Investigator would either compromise patient safety or interfere with the\n             evaluation of the safety of the test drug including, but not limited to,\n             myelodysplastic syndromes; New York Heart Association class III-IV heart disease;\n             unstable angina pectoris; serious cardiac arrhythmia requiring medication or a\n             pacemaker/automatic implantable cardioverter defibrillator; myocardial infarction\n             within the past 6 months; uncontrolled hypertension; severe peripheral vascular\n             disease; ongoing hemodialysis or peritoneal dialysis; poorly controlled severe chronic\n             obstructive pulmonary disease; ongoing/active infection requiring antibiotics; and\n             uncontrolled hypothyroidism or hyperthyroidism\n\n          -  Major surgery within 6 weeks of enrollment\n\n          -  Known history of human immunodeficiency virus, hepatitis C, or hepatitis B infection\n\n          -  Pregnancy or breast-feeding
Inclusion Criteria\n\n        Each patient must meet all of the following inclusion criteria to be enrolled in the study:\n\n          -  Male or female patients 18 years or older.\n\n          -  Must be diagnosed with colorectal cancer (CRC) with liver metastasis and eligible and\n             scheduled for resection of liver metastases as part of their standard of care\n             treatment plan. The planned surgery must occur greater than 14 days after the day of\n             imaging.\n\n          -  Patients must consent to provide the sponsor with tumor tissue samples from their\n             resected liver metastases.\n\n          -  Easter Cooperative Oncology Group (ECOG) performance status of 0 to 1.\n\n          -  Female patients who are post menopausal, surgically sterile, or agree to practice\n             effective methods of contraception from the time of signing the informed consent form\n             through 60 days after the dose of [68Ga]MLN6907 or agree to practice true abstinence.\n\n          -  Male patients who agree to practice effective barrier contraception during the entire\n             study treatment period and through 4 months after the dose of [68Ga]MLN6907 or agree\n             to practice true abstinence.\n\n          -  Voluntary written consent must be given before performance of any study-related\n             procedure not part of standard medical care, with the understanding that consent may\n             be withdrawn by the patient at any time without prejudice to future medical care.\n\n          -  Suitable venous access for the study-required, blood sampling (ie, including PK\n             sampling)\n\n          -  Adequate hepatic function as defined in the protocol.\n\n          -  Adequate renal function as defined in the protocol.\n\n          -  Hemoglobin ? 9 g/dL.\n\n          -  Recovery from all adverse effects from prior antitumor therapy to at least Common\n             Terminology Criteria for Adverse Events (CTCAE) (V4.03) Grade 1.\n\n        Exclusion Criteria\n\n        Patients meeting any of the following exclusion criteria are not to be enrolled in the\n        study.\n\n          -  Female patients who are lactating and breastfeeding or have a positive serum pregnancy\n             test during the screening period or a positive urine pregnancy test on Day 1 before\n             the first dose of [68Ga]MLN6907.\n\n          -  Any serious medical or psychiatric illness, condition, or personal circumstance,\n             including severe claustrophobia, severe dyspnea, severe back pain, etc., that, in the\n             judgment of the investigator or project clinician, might potentially interfere with\n             the procedures required in this study.\n\n          -  Involvement in an investigative radioactive or other research procedure within 4 weeks\n             prior to administration of [68Ga]MLN6907.\n\n          -  Major surgery within 14 days prior to administration of [68Ga]MLN6907 5. Serious\n             infection (viral, bacterial, or fungal) within 14 days before administration of\n             [68Ga]MLN6907 or evidence of active infection during screening.\n\n          -  Life-threatening illness unrelated to cancer.\n\n          -  Clinically significant central nervous system (CNS) metastases.\n\n          -  Known inflammatory bowel disease.\n\n          -  Known hepatitis B surface antigen-positive or known or suspected active hepatitis C\n             infection (testing not required).\n\n          -  History of any hypersensitivity to any component of [68Ga]MLN6907.\n\n          -  Symptomatic cardiac disease, including ventricular dysfunction, coronary artery\n             disease, or arrhythmias, if this would, in the opinion of the investigator or project\n             clinician, interfere with assessment of efficacy or safety of [68Ga]MLN6907.\n\n          -  Admission or evidence of addictive disorders (eg, illicit drug use, drug abuse, or\n             alcohol abuse) that would limit compliance with study requirements.\n\n          -  Inability to lie flat for the duration of image acquisition.
Inclusion criteria (for all subjects)\n\n          -  Male and/or female subjects 18-75 years of age\n\n          -  Females must be of non-childbearing potential . All non-postmenopausal females must\n             have a confirmed negative serum pregnancy\n\n          -  Subjects in good health condition as determined by no clinically significant findings\n             from medical history and physical examination.\n\n          -  Body mass index (BMI) between ?18.0 and ?38.0 kg/m2, with body weight ? 50 kg and no\n             more than 140 kg\n\n          -  Laboratory values must be within normal limits (correction allowed) or considered\n             clinically insignificant\n\n          -  Do not participate in any other clinical trials with a BRAF or other RAF inhibitors\n\n        Additional inclusion criteria for patients with normal hepatic function (Control group):\n\n          -  Absence of clinically significant deviation from normal in medical history, physical\n             examination, vital signs, electrocardiograms and clinical laboratory determinations.\n\n          -  Must match to at least one hepatic impairment subject by age, gender and bodyweight\n\n        Additional inclusion criteria for hepatic impaired subjects:\n\n          -  Confirmed hepatic disease\n\n          -  Stable Child-Pugh status within 28 days prior to dosing.\n\n        Exclusion criteria for all subjects\n\n          -  Participation in any clinical investigation within 4 weeks prior to dosing\n\n          -  Significant acute illness within the two weeks prior to dosing\n\n          -  History of immunodeficiency diseases, including a positive HIV\n\n          -  History of malignancy of any organ system, treated or untreated, within 5 years\n\n          -  Any prior history of keratoacanthoma and/or cutaneous squamous cell carcinoma\n\n          -  A known diagnosis of any of the RASopathies, such as NF-1, Noonan syndrome, or related\n             conditions.\n\n          -  History of drug or alcohol abuse within the 6 months prior to dosing\n\n          -  Smoking: urine cotinine levels below 500 ng/mL on Day -1.\n\n          -  Use of drugs known to affect CYP3A4 and/or CYP2C8 including both (strong or moderate)\n             inhibitors and inducers, within 7 days prior to dosing\n\n          -  Administration of medications that prolong the QT interval within 4 weeks prior to\n             dosing and until EOT.\n\n          -  History or current diagnosis of cardiac disease indicating significant risk of safety\n\n          -  Any surgical or medical condition which might significantly alter the absorption,\n             distribution, metabolism or excretion of drugs.\n\n        Additional exclusion criteria for healthy subjects (control group):\n\n          -  Clinical evidence of liver disease or liver injury\n\n          -  History or presence of renal impairment as indicated by abnormal creatinine or BUN\n             values\n\n          -  A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C antibody\n\n        Additional exclusion criteria for subjects with hepatic impairment:\n\n          -  Alcohol or drug abuse within one month prior to dosing or evidence of such\n\n          -  History of liver transplantation at any time in the past and is on immunosuppressant\n             therapy.\n\n          -  Encephalopathy Grade 3 or worse within 28 days of dosing.\n\n          -  History of surgical portosystemic shunt.\n\n          -  Life expectancy ?3 months\n\n        Other protocol-defined inclusion/exclusion may apply.
For inclusion in the study patient should fulfil the following criteria:\n\n        1. Male or female, aged at least 18 years. 2. Histological or cytological confirmation\n        diagnosis of NSCLC. 3. Radiological documentation of disease progression while on a\n        previous continuous treatment with an EGFR TKI, eg gefitinib, erlotinib or afatinib. In\n        addition, other lines of therapy may have been given. All patients must have documented\n        radiological progression on the last treatment administered prior to enrolling in the\n        study.\n\n        4. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR\n        TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).\n\n        5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration\n        over the previous 2 weeks (Appendix G).\n\n        6. Patients must have a life expectancy of ?12 weeks as estimated at the time of screening.\n\n        7. Females should be using adequate contraceptive measures and must have a negative\n        pregnancy test prior to start of dosing if of child-bearing potential, or must have\n        evidence of non-child-bearing potential by fulfilling one of the following criteria at\n        screening: Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least\n        12 months following cessation of all exogenous hormonal treatments. Women under 50 years\n        old would be considered post-menopausal if they have been amenorrhoeic for 12 months or\n        more following cessation of exogenous hormonal treatments and with LH and FSH levels in the\n        post-menopausal range for the institution. Documentation of irreversible surgical\n        sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not\n        tubal ligation.\n\n        8. Male patients should be willing to use barrier contraception, ie, condoms, until 6\n        months after last study drug is taken.\n\n        9. Contact lens wearers must be prepared to not wear contact lenses and wear glasses for\n        the duration of the rifampicin dosing.\n\n          1. Participation in another clinical study with an IP during the last 14 days (or a\n             longer period depending on the defined characteristics of the agents used).\n\n          2. Treatment with any of the following: Treatment with an EGFR TKI (eg, erlotinib or\n             gefitinib) w/in 8 days or approx. 5 x half-life, whichever is the longer, of the first\n             dose of study treatment; any cytotoxic chemo, investigational agents or other\n             anticancer drugs from a previous treatment regimen w/in 14 days of the first dose of\n             study treatment; major surgery (excluding placement of vascular access) w/in 4 weeks\n             of the first dose of study treatment; radiotherapy with a limited field of radiation\n             for palliation w/in 1 week of the first dose of study treatment, with the exception of\n             patients receiving radiation to more than 30% of bone marrow or with a wide field of\n             radiation which must be completed w/in 4 weeks of the first; patients currently\n             receiving (or unable to stop use prior to receiving the first dose) medications or\n             herbal supplements known to be potent inhibitors of CYP3A4 (at least 1 week prior) and\n             potent inducers of CYP3A4 (at least 3 week prior). All patients must avoid concomitant\n             use of any medications, herbal supplements and/or ingestion of foods with known\n             inducer/inhibitory effects on CYP3A4.\n\n          3. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of\n             starting study treatment with the exception of alopecia and Grade 2, prior\n             platinum-therapy related neuropathy.\n\n          4. Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade,\n             or other products containing grapefruit or Seville oranges within 7 days of the first\n             administration of the IP until the final PK sample collection on Day 78 of Part A.\n\n          5. Spinal cord compression or brain metastases unless asymptomatic, stable and not\n             requiring steroids for at least 4 weeks prior to start of study treatment.\n\n          6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled\n             hypertension and active bleeding diatheses, which in the Investigator's opinion makes\n             it undesirable for the patient to participate in the study or which would jeopardise\n             compliance with the protocol, or active infection including hepatitis B, hepatitis C\n             and HIV. Screening for chronic conditions is not required.\n\n          7. Inadequate bone marrow reserve or organ function as demonstrated by any of the\n             following laboratory values: ANC <1.5 x 10^9/L; Platelet count <100 x 10^9/L;\n             Haemoglobin <90 g/L; ALT >2.5 times the ULN if no demonstrable liver metastases or >5\n             times ULN in the presence of liver metastases; AST >2.5 times ULN if no demonstrable\n             liver metastases or >5 times ULN in the presence of liver metastases; Total bilirubin\n             >1.5 times ULN if no liver metastases or >3 times ULN in the presence of documented\n             Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; creatinine\n             >1.5 times ULN concurrent with creatinine clearance <50 ml/min (measured or calculated\n             by Cockcroft and Gault equation); confirmation of creatinine clearance is only\n             required when creatinine is >1.5 times ULN.\n\n          8. Any of the following cardiac criteria: Mean resting corrected QT interval corrected\n             for heart rate using Fridericia's correction factor (QTcF) >470 msec obtained from 3\n             electrocardiograms (ECGs); any clinically important abnormalities in rhythm,\n             conduction or morphology of resting ECG eg, complete left bundle branch block, third\n             degree heart block, second degree heart block, PR interval >250 msec; any factors that\n             increase the risk of QTc prolongation or risk of arrhythmic events such as heart\n             failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome\n             or unexplained sudden death under 40 years of age or any concomitant medication known\n             to prolong the QT interval.\n\n          9. Patients unable to swallow oral medication or patients with GI disorders or\n             significant GI resection likely to interfere with the absorption of AZD9291.\n\n         10. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required\n             steroid treatment, or any evidence of clinically active ILD.\n\n         11. Women who are breastfeeding.\n\n         12. Patients with a known hypersensitivity to AZD9291 or rifampicin or any of the\n             excipients of the products.\n\n         13. Concomitant medication contraindicated for use with rifampicin (including, but not\n             limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide,\n             triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methyl-glutaryl coenzyme A\n             (HMG-CoA)-reductase inhibitors metabolised by CYP3A4, such as lovastatin and\n             simvastatin, ergot alkaloids metabolised by CYP3A4, such as dihydroergotamine,\n             ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine).\n\n         14. For optional genetic research: .Previous allogenic bone marrow transplant or\n             Non-leukocyte depleted whole blood transfusion within 120 days of the date of the\n             genetic sample collection.
Key Inclusion Criteria Includes:\n\n        Patients meeting all of the following criteria may be enrolled in the study:\n\n          1. Must be able to understand and voluntarily sign an ICF.\n\n          2. Must be registered into the mandatory POMALYST Risk Evaluation and Mitigation Strategy\n             (REMS)™ program, and be willing and able to comply with the requirements of the\n             POMALYST REMS™ program (Appendix 9.3).\n\n          3. Must be ? 18 years of age at the time of signing the ICF.\n\n          4. Must be able to adhere to the study visit schedule and other protocol requirements.\n\n          5. Must have a documented diagnosis of MM and have relapsed or relapsed and refractory\n             disease. Patients must have received at least 2 lines of prior therapies. Patients\n             must have relapsed after having achieved at least stable disease for at least 1 cycle\n             of treatment to at least 1 prior regimen and then developed PD. Relapsed and\n             relapsed-and-refractory patients must have documented evidence of PD during or within\n             60 days (measured from the end of the last cycle) of completing treatment with the\n             last antimyeloma drug regimen used just prior to study entry.\n\n          6. Patients must have undergone prior treatment with at least 2 cycles of lenalidomide\n             and at least 2 cycles of a proteasome inhibitor (either in a separate regimen or\n             within the same regimen.\n\n          7. Must not be a candidate for autologous stem cell transplant (ASCT), have declined the\n             option of ASCT, or have relapsed after prior ASCT.\n\n          8. Must have measurable levels of myeloma paraprotein in serum (? 0.5 g/dL) or urine (?\n             0.2 g/24 hours). Patients who do not have myeloma paraprotein must have serum free\n             light chain (SFLC) concentration of ? 10 mg/dL, provided SFLC ratio is abnormal.\n             Nonsecretory myeloma is excluded.\n\n          9. Must have Eastern Cooperative Oncology Group performance status score of 0, 1, or 2.\n\n         10. Females of childbearing potential must have a negative serum or urine pregnancy test\n             as described in Appendix 9.3 for the POMALYST REMS™ program. Females of childbearing\n             potential and males must either commit to continued abstinence from heterosexual\n             intercourse or must abide by birth control requirements as described in Appendix 9.3\n             for the POMALYST REMS™ program.\n\n         11. Must agree to refrain from donating blood while on study drug and for 28 days after\n             discontinuation from this study.\n\n         12. Must agree not to share study medication with another person.\n\n         13. Must be able to take ASA (81 or 325 mg) daily as prophylactic anticoagulation.\n             Patients intolerant to ASA may use low molecular weight heparin. Lovenox is\n             recommended. Coumadin will be allowed provided the patient is fully anticoagulated,\n             with an international normalized ratio of 2 to 3.\n\n        Key Exclusion Criteria Includes:\n\n        Patients meeting any of the following criteria will be excluded from enrollment in the\n        study:\n\n          1. Any serious medical condition, laboratory abnormality, or psychiatric illness that\n             would prevent the patient from signing the ICF or from following the study\n             requirements.\n\n          2. Pregnant or lactating females.\n\n          3. Prior therapy with histone deacetylase inhibitor or pomalidomide.\n\n          4. Any of the following laboratory abnormalities:\n\n               -  ANC < 1,000/µL\n\n               -  Platelet count < 75,000/ µL for patients in whom < 50% of bone marrow nucleated\n                  cells are plasma cells, or a platelet count < 50,000 for patients in whom ? 50%\n                  of bone marrow nucleated cells are plasma cells\n\n               -  Hemoglobin < 8 g/dL (< 4.9 mmol/L; prior red blood cell transfusion or\n                  recombinant human erythropoietin use is permitted).\n\n               -  Creatinine clearance < 45 mL/min according to Cockcroft-Gault formula. If\n                  creatinine clearance calculated from the 24 hour urine sample is ? 45 mL/min,\n                  patient will qualify for the trial.\n\n               -  Serum glutamic oxaloacetic transaminase/aspartate aminotransferase, or serum\n                  glutamic pyruvic transaminase/alanine aminotransferase > 3.0 × ULN\n\n               -  Serum total bilirubin > 2.0 mg/dL\n\n          5. Prior history of malignancies, other than MM, unless the patient has been free of the\n             disease for ? 3 years. Exceptions include the following:\n\n               -  Basal or squamous cell carcinoma of the skin\n\n               -  Ductal carcinoma in situ; or cervical intraepithelial neoplasia\n\n               -  Carcinoma of the prostate with a current prostate-specific antigen below the\n                  upper limit of normal\n\n          6. Corrected QT interval (QTc) using Fridericia's formula value > 480 msec at Screening;\n             family or personal history of long QTc syndrome or ventricular arrhythmias including\n             ventricular bigeminy at Screening; previous history of drug-induced QTc prolongation\n             or the need for treatment with medications known or suspected of producing prolonged\n             QTc intervals on electrocardiogram.\n\n          7. Known human immunodeficiency virus, hepatitis B virus, and known or suspected active\n             hepatitis C virus infection.\n\n          8. Hypersensitivity to thalidomide, lenalidomide, pomalidomide, or dexamethasone (such as\n             Steven Johnson Syndrome). Hypersensitivity, such as rash, that can be medically\n             managed is allowable.\n\n          9. Peripheral neuropathy ? Grade 2 despite supportive therapy.\n\n         10. Radiotherapy or systemic therapy (standard or an investigational or biologic\n             anticancer agent) within 14 days of initiation of study drug treatment.\n\n         11. Current enrollment in another clinical trial involving treatment and/or receiving an\n             investigational agent for any reason.\n\n         12. Inability or unwillingness to comply with birth control requirements or any of the\n             POMALYST REMS™ requirements per Appendix 9.3.
For inclusion in the study, patients should fulfil the following criteria:\n\n          1. Male or female, aged at least 18 years.\n\n          2. Histological or cytological confirmation diagnosis of NSCLC.\n\n          3. Radiological documentation of disease progression while on a previous continuous\n             treatment with an EGFR TKI, eg, gefitinib or erlotinib. In addition, other lines of\n             therapy may have been given. All patients must have documented radiological\n             progression on the last treatment administered prior to enrolling in the study.\n\n          4. Confirmation that the tumour harbours an EGFR mutation known to be associated with\n             EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).\n\n          5. ECOG performance status 0-1 with no deterioration over the previous 2 weeks.\n\n          6. Patients must have a life expectancy of ?12 weeks as estimated at the time of\n             screening.\n\n          7. Evidence of non-childbearing status for women of childbearing potential, or\n             post-menopausal status: negative urine or serum pregnancy test within 28 days of study\n             treatment, confirmed prior to treatment on Day 1 of Part A, or post menopausal status.\n             Females should be using adequate contraceptive measures and must have a negative\n             pregnancy test prior to start of dosing if of child-bearing potential or must have\n             evidence of non-child-bearing potential by fulfilling one of the following criteria at\n             screening: post-menopausal defined as aged more than 50 years and amenorrhoeic for at\n             least 12 months following cessation of all exogenous hormonal treatments; women under\n             50 years old would be consider postmenopausal if they have been amenorrhoeic for 12\n             months or more following cessation of exogenous hormonal treatments and with LH and\n             FSH levels in the post-menopausal range for the institution; documentation of\n             irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or\n             bilateral salpingectomy but not tubal ligation.\n\n          8. Male patients should be willing to use barrier contraception, ie, condoms, until 6\n             months after last study drug is taken.\n\n        Patients should not enter the study if any of the following exclusion criteria are\n        fulfilled:\n\n          1. Participation in another clinical study with an IP during the last 14 days (or a\n             longer period depending on the defined characteristics of the agents used).\n\n          2. Treatment with any of the following: Treatment with an EGFR TKI w/in 8 days or\n             approximately 5x half-life, whichever is the longer, of the first dose of study\n             treatment; Any cytotoxic chemotherapy, investigational agents or other anticancer\n             drugs w/in 14 days of the first dose of study treatment; Major surgery (excluding\n             placement of vascular access) within 4 weeks of the first dose; Radiotherapy with a\n             limited field of radiation for palliation within 1 week of the first dose of study\n             treatment, with the exception of patients receiving radiation to more than 30% of the\n             bone marrow or with a wide field of radiation which must be completed within 4 weeks\n             of the first dose of study treatment; Patients currently receiving (or unable to stop\n             use prior to receiving the first dose of study treatment) medications or herbal\n             supplements known to be potent inhibitors of CYP2C8 and of CYP3A4 (at least 1 week\n             prior) and potent inducers of CYP3A4 (at least 3 week prior). All patients must try to\n             avoid concomitant use of any medications, herbal supplements and/or ingestion of foods\n             with known inducer/inhibitory effects on CYP3A4, CYP2C8, and/ or CYP1A2.\n\n          3. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of\n             starting study treatment with the exception of alopecia and Grade 2, prior\n             platinum-therapy related neuropathy.\n\n          4. Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade,\n             or other products containing grapefruit or Seville oranges within 7 days of the first\n             administration of the IP until the end of Part A.\n\n          5. Spinal cord compression or brain metastases unless asymptomatic, stable and not\n             requiring steroids for at least 4 weeks prior to start of study treatment.\n\n          6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled\n             hypertension and active bleeding diatheses, which in the Investigator's opinion makes\n             it undesirable for the patient to participate in the study or which would jeopardise\n             compliance with the protocol, or active infection including hepatitis B, hepatitis C\n             and human immunodeficiency virus (HIV). Screening for chronic conditions is not\n             required.\n\n          7. Inadequate bone marrow reserve or organ function as demonstrated by any of the\n             following laboratory values: ANC <1.5 x 10^9/L; Platelet count <100 x 10^9/L;\n             Haemoglobin <90 g/L; ALT >2.5 x the institutional ULN if no demonstrable liver\n             metastases or >5 x institutional ULN in the presence of liver metastases; AST >2.5 x\n             institutional ULN if no demonstrable liver metastases or >5 x institutional ULN in the\n             presence of liver metastases; Total bilirubin >1.5 x institutional ULN if no liver\n             metastases or >3 x institutional ULN in the presence of documented Gilbert's Syndrome\n             or liver metastases; Creatinine >1.5 x institutional ULN concurrent with creatinine\n             clearance <50 mL/min (measured or calculated by Cockcroft-Gault formula); confirmation\n             of creatinine clearance is only required when creatinine is >1.5 x institutional ULN.\n\n          8. Any of the following cardiac criteria: Mean resting corrected QT interval corrected\n             for heart rate using Fridericia's correction factor (QTcF) >450 msec obtained from 3\n             ECGs; Any clinically important abnormalities in rhythm, conduction or morphology of\n             resting ECG eg, complete left bundle branch block, third degree heart block, second\n             degree heart block, PR interval >250 msec; Any factors that increase the risk of QTc\n             prolongation or risk of arrhythmic events such as heart failure, hypokalaemia,\n             congenital long QT syndrome, family history of long QT syndrome or unexplained sudden\n             death under 40 years of age or any concomitant medication known to prolong the QT\n             interval.\n\n          9. Patients unable to swallow oral medication or patients with GI disorders or\n             significant GI resection likely to interfere with the absorption of AZD9291.\n\n         10. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation\n             pneumonitis which required steroid treatment, or any evidence of clinically active\n             ILD.\n\n         11. Women who are breastfeeding.\n\n         12. Patients with a known hypersensitivity to AZD9291 or itranconazole or any of their\n             excipients.\n\n        12. Concomitant medication contraindicated for use with itraconazole (including, but not\n        limited to): cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide,\n        triazolam, levacetylmethadol (levomethadyl), 3-hydroxy-3-methyl-glutaryl coenzyme A\n        (HMG-CoA)- reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin,\n        ergot alkaloids metabolized by CYP3A4, such as dihydroergotamine, ergometrine (ergonovine),\n        ergotamine and methylergometrine (methylergonovine).\n\n        13. For optional genetic research: Previous allogenic bone marrow transplant or\n        non-leukocyte depleted whole blood transfusion within 120 days of sample collection.
Inclusion Criteria:\n\n        Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB\n        to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of\n        non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon\n        agreement with the Sponsor, whose disease has progressed despite previous antineoplastic\n        therapy or for whom no further effective standard therapy is available\n\n          -  Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation\n\n          -  Evidence of measurable disease as determined by RECIST v1.1\n\n          -  World Health Organization (WHO) Performance Status ? 2\n\n          -  Negative serum pregnancy test within 72 hours prior to the first study dose in all\n             women of childbearing potential\n\n        Exclusion Criteria:\n\n        Progressive disease following prior treatment with RAF-inhibitors in combination with\n        MEK-inhibitors\n\n          -  Symptomatic or untreated leptomeningeal disease\n\n          -  Symptomatic brain metastases. Patients are not permitted to receive enzyme inducing\n             anti-epileptic drugs\n\n          -  Known acute or chronic pancreatitis\n\n          -  History or current evidence of retinal disease, retinal vein occlusion or\n             ophthalmopathy\n\n          -  Clinically significant cardiac disease\n\n          -  Patients with abnormal laboratory values at Screening/baseline\n\n          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly\n             alter the absorption of oral LGX818/MEK162\n\n          -  Previous or concurrent malignancy\n\n          -  Pregnant or nursing (lactating) women\n\n          -  For addition of LEE011 in the triple combination, congenital long QT syndrome or\n             family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ? 3,\n             brain metastases at baseline, abnormal coagulation results PT/INR >1.5 x ULN or aPTT\n             >1.5 x ULN.\n\n        Other protocol-defined inclusion/exclusion criteria may apply
For inclusion in the study as a patient with hepatic impairment, the following criterion\n        must be met:\n\n        1. Patients must have stable chronic hepatic impairment for at least 2 weeks prior to Day\n        1, see Section 4.1.1. Patients with hepatic metastases and/or HCC are eligible for the\n        study, providing the hepatic metastases or HCC are not the sole reason for any changes in\n        liver function satisfying the criteria for mild or moderate hepatic impairment as defined\n        by the Child Pugh criteria. Patients must have globally impaired hepatic function to\n        participate in the study.\n\n        For inclusion in the study as a patient with normal hepatic function, the following\n        criteria must be met:\n\n          1. Negative result for serum hepatitis B surface antigen and hepatitis C antibody\n\n          2. Total bilirubin less than or equal to1.5 x institutional ULN, albumin and prothrombin\n             time within normal limits and must not have ascites (unless related to disease under\n             study) or encephalopathy.\n\n          3. AST and ALT less than or equal to2.5 x institutional ULN unless liver metastases are\n             present in which case it must be less than or equal to5 x ULN.\n\n        All patients must fulfil the following criteria:\n\n          1. Male or female, aged at least 18 years.\n\n          2. Histological or, where appropriate, cytological confirmation of any malignant solid\n             tumour refractory or resistant to standard therapy or for which no suitable effective\n             standard therapy exists. Tumours in which inhibition of the EGFR pathway is considered\n             relevant by the Investigator are not mandated but are encouraged.\n\n          3. ECOG performance status less than or equal to2.\n\n          4. Patients must have a life expectancy of greater than or equal to12 weeks, as estimated\n             at the time of screening.\n\n          5. Females should be using adequate contraceptive measures and must have a negative\n             pregnancy test prior to start of dosing if of child-bearing potential or must have\n             evidence of non-child-bearing potential by fulfilling one of the following criteria at\n             screening: post-menopausal defined as aged more than 50 years and amenorrhoeic for at\n             least 12 months following cessation of all exogenous hormonal treatments; women under\n             50 years old would be consider postmenopausal if they have been amenorrheic for 12\n             months or more following cessation of exogenous hormonal treatments and with LH and\n             FSH levels in the postmenopausal range for the institution; documentation of\n             irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or\n             bilateral salpingectomy but not tubal ligation\n\n          6. Male patients should be willing to use barrier contraception, ie, condoms, until 6\n             months after last study drug is taken.\n\n        Exclusion criteria:\n\n          1. Participation in another clinical study with an IP during the last 14 days (or a\n             longer period depending on the defined characteristics of the agents used).\n\n          2. Treatment in the previous 3 months before dosing in this study with any drug known to\n             have a well-defined potential for fulminant hepatotoxicity (eg, halothane and\n             methotrexate).\n\n          3. Treatment with any of the following: an EGFR TKI w/in 8 days or approximately 5x\n             half-life, whichever is the longer, of the first dose of study treatment; Any\n             cytotoxic chemotherapy, investigational agents or other anticancer drugs w/in 14 days\n             of the first dose of study treatment; Major surgery (excluding placement of vascular\n             access) w/in 4 weeks of the first dose; Radiotherapy with a limited field of radiation\n             for palliation within 1 week of the first dose of study treatment, with the exception\n             of patients receiving radiation to more than 30% of the bone marrow or with a wide\n             field of radiation which must be completed within 4 weeks of the first dose of study\n             treatment; Patients currently receiving (or unable to stop use prior to receiving the\n             first dose of study treatment) medications or herbal supplements known to be potent\n             inhibitors of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3\n             week prior) (Appendix H). All patients in Part B and continued access must try to\n             avoid concomitant use of any medications, herbal supplements and/or ingestion of foods\n             with known potent inducer/inhibitory effects on CYP3A4 (Appendix H).\n\n          4. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of\n             starting study treatment with the exception of alopecia and Grade 2 prior\n             platinum-therapy related neuropathy.\n\n          5. Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade,\n             or other products containing grapefruit or Seville oranges within 7 days of the first\n             administration of the IP until final PK sample collection on Day 22.\n\n          6. Spinal cord compression or brain metastases unless asymptomatic, stable and not\n             requiring steroids for at least 4 weeks prior to start of study treatment.\n\n          7. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled\n             hypertension and active bleeding diatheses, which in the Investigator's opinion makes\n             it undesirable for the patient to participate in the study or which would jeopardise\n             compliance with the protocol, or active infection including hepatitis B, hepatitis C\n             and human immunodeficiency virus (HIV). Screening for chronic conditions is not\n             required.\n\n          8. Inadequate bone marrow reserve or organ function as demonstrated by any of the\n             following laboratory values: ANCless than1.5x10.9/L; platelet count less\n             than100x10.9/L; haemoglobinless than90 g/L; Creatinine greater than1.5 x institutional\n             ULN concurrent with creatinine clearance less than50 mL/min (measured or calculated by\n             Cockcroft-Gault formula); confirmation of creatinine clearance is only required when\n             creatinine is greater than1.5 x institutional ULN.\n\n          9. Any of the following cardiac criteria: Mean resting corrected QT interval corrected\n             for heart rate using Fridericia's correction factor (QTcF) greater than470 msec\n             obtained from 3 ECGs; Any clinically important abnormalities in rhythm, conduction or\n             morphology of resting ECG eg, complete left bundle branch block, third degree heart\n             block, second degree heart block, PR interval greater than250 msec; Any factors that\n             increase the risk of QTc prolongation or risk of arrhythmic events such as heart\n             failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome\n             or unexplained sudden death under 40 years of age or any concomitant medication known\n             to prolong the QT interval.\n\n         10. Patients unable to swallow oral medication or patients with GI disorders or\n             significant GI resection likely to interfere with the absorption of AZD9291.\n\n         11. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation\n             pneumonitis which required steroid treatment, or any evidence of clinically active\n             ILD.\n\n         12. Women who are breastfeeding.\n\n         13. Patients with a known hypersensitivity to AZD9291 or any of its excipients. Patients\n             with normal hepatic function should not have a history or presence of hepatic disease\n             known to interfere with the absorption, distribution, metabolism or excretion of\n             AZD9291.\n\n        Patients with mild or moderate hepatic function should not enter if the following are\n        fulfilled:\n\n          1. Patients with hepatic encephalopathy within the last 4 weeks prior to Day 1.\n\n          2. Fluctuating or rapidly deteriorating hepatic function as indicated by widely varying\n             or worsening of clinical and/or laboratory signs of hepatic impairment within the\n             screening period.\n\n          3. Presence of acute liver disease caused by drug toxicity or by an infection.\n\n          4. Severe portal hypertension or surgical porto-systemic shunts.\n\n          5. Biliary obstruction or other causes of hepatic impairment not related to parenchymal\n             disorder and/or disease of the liver.\n\n          6. Oesophageal variceal bleeding within the past 2 months.\n\n          7. Anticoagulant therapy with warfarin or related coumadine.NOTE: Preferred format\n             includes lists of inclusion and exclusion criteria
Inclusion Criteria:\n\n          -  Age ? 18 years\n\n          -  Metastatic colorectal cancer\n\n          -  Progression on or following standard therapy, or no standard therapy (phase Ib).\n             Progression on or following at least 2-prior fluoropyrimidine-containing chemotherapy\n             regimens (phase II)\n\n          -  Written documentation of mutant or wild-type RAS\n\n          -  Life expectancy ? 3 months\n\n          -  ECOG performance status ? 2\n\n        Exclusion Criteria:\n\n        Phase II arms 1 and 4 only: previous treatment with cetuximab, panitumumab, and/or other\n        EGFR inhibitors\n\n          -  Previous treatment with MEK-inhibitors\n\n          -  History of severe infusion reactions to monoclonal antibodies.\n\n          -  Symptomatic or untreated leptomeningeal disease\n\n          -  Symptomatic brain metastasis\n\n          -  Current evidence of retinal disease; history of CSR, RVO or ophthalmopathy as assessed\n             by ophthalmologic examination at baseline that would be considered a risk factor for\n             CSR/RVO and history of keratitis.\n\n          -  Acute or chronic pancreatitis\n\n          -  Clinically significant cardiac disease\n\n          -  Not adequate hematologic, renal and hepatic function
Inclusion criteria:\n\n        In the dose escalation part: patients with high MET tumor expression, evaluable or\n        measurable solid tumors for which no standard therapy is available.\n\n        In the expansion cohorts: in the first cohort, patients with diagnosed MET gene amplified\n        including NSCLC patients and measurable tumors for which no standard therapy is available\n        will be eligible. In the second cohort, patients with advanced P-MET positive measurable\n        solid tumor without MET- gene amplification for which no standard therapy is available will\n        be eligible.\n\n        Exclusion criteria:\n\n        Patient less than 18 years old. ECOG performance status >2. Any serious active disease or\n        co-morbid condition, which, in the opinion of the Investigator, may interfere with the\n        safety or the compliance with the study.\n\n        Poor bone marrow reserve as defined by absolute neutrophil count <1.5 x 10^9/L or platelets\n        <100 x 10^9/L.\n\n        Poor organ function as defined by one of the following:\n\n          -  Total bilirubin >1.5 x ULN\n\n          -  AST, ALT, alkaline phosphatase >2.5 x ULN or >5 x ULN in case of documented liver\n             metastasis. Alkaline phosphatase up to 5 x ULN in case of osteolytic bone metastasis\n             without liver metastases is allowed\n\n          -  Serum creatinine >1.5 x ULN or\n\n          -  Serum creatinine between 1.0 and 1.5 x ULN associated with calculated creatinine\n             clearance <60 mL/min\n\n          -  Proteinuria >500 mg/24H Pregnant or breast-feeding women. No use of effective birth\n             control methods, when applicable. No measurable or evaluable tumor lesion in the Dose\n             Escalation part, and no measurable lesions in the expansion cohorts.\n\n        Brain metastasis (other than totally resected or previously pre-irradiated and no\n        progressive/relapsing) or lepto-meningeal carcinomatosis.\n\n        No resolution of any specific toxicities (excluding alopecia) related to any prior\n        anti-cancer therapy to grade ?1 according to the NCI CTCAE v.4.03.\n\n        Wash out period of less than 3 weeks from previous antitumor therapy or any investigational\n        treatment (and less than 6 weeks in case of prior nitroso-urea and or mitomycin C\n        treatment).\n\n        Any surgery with major risk of bleeding performed less than 10 days prior to study\n        treatment administration.\n\n        Any other severe underlying medical conditions, which could impair the ability to\n        participate in the study or the interpretation of its results.\n\n        Patients treated with potent CYP3A inhibitor unless it can be discontinued at least 2 weeks\n        prior to study treatment or 5 elimination half-life, whichever is the longest.\n\n        Patients treated with potent and moderate CYP3A inducers unless it can be discontinued at\n        least 2 weeks prior to study treatment or 5 elimination half-life, whichever is the\n        longest. Patients treated with weak CYP3A inducers such as dexamethasone are eligible.\n\n        Known hypersensitivity or any adverse event related to the study drug excipient.\n\n        Prior treatment with any compound in the same class. Mean QTc interval prolongation.\n\n        The above information is not intended to contain all considerations relevant to a patient's\n        potential participation in a clinical trial.
Inclusion criteria for the Phase 1:\n\n          1. Subjects must have a metastatic or unresectable locally advanced malignant solid\n             tumor, histologically confirmed by the Laboratory of Pathology, NCI. Efforts will be\n             made, as much as possible, to enroll subjects with tumor types with known increased\n             expression of CEA or MUC-1 (such as lung, breast, ovarian, prostate, colorectal,\n             pancreatic, bladder, gastric, cervix, etc.).\n\n          2. Subjects may have measurable or nonmeasurable but evaluable disease. Subjects with\n             surgically resected or ablated metastatic disease at high risk of relapse are also\n             eligible.\n\n             Prior therapy: Subjects must have completed or had disease progression on at least one\n             prior line of disease-appropriate therapy for locally advanced or metastatic disease,\n             or not be candidates for therapy of proven efficacy for their disease.\n\n          3. Subjects with EGFR or ALK genomic tumor aberrations should have disease progression on\n             FDA-approved therapy for these aberrations.\n\n          4. There should be a minimum of 4 weeks from any prior chemotherapy, immunotherapy and/or\n             radiation, with the exception of hormonal therapy for prostate and breast cancers,\n             HER2-directed therapy for HER2+ breast cancer (3+ IHC or FISH+), maintenance therapy\n             for colorectal or pancreatic cancer, and erlotinib in EGFR-mutated lung cancer under\n             the condition that subjects are on these therapies for at least two months before\n             start of trial treatment. There should be a minimum of 6 weeks from any prior antibody\n             therapies (such as ipilimumab or anti-PD1/PDL1) due to prolonged half-life.\n\n          5. Subjects must have recovered (Grade 1 or baseline) from any clinically significant\n             toxicity associated with prior therapy. Typically, this is 3-4 weeks for subjects who\n             most recently received cytotoxic therapy, except for the nitrosoureas and mitomycin C,\n             for which 6 weeks is needed for recovery.\n\n          6. Men or women, age ? 18 years.\n\n          7. Eastern Cooperative Oncology Group (ECOG) performance status ? 1 or Karnofsky ? 70%.\n\n          8. Subjects must have normal organ and marrow function as defined below\n\n             a. Serum creatinine ? 1.5 x upper limit of normal (ULN) OR creatinine clearance (CrCl)\n             ? 40 mL/min (if using the Cockcroft-Gault formula below): i. Female CrCl = [(140 - age\n             in years) x weight in kg x 0.85] / [72 x serum creatinine in mg/dL] ii. Male CrCl =\n             [(140 - age in years) x weight in kg x 1.00] / [72 x serum creatinine in mg/dL] b.\n             Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ? 3 x the ULN c.\n             Total bilirubin ? 1.5 x ULN OR in subjects with Gilbert's syndrome, a total bilirubin\n             ? 3.0 x ULN d. Hematological eligibility parameters (within 16 days of starting\n             therapy): i. Platelet count ? 100,000/µL ii. Absolute neutrophil count (ANC) ? 1/ µL\n\n          9. Subjects must have baseline pulse oximetry > 90% on room air.\n\n         10. The effects of CV301 on the developing human fetus are unknown. For this reason, women\n             of child-bearing potential (WOCBP) and men must agree to use adequate contraception\n             (hormonal or barrier method of birth control; abstinence) prior to trial entry and for\n             the duration of trial participation and for a period of 4 months after the last\n             vaccination therapy. Should a woman become pregnant or suspect she is pregnant while\n             she or her partner is participating in this trial, she should inform her treating\n             physician immediately.\n\n         11. Subjects with prostate cancer must continue to receive GnRH agonist therapy (unless\n             orchiectomy has been done).\n\n         12. Subjects must be able to understand and be willing to sign a written informed consent\n             document.\n\n        Inclusion criteria for the Phase 1b and Randomized Phase 2:\n\n          1. Histologically confirmed non-squamous NSCLC, metastatic or unresectable locally\n             advanced. Actionable EGFR mutations and ALK/ROS-1 translocations targetable with FDA\n             approved therapy must be evaluated and found not to be present by standard methods.\n             Expression of PD-L1 must have been determined with a validated method or tumor sample\n             must be available for PD-L1 expression determination.\n\n          2. Patient population:\n\n             • Phase 1b, Cohort 1 (Nivolumab + CV301): Patients with progression on or after prior\n             platinum, with or without switch maintenance chemotherapy are eligible\n\n             • Phase 1b, Cohort 2 and Phase 2 (Pembrolizumab + CV301): Patients must have been on\n             Pembrolizumab as first-line therapy for NSCLC as per FDA approved indications in first\n             line for at least 11 weeks and assessed by RECIST to have CR, PR, or SD at week 12\n             (+/- 1 week).\n\n             As of June 2017, FDA-approved indications for front-line treatment include 2\n             indications for Pembrolizumab:\n\n               -  As a single agent for the first-line treatment of patients with metastatic NSCLC\n                  whose tumors have high PD-L1 expression (Tumor Proportion Score (TPS) ?50%) as\n                  determined by an FDA-approved test, with no EGFR or ALK genomic tumor\n                  aberrations.\n\n               -  In combination with pemetrexed and carboplatin, as first-line treatment of\n                  patients with metastatic nonsquamous NSCLC. This indication is approved under\n                  accelerated approval based on tumor response rate and progression-free survival.\n                  Continued approval for this indication may be contingent upon verification and\n                  description of clinical benefit in the confirmatory trials.\n\n             Pemetrexed single agent maintenance after the initial 4 cycles of pemetrexed in\n             combination with carboplatinum and Pembrolizumab is allowed and optional as per\n             investigator or institutional standard practice.\n\n          3. In case of metastatic recurrence of a previous early stage NSCLC, any chemotherapy or\n             radiation therapy must have finalized more than 12 months before the start of the\n             first-line treatment, either Pembrolizumab alone or in combination with pemetrexed and\n             carboplatinum.\n\n          4. ECOG performance status 0 and 1.\n\n          5. Men or women, age ? 18 years\n\n          6. Have normal organ and marrow function as defined below:\n\n               -  Serum creatinine ? 1.5 x upper limit of normal (ULN) OR creatinine clearance\n                  (CrCl) ? 40 mL/min (if using the Cockcroft-Gault formula below):\n\n                  i. Female CrCl = [(140 - age in years) x weight in kg x 0.85] / [72 x serum\n                  creatinine in mg/dL] ii. Male CrCl = [(140 - age in years) x weight in kg x 1.00]\n                  / [72 x serum creatinine in mg/dL]\n\n               -  ANC > 1/µL\n\n               -  Platelets ? 100 000/µL\n\n               -  Hemoglobin > 9 g/dL\n\n               -  Total bilirubin ? 1.5 x institutional ULN or direct bilirubin < ULN if total\n                  bilirubin > 1.5-3.0 x ULN\n\n               -  AST/ALT < 2.5 × institutional ULN, or < 5 x ULN, if liver metastases are present\n\n          7. Have measurable disease by computed tomography (CT)/Magnetic resonance imaging (MRI)\n             per RECIST 1.1.\n\n          8. Willingness and ability to comply with scheduled visits, treatment plan, laboratory\n             tests, and other trial procedures.\n\n          9. Able to understand and be willing to sign a written informed consent document.\n\n         10. WOCBP must use appropriate method(s) of contraception. WOCBP should use an adequate\n             method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab\n             to undergo five half-lives) after the last dose of investigational drug (Phase 1b,\n             Cohort 1). WOCBP should use an adequate method to avoid pregnancy for at least 4\n             months (as per approved Pembrolizumab prescribing information) after the last dose of\n             investigational drug (Phase 1b, Cohort 2 and Phase 2).\n\n         11. Women of childbearing potential must have a negative serum or urine pregnancy test\n             (minimum sensitivity 25 IU/L or equivalent units of ?-human choriogonadotropin (HCG))\n             at screening. They must have confirmation by a negative urine pregnancy test within 24\n             hours prior to the first dose of Nivolumab (Phase 1b, Cohort 1), or within 24 hours\n             prior to the first dose of Pembrolizumab in the setting of this trial (Phase 1b,\n             Cohort 2 and Phase 2).\n\n         12. Men who are sexually active with WOCBP must use any contraceptive method with a\n             failure rate of less than 1% per year. Men receiving Nivolumab and who are sexually\n             active with WOCBP will be instructed to adhere to contraception for a period of 31\n             weeks after the last dose of investigational product. Women who are not of\n             childbearing potential (ie, who are postmenopausal or surgically sterile) as well as\n             azoospermic men, do not require contraception.\n\n         13. Subjects must have, prior to trial treatment, at least 10 unstained tissue slides (or\n             a tissue block from which 10 slides can be cut) from a prior biopsy or surgical\n             resection for submission for research purposes. Optional for Phase 1b. Mandatory for\n             Phase 2.\n\n        Exclusion Criteria:\n\n          1. Subjects with EGFR mutations, ALK or ROS-1 translocations candidates to targeted\n             therapy.\n\n          2. Squamous histology of NSCLC.\n\n          3. Other concurrent investigational agents (subjects are eligible to enroll 4 weeks after\n             completion of prior investigational agent).\n\n          4. More than 1 prior chemotherapy regimen for locally advanced or metastatic NSCLC with\n             the exception of the Phase 1 portion, in which multiple therapies are allowed in all\n             tumor types. Any prior chemotherapy regimen different from pemetrexed-carboplatinum in\n             combination with Pembrolizumab as first-line chemotherapy for candidates to\n             Pembrolizumab maintenance of first line (Phase 1b and Phase 2).\n\n          5. Concurrent chemotherapy or radiotherapy or other immunotherapy not explicitly allowed\n             by inclusion criteria for that phase of study.\n\n          6. Subjects treated with PD-1/L1 or any other experimental immunotherapeutic agents\n             outside the parameters established in the inclusion criteria, are excluded from\n             enrollment into Phase 1b and 2, but can be enrolled into Phase 1.\n\n          7. Other malignancy within last 5 years with an estimated risk of recurrence higher than\n             50%. Examples of low risk of recurrence malignancies are non-melanoma skin cancer, in\n             situ cervical, superficial bladder cancer, colorectal cancer stage I and II, breast\n             cancer stages I and II, prostate cancer stages I and II, etc.\n\n          8. Patients with metastatic lesions in the brain.\n\n          9. History of allergy or untoward reaction to prior vaccination with vaccinia virus,\n             aminoglycoside antibiotics or egg products; history of allergy to smallpox\n             vaccination.\n\n         10. Active infection within 72 hours prior to vaccination.\n\n         11. Subjects should have no known evidence of being immunocompromised as listed below:\n\n               1. Human immunodeficiency virus (HIV) positivity, chronic hepatitis infection,\n                  including B and C\n\n               2. Active, known or suspected autoimmune disease. Subjects are permitted to enroll\n                  if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to\n                  autoimmune condition only requiring hormone replacement, psoriasis not requiring\n                  systemic treatment, or conditions not expected to recur in the absence of an\n                  external trigger\n\n               3. Immunosuppressive therapy post-organ transplant\n\n               4. Asplenia is an exclusion for Phase 1b and Phase 2, but is not an exclusion for\n                  Phase 1.\n\n         12. Altered immune function, including, but not limited to: inflammatory bowel disease;\n             active infectious enteritis; eosinophilic enteritis; lupus erythematosus; ankylosing\n             spondylitis; scleroderma; multiple sclerosis. These criteria do not include all\n             diseases with an immune-related component, but are not auto-immune in nature or have a\n             primary alteration in the general immune function that may interfere with the vaccine\n             mechanism of action, for example celiac disease.\n\n         13. Concurrent chronic use of systemic steroids, except for physiologic doses of systemic\n             steroids for replacement, defined as 5 mg of prednisone per day or equivalent, or\n             local (topical, nasal, ophthalmic or inhaled) steroid use or prior concomitant use\n             with chemotherapy. Systemic steroids must have been discontinued ? 2 weeks prior to\n             randomization. Prior use of corticoids in short-term schemes (duration shorter than 3\n             days) for indications such as prophylaxis of reactions to intravenous contrast for\n             imaging studies or chemotherapy-related AEs are not considered part of this exclusion.\n             Prior use of corticoids for brain metastasis ending before day -14 is not considered\n             part of this exclusion criteria.\n\n         14. Subjects with interstitial lung disease that is symptomatic or may interfere with the\n             detection or management of suspected drug-related pulmonary toxicity.\n\n         15. Pregnant or breastfeeding women.\n\n         16. Clinically significant cardiomyopathy, coronary disease, heart failure New York Heart\n             Association class III or IV, or cerebrovascular accident within 1 year.\n\n         17. Uncontrolled intercurrent illness, which would interfere with the ability of the\n             subject to carry out the treatment program.\n\n         18. Any other condition, which would, in the opinion of the Principal Investigator or\n             Medical Monitor, indicate the subject is a poor candidate for treatment with CV301 or\n             would jeopardize the subject or the integrity of the data obtained.\n\n         19. Medical or psychological impediment to compliance with
Inclusion Criteria:\n\n        Locally advanced or metastatic NSCLC that has been cytologically or histologically\n        confirmed\n\n        ALK rearrangement based on FDA approved test (e.g. Vysis breakapart FISH or IHC using\n        Ventana)\n\n        ECOG PS ?2\n\n        Age of ? 18 years\n\n        Brain lesions may be used as target lesions if progressing, ?10mm in longest diameter and\n        if they were not previously treated with any of the following:\n\n          -  Whole brain radiation therapy (WBRT) within 3 months\n\n          -  Stereotactic radiosurgery (SRS)\n\n          -  Surgical resection Availability of core biopsy of progressive lesion taken within 60\n             days prior to D1 of treatment under study therapy or willing to undergo tumor biopsy:\n             NOTE:. All subjects must consent to provide tumor blocks or slides.\n\n          -  If archival tissue is not available and biopsies to obtain fresh tumor tissue cannot\n             be performed with minimal risk to the subject, subjects may be permitted to enroll on\n             the study with prior approval of the Study PI.\n\n          -  In the situation the patient undergoes biopsy within 60 days prior to D1. and there is\n             insufficient tumor tissue subjects for the correlative science part of the protocol\n             patient will be permitted to enroll on the study with prior approval of the study PI\n\n          -  In the situation the patient undergoes molecular testing or next-generation sequencing\n             as part of standard care there must be sufficient tumor sample available for\n             participation in the study (i.e. a next generation sequencing report is not sufficient\n             for enrollment)\n\n        Recovered from toxicities related to prior anticancer treatment to ?Grade 2 or baseline\n        with the exception of alopecia\n\n        Have normal QT interval on ECG evaluation QT corrected Fridericia (QTcF) of ? 450 ms in\n        males or ? 470 ms in females\n\n        Adequate organ function defined as:\n\n        Absolute neutrophil count (ANC) ?1500/µL Platelets ?75,000/µL Hemoglobin? 10g/dL AST /ALT ?\n        2.5 x upper limit of normal (ULN); ? 5 x ULN if liver metastasis Total serum bilirubin ?\n        1.5 x ULN Serum creatinine ? 1.5 x UNL Serum amylase ? 1.5 x UNL\n\n        At least 1 measurable lesion per RECIST version 1.1\n\n        Negative serum pregnancy test within 7 days of D1 of treatment in women of child bearing\n        potential (WOCBP)\n\n        If fertile, willing to use highly effective form of contraception (defined as a combination\n        of at least two of the following methods: condom or other barrier methods, oral\n        contraceptives, implantable contraceptives, intrauterine devices) during the dosing period\n        and for at least 4 months after\n\n        Ability to provide signed informed consent and willing and able to comply with all study\n        requirements\n\n        Inclusion criteria for cohort assignment:\n\n        Cohort A: Progressive disease on any next generation ALK inhibitor except first line\n        alectinib or brigatinib (any line)\n\n        Cohort B: Progressive disease on first-line therapy with alectinib, and no other ALK\n        inhibitors\n\n        Cohort C: Previous treatment brigatinib at 180 mg daily for ?4 weeks without > grade 2\n        drug-related toxicities and with radiographic evidence of progressive disease and no\n        intervening systemic therapies such as chemotherapy, immunotherapy or another ALK inhibitor\n        (radiation therapy allowed as intervening therapy). Patients who are treated on cohorts A\n        and B will be allowed to enroll in cohort C if the meet the inclusion and exclusion\n        criteria\n\n        Exclusion Criteria for cohorts A, B, and C:\n\n        Patients meeting any of the following exclusion criteria will not be able to participate in\n        this study:\n\n        History or the presence of pulmonary interstitial disease, drug-related or immune-related\n        pneumonitis, or radiation pneumonitis requiring medical management within 6 months of trial\n        enrollment\n\n        Prior treatment with brigatinib for cohorts A and B\n\n        History of or active significant gastrointestinal (GI) bleeding within 3 months\n\n        Malabsorption syndrome or other GI illness that could affect oral absorption of the study\n        drug\n\n        Received cytotoxic chemotherapy, investigational agents or radiation within 7 days prior to\n        D1 of study treatment\n\n        Received prior ALK TKI therapy within 7 days prior to D1 of treatment under study drug. 7\n        day wash out period is required after prior ALK inhibitor treatment.\n\n        Have significant, uncontrolled, or active cardiovascular disease, specifically including,\n        but not restricted to:\n\n          -  Myocardial infarction (MI) within 6 months of trial enrollment\n\n          -  Unstable angina within 6 months of trial enrollment\n\n          -  Congestive heart failure (CHF) with 6 months prior to trial enrollment\n\n          -  Any history of ventricular arrhythmia\n\n          -  Cerebrovascular accident or transient ischemic attack within 6 months of D1 of study\n             treatment\n\n          -  Clinically significant atrial arrhythmia or severe baseline bradycardia defined as\n             resting heart rate < 60 beat per minute\n\n          -  Uncontrolled hypertension defined as baseline SBP> 160 and DBP > 100 on 3 separate\n             clinic visits or past history of hypertensive urgency, emergency or encephalopathy\n\n        Have been diagnosed with another primary malignancy within the past 3 years (except for\n        adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer,\n        which are allowed within 3 years)\n\n        Have symptomatic CNS metastases which require an increasing dose of corticosteroids within\n        the last 2 weeks to remain asymptomatic.\n\n        Have active infection requiring intravenous antibiotics\n\n        Pregnant or breastfeeding\n\n        Have any condition or illness that, in the opinion of the investigator, would compromise\n        patient safety or interfere with evaluation of the study drug.
Inclusion Criteria:\n\n          -  Eligible patients will be considered for inclusion if they meet all of the following\n             criteria. (All necessary baseline studies for determining eligibility must be obtained\n             within 21 days prior to enrollment.)\n\n               1. Male or female patient who is at least 18 years of age.\n\n               2. Patient has given voluntary written informed consent before performance of any\n                  study-related procedures not part of standard (non-investigational) medical care.\n\n               3. Patient has been previously diagnosed with MM based on standard criteria.\n\n               4. Patient has received:\n\n                    1. At least 2 prior therapies including a proteasome inhibitor (? 2 cycles) and\n                       lenalidomide (? 2 cycles), and\n\n                    2. Has achieved at least stable disease (SD) for ? 1 cycle of treatment on ? 1\n                       prior treatment, and\n\n                    3. Has demonstrated disease progression subsequent to treatment, during or\n                       within 90 days following completion of the most recent therapy.\n\n               5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status score\n                  ? 2.\n\n               6. Patient has measurable disease defined as at least 1 of the following:\n\n                    1. Serum M protein ? 0.5 /dL (?5 g/L)\n\n                    2. Urine M protein ? 200 mg/24 hours\n\n                    3. Serum free light chain (FLC) assay: Involved FLC assay ?10 mg/dL (?100 mg/L)\n                       and an abnormal serum FLC ratio (<0.26 or >1.65)\n\n               7. Clinical Laboratory Inclusion Criteria: The following laboratory results must be\n                  met within 14 days (or as stipulated) prior to study drug (treatment)\n                  administration:\n\n                    1. Absolute neutrophil count (ANC) ? 1000 cells/?l (growth factor cannot be\n                       used within the previous 7 days).\n\n                    2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2.5 ×\n                       upper limit of normal (ULN).\n\n                    3. Platelet count ? 50,000/?l (without platelet transfusion in the previous 7\n                       days).\n\n                    4. Total bilirubin ? 1.5 mg/dL.\n\n                    5. Serum creatinine ? 2.0 mL/dL and creatinine clearance ? 40 mL/min\n                       (calculated by the Cockcroft-Gault Equation or per 24 hour urine\n                       collection).\n\n                    6. Serum albumin ? 3.2 g/dL in the absence of receipt of (IV) albumin within\n                       the previous 72 hours.\n\n                    7. Serum creatine phosphokinase (CPK) ? 2.5 × the ULN.\n\n                    8. Serum calcium (corrected for albumin) level at or below the ULN range\n                       (treatment of hypercalcemia is allowed and patient may enroll if\n                       hypercalcemia returns to normal range with standard treatment).\n\n               8. Left ventricular ejection fraction (LVEF) ? institutional lower limit of normal\n                  as measured by multigated acquisition scan (MUGA) scan or 2-dimensional\n                  echocardiography (ECHO) within 28 days prior to start of therapy and no\n                  clinically significant abnormalities on a 12-lead electrocardiogram (ECG).\n\n               9. Females of childbearing potential (FCBP)* must have a negative serum or urine\n                  pregnancy test prior to initiation of the SL-401 Run in Cycle (if required) and\n                  repeated with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to\n                  and again within 24 hours of starting Pomalidomide and must either commit to\n                  continued abstinence from heterosexual intercourse or begin 2 acceptable methods\n                  of birth control, 1 highly effective method and 1 additional effective method at\n                  the same time, at least 28 days before she starts taking Pomalidomide through 30\n                  days after the last dose of Pomalidomide and 60 days after the last dose of\n                  SL-401. FCBP must also agree to ongoing pregnancy testing during the entire\n                  duration of treatment. Men must agree to use a latex or synthetic condom during\n                  sexual contact with a FCBP even if they have had a vasectomy from the time of\n                  signing the informed consent form through 60 days after the last dose of\n                  Pomalidomide or SL-401. These same patients must not donate sperm. All patients\n                  must be counseled at a minimum of every 28 days about pregnancy precautions and\n                  risks of fetal exposure. All patients enrolled into this study, must agree to be\n                  registered in and must comply with all requirements of the Pomalidomide REMS(TM)\n                  program.\n\n                    -  An FCBP is a sexually mature female who: 1) has not undergone a hysterectomy\n                       or bilateral oophorectomy; or 2) has not been naturally postmenopausal for\n                       at least 24 consecutive months (i.e., has had menses at any time in the\n                       preceding 24 consecutive months).\n\n        Exclusion Criteria:\n\n        Patients will be ineligible for this study if they meet any 1 of the following criteria:\n\n          1. The patient has an active malignancy and/or cancer history that may confound the\n             assessment of the study endpoints. Patients with a past cancer history (within 2 years\n             of entry) with substantial potential for recurrence and/or ongoing active malignancy\n             must be discussed with the Sponsor before study entry. Patients with the following\n             neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ\n             (including superficial bladder cancer), cervical intraepithelial neoplasia,\n             organ-confined prostate cancer with no evidence of progressive disease.\n\n          2. Prior therapy with SL-401 or received any investigational drug within the prior 30\n             days or 5 half-lives of the investigational drug, whichever is longer.\n\n          3. Prior anti-cancer therapy (chemotherapy, targeted agents, radiotherapy, and\n             immunotherapy) within the prior 14 days except for alkylating agents (e.g., melphalan)\n             within the prior 28 days.\n\n          4. POM-refractory disease (i.e., non-responsive to prior POM [either as monotherapy or in\n             combination] or relapse/progressive disease within 60 days of prior POM (either as\n             monotherapy or in combination). Prior POM exposure is permitted, provided the\n             patient's MM is not considered POM-refractory as defined above.\n\n          5. Primary refractory MM defined as disease that is non-responsive in patients that have\n             never achieved at least stable disease or better with any therapy.\n\n          6. Any > grade 1 (according to the National Cancer Institute [NCI] Common Terminology\n             Criteria for Adverse Events [CTCAE], v.4.03) adverse reaction unresolved from previous\n             treatments or not readily managed and controlled with supportive care. The presence of\n             alopecia of any grade and peripheral neuropathy ? grade 2 without pain is allowed.\n\n          7. Previous allogeneic stem cell transplantation with active graft-versus-host-disease,\n             or treatment with immunosuppressive therapy in the 2 months prior to study entry.\n\n          8. Daily requirement for corticosteroids >10 mg prednisone daily (or equivalent); inhaled\n             corticosteroids are permitted.\n\n          9. Patient is known to be human immunodeficiency virus positive, or have chronic or\n             active hepatitis B (core- or surface antigen-positive) or active hepatitis C\n             infection.\n\n         10. Clinically significant cardiovascular disease (e.g., uncontrolled or any New York\n             Heart Association [NYHA] Class 3 or 4, congestive heart failure, uncontrolled or\n             unstable angina, history of myocardial infarction or stroke within 6 months prior to\n             study entry, uncontrolled hypertension or clinically significant arrhythmias not\n             controlled by medication)\n\n         11. Uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive\n             pulmonary disease, pulmonary hypertension) that in the opinion of the Investigator\n             would put the patient at significant risk for pulmonary complications during the\n             study.\n\n         12. Uncontrolled intercurrent illness including, but not limited to, uncontrolled\n             infection, disseminated intravascular coagulation, or psychiatric illness/social\n             situations that would limit compliance with study requirements.\n\n         13. History of erythema multiforme or severe hypersensitivity to prior Immunomodulatory\n             Drugs (IMiDs) such as thalidomide and lenalidomide.\n\n         14. The patient is receiving medications that are strong inhibitors of CYP1A2. Patients\n             should have discontinued strong CYP1A2 inhibitors (e.g., ciprofloxacin and\n             fluvoxamine) at least 5 half-lives before beginning study drug.\n\n         15. The patient continues to smoke cigarettes, which can induce CYP1A2.\n\n         16. Inability to tolerate thromboprophylaxis.\n\n         17. Pregnant or breast feeding. -
Key Inclusion Criteria [(Non-Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL)]:\n\n          1. Have documented CD20+ B-cell NHL or documented HL, with active disease that is either\n             not responsive to or relapsed after prior therapy, for whom no standard of care\n             options exists.\n\n          2. Must have at least 1 bi-dimensionally measurable lesion (?1.5 cm) documented by\n             diagnostic imaging (CT, PET-CT or MRI).\n\n          3. Eastern Cooperative Oncology Group (ECOG) performance status ?1\n\n          4. Life expectancy of at least 6 months\n\n          5. Adequate bone marrow function\n\n          6. Adequate organ function\n\n          7. Willing and able to comply with clinic visits and study-related procedures\n\n          8. Provide signed informed consent\n\n        Key Exclusion Criteria (NHL and HL):\n\n          1. Primary central nervous system (CNS) lymphoma, or known or suspected CNS involvement\n             by nonprimary CNS NHL\n\n          2. History of or current relevant CNS pathology\n\n          3. Ongoing or recent (within 2 years) evidence of significant autoimmune disease that\n             required treatment with systemic immunosuppressive treatments, which may suggest risk\n             for iAEs\n\n          4. Prior allogeneic stem cell transplantation\n\n          5. Prior treatment with an agent that blocks the programmed death-1/ programmed\n             death-ligand 1 (PD-1/PD-L1 pathway), unless benefit was demonstrated\n\n          6. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or\n             hepatitis C infection or other uncontrolled infection\n\n          7. History of hypersensitivity to any compound in the tetracycline antibiotics group\n\n          8. Known hypersensitivity to both allopurinol and rasburicase\n\n          9. Pregnant or breastfeeding women\n\n         10. Continued sexual activity in men or women of childbearing potential who are unwilling\n             to practice adequate contraception during the study\n\n         11. Prior treatment with idelalisib
Inclusion Criteria:\n\n        Main inclusion criteria all patients, Part 1 and Part 2:\n\n          -  Male or female, at least 18 years of age at the time of informed consent\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1\n\n          -  Life expectancy >3 months assessed during Screening\n\n          -  Documented (histologically- or cytologically-proven) solid tumor malignancy that is\n             locally advanced or metastatic, and that is refractory to standard therapy or for\n             which no standard therapy is available or accessible\n\n          -  Tumor documented to be KRAS WT by local assessment (i.e. the tumor must express the\n             KRAS WT, exon 2, 3 and 4)\n\n        Additional main inclusion criteria applicable to Part 2 ONLY:\n\n          -  Measurable disease according to RECIST v1.1 that has been confirmed by computed\n             tomography (CT) or magnetic resonance imaging (MRI) within 4 weeks prior to Cycle\n             1/Day 1 (C1/D1)\n\n          -  Tumor documented to be KRAS WT by local assessment according to institutional\n             standards.\n\n          -  Basket Cohort ONLY:\n\n               -  Confirmed MET-amplification by local assessment\n\n               -  No prior therapy with MET-targeting agents (except a subset of patients having\n                  received prior therapy with a MET-targeting TKI)\n\n               -  Willingness to undergo a pre- and post-dosing biopsy (maximum of 2 biopsies) from\n                  primary or metastatic tumor site(s) considered safely accessible for biopsy\n\n          -  NSCLC Cohort ONLY:\n\n               -  Documented METex14 mutations (patients need not be MET-amplified and may have\n                  received prior therapy with a MET-targeting TKI). Patients with malignancies\n                  other than NSCLC may be considered for entry to this cohort following discussion\n                  with the Sponsor's Medical Monitor(s).\n\n        Exclusion Criteria:\n\n        Main exclusion criteria all patients, Part 1 and Part 2:\n\n          -  Any antineoplastic agent for the primary malignancy (standard or investigational)\n             without delayed toxicity within 4 weeks or 5 plasma half-lives, whichever is shortest,\n             prior to C1/D1, except: nitrosoureas and mitomycin C within 6 weeks prior to C1/D1\n\n          -  Immunosuppressive or systemic hormonal therapy within 2 weeks prior to C1/D1 with\n             specified allowed exceptions\n\n          -  Use of hematopoietic growth factors within 2 weeks prior to C1/D1\n\n          -  Active second malignancy or history of another malignancy within the last 3 years,\n             with specified allowed exceptions\n\n          -  Central nervous system (CNS) malignancy including primary malignancies of the CNS\n             and/or known, untreated CNS or leptomeningeal metastases, or spinal cord compression;\n             patients with any of these not controlled by prior surgery or radiotherapy, or\n             symptoms suggesting CNS involvement for which treatment is required\n\n          -  Inadequate recovery from an acute toxicity associated with any prior antineoplastic\n             therapy\n\n          -  Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery from any\n             prior surgical procedure\n\n          -  Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within\n             1 month prior to C1/D1, unless adequately treated and stable\n\n          -  Active uncontrolled bleeding or a known bleeding diathesis\n\n          -  Significant cardiovascular disease or condition\n\n          -  Abnormal hematologic, renal or hepatic function\n\n        Additional main exclusion criteria applicable to Part 2 ONLY:\n\n          -  Prior therapy with MET-inhibiting agents (exceptions will be a subset of patients that\n             will be entered to the Basket Cohort after having received prior therapy with a\n             MET-targeting TKI, and patients entered to the NSCLC Cohort who may have received\n             prior therapy with a MET-targeting TKI)\n\n          -  Prior therapy with antibody to hepatocyte growth factor (HGF)\n\n          -  Basket Cohort ONLY: Tumor status demonstrating MET-polysomy in the absence of\n             MET-amplification, as specified. Patients in the NSCLC Cohort with polysomy are\n             eligible.\n\n          -  Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless there is\n             documented progression of the lesion following the radiotherapy
Participant agrees not to participate in another interventional study while on treatment. Randomization Inclusion Criteria
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while receiving study drug and participating in the present study.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
Subject agrees not to participate in another interventional study while on treatment.
TURNSTILE I - SCREENING:
TURNSTILE II - TREATMENT:
TURNSTILE I - SCREENING
TURNSTILE II - TREATMENT
Patients must have a lesion amenable to resection for the generation of TIL (Turnstile I)
Patients receiving cytotoxic agents will be evaluated by the PI or his designee for eligibility suitability (Turnstile I)
Patients must have adequate TIL available (Turnstile II); pre-rapid expansion procedure (Pre-REP) TIL generated in the similar clinical trial 2004-0069 may also be utilized for Turnstile II
Patients must have at least one biopsiable measurable metastatic melanoma, lesion > or = to 1 cm (Turnstile II)
Patients may have brain lesions =< 1 cm each; the PI or designee will approve the treatment (Turnstile II)
Clinical performance status of ECOG 0-2 within 30 days of signing informed consent (Turnstile II)
Hemoglobin greater than or equal to 8.0 g/dl (Turnstile II)
Serum creatinine less than or equal to 1.6 mg/dl (Turnstile II)
MRI/CT/PET of the brain within 30 days of lymphodepletion (Turnstile II)
Patients who are pregnant or nursing (Turnstile I)
Women who are pregnant will be excluded (Turnstile II)
TURNSTILE I INCLUSION CRITERIA:
Patients must have a lesion amenable to resection for the generation of TIL (Turnstile I)
Patients must have adequate TIL available (Turnstile II)
Patients must have at least one biopsiable and measurable metastatic melanoma lesions >= 1 cm (Turnstile II)
Patients may have brain lesions which measure =< 1 cm each (Turnstile II)
Pregnancy testing will be performed within 14 days prior to treatment (Turnstile II)
Clinical performance status of ECOG 0-2 within 14 days of lymphodepletion (Turnstile II)
Hemoglobin greater than or equal to 8.0 g/dl (Turnstile II)
Serum creatinine less than or equal to 1.6 mg/dl (Turnstile II)
Patients who are pregnant or nursing (Turnstile I)
Has had prior systemic cancer therapy within the past four weeks at the time of the start of the lymphodepletion regimen (Turnstile II)
Women who are pregnant will be excluded (Turnstile II)
Patients must be HLA-A2 for cohort A (Turnstile II-Chemotherapy/Cell Infusion-Inclusion Criteria)
Patients must have adequate TIL available (Turnstile II)
Patients must have measurable metastatic melanoma (Turnstile II - Chemotherapy/Cell Infusion -Inclusion Criteria)
Pregnancy testing will be performed within 7 days prior to treatment (Turnstile II)
Clinical performance status of ECOG 0 - 2 at the time of chemotherapy infusion (Turnstile II - Chemotherapy/Cell Infusion - Inclusion Criteria)
Absolute neutrophil count greater than or equal to 750/mm^3 (Turnstile II - Chemotherapy/Cell\r\nInfusion- Inclusion Criteria)
Platelet count greater than or equal to 75,000/mm^3 (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria)
Hemoglobin greater than or equal to 8.0 g/dl (Turnstile II - Chemotherapy/Cell Infusion)
Serum alanine aminotransferase (ALT) less than three times the upper limit of normal (Turnstile II - Chemotherapy/Cell Infusion- Inclusion Criteria)
Serum creatinine less than or equal to 1.6 mg/dl (Turnstile II - Chemotherapy/Cell Infusion-Inclusion Criteria)
Is not receiving B-RAF treatment (Cohort C) (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
Women who are pregnant or nursing will be excluded (Turnstile II - Chemotherapy/Cell Infusion Exclusion Criteria)
{Turnstile 
{Turnstile 
{Turnstile 
{Turnstile 
{Turnstile 
{Turnstile 
{Turnstile 
{Turnstile 
{Turnstile 
(Turnstile 1 & Turnstile 2) Willing and able to give informed consent.
Patients treated with prior surgery are eligible for this study if they otherwise meet eligibility criteria
Patients with INRG stage L2 tumors without amplification of MYCN regardless of tumor histology (may meet criteria for may meet criteria for high risk classification but are not eligible for this trial)
Note: Patients diagnosed with anaplastic large cell lymphoma (ALCL) harboring a gene rearrangement of interest may be eligible provided they meet all other inclusion/exclusion criteria
Patients crossing over from monotherapy to combination therapy do not have to be fully rescreened; however, they do need to meet performance status, organ function, and blood parameters and not meet any of the exclusion criteria
Please note: patients who do not meet the above criteria because of Gilbert’s syndrome are still eligible
Patients must meet the following laboratory criteria:
Patients screened for this trial should be expected to meet the criteria for treatment
Subjects with treated brain metastases are eligible provided they meet the following criteria:
Grade I meningiomas will be allowed as long as they meet criteria for progression
To be eligible for participation in the study, patients must meet all of the following inclusion criteria:
Patients with brain metastases unless they meet the criteria
Patients must meet ONE of the criteria outlined in either a, b, c OR d:
Participant must meet the following criteria as indicated on the clinical laboratory tests:
Each patient must meet the following criteria:
Patients must not meet any of the following criteria:
Patients who do not meet inclusion criteria
NOTE: Patients are expected to initiate therapy as close to day +100 as possible; no patient may initiate therapy before day +70 and initiation of therapy beyond day +130 is allowed ONLY for patients who meet all eligibility criteria except for hematologic parameters, in which case patients may be delayed until their hematologic laboratories meet criteria but no later than day +180; regardless of the time of therapy initiation, patients must meet all eligibility criteria and must have completed all consent documentation and screening procedures within the specified window
DONOR: Failure to meet institutional criteria for stem cell donation
Patient has a WHO performance status 0-2. Patients in Arm 1 to 4 must also meet the following inclusion criteria:
Meet standard criteria for RIT:\r\n* < 25% marrow involvement with FL\r\n* No evidence of myelodysplasia
Must meet the following clinical laboratory criteria at study entry:
Patients who have had brain metastases unless they meet the criteria.
Note: Hematology and other lab parameters that are =< grade 2 but still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy.
Failure to meet any of the criteria set forth in the inclusion criteria section
Meet the following disease activity criteria:
All patients must meet the following inclusion and exclusion criteria; NO EXCEPTIONS WILL BE GIVEN
Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 4 weeks before obtaining sample
Subjects who fail to meet the above criteria
Patients must meet eligibility in at least 1 of the following 6 groups:
LYMPHODEPLETION: Subjects must have autologous transduced activated T-cells that meet the certificate of analysis (CofA) acceptance criteria
Subjects must meet all of the following criteria to be included in this study:
Subjects who meet any of the following criteria will be excluded from this study:
Each patient must be positive for HLA-A*02 and meet all of the following inclusion criteria to be enrolled in the study
Patients must have baseline evaluations performed prior to the first dose of study drug and must meet all inclusion and exclusion criteria
Must meet one or more of the consensus criteria for initiating treatment MM Participants:
Lysate must meet release criteria
Subject for whom tumor lysate does not meet release criteria
Patients are required to meet the following criteria to proceed to AHSCT:
Osteosarcoma participants receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet only Inclusion Criteria Numbers 6 through 17 (after progression in Cohort 2B).
Osteosarcoma participants receiving combination therapy of lenvatinib with ifosfamide and etoposide should meet all the exclusion criteria, with the exception of Criterion Number 6.
Patients are required to meet criteria for initiation of therapy for their B-NHL according to published guidelines by the National Comprehensive Cancer Network (NCCN)
Meet criteria for a current major depressive episode or suicidality
Patients must meet the following clinical criteria to receive CMVpp65-CTL infusions
Patient does not meet the requirements for prior ipilimumab treatment listed in inclusion above
Patients who have had prior treatment with 131I-MIBG who do not meet the re-treatment criteria
Patients must meet IWCLL 2008 Guideline [13] criteria for active disease requiring treatment. Each patient with NHL must meet all of the following inclusion criteria to be enrolled on the study:
Patients must have relapsed or refractory disease after at least one prior therapy and not have traditional options available or decline these. All patients must meet all of the following inclusion criteria to be enrolled on the study:
Central nervous system (CNS) metastases which do not meet the criteria outlined in the inclusion criteria
Note: patients enrolled after chemotherapy do not have to meet the above criteria
Must meet the following laboratory criteria:
Failure to meet inclusion criteria;
Females who are of childbearing potential must practice effective contraception and meet the following criteria:
Must meet following requirements:
patients with CRPC must meet PCWG3 criteria for disease progression at trial entry
Female patients are eligible for the study if they meet the following criteria:
Note: Hematology and other lab parameters that are ? grade 2 BUT still meet criteria for study entry are allowed; furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy
Subjects must have adequate renal, hepatic and bone marrow function based on screening laboratory assessments. Baseline hematologic studies and chemistry and coagulation profiles must meet the following criteria:
DONOR: Failure to meet institutional criteria for donation as described in the Standard Practice Guidelines
Patients with prior progressive disease who do not meet criteria above, are eligible as long as they have not been off treatment for > 3 months prior to enrollment on NANT 2011-04
Subjects must meet certain laboratory criteria
Central nervous system (CNS) metastases which do not meet the criteria outlined in inclusion criteria
Biopsy does not meet inclusion criteria
PHASE II: For participation in the imaging research studies, patients must meet the additional following criteria:
-\n\n        All patients must meet the following inclusion criteria:\n\n          1. Metastatic or unresectable locally advanced NSCLC\n\n          2. Evidence of a tumor with one or more EGFR mutations excluding exon 20 insertion\n\n          3. Biopsy of either primary or metastatic tumor tissue within 60 days of dosing\n\n          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1\n\n          5. Minimum age of 18 years\n\n          6. Adequate hematological and biological function\n\n          7. Written consent on an IRB/IEC-approved Informed Consent Form (ICF) prior to any\n             study-specific evaluation\n\n        Phase 2 Cohorts must also meet the following inclusion criteria:
Patients should not meet criteria for post PV or post ET-myelofibrosis (MF)
Patients should not meet criteria for post PV or post ET-myelofibrosis (MF)
Subject must meet the following criteria as indicated on the clinical laboratory tests:
NSCLC patients must meet criteria for MET and/or Axl expression or,
HNSCC patients must meet criteria for MET and/or Axl expression or,
Patients must meet pre-entry requirements
The patient must meet one of the following (a) or (b) or (c):
The patient must meet one of the following (a) or (b) or (c):
Meet baseline laboratory data criteria
Must meet all inclusion criteria defined in main study and in addition the following criteria must be met:
Part 1 Dose Escalation subjects must meet 1 of the following criteria:
Part 2 Dose Expansion subjects must meet 1 of the following criteria:
Laboratory tests must meet minimum safety requirements
Patients who do not meet parent protocol criteria to continue study treatment.
Patients must meet the following laboratory criteria at screening:
Patients with prior radiation therapy are eligible if they meet the following criteria:
Subjects in the combination therapy cohorts must meet the above inclusion criteria and be eligible to receive paclitaxel or FOLFIRI per most current prescribing information, or at the discretion of the Investigator.
Subjects enrolled on the combination therapy phase must not meet the above exclusion criteria and must be eligible to receive paclitaxel or FOLFIRI per most current prescribing information, or at the discretion of the Investigator.
Successful T cell test expansion (to be performed as part of inclusion criteria until 3 subjects meet all enrollment criteria)
Patients are permitted to washout current drug therapy to meet these entry criteria if they have a known diagnosis of Cushing's disease.
Subject must meet the following criteria as indicated on the clinical laboratory tests:
Patients must meet the following laboratory criteria:
Note: Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, be initiated on study treatment; there can be no exceptions to this rule, although during protocol development, discussions about certain criteria are possible and may be amended, depending on new data and specific study requirements; where patients that do not meet the inclusion criteria are incorrectly started on treatment, or where patients subsequently fail to meet the study criteria post initiation, the investigator should inform the AZD2014 team immediately; the AZD2014 team is to ensure all such contacts are appropriately documented
Subjects must meet the following criteria:
Must meet the following clinical laboratory criteria at study entry:
Must meet one of the following two criteria:
Baseline hematologic studies and chemistry profiles must meet the following criteria:
Patients must meet all of the following criteria to be enrolled in the study:
Subject must meet the following criteria as indicated on the clinical laboratory tests.
Patients failing to meet the inclusion criteria
Central nervous system (CNS) metastases which do not meet the criteria outlined in inclusion criteria
Failure to meet any of the criteria set forth in inclusion
Lysate must meet release criteria
Subject for whom tumor lysate does not meet release criteria
Patients must meet the following laboratory criteria:
Adequate hematologic function Arm A (except for CLL subjects with significant BM involvement by biopsy) must meet the following criteria:
Platelet count ? 75,000/mm3 Arms B, C, and D must meet the following criteria:
CRITERIA FOR RANDOMIZATION\r\n* Participants must meet the following criteria to qualify for HD-ADE versus Clo/AraC randomization; participants who do not meet these criteria may still be enrolled, but will be treated on HD-ADE arm and will NOT be randomized
LOW RISK MEDULLOBLASTOMA (patients must meet all of the following criteria):
Patients less than 3 years of age at diagnosis must meet one of the two following criteria:
DONOR: Failure to meet FHCRC criteria for stem cell donation
DONOR: Failure to meet institutional criteria for donation as described in the Standard Practice Guidelines
Central nervous system (CNS) metastases which do not meet the criteria outlined in the inclusion criteria
Patients must meet diagnostic criteria for NF2 including presence of bilateral VS (10 patients) or idiopathic VS without evidence of genetic syndrome (10 patients)
Patients must meet laboratory, and bone marrow histological criteria for primary myelofibrosis as defined by World Health Organization (WHO) diagnostic criteria as follows: WHO diagnostic criteria for PMF Proposed Criteria for PMF Major Criteria
Subjects in Cohort 2 of Arm C must meet the following criteria:
Participant must meet at least one of the following criteria in the judgment of the investigator or sub-investigator:
Central nervous system (CNS) metastases which do not meet the criteria outlined in inclusion criteria
ALC ? 900/?l (Note: Patients with AML are not required to meet these hematologic criteria).
Cardiac Exclusion Criteria: Patients will be excluded if these meet any of the following:
Prior therapy must meet all of the following criteria:
For leukapheresis, patients must meet the following criteria (any exceptions to this will require prior approval by the apheresis director and principal investigator [PI]):
Patients who do not meet the above inclusion criteria will not receive leukapheresis
Subjects who fail to meet the above criteria
Subject must meet the following criteria as indicated on the clinical laboratory tests*:
Meet all eligibility criteria with the exception of:\r\n* Prior therapy with trametinib will be permitted\r\n* All laboratory parameters must be met as outlined except for ALT and total bilirubin, which must meet criteria for continued therapy\r\n* Patients who are eligible for cross-over will not need to undergo another ophthalmologic examination
Specifically, subjects must meet one or more of the following criteria:
Patients must meet one or more of the following indications for treatment:
Patients must have at least ONE of the following (lesions may have received prior radiation therapy as long as they meet the other criteria listed below):
Patients with known bone marrow metastatic disease will be eligible for study as long as they meet hematologic function criteria above.
Patients eligible for HSCT at the time of screening. However, patients who meet one or both of the following criteria may be eligible for study participation:
Meet at least one of the criteria below:
Patients must meet criteria for acute lung injury
Failure to meet any of the criteria set forth in Section 3.1.
Must meet all inclusion and exclusion criteria
Patients previously treated with carfilzomib are eligible as long as they meet the following criteria:
Patients must meet pre-entry requirements
Usability Test interview participants must meet criteria above and may also include patients who have undergone one or more cycles of treatment
Patient’s disease status should meet criteria as outlined by institutional master protocol
Patients on full dose anticoagulants (e.g., warfarin or LMW heparin) must meet both of the following criteria:
If they are not patients of Massey Cancer Center or do not meet the inclusion criteria listed above
Meet all screening requirements
Meet screening criteria
Children who do not meet the above criteria
Meet screening criteria
Meet all inclusion criteria above
Patients are to be excluded from randomization for Aim 2 of this study if they meet any of the following criteria:
Subjects with bilateral disease are eligible if they meet other eligibility criteria
Patients who will be enrolled on the observational arm should meet the 2nd, 3rd, and 4th inclusion criteria only
Patients who will be enrolled on the observational arm should not meet the 3rd and 4th exclusion criteria only
meet diagnostic criteria for chronic insomnia (i.e., lasting for at least one month)
DONOR: Failure to meet Fred Hutchinson Cancer Research Center (FHCRC) or local criteria for stem cell donation
If women have had a hysterectomy and still have their ovaries, they must meet the FSH criteria described above
GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all subprotocol criteria at time of enrollment onto the APEC1621 screening protocol, but will need to meet all criteria prior to enrollment on any assigned treatment subprotocol; patients must be enrolled onto a subprotocol within 8 weeks (56 days) of treatment assignment
Participants must meet any one of the following 6 criteria:
Laboratory (lab) results do not meet inclusion criteria
Any lab results that do not meet inclusion criteria after the Screen 1 blood tests
IF PROTOCOL 2546 SERVES AS AN ADJUNCT PROTOCOL, THE PATIENTS ONLY NEEDS TO MEET INCLUSION CRITERIA 1 THROUGH 5A
IF PROTOCOL 2546 SERVES AS AN ADJUNCT PROTOCOL, THE PATIENT ONLY NEEDS TO MEET EXCLUSION CRITERIA 1 THROUGH 3
DONOR: Failure to meet local criteria for stem cell donation
Subject presenting with bilateral breast cancer may be enrolled if BOTH cancers meet all of the inclusion and none of the exclusion criteria
Use of antidepressants is permitted if dose has been the same for at least 12 weeks prior to study entry if patient still DOES NOT meet exclusion criteria #3
Patients failing to meet the inclusion criteria
Subjects who do not meet the above mentioned inclusion criteria
Patients with a locoregional tumor recurrence following surgery will be eligible provided they meet other eligibility criteria
Patients must meet eligibility criteria for 131I-MIBG therapy
Does not meet above criteria of suspicious PSA elevation
Biopsy does not meet inclusion criteria
All subjects enrolled into either Part 1 or Part 2 must meet all of the following inclusion criteria to be eligible:
Subject must meet the following criteria as indicated on the clinical laboratory tests:
Does not meet histologic criteria
The participant must meet the following criteria relevant to their specific diagnosis:
Must meet at least 1 of the following 3 criteria for progressive metastatic disease, according to Prostate Cancer Working Group 2 (PCWG2) criteria:
Admission or evidence of illicit drug use, drug abuse, or alcohol abuse. Entry Criteria for Continuation to Optional Part B: After completing Part A of the study, participants may choose to enter the optional Part B of the study. To be eligible for the optional Part B, participants must have completed Part A and be reassessed to determine if they meet the entry criteria for optional Part B. Only participants who meet the following criteria may enter into Part B:
Participants with a history of CNS metastases are eligible provided they are stable and meet the criteria details in the protocol.
Patients eligible for this companion sample collection protocol must not meet any of the exclusion criteria in the CLEE011A2404 study, in addition to the following:
Previous treatment with regorafenib AND TAS-102 (this applies to phase II only; if patients have previously received either regorafenib OR TAS-102, they must be able to receive the alternate regimen if randomized to the standard of care arm)
Prior treatment with regorafenib
Prior use of regorafenib
Prior use of regorafenib
Patients who have received prior treatment with avapritinib or regorafenib.
Received at least one line of therapy with sorafenib and/or regorafenib with evidence of disease progression clinically or radiographically as deemed by investigator, or refused therapy with sorafenib and/or regorafenib; no more than two lines of prior therapy are allowed
Up to 5 of the 15 patients will be allowed to have had other approved or investigational drugs after prior progression of regorafenib monotherapy; (all patients enrolled in this trial must have had prior progression on regorafenib therapy); this may include TAS102, off-label therapy that may have been prescribed based on tumor genomic profiling or any investigational agents on a clinical trial
No more than grade 2 toxicity with last previous cycle of regorafenib mono therapy
Patients must have progressed on imatinib, sunitinib, and regorafenib or have documented intolerance to any of these treatments.
REGORAFENIB INCLUSION CRITERIA: ECOG performance status 0-1
REGORAFENIB INCLUSION CRITERIA: Life expectancy >= 12 weeks
REGORAFENIB INCLUSION CRITERIA: Platelets >= 100,000/mm^3
REGORAFENIB INCLUSION CRITERIA: Hemoglobin >= 9 g/dL
REGORAFENIB EXCLUSION CRITERIA: Uveal melanoma
REGORAFENIB EXCLUSION CRITERIA: Previous assignment to treatment during this study; patients permanently withdrawn from study participation will not be allowed to reenter
REGORAFENIB EXCLUSION CRITERIA: Previously identified allergy or hypersensitivity to components of regorafenib formulation
REGORAFENIB EXCLUSION CRITERIA: Diagnosis of concurrent malignancy or previous malignancy within 3 years before study drug administration (exceptions are superficial skin cancers, or any in situ cancers deemed curatively treated and without evidence of disease for more than 3 years before regorafenib treatment)
REGORAFENIB EXCLUSION CRITERIA: Any hemorrhage or bleeding event >= grade 3 within 4 weeks prior to start of regorafenib
REGORAFENIB EXCLUSION CRITERIA: Major surgical procedure or significant traumatic injury within 28 days before start of regorafenib
Advanced solid tumor that has progressed during or after treatment with approved therapies or for which there is no standard effective therapy available\r\n* Note: patients with solid tumors for which regorafenib would be considered a standard treatment are eligible as long as regorafenib has not been previously administered
Previous therapy with regorafenib
Prior systemic therapy for HCC; prior exposure to regorafenib.
Prior treatment with TAS-102 or regorafenib
Prior use of regorafenib
Prior treatment with regorafenib
Received FOLFOX within 6 weeks before starting regorafenib
Prior use of regorafenib.
Prior regorafenib use with disease progression (expanded cohort only)
Prior failure to tolerate regorafenib at 120 mg/day
Prior treatment with regorafenib
Histologically confirmed metastatic and/or unresectable GIST; patients must demonstrate prior failure to at least imatinib, sunitinib and regorafenib (4th line and beyond); any number of previous therapies for GIST is allowed; failure of imatinib is defined as either prior intolerance to imatinib therapy or prior progression of disease on imatinib in the metastatic setting or progression during adjuvant imatinib, or within 3 months of completing adjuvant imatinib; failure of sunitinib and regorafenib is defined only as prior progression of disease on sunitinib or on regorafenib as assessed by the investigator
Patients with intolerance to sunitinib and/or regorafenib
Prior use of regorafenib or other anti VEGF drugs
Prior use of regorafenib
Subject has previously received regorafenib;
For patients to be treated with a regimen containing regorafenib:
Known hypersensitivity to regorafenib
Prior treatment with regorafenib
Prior treatment with regorafenib.
Prior use of regorafenib; subjects permanently withdrawn from study participation will not be allowed to re-enter study
Prior use of regorafenib
Prior use of regorafenib
Prior treatment with refametinib or regorafenib.
Prior treatment with regorafenib.
Pretreatment with regorafenib.
Subjects who in the opinion of the subject and investigator would benefit more from regorafenib treatment (except where regorafenib is not reimbursed in the country)
Prior treatment with Regorafenib
Prior use of regorafenib
Prior use of regorafenib
Patients with a clinical diagnosis of cancer that are within +/- 3 days of initiating treatment with sorafenib, sunitinib, or regorafenib.\r\n* Note: patients treated with a combination regimen that includes sorafenib, regorafenib, or sunitinib are eligible.
Patients may not be receiving any other investigational agents.\r\n* Note: it is acceptable to be on combination therapy including either sorafenib, regorafenib, and/or sunitinib.
Advanced cancer patient scheduled to receive regorafenib
Prior use of regorafenib
CLL: must have either 1) failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine (FLU) (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog); 2) failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at any time point; or 3) have “17p deletion” cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in first (1st) CR; 4) patients with a diagnosis of CLL (or small lymphocytic lymphoma) that progresses to prolymphocytic leukemia (PLL); or 5) patients with T-cell CLL or PLL
Previously treated for CLL/SLL, but there is not a requirement nor restriction for the specific prior treatments received
Patients who have had prior (within 8 weeks of initiation of DMF) or concurrent antibody therapy directed against CLL (i.e., Rituxan and Campath)
If patient has CLL must have a negative Coombs test
Relapsed or refractory SLL/CLL, WM, B-cell NHL who have received at least 2 prior lines of systemic therapy.
For CLL subjects, symptomatic disease that mandates treatment (Halleck et al. 2008).
Major inclusion criteria\n\n        Diagnosis/Trial Population\n\n          -  Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL):\n\n               -  history of diagnosis of CLL or SLL that meets IWCLL diagnostic criteria\n\n               -  histologically confirmed diagnosis of SLL by lymph node biopsy\n\n               -  indication for treatment as defined by the IWCLL guidelines\n\n          -  Patients must have both of the following:\n\n               -  relapsed or refractory disease while receiving a BTKi therapy or intolerance of\n                  such therapy\n\n               -  single-agent or combination therapy with a BTKi for at least one month must be\n                  the patient's most recent prior anticancer therapy\n\n          -  ECOG performance status of 0 to 2\n\n          -  Patients with a past medical history of autologous or allogeneic stem cell\n             transplantation must exhibit full hematological recovery\n\n        Laboratory Values\n\n        • Patients must meet adequate bone marrow function and adequate hepatic and renal function\n\n        Other Inclusion Criteria\n\n        • Females of childbearing potential must use a highly effective method of contraception\n\n        Major exclusion criteria\n\n        Diagnosis\n\n        • Patients who have:\n\n          -  non-Hodgkin's lymphomas other than CLL/SLL\n\n          -  transformed CLL/SLL or Richter's syndrome\n\n          -  active and uncontrolled autoimmune cytopenia\n\n        Previous and Current Treatment\n\n          -  Patients who have received treatment with a BTK inhibitor within 5 days prior to Day 1\n             dosing\n\n          -  Patients who have, within 14 days prior to D1 dosing:\n\n               -  not discontinued CD20-targeted therapy, chemotherapy, radiotherapy,\n                  investigational anticancer therapy or other lymphoma specific therapy\n\n               -  systemic corticosteroids in doses greater than prednisone equivalent to 20 mg/day\n                  with the exception of patients with signs of rapidly progressing disease\n\n               -  received live vaccines with the exception of vaccination against influenza with\n                  inactivated virus or for pneumococcal diseases
Prior treatment for FL, MZL, SLL, MCL, WM with ? 2 or for CLL or non-GCB DLBCL ? 1 chemotherapy-based or immunotherapy-based regimen, and not transplant eligible and have had either progressive disease (PD) or no response to previous treatment
ofatumumab (terminal half-life in CLL = 17.6 days); required washout = 88 days (13 weeks)
CLL/SLL PATIENTS (ARM A) ONLY
Patients must be previously treated with at least one prior line of therapy; EXCEPTION: CLL patients with Richter’s transformation or Hodgkin transformation do not need prior therapy to enroll\r\n* NOTE:\r\n** Prior chemotherapy or biologic novel therapy or anti-cancer monoclonal antibody based therapy for treatment of CLL will be considered prior therapy; nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate or EGCG, found in green tea or other herbal treatments) will not be considered “prior treatment”\r\n** Prior oral corticosteroid therapy for an indication other than CLL will not be considered “prior treatment”\r\n** Previous use of corticosteroids in the combination with other therapy for treatment of autoimmune complications of CLL does constitute prior therapy for CLL
A histologically confirmed diagnosis of CLL/SLL/B-cell PLL according the International Workshop on CLL/SLL/B-cell PLL or variant of these (International Workshop on CLL [IWCLL] or World Health Organization [WHO] Criteria) and meet criteria for treatment or have need for cytoreduction for stem cell transplantation or alternative cell therapy; OR
Patients who have had prior (within 8 weeks of initiation of UC-961) or concurrent antibody therapy directed against CLL (i.e., Rituxan® and Campath®)
Diagnosis of CLL by 2008 IWCLL criteria and with Rai stage intermediate or high risk CLL. Cohort 8 patients must have a diagnosis of PTCL.
Subjects must require treatment based on International Workshop on CLL (IWCLL) 2008 criteria
Inclusion Criteria:\n\n        To be eligible for inclusion in the primary escalation and expansion cohort 1 in this\n        study, patients must meet all of the following criteria:\n\n          1. Age 18 years or older\n\n          2. Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL):\n\n               1. History of histologically documented CLL or SLL that meets IWCLL diagnostic\n                  criteria according to the 2008 guidelines, and\n\n               2. Indication for treatment as defined by the 2008 IWCLL guidelines, or the need for\n                  disease reduction prior to allogeneic transplantation\n\n        Exclusion Criteria:\n\n        Patients who meet any of the following criteria are not eligible for the primary escalation\n        and expansion cohorts of this study:\n\n          1. Current or past transformation of CLL/SLL to prolymphocytic leukemia (PLL),\n             non-Hodgkin lymphoma, or Hodgkin lymphoma aggressive lymphoma outlined in the\n             inclusion criteria for the optional cohort.\n\n          2. Active and uncontrolled autoimmune cytopenia(s)\n\n          3. Any of the following prior therapies within 14 days prior to cycle 1, day 1:\n\n               1. Major surgery\n\n               2. Corticosteroids greater than 20 mg / day prednisone (or equivalent), unless used\n                  by inhalation or topical route, or unless necessary for premedication before\n                  iodinated contrast dye, or for autoimmune hemolytic anemia\n\n               3. Cytotoxic chemotherapy or biologic therapy, excepting BCR pathway kinase\n                  inhibitors for which no wash out is required (but must be stopped before cycle 1\n                  day 1)
Other concurrent low-grade malignancies such as CLL (Rai 0) may be considered after discussion and permission from Sponsor
Histological diagnosis of CLL/SLL or MCL as documented in medical records.
Diagnosis of CLL per the WHO classification
CLL–must have either 1) failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine (FLU) (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog); 2) failed FLU-cyclophosphamide (CY)-rituximab (FCR) combination chemotherapy at any time point; or 3) have “17p deletion” cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR; or 4) patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL; 5) patients failing to achieve a response to ibrutinib as first-line therapy; 6) patients not responding to ibrutinib, idelalisib, or venetoclax as salvage therapy or intolerant of these agents as salvage therapy due to side effects; all CLL patients must have received prior myelosuppressive chemotherapy
Received other investigational therapeutic agent for CLL/SLL within 21 days of starting venetoclax
Subjects must be diagnosed with CLL/SLL and do not meet the IWCLL criteria for treatment
Patients whose expected time to CLL/SLL treatment, according to our nomogram posted on the leukemia protocol priority list, is two years or less
Part 2 (Cohort Expansion): Diagnosis of DLBCL, FL, MCL, HL, CLL/SLL, ALL, MM, or AML as documented in medical records.
Patients will have a diagnosis of CLL or small lymphocytic lymphoma (SLL) who meet one or more criteria for active disease as defined by the International Working Group for CLL (IWCLL) and are: a) cohort 1: refractory to or relapsed after at least one prior therapy; or b) cohort 2: untreated patients with high-risk molecular features such as del(17p), mutated TP53, del(11q), unmutated IGHV gene, or are > 65 years of age; or cohort 3: patients with CLL who have been on ibrutinib for at least 12 months with a partial response
Patients with a diagnosis of CLL/SLL who are refractory to and/or relapsed after at least one prior therapy will be eligible (cohort 1); untreated patients with high-risk features (del(17p), or mutated TP53, or del(11q), or unmutated immunoglobulin heavy chain variable [IGHV], or >= 65 years of age) are eligible (cohort 2) provided they have active disease requiring treatment as defined by the International Working Group for CLL (IWCLL)
Patients with a diagnosis of CLL/small lymphocytic lymphoma (SLL), with mutated (> 2% deviation from germ line) IGHV gene, who meet criteria to initiate first-line treatment per International Workshop on CLL Working Group (IWCLL) 2008 guidelines
Patients must not have received prior CLL-directed therapy
Must have received one prior therapy for CLL
No previous treatment for CLL
Patients must have histologically confirmed B cell CLL (B-CLL) with low or intermediate risk disease as defined by the modified Rai criteria
Patients less than 30 days from last treatment for CLL
Each patient with CLL/SLL must meet all of the following inclusion criteria to be enrolled on the study:
Patients must have met the diagnostic criteria for CLL/SLL according to the IWCLL 2008 [13] or WHO Guidelines at some point during their disease course:
Patient must have relapsed or refractory CLL/SLL following at least one purine analog-containing regimen (or after one non-purine analog containing regimen if there is a relative contraindication to purine-analog containing therapy) and not have traditional options available or decline these. Patients with prolymphocytic leukemia (PLL)-CLL or PLL transformation of CLL are eligible.
No prior CLL-directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment
Poor-risk CLL or SLL as follows: 11q deletion disease that has progressed after a combination chemotherapy regimen, 17p deletion disease, or histologic conversion; patients with transformed lymphomas must have stable disease or better
Patients with CLL, SLL, or prolymphocytic leukemia must have < 20% bone marrow involvement by malignancy (to lower risk of graft rejection)
CLL: \r\n* Patients with either a:\r\n** Diagnosis of T-cell CLL or T-cell prolymphocytic leukemia (PLL) who have failed initial chemotherapy, patients with T cell CLL or PLL or \r\n** Diagnosis of B-cell CLL, B-cell small lymphocytic lymphoma, or B-cell CLL that progressed to PLL who either:\r\na) Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine (or another nucleoside analog, e.g. 2-chlorodeoxyadenosine [CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing fludarabine (or another nucleoside analog)\r\nb) Failed any aggressive chemotherapy regimen, such as fludarabine, cyclophosphamide and rituximab (FCR), at any time point\r\nc) Have \17p deletion\ cytogenetic abnormality and relapsed at any time point after initial chemotherapy\r\n* Harvesting criteria for autologous HCT: \r\n** Previously collected PBMC may be used\r\n** Circulating CLL cells < 5000\r\n* Marrow involvement with CLL cells < 50%
During phase I: all patients with relapsed disease will be eligible if they have received at least 1 prior standard CLL therapy and no more than 4 prior therapies (one of which must be a purine analog and/or an alkylating agent)
Previous treatment for CLL with chemotherapy or monoclonal antibodies
A diagnosis of CLL as defined by IWCLL 2008 criteria and currently on treatment with ibrutinib for at least 18 months with residual disease and without evidence of disease progression.
A diagnosis of CLL as defined by IWCLL 2008 criteria and currently on treatment with ibrutinib without evidence of disease progression.
Small lymphocytic lymphoma (SLL), or chronic lymphocytic leukemia (CLL) with progressive disease following standard therapy; patients with progressive CLL following standard therapy who meet European Bone Marrow Transplant (EBMT) consensus guidelines of indications for allogeneic stem cell transplantation; this includes patients with (1) lack of response or early relapse within 1 year of receiving a purine analog-containing treatment regimen, (2) disease relapse within 2 years of receiving a purine analog combination therapy or after other therapies such as autologous stem cell transplantation, and (3) CLL associated with tumor protein (p)53 mutations or deletions and/or deletion (del) (17p) requiring therapy; patients must have chemosensitive disease with at least a partial response (PR) or stable disease (SD) with last treatment regimen
Use of any anticancer medication from documented PD on Study IPI-145-07 to enrollment (Note: corticosteroids to manage CLL/SLL-related symptoms are allowed)
Any previous treatment (chemotherapy, radiotherapy, and/or monoclonal antibodies) intended specifically to treat CLL
Patients must be previously untreated\r\n* Note: Prior chemotherapy or monoclonal antibody based therapy for treatment of CLL or SLL will be considered prior therapy; nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate or EGCG, found in green tea or other herbal treatments or supplemental vitamins) will not be considered “prior treatment”; prior corticosteroid therapy for an indication other than CLL/SLL will not be considered “prior treatment”
Date of CLL/SLL diagnosis ? 24 months prior to registration
Received at least 2 prior therapies (regimens) for CLL
FOR PATIENTS WITH MM OR CLL:
Diagnosis of CLL.
Must have received ? 1 prior therapies for CLL.
Diagnosis of CD20+ CLL.
Any prior systemic treatment for CLL.
Diagnosis of CLL/SLL that meets IWCLL diagnostic criteria (Hallek 2008), with active disease meeting at least 1 IWCLL criteria for requiring treatment.
Any prior therapy used for treatment of CLL/SLL
Relapsed or refractory CLL pre-treated with at least one prior line of systemic therapy for CLL.
Prior diagnosis of CLL
Must have received ? 1 prior therapy for CLL
No prior therapy for CLL/SLL, including chemotherapy and/or radiotherapy is allowed
Patients must have a diagnosis of CLL/small lymphocytic lymphoma (SLL) or prolymphocytic leukemia (PLL) and be previously treated; given the poor outcome of CLL/SLL/PLL patients with 17p deletion (del) or tumor protein (TP)53 mutation to standard frontline chemo-immunotherapy, such patients will be eligible if they are untreated
Prior treatment\r\n* Patients must not have had prior therapy for CLL (except palliative steroids or treatment of autoimmune complications of CLL with rituximab or steroids)\r\n* Treatment with rituximab and/or high dose corticosteroids for autoimmune complications of CLL must be complete at least 4 weeks prior to enrollment; palliative steroids must be at a dose not higher than 20 mg/day of prednisone or equivalent corticosteroid at the time of registration
Diagnosis of relapsing/refractory or previously untreated CLL
Patients will have a diagnosis of CLL or small lymphocytic lymphoma (SLL) who meet one or more criteria for active disease as defined by the International Working Group for CLL (IWCLL) and are: a. Cohort 1: refractory to and/or relapsed after at least one prior therapy OR b. Cohort 2: untreated patients with high-risk molecular features such as del(17p), mutated TP53, del(11q), unmutated IGHV gene, or are > 65 years of age
Treatment-naïve CLL patients must meet the following requirements (Phase II only):\r\n* Symptomatic disease as defined by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria\r\n* Received no prior chemotherapy, immunotherapy, or targeted therapy for the treatment of CLL with the exceptions of palliative loco-regional radiotherapy and corticosteroids for symptom control
Cohort B-1: SLL/CLL: 1) Deletion of short arm of chromosome 17 or 11 q based on institutional assessment 2) Relapsed/refractory after at least 1 prior systemic therapy 3) Active disease based in IWCLL criteria
Participants who have received previous CLL therapy, including investigational therapies
CLL requiring treatment according to IWCLL criteria
Must have a confirmed diagnosis of CLL and an indication for treatment as per IW-CLL 2008 criteria
No prior therapy for CLL due to the patient’s meeting IW-CLL 2008 criteria for treatment
Men and women ? 18 years of age with a confirmed diagnosis of CLL, which has relapsed after, or been refractory to, ? 1 previous treatments for CLL; however, subjects with 17p deletion are eligible if they have relapsed after, or been refractory to, 1 prior treatment for CLL.
Patients must have not received any prior treatment for CLL or SLL
Any indication to start treatment for CLL based on NCI-WG criteria
Prior therapy for CLL/SLL
Men and women ? 18 years of age with a confirmed diagnosis of CLL/SLL, which has relapsed after, or been refractory to, ? 2 previous treatments for CLL/SLL; however, subjects with 17p deletion are eligible if they have relapsed after, or been refractory to, 1 prior treatment for CLL/SLL.
Subjects have been diagnosed with measurable CLL/SLL.
Diagnosis of active CLL or SLL that meets at least one of the IWCLL 2008 criteria for requiring treatment (Binet Stage ? B and/or Rai Stage ? I)
Disease that has progressed during or relapsed after at least one previous CLL/SLL therapy
CLL with an indication for treatment based on iwCLL guidelines and clinical measurable disease, or
Subjects with CLL or SLL and high-risk features must have failed at least 2 lines of prior therapy, including a BTKi.
Subjects with CLL or SLL and standard-risk features must have failed at least 3 lines of prior therapy, including a BTKi.
Patients must have a pathological diagnosis of B-cell CLL
Relapsed or refractory CLL or SLL following at least 1 prior line of systemic therapy consisting of at least 2 cycles of a chemotherapy-containing regimen
Patient has not received any prior treatment for CLL in the past
Patients must have a diagnosis of CLL/SLL and be previously treated
Presence of 2008 IWCLL/ NCI-WG indication for CLL treatment
Previous treatment for CLL- including therapy with immunomodulatory agents Revlimid or thalidomide, regardless of response
Must have a documented diagnosis of B-cell CLL.
Prior treatment for B-cell CLL.
confirmed CLL diagnosis and active CLL requiring treatment
not been treated for CLL before
prior CLL therapy
For recipients with CLL or PLL, treatment failure for a specified therapy is defined as relapse within 6 months or failure to achieve remission \r\n* Recipients who are ineligible for a specified therapy (e.g., due to refractory cytopenias) may be considered for enrollment in this protocol\r\n* Recipients who have a 17p/p53 deletion who have never received fludarabine will be eligible\r\n* Recipients who have had Richter’s transformation who have not received prior chemotherapy for their CLL will be eligible
Patients with a diagnosis of CLL (or SLL) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL)
CLL that warrants treatment
Patients with diagnoses of CLL/SLL or non-Hodgkin lymphoma (NHL) patients, who meet the criteria of either relapse or progression at any time point after allogeneic HCT or those who experience persistent stable disease or persistent disease with regression between days 28 and 100 post-transplant using standard morphologic, flow cytometric, and/or imaging studies and following the disease response evaluation criteria established by the International Workshop on CLL (IWCLL) for CLL and those following Cheson 2007 criteria for NHL
No prior therapy for CLL other than corticosteroids for disease complications.
CLL that warrants treatment
Confirmed diagnosis of CLL or SLL based on IWCLL Criteria
No prior therapy for CLL other than corticosteroids for disease complications
CLL that warrants treatment
History of a non-CLL malignancy except for the following:
Manipulated B-CLL cells available (at least 6 injections)
CIRS ? 6; 2. Creatinine Clearance < 70 mL/min; 3. Subject is not a candidate for a chemoimmunotherapy in the opinion of investigator. ii. Treatment with an approved BTK inhibitor is not required if subject has contraindications or is not a candidate for such a therapy in the opinion of the investigator. b. For Arm B, subjects with treatment-naïve or R/R CLL must meet the following criteria: i. Dose Escalation Phase: Subjects must not have received prior treatment with ibrutinib (or any other approved BTK inhibitors) and must have either R/R CLL or treatment naïve (ie, first-line) CLL if the subject:
is unfit for standard chemoimmunotherapy meeting at least 1 of the following co-morbidity criteria: a. CIRS ? 6; b. Creatinine Clearance < 70 mL/min; c. Subject is not a candidate for a chemoimmunotherapy in the opinion of the investigator. The reason for not being a candidate must be documented in CRF. ii. Dose Expansion Phase: Subjects must not have received prior treatment with ibrutinib (or any other approved BTK inhibitors) and must have high risk CLL. High risk is defined as: 1) 17p- and/or TP53 mutation positive in treatment naïve CLL; or 2) 17p- and/or TP53 mutation positive, and/or complex karyotype, and/or progression < 24 months after completion of 1st line chemoimmunotherapy in R/R CLL c. Subjects with R/R SLL or CLL with bulky disease (at least one lymph node measuring > 5.0 cm in diameter) are considered at higher risk for developing a TFR and may only be enrolled upon discussion with the sponsor's medical monitor and agreement to close medical management.
SLL / CLL SUBJECTS:
Intermediate or High risk, poor prognosis CLL/SLL
CLL and NHL Subjects:
CLL or SLL patients only (does not apply to MBL patients): Rai stage 0-1 (both CLL and SLL patients can be staged using the Rai system)
Patients must be previously untreated and must NOT have any of the following indications for chemotherapy:\r\n* Evidence of progressive marrow failure as manifested by the development of or worsening anemia (=< 11 g/dL) and/or thrombocytopenia (=< 100 x 10^9/L) not due to autoimmune disease\r\n* Symptomatic or progressive lymphadenopathy, splenomegaly or hepatomegaly\r\n* One or more of the following disease-related symptoms:\r\n** Weight loss >= 10% within the previous 6 months\r\n** Extreme fatigue attributed to CLL\r\n** Fevers > 100.4 degree Fahrenheit (o^F) for 2 weeks without evidence of infection\r\n** Drenching night sweats without evidence of infection\r\nNote: 1) Prior chemotherapy or monoclonal antibody based therapy for treatment of CLL or SLL will be considered prior therapy; nutraceutical treatments with no established benefit in CLL (such as epigallocatechin gallate or EGCG, found in green tea or other herbal treatments) will not be considered “prior treatment”\r\n2) Prior corticosteroid therapy for an indication other than CLL/SLL will not be considered “prior treatment”; previous use of corticosteroids for treatment of autoimmune complications of CLL/SLL does not constitute prior therapy for CLL/SLL
Confirmed diagnosis of CD20-positive CLL (per IWCLL guidelines, Hallek et al 2008)
Previously untreated CLL requiring treatment according to the IWCLL guidelines (Hallek et al 2008), as assessed by the investigator
Adequate baseline bone marrow function unless it due to underlying CLL disease No previous treatment for CLL by chemotherapy, radiotherapy, or immunotherapy
For dose expansion monotherapy: CLL, HL, NHL
Subjects enrolled into the relapsed subject cohort must also meet the following criteria: Relapsed CLL: defined as a subject who has received at least one prior CLL therapy and previously achieved a complete or partial remission/response lasting at least 6 months.
Refractory CLL: defined as treatment failure (failure to achieve a CR or PR) or disease progression within 6 months of the last anti-CLL therapy.
Known central nervous system involvement by CLL. Screening laboratory values: Platelets less than 100 x 109/L (unless due to CLL involvement of the bone marrow). Neutrophils less than 1.5 x 109/L (unless due to CLL involvement of the bone marrow). Serum creatinine greater than 1.5 times the upper limit of normal (ULN); subjects with a serum creatinine greater than 1.5 x ULN will be eligible if the calculated creatinine clearance [Cockcroft, 1976] is greater than or equal to 30 mL/min. Total bilirubin greater than 1.5 times ULN (unless due to liver involvement by CLL or Gilbert's disease). Transaminases greater than 2.5 times ULN.
For patients with SLL, CLL, or PLL, =< 20% of bone marrow cellularity involved by this process
At least one criterion for active disease as defined by the International Workshop on CLL.
Prior CLL therapy
Patients will have a diagnosis of CLL or SLL who meet one or more criteria for active disease as defined by the International Working Group for CLL (IWCLL) and are relapsed and/or refractory after at least one prior therapy
Patients with B cell CLL/SLL who have active disease that meets 2008 International Workshop on CLL/National Cancer Institute-Working Group (IWCLL/NCI-WG) criteria to initiate treatment
Surface ROR1 expression by < 5% of CLL cells
Inclusion Criteria MEI-401 Alone:\n\n          -  Diagnosis of relapsed/refractory CLL and/or relapsed/refractory SLL or FL\n\n          -  No prior therapy with PI3Kd inhibitors\n\n          -  No prior therapy with Bruton tyrosine kinase (BTK) inhibitors unless the subject was\n             intolerant of BTK therapy\n\n          -  Subject must have failed at least 1 prior systemic therapy\n\n          -  QT-interval corrected according to Fridericia's formula (QTcF) ? 450 milliseconds (ms)\n\n          -  Left ventricular ejection fraction >50%\n\n          -  For subjects, except those with CLL, must have at least one bi-dimensionally\n             measurable nodal lesion >1.5 cm, as defined by Lugano Classification\n\n          -  Willingness to participate in collection of pharmacokinetic samples\n\n          -  A negative serum pregnancy test within 14 days of study Day 0, for females of\n             childbearing potential\n\n        Inclusion Criteria ME-401 in Combination with Rituximab\n\n          -  Diagnosis of relapsed/refractory CLL SLL or FL, MZL, DLBCL and high-grade B-cell\n             lymphoma. Subjects must meet the following criteria for relapsed or refractory\n             disease:\n\n               1. Relapsed disease: a subject who previously achieved a CR or PR, but demonstrated\n                  disease progression after a response duration of >6 months\n\n               2. Refractory disease: a subject who demonstrated disease progression within 6\n                  months of most recent therapy\n\n          -  No prior therapy with PI3K? inhibitors\n\n          -  No prior therapy with Bruton tyrosine kinase (BTK) inhibitors unless the subject was\n             intolerant of BTK therapy\n\n          -  Subjects with CLL, SLL, FL, and MZL must have a failure of at least 1 prior systemic\n             therapy and be considered by the investigator a candidate for therapy with a\n             rituximab-based regimen; subjects with DLBCL and high-grade B-cell lymphoma must have\n             a failure of at least 2 prior therapies.\n\n          -  QT-interval corrected according to Fridericia's formula (QTcF) ?450 milliseconds (ms)\n\n          -  Left ventricular ejection fraction >50%\n\n          -  For subjects, except those with CLL, must have at least one bi-dimensionally\n             measurable nodal lesion >1.5 cm, as defined by Lugano Classification\n\n          -  Willingness to participate in collection of pharmacokinetic samples\n\n          -  A negative serum pregnancy test within 14 days of study Day 0 for females of\n             childbearing potential\n\n        Exclusion Criteria:\n\n          -  Known histological transformation from CLL to an aggressive lymphoma\n\n          -  Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia\n\n          -  Subjects who have tested positive for hepatitis B surface antigen and/or hepatitis B\n             core antibody\n\n          -  Positive for hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV)\n             antibody\n\n          -  Ongoing drug-induced pneumonitis\n\n          -  History of clinically significant cardiovascular abnormalities
Progression of CLL or MCL or FL or HD at time of transplant
Subjects must be diagnosed with CLL and do not meet the IWCLL criteria for treatment
Subjects must have discontinued all drugs used to treat CLL no later than day -30
Relapsed after or refractory to at least one prior CLL-directed therapy that was instituted due to patient previously meeting IWCLL 2008 criteria for treatment
PILOT III: CLL survivors
Chronic lymphocytic leukemia (CLL) – must have either:\r\n* Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine phosphate (FLU) (or another nucleoside analog) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog) \r\n* Failed FLU-cyclophosphamide (CY)-rituximab (FCR) combination chemotherapy at any time point; or \r\n* Have “17p deletion” cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR\r\n* Patients with a diagnosis of CLL (or small lymphocytic lymphoma) that progresses to prolymphocytic leukemia (PLL); or \r\n* Patients with T-cell CLL or PLL
Subject diagnosed with chronic lymphocytic leukaemia (CLL) who is receiving only oral cancer therapy (subject receiving intra-venous cancer therapy for CLL or intra-venous cancer therapy in combination with oral therapy may be enrolled).
Participant treats patients with CLL
Patient diagnosed with CLL < 60 days ago
Diagnosis of either Non-CLL B cell malignancy or CLL/SLL
Platelet count >= 30,000/uL (platelet values in accordance with ongoing ibrutinib studies for patients with CLL), unless cytopenias are due to bone marrow highly infiltrated with CLL cells, e.g. > 80%; AND
PRE-REGISTRATION
PRE-REGISTRATION INCLUSION CRITERIA:
PRE-REGISTRATION INCLUSION CRITERIA
Registration must be completed =< 28 days of pre-registration
Pre-registration Eligibility Inclusion Criteria for the PIK3CA Mutant Cohort (closed 03/17/2016)
INCLUSION CRITERIA FOR PRE-REGISTRATION (PATIENTS WITH UNKNOWN HER2 MUTATION STATUS TO HAVE TUMOR TISSUE SCREENED):
PRE-REGISTRATION (OPTIONAL)
PRE-REGISTRATION INCLUSION CRITERIA:
PRE-REGISTRATION
PRE-REGISTRATION- INCLUSION CRITERIA
=< 28 days post pre-registration
FIRST REGISTRATION-INCLUSION:
SECONDARY REGISTRATION-INCLUSION:
PRE-REGISTRATION: Determined by study doctor that patient is unlikely to meet inclusion criteria after screening.
PRE-REGISTRATION:
PRE-REGISTRATION
PRE-REGISTRATION
PRE-REGISTRATION
c-KIT mutation status determination, local versus central assessments; at least one must apply:\r\n* Performed locally by polymerase chain reaction (PCR) and sequencing prior to pre-registration: The melanoma harbors at least one mutation in exon 9, 11, 13, 17 or 18 of the c-KIT gene; NOTE: registration to step 1 may occur upon confirmation of pre-registration Or\r\n* Performed locally by PCR and sequencing prior to pre-registration: if the melanoma harbors at least one mutation in the c-KIT gene but is not in an exon listed or is uncertain whether it is in one of these exons then eligibility to register to step 1 requires approval of a designated central reviewer; submit the cKIT report within 24 hours after pre-registration as indicated Or\r\n* If local assessment is not possible, metastatic (preferred) or primary tumor tissue should be on hand PRIOR to pre-registration and will be submitted to Massachusetts General Hospital – Pathology (MGH) within 5 working days following pre-registration as outlined; if submission of tissue will be submitted more than 5 working days after pre-registration, immediately notify MGH (Massachusetts General Hospital) to discuss the potential submission timeline\r\n* IMPORTANT: if the c-KIT status will be determined by MGH, strict attention is to be paid to the timeframes dictated; specifically, clinical assessments which must fall within 4 weeks of registration to treatment (step 1) may be performed or repeated during pre-registration to fall within the required timeframe
PRE-REGISTRATION INCLUSION CRITERIA: Scheduled for a transurethral resection of bladder tumor (TURBT)
PRE-REGISTRATION INCLUSION CRITERIA: Be a candidate for radical cystectomy
PRE-REGISTRATION INCLUSION CRITERIA: Willing to submit tissue for required correlative research
PRE-REGISTRATION INCLUSION CRITERIA
PRE-REGISTRATION-INCLUSION CRITERIA
PRE-REGISTRATION INCLUSION
REGISTRATION INCLUSION
PRE-REGISTRATION INCLUSION:
REGISTRATION INCLUSION:
PRE-REGISTRATION INCLUSION CRITERIA
PRE-REGISTRATION INCLUSION CRITERIA
PRE-REGISTRATION INCLUSION CRITERIA
PRE-REGISTRATION INCLUSION CRITERIA