The patient must be willing to undergo repeat biopsy at week 16 (for the first 20 patients in the phase 2 part of the study)
Feasibility Phase: Patients must be < 21 years of age at the time of enrollment; please note: the feasibility phase is complete, effective with amendment #1
For Phase 1b, must have advanced refractory solid tumors in any line of therapy.
For Phase 2 only, more than 1 prior line of therapy for their tumor type.
Phase I (dose escalation and \pre-treated\ expansion cohort only): refractory to or not amenable or eligible for established MDS therapy (HMA, lenalidomide)
Phase I/II: Patients must have received ? 2 units of RBCs for hemoglobin ? 9.0 g/dL within 8 weeks prior to start of treatment.
Phase II only: Patients with a deletion 5q cytogenetic abnormality.
PHASE I: Patients must have biopsiable disease and be amenable to having two research biopsies
Patients enrolled in Cohorts 1-5, Cohort A, Cohort B and Phase 2 Doublet must be refractory to all therapies known to confer clinical benefit to their disease.
Neutrophils >= 1.5 x 10^9/L (for treatment phase)
Platelets >= 100 x 10^9/L (for treatment phase)
Clinically significant cardiovascular disease, including:\r\n* Corrected QT (QTc) interval by Bazett’s formula > 480 ms (for treatment phase)\r\n* Symptomatic bradycardia < 45 beats per minute (for treatment phase)\r\n* Other clinically significant electrocardiogram (ECG) abnormalities (e.g. bundle branch block) may be eligible after discussion with the principal investigator (for treatment phase)\r\n* Clinically uncontrolled hypertension in the investigator’s opinion (for treatment phase)\r\n* The following within 6 months prior to cycle 1 day 1:\r\n** Congestive heart failure (New York Heart class III or IV) (for treatment phase)\r\n** Cardiomyopathy (for treatment phase)\r\n** Arrhythmia or conduction abnormality requiring medication; note: patients with atrial fibrillation/flutter adequately controlled by medication in the opinion of the treating physician and arrhythmias controlled by pacemakers are eligible (for treatment phase)\r\n** Severe / unstable angina, coronary artery/peripheral bypass graft, or myocardial infarction (for treatment phase)\r\n** Cerebrovascular accident or transient ischemia (for treatment phase)
For Phase 1, only subjects HER2 or HER3 molecular/genetic alterations will be enrolled.
Prior therapy with irinotecan (for expansion phase II only)
History of transformation of indolent disease to DLBCL (expansion-phase only)
Phase 1: Subjects who have received prior alectinib therapy
Phase 2:
COHORT II
Participants who have demonstrated intolerance to 125 mg of palbociclib are ineligible for the phase I portion
RANDOMIZED PHASE II CLINICAL TRIAL: Patients received up to 2 prior regimens for their metastatic disease
RANDOMIZED PHASE II CLINICAL TRIAL: Patients are candidates for chemotherapy with carboplatin and gemcitabine
RANDOMIZED PHASE II CLINICAL TRIAL: ECOG performance status 0-2
RANDOMIZED PHASE II CLINICAL TRIAL: Within 10 days of registration: Platelets >= 100,000 / mcL
RANDOMIZED PHASE II CLINICAL TRIAL: Patients participating in another trial of an investigational agent within 4 weeks of the first dose of the study
RANDOMIZED PHASE II CLINICAL TRIAL: Patients with tumors that cannot be measured or clinically followed (i.e. evaluable disease)
RANDOMIZED PHASE II CLINICAL TRIAL: Patients who received prior therapy using carboplatin/gemcitabine within 12 months prior to their enrollment or subjects whose tumor progressed while on treatment with carboplatin or cisplatin
RANDOMIZED PHASE II CLINICAL TRIAL: Patients with baseline grade 2 neuropathy
RANDOMIZED PHASE II CLINICAL TRIAL: Life expectancy of less than 3 months
RANDOMIZED PHASE II CLINICAL TRIAL: Patients known to be carriers of hepatitis virus B and C
RANDOMIZED PHASE II CLINICAL TRIAL: Active substance abuse or psychiatric disorders
RANDOMIZED PHASE II CLINICAL TRIAL: Subjects who do not consent to providing pre and post treatment tissue sample for future research would not be eligible to participate in the trial
Allowable prior therapy\r\n* Phase 1: Progressed on standard of care therapy, if one is available\r\n* Phase 2: MPNST with 0-3 prior cytotoxic systemic therapies (no prior radiotherapy is necessary)
For phase 2 specifically, agree to pre- and on-treatment tumor biopsies
For the phase I cohort, subjects with one prior systemic treatment are eligible
PHASE I SUBJECTS ONLY: Patients must not have received prior navitoclax, unless the patient received < 7 days of navitoclax lead-in on this or another study and had to stop for reasons other than toxicity or disease progression; in the phase II portion of the study
Pts who have received prior treatment with carfilzomib (Phase II only)
Pts who have received prior treatment with pomalidomide (Phase II only)
Pts who have received prior treatment with both carfilzomib & pomalidomide (Phase I only)
PHASE I
PHASE II: Patients must have received at least one prior chemotherapy or radiation regimen prior to radiographic progression
PHASE II: Patients for whom tumor biopsy and/or resection is clinically indicated and who are eligible for and enrolled on the phase II component (any stratum) will also be eligible for the optional target validation stratum
PHASE II: Tumor must be measurable in at least two dimensions on imaging
Steroid treatment within seven (7) days prior to study treatment. Patients that require intermittent use of bronchodilators, topical steroids or local steroid injections will not be excluded from the study. Patients who have been stabilized to 10 mg Prednisolone PO QD (or equivalent), daily (or less) at least seven (7) days prior to study drug administration are allowed. Phase 2 Tumor-specific Eligibility Criteria Phase 2 patients must meet the cohort-specific inclusion/exclusion criteria in addition to the general inclusion/exclusion criteria for Phase 1 and Phase 2 study listed above. Cohort 1: Patient Population: Relapsed/Refractory SCLC
PHASE II EXCLUSION CRITERIA: Patients who received prior anti-tumoral radionuclide therapy (with unsealed sources) are not eligible for the study
PHASE II EXCLUSION CRITERIA: Logistical or psychological hindrance to participation in clinical research
Phase 1b:
Participant with bone-only disease (Phase 1 only). Note: Phase 2 participants may have predominantly lytic bone-only disease.
For participants in MTD/OBD cohort expansion and Phase 2 only: participant has measurable disease.
Phase II only: Measurable disease according to RECIST v1.1 (Section 8) obtained by imaging within 28 days prior to study registration. Phase Ib: subjects may enroll with or without measurable disease.
Phase II only: Subjects must have presence of peripheral blood levels of IgG anti-?-glucan antibody (ABA) of ? 20 ?g/mL as determined by an ELISA test within 90 days prior to study registration.
Phase II: Patients with advanced/metastatic tumors in the below selected indications, with at least one measurable lesion as determined by RECIST v1.1 or RANO
Phase I Dose Escalation:
Phase I Extension and Phase II: Male or female patients >/= 65 years of age with previously untreated AML ineligible for receiving standard intensive therapy
Phase I extension and Phase II only: Prior treatment with a hypomethylating agent, such as prior treatment for MDS.
Expansion phase: Tumor-specific cohort(s) at the RD:
One or more high-risk features identified:\r\n* Tumor diameter >= 1 cm (phase I component) or >= 2 cm (phase II component)\r\n* Tumor standardized uptake value maximum (SUVmax) >= 6.2\r\n* Moderately, poorly differentiated or undifferentiated histology
Phase 1 (dose escalation) subjects must have either:
Phase 2 (expansion) subjects must have either MDS or relapsed/refractory AML
PHASE IB: No prior treatment with erlotinib is allowed for pancreatic cancer patients
PHASE IB: ECOG PS 0-1
PHASE IB: Transaminases (AST and/or ALT) =< 2.5 x ULN
PHASE IB: PT (or INR) and PTT =< 1.5 x ULN
Patients enrolled in the expansion phase must be willing to undergo pre and post-Cycle 1 biopsies.
Confirmed advanced hematologic malignancies; Phase 1:
PHASE II: Confirmed CD19+ leukemia recurrence defined as >= 0.01% disease in the marrow or isolated extramedullary disease following allogeneic HCT OR
PHASE II: For those subjects with marrow involvement, the first 15 subjects enrolled after the 03.28.2017 amendment must have detectable disease at the time of enrollment
For phase 1, patients with multifocal low-grade Ta histology will be eligible for participation
For phase 2, individuals with Ta disease only must have documentation of high-grade histology
For phase 2, prior intravesical treatment with nab-rapamycin or gemcitabine is not allowed
PHASE I ONLY:
Phase II only: patients with colorectal cancer with known microsatellite instability (MSI)-high disease who have previously been treated with immunotherapy or who have refused treatment with immunotherapy
PART II: ECOG 0-1
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)
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.
Phase 2 Cohort: ocular melanoma
Metastatic melanoma, gastrointestinal, or genitourinary cancer with at least one lesion that is resectable; only patients with metastatic gastrointestinal cancer will be eligible for enrollment on the phase I portion of the study; patients with metastatic melanoma, gastrointestinal, or genitourinary cancer will be eligible for enrollment on the phase II portion of the study
Expansion Phase: Patients must have progressed while receiving an androgen-directed therapy, as follows:
Dose Escalation Phase and Expansion Phases will exclude patients for the following:
Dose Escalation Phase and Expansion Phase Cohort A:
Expansion Phase Cohort B: Require urgent disease response or stabilization
Patients with leukemic/blast phase transformation MPN
In the Phase 2 part, prior olaratumab/doxorubicin combination therapy in 1 prior treatment line is allowed.
The participant has adequate hematologic, organ, and coagulation function within 2 weeks (14 days) prior to enrollment (Phase 1b) or randomization (Phase 2).
PHASE II: Patients must have received at least one prior chemotherapy or radiation regimen prior to progression
PHASE II: At least 3 months must have elapsed since the last dose of irradiation to the target tumor(s) at the time of enrollment
PHASE I
PHASE II
PHASE I AND II
No more than 1 prior chemotherapy regimen in the metastatic setting for the phase 2 portion; patients in the phase 1 portion could have received any number of prior lines of therapy
Prior fulvestrant for metastatic breast cancer will be allowed for phase 1 portion but not for the phase 2 portion
Completion of phase 1 lymphedema care in the past 8 weeks;
The inability to participate/complete phase 1 care due to:
Phase 1b:
Planned vacation or dental work during the study phase
Phase II Exclusion Criterion Only: Patients previously treated with whole brain radiation therapy (WBRT)
FOR PHASE Ib PORTION OF THE STUDY:
FOR PHASE II PORTION OF THE STUDY:
Hemoglobin >= 8 g/dL (phase Ib) or >= 10 g/dL (for phase II portion)\r\n* For phase Ib portion only: patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator; however, initial study drug treatment must not begin earlier than the day of the erythrocyte transfusion
FOR PHASE Ib ONLY:
FOR PHASE II ONLY:
PHASE I: Philadelphia chromosome positive ALL must have failed at least 1 TKI
PHASE II: Patients who are between T+40 and T+100 after allogeneic transplantation
PHASE II: Patients who have >= 80% donor chimerism after allogeneic transplantation
PHASE II: Philadelphia chromosome positive ALL must have failed at least 1 TKI
Cohort 1: Phase II: patient must have HER2+ (regardless of hormonal receptor status) stage III IBC
Metastatic renal cell carcinoma\r\n* During Phase I - All prior treatments or none are allowed\r\n* During Phase II/Cohort A - No prior treatments are allowed\r\n* During Phase II/Cohort B - Must have at least one prior treatment with a PD1 inhibitor
For the treatment phase: Patients with any histological subtype are eligible
Patient must agree to the required research biopsies at baseline and after the two-week treatment with endocrine therapy in the initial part of the study (“window phase”); or at baseline and after two-week treated with endocrine therapy plus or minus palbociclib for those patients enrolled directly into the treatment phase of the study
PHASE IB DOSE EXPANSION: Histologically confirmed classical or lymphocyte predominant Hodgkin’s disease
PHASE II: Histologically confirmed B-cell NHL:\r\n* Cohort 1: with only de novo DLBCL,\r\n* Cohort 2: with only FL of grade 1, 2 or 3a
Prior treatment\r\n* Phase I: exposure to 2-3 prior lines of therapy or no therapeutic options\r\n* Phase II: previously untreated for symptomatic MM\r\n* EXCEPTION: =< 7 days with pulse steroids or localized radiation therapy, without curative intent, for a myeloma-related complication prior to registration is allowed, as considered necessary by the treating physician
Myeloma Frailty Score:\r\n*NOTE: this will include calculating a frailty score (based on age, activities of daily living, instrumental activities of daily living and Charlson comorbidity index)\r\n** Phase I: “intermediate fitness” or “frail”; NOTE: no “fit” patients will be included in the phase 1 portion of the trial which is being done to determine the MTD of the 3-drug combination\r\n** Phase II: transplant-ineligible as per their treating physician; NOTE: all the patients with “intermediate fitness” or “frail” status will be considered transplant-ineligible; other reasons to consider transplant ineligibility may include, but are not limited to: financial constraints or patient preference; in case such patients have a frailty score of “fit”, it should be duly noted by the treating physician
Phase I: active dermatologic disease >= grade 3
Phase I portion of the study: Patients with histologically confirmed classical hairy cell leukemia (HCL)
Chronic myelogenous leukemia in chronic or accelerated phase; chronic phase patients must failed at least two different TKIs, been intolerant to all available TKIs or have T315I mutation
Chronic myeloid leukemia (CML) >= 1st chronic phase, after failed >=2 lines of tyrosine kinase inhibitors; patients who progressed to blast phase must be in morphologic remission at transplant
Phase II only: blood EGF level >= pg/mL at baseline (to be determined based on Phase I results)
Phase Ia (dose-escalation)
Phase Ib (dose expansion
For Phase I portion: patient must be a candidate for nivolumab as standard of care regardless of line of therapy; for Phase II portion: patient must be a candidate for nivolumab as second-line therapy for advanced stage NSCLC
Phase II archived tissue collection: will be requested when available, but is not mandatory for inclusion
Phase II mandatory pre-treatment and post-treatment fresh biopsies to determine PD-L1 and EGFR expression and other biomarkers
No more than two prior disease relapses to be eligible for the phase I portion of the study and no more than one prior relapse to be eligible for phase II
CML with accelerated or blast phase with < 20% blasts after therapy
Evaluable disease in the phase I, and measurable disease for the phase II study
Central nervous system metastases, including lymphomatous meningitis will be allowed in the phase II study, but will not be allowed in the phase I
PHASE I:
PHASE II: Patients must have measurable disease according to RECIST 1.1 criteria that is amenable to biopsy and be willing to undergo pre- and post-treatment tumor biopsies; lesions to be biopsied do not have to be those used for measurement
PHASE II: Patients must be able to swallow pills
Prior chemotherapies more than 2 lines (Phase II part only) .
No leukemic phase >5,000/µL circulating tumor cells.
During the Phase II trial, patient must have been treated with enzalutamide or other second-generation androgen receptor antagonist before enrollment into this trial, and is tested positive for AR-V7
PHASE I: Patients do not need to have measurable disease to enroll on phase I
PHASE II SCLC: Radiographic evidence of disease progression after initial therapy should have been documented
PHASE II SCLC: Platelets >= 100,000/mcL without growth factor support
PHASE I AND II SCLC AND UROTHELIAL CARCINOMA EXPANSION COHORT: Patients who are receiving any other investigational agents
PHASE I AND II SCLC AND UROTHELIAL CARCINOMA EXPANSION COHORT: Hypersensitivity to study therapies and its excipients
PHASE I AND II SCLC AND UROTHELIAL CARCINOMA EXPANSION COHORT: Any chronic or concurrent acute liver disease
CML in any phase
Chronic myeloid leukemia (CML) second chronic phase or accelerated phase
Patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study
Patients in late chronic phase (i.e., time from diagnosis to treatment > 12 months), accelerated or blast phase are excluded; the definitions of CML phases are as follows: \r\n* Early chronic phase: \r\n** Time from diagnosis to therapy 12 months\r\n** Late chronic phase: \r\n*** Time from diagnosis to therapy > 12 months\r\n* Blastic phase: \r\n** Presence of 30% blasts or more in the peripheral blood or bone marrow\r\n* Accelerated phase CML: \r\n** Presence of any of the following features: \r\n*** Peripheral or marrow blasts 15% or more\r\n*** Peripheral or marrow basophils 20% or more\r\n*** Thrombocytopenia < 100 x 109/L unrelated to therapy\r\n*** Documented extramedullary blastic disease outside liver or spleen
For the phase 1b study, patients may have had the diagnosis of BOS for any period of time; for the phase 2 study, patients must be within 2 years from the time of diagnosis; patients may be at any time interval after SCT as long as the criteria for chronic GVHD and BOS are met
PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Have measurable disease consisting of a minimal volume of 1 cm^3
PHASE I: Any number of prior relapses
PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Has tumor localized primarily to the posterior fossa, spinal cord, or an unresectable location
PHASE I AND PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Is =< 12 weeks from completing external beam radiotherapy; patients with proven progressive disease (PD) by resection or with new lesions outside of the radiation field should not be excluded even if they are within 12 weeks of external radiation therapy (XRT), per Response Assessment in Neuro-Oncology (RANO) criteria for early PD
PHASE I AND PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Is currently participating in a study of an investigational agent or using an investigational device for therapeutic purposes; concurrent use of Optune device is not allowed
PHASE II DOSE EXPANSION IN RECURRENT GBM UNDERGOING RESECTION: Has known gliomatous meningitis, subependymal spread, extracranial disease, or multifocal disease
PHASE I: Has known gliomatous meningitis, subependymal spread, or extracranial disease
In addition, patients enrolled on the phase 1 dose escalation, phase 1 expansion or phase II trial must be willing and able to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 3 months prior to initiation of treatment on day 1, and must be obtained after most recent treatment; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the sponsor)
Randomized phase II: tumor proportional score of PD-L1 >= 1%.
PHASE I: Patients must have a Gynecologic Oncology Groups (GOG) performance status of 0, 1, or 2
PHASE I: Patients must meet pre-entry requirements as specified
PHASE II: Patients must have a GOG performance status of 0, 1, or 2
PHASE II: Creatinine < 1.5 x the institutional ULN
PHASE II: Bilirubin < 1.5 x ULN
PHASE II: AST and ALT < 3 x ULN
PHASE II: ALP < 2.5 x ULN
PHASE II: Patients must meet pre-entry requirements as specified
PHASE I: No blood transfusions 28 days prior to study entry
PHASE II:\r\n* Patients without measurable disease by imaging\r\n* Patients with persistent platinum-refractory disease after primary therapy
PHASE II: Recovery from effects of recent surgery, radiotherapy, or chemotherapy must be demonstrated
PHASE II: Any other therapy directed at treating the cancer including chemotherapy, biologic/targeted agents, and immunologic agents, must be discontinued at least three weeks prior to enrollment
PHASE II: Any prior radiation therapy must be discontinued at least four weeks prior to enrollment
PHASE II: Concomitant use of known potent CYP3A4 inhibitors
PHASE II: Patients who are receiving any other investigational agent
PHASE II: Patients who have previously received anti-CTLA-4 antibody therapy
PHASE II: No blood transfusions 28 days prior to study entry
Phase II only: patients volunteering for the Phase II part of the protocol must be willing to undergo a research endoscopy for tissue collection on day 8 (+/- 2 days) from the beginning of therapy
PHASE II: No contraindications to MRI
Patients previously treated with alectinib (Note: this only applies to the phase II portion of the study; participants entering the phase I portion of the study will still be eligible if previously treated with alectinib)
Life expectancy of ? 3 months (Phase Ia, Arm A) or ? 6 months (Phase Ia, Arm B and Phase Ib)
Prior RT to the same region within 12 months (Phase Ia, Arm A; subjects with tumors localized in the head and neck region or thorax) or at any time previously (Phase Ia, Arm B; treatment-naïve subjects with SCCHN and Phase Ib; treatment-naïve subjects with Stage III A/B NSCLC or SCCHN)
Histological confirmation of expressing CD20 antigen as determined by pathology at the respective institution and central pathology review at Mayo Clinic Rochester; Notes: for phase I, all types of B-cell lymphomas are allowed to participate; for phase II, only DLBCL patients are allowed to participate; for phase I only, patients with primary mediastinal large B-cell (PMLBCL) or transformed lymphoma are allowed to participate; additional notes regarding slide submission: central pathology review is mandatory, but is retrospective in nature; slides must be submitted =< 30 days after registration to allow for confirmation of DLBCL diagnosis and to have sufficient material for GCB/ABC assessment by a gene-expression profiling method; patients can be enrolled prior to submission of slides; for phase II, if central review of pathology shows that the patient does not have DLBCL or the amount of formalin-fixed paraffin-embedded (FFPE) material is not considered sufficient for cell-of-origin (COO) analysis, the patient may remain on the study but the patient should be replaced
PHASE II COMPONENT: The population will be restricted to relapsed/refractory sarcomas
PHASE II: Patients may only have measurable disease
Patients cannot have concurrent enrollment on other phase I, II, or III investigational treatment studies
PHASE I: Patients must have evaluable disease
PHASE II: No more than two prior VEGF-pathway targeted agents
BOTH PHASE I AND PHASE II:
PHASE I:
PHASE II:
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPatients are allowed to have received prior anti-angiogenesis therapy with the exception of prior cediranib
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPatients must be microsatellite instability (MSI)-stable (or low)
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPatients must have at least one focus of metastatic disease that is amenable to pre- and on-treatment biopsy
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nAll patients must have measurable disease
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nECOG performance status =< 2
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nAbsolute neutrophil count >= 1,500/mcL
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nWhite blood cell (WBC) >= 3,000/mcL
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPlatelets >= 100,000/mcL
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nHemoglobin (Hgb) >= 9 g/dL in the absence of packed red blood cell transfusion 28 days prior to dosing
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nCreatinine =< 1.5 X within normal institutional limits OR measured creatinine clearance >= 50 mL/min/1.73 m^2
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nAbility of subject to understand and the willingness to record twice-daily blood pressure readings
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPatients who were previously treated with cediranib
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nMajor surgical procedure (as defined by the investigator) within 30 days prior to the first dose of MEDI4736 or still recovering from prior surgery
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nHistory of auto-immune disease requiring steroid maintenance, or history of primary immunodeficiency
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nSignificant hemorrhage (> 30 mL bleeding/episode within 3 months before study enrollment) or hemoptysis (> 5mL fresh blood within 28 days before study enrollment)
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nCurrent signs and/or symptoms of bowel obstruction or signs and/or symptoms of bowel obstruction within 28 days before study enrollment
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nCurrent dependency on total parenteral nutrition (TPN) or IV fluid hydration
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nPregnant and breastfeeding women are excluded from this study
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nHBV-or HCV-positive patients are ineligible
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nKnown history of previous clinical diagnosis of tuberculosis
PHASE II COLORECTAL CANCER COHORT 6 (MEDI+C ONLY):\r\nNo baseline features suggestive of myelodysplastic syndrome or acute myelogenous leukemia on peripheral blood smear or bone marrow biopsy, if clinically indicated
Any number of metastatic disease is allowed in the pilot phase of the trial\r\n* For the phase II, metastatic patients will be allowed only if all sites of metastasis has been treated either surgically or radio-surgically; (if limited sites of metastasis are present, all of which can be resected during the nephrectomy, then the patient can be eligible)
In the phase I portion, patients with relapsed or refractory AML/MDS are also eligible, as per the treating physician’s discretion
For phase 1b: HER2 negative, as defined for phase II; any ER/PR (negative or positive) can be enrolled in the phase 1b portion
Patient may be required to undergo leukapheresis (depending on the study phase/cohort) and must agree to leukapheresis if so assigned
Patients must have had at least one prior therapy to be eligible for either phase I or II, unless they are either not candidates for or refuse cisplatin-based therapy
There is no limit to the number of prior treatments for this phase I trial
There is a high likelihood that the patient, in the opinion of the principal investigator (PI) or lead associate investigator (LAI), will meet the research phase eligibility criteria and proceed to transplant after induction phase therapy is completed
RESEARCH PHASE INCLUSION CRITERIA: The malignancy must be restaged prior to research phase and must not have progressed during induction chemotherapy (stable disease or better); persons with acute leukemia, MDS/RAEB-I or -II or CML with previous accelerated or blast phase must have < 5% blasts in the bone marrow; persons with chronic phase CML may have up to 10% blasts in the bone marrow
Relapsed or refractory B-cell ALL or CML in lymphoid blast phase; Philadelphia chromosome must be present at screening (as determined by cytogenetic analysis, fluorescence in situ hybridization [FISH], or polymerase chain reaction [PCR] [i.e., BCR-ABL positive]); Note: patients with CML who have received treatment with tyrosine kinase inhibitors for their CML, and have progressed to lymphoid blast phase are eligible for frontline treatment; Frontline Ph+ ALL or CML-lymphoid blast phase (LBC) Cohort: Patients with newly-diagnosed Ph+ ALL or CML-LBC, who have received no or minimal treatment (minimal treatment is defined as treatment with steroids/hydroxyurea of =< 2 week duration; vincristine =< 2 doses; tyrosine kinase inhibitor of =< 4 week duration; =< 2 doses of cytarabine) and are >= 60 years or older are eligible; patients must have bone marrow blasts > 5% at the time of screening
In the phase I portion of the study all patients with relapsed or refractory AML are eligible; for the Phase II portion of the study, patients must have AML progressing from prior MPN (MPN-BP) or have myelodysplastic syndrome (MDS)/MPN with more than 20% blasts; temporary prior measures to control blood counts, such as apheresis or Hydrea are allowed; patients with newly diagnosed or previously treated disease are eligible as long as prior therapy does not include hypomethylating agents; prior therapy for ruxolitinib for MPN is allowed
COHORT II:
Patients with a history of noninfectious pneumonitis will be excluded during the dose-escalation phase of the trial
In the phase II portion of the study, patients that have been previously treated with any systemic therapy for GIST are not permitted to enroll, with the exception of adjuvant imatinib systemic therapy or exposure to imatinib within 4 weeks of signing consent
Phase Ib: 0 or 1
Phase II: 0, 1 or 2
Chronic myeloid leukemia (CML): a. failed to achieve cytogenetic remission or have cytogenetic relapse after treatment with at least 2 tyrosine kinase inhibitors, or b. accelerated phase or blast phase at any time
PHASE II ONLY: Isolated extramedullary relapse
PHASE I (ARMS A, B, C, D, E, F, G, H, I, X, Y, Z)
RANDOMIZED PHASE II (ARMS K AND L): ECOG-ACRIN performance status between 0-2
RANDOMIZED PHASE II (ARMS K AND L): ANC >= 1500/mcL (1.5 x 0^9/L), obtained within 2 weeks prior to registration
RANDOMIZED PHASE II (ARMS K AND L): Platelets >= 75,000/mcL (75 x 10^9/L), obtained within 2 weeks prior to registration
RANDOMIZED PHASE II (ARMS K AND L): AST/ALT =< 2.5 x upper limit of normal (ULN), obtained within 2 weeks prior to registration
RANDOMIZED PHASE II (ARMS K AND L): Patient must have no current or prior history of CNS involvement
RANDOMIZED PHASE II (ARMS K AND L): Patients must not have previously existing hypersensitivity to brentuximab vedotin or ipilimumab
RANDOMIZED PHASE II (ARMS K AND L): Patients must not be participating in any other clinical trial or taking any other experimental medications within 21 days prior to registration
RANDOMIZED PHASE II (ARMS K AND L): Patients must not currently be smoking tobacco or other agents
For Phase I Only: Patients are eligible regardless of their FLT3 mutation status.
For Phase II only: Patients must have evidence of FLT3 ITD in their most recent assessment.
For Phase I/Ib enrollment, patients with a CLIA confirmed EGFR mutation may be treatment naive; all other patients must have received at least one previous line of therapy; there will be no limits to prior lines of treatment for the Phase 1 portion
For the phase I portion of the study, patients may be included without a CCyR provided they remain in chronic or accelerated phase CML and have at least a CHR. For the Phase II portion of the study patients must be in complete cytogenetic remission (CCyR), regardless of the stage of disease they had at the time they started therapy with TKI.
For the phase I portion of the study, patients in blast phase. For the phase II portion of the study, patients in accelerated or blast phase.
Chronic myelogenous leukemia (CML) failing to respond to or not tolerating imatinib, dasatinib, or nilotinib in first chronic phase of disease; or CML in accelerated phase or second chronic phase
For the dose escalation phase, the trial population will be limited to solid tumor types
Phase Ib: no restriction on prior therapy
Phase II cohorts only: Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Phase Ib patients need not have disease accessible to biopsy
Chronic myelogenous leukemia (CML) failing to respond to or not tolerating Imatinib or dasatinib in first chronic phase of disease; CML in accelerated phase, second chronic phase, or in CR after accelerated phase or blast crisis
Prior systemic therapy: (a) Phase 1b: Any number of lines of prior therapy; (b) Phase 2: Progressed after 1 or 2 lines of prior chemotherapy
Chronic myeloid leukemia (CML) second chronic phase or accelerated phase
Availability of tumor specimens is mandatory for patients in the confirmation phase;
PREREGISTRATION (STEP 0): Patient has pathologically-confirmed chronic phase-CML on a first line TKI and must meet the following criteria:\r\n* This diagnosis of chronic phase-CML must be confirmed by a bone marrow aspirate and/or biopsy with =< 10 % myeloid blasts within two weeks prior to registration; patients with diagnoses of accelerated or blast phase CML are not eligible\r\n* The patient has to be on first-line TKI therapy (the same TKI) for at least 2 years prior to pre-registration\r\n** Dasatinib: 50 – 180 mg per day\r\n** Imatinib: 200 – 800 mg per day\r\n** Nilotinib: 300 – 400 mg every 12-24 hours\r\n* Has been in MMR (i.e. MR^3) but still have detectable BCR-ABL transcript by a standard real-time quantitative polymerase chain reaction (RQ-PCR) assay with a limit of detection (sensitivity) of 4.5 for at least 12 months from the first documentation of the MMR\r\n* Patient has not achieved MR^4.5 (complete molecular remission [CMR]) within the time of initiation of TKI therapy and pre-registration
Phase I only: Diagnosis of advanced/metastatic NSCLC for which no standard treatment option; Phase II only: Advanced NSCLC patients who have received at least 1 platinum-based systemic chemotherapy regimen
History of symptomatic Clostridium difficile infection within 1 month prior to dosing Additional phase specific exclusion criteria: Phase Ib Dose Escalation Arm A (Venetoclax and Cobimetinib)
Phase II temporarily suspended as requested by the FDA due to IND Safety Report of 07 October 2016
Disease status: phase I: patients with refractory solid tumors must have evaluable disease, patients with NF1 PN must have measurable disease, patients with refractory leukemia must have M2 or M3 bone marrow; phase II: patients must have measurable disease; phase II temporarily suspended as requested by the FDA due to IND Safety Report of 07 October 2016
Individuals with malignant peripheral nerve sheath tumors will not be eligible to participate in the phase II portion of the trial
Drugs that strongly inhibit or potentiate cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4):\r\n* During Phase I: patients who have received these drugs within 14 days or within 5 half-lives of the drug (whichever is longer) prior to study initiation will be excluded\r\n* During Phase II: these drugs should be avoided if possible
An additional eligibility requirement for phase II study includes the presence of radiographically measurable disease with the exception of MIBG-positive NB or NB with bone marrow involvement:\r\n* Measurable disease is defined as the presence of at least one solid lesion on MRI or CT scan that can be accurately measured with the longest diameter of at least 10 mm in at least one dimension\r\n* Patients with NB who do not have measurable soft tissue disease but have MIBG-positive evaluable skeletal disease are eligible for phase II study\r\n* Patients with NB who have evidence of tumor cells in bone marrow are eligible for phase II study
PHASE II: All patients enrolled in the Phase II portion of this trial must have a history of biopsy-proven ovarian, fallopian tube or primary peritoneal cancer
For phase II part of the trial: =< 3 prior lines of treatment in the metastatic setting for the current breast cancer; however, there is no limit on number of prior line of therapy in phase I part of the trial
To be eligible for the phase 2 efficacy phase:\r\n* Relapse patients:\r\n** Patients must be in first marrow relapse, and \r\n** Patients must not have received prior re-induction therapy; donor lymphocyte infusion (DLI) is considered a re-induction attempt
Phase II: Pathologically confirmed relapsed or refractory HL; no restriction in number of prior lines of therapy
PHASE I STUDY -- ARM A (DOSE LEVEL 1) AND ARM B (DOSE LEVEL 2)
RANDOMIZED PHASE II STUDY -- ARMS C AND D
PHASE II: Patients must have measurable disease outside of the primary tumor (pancreas) by RECIST 1.1 criteria; baseline measurements and evaluations of all sites of disease must be obtained =< 4 weeks prior to randomization
PHASE II: Patients must NOT have received prior Wee1 inhibitors or AZD1775
PHASE II: Patients must NOT have received gemcitabine or nab-paclitaxel in a metastatic setting
PHASE II: Patients with biliary stents are allowed
PHASE II: For participation in the imaging research studies, patients must meet the additional following criteria:
PHASE II: The patient has consented in writing to participate in one of the imaging research studies
Disease status: \r\n* Phase 1 (Part A):\r\n** Patients must have either measurable or evaluable disease \r\n* Phase 2 (Part B):\r\n** Ewing sarcoma or peripheral PNET: patients must have measurable disease\r\n* Phase 2 (Part C):\r\n** Acute lymphoblastic leukemias (ALL): patients with ALL must have an M3 marrow with or without extramedullary site of relapse OR an M2 bone marrow with an extramedullary site of relapse; patients with CNS 3 status are not eligible for enrollment
For Part C (Phase 2): recurrent ALL patients with CNS 3 status are not eligible
PHASE I:
PHASE II:
PHASE I AND II:
Patients who are in accelerated phase or blast phase CML
PHASE II: Leukocytes >= 3,000/mm^3
Patients must have histologically or cytologically confirmed squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal (GE) junction\r\n* For the phase I study, patients can have disease that is deemed resectable or unresectable\r\n* For the phase II study, patients must have disease that is resectable
* Phase 2 (Part B): Patients with ALK+ relapsed or refractory neuroblastoma
Subjects enrolled in phase II part of the protocol should not have metastatic disease; however, patients with oligometastatic disease that can be treated with localized treatment with definitive intent are eligible
Chronic myelogenous leukemia (CML)\r\n* Chronic phase CML, refractory to imatinib treatment\r\n* Accelerated phase CML
Phase 2 expansion: NSCLC
Phase 2 expansion: Melanoma
Phase 2 expansion: SCCHN
Phase 2 expansion: Ovarian cancer
Phase 2 expansion: Relapsed or refractory DLBCL
Phase 2 expansion: TNBC
Phase 2 expansion: RCC
Phase 2 expansion: MSI high CRC
Phase 2 expansion: Gastric Cancer
Disease Status Requirements: Phase 1: ALK-positive NSCLC and ROS1-positive patients must either be treatment naïve in the advanced setting or have had disease progression after at least 1 previous ALK/ROS1 inhibitor therapy(ies). Phase 2: ALK-positive NSCLC patients must either be or have had:
Patients will be excluded from the Induction Phase and the Maintenance Phase if administration of their chemotherapy would be inconsistent with the current local labelling (SmPC) (e.g., in regard to contraindications, warnings/precautions or special provisions) for that chemotherapy. Investigators should check updated labelling via relevant websites at the time of entry into the Induction Phase and the Maintenance Phase
In the Phase 2 portion of the protocol only, subjects must have measurable disease according to response criteria appropriate for their type of cancer (as explained in Section 9.1).
Phase 1 and 2 (except Phase 2 subjects with known lymphoma) >=1500 cells/mm3
Phase 1 and 2 (except Phase 2 subject with known lymphoma) >=100,000 cells/mm3
Escalation Phase [Inclusion]\n\n          -  Locally advanced or metastatic adult solid tumor that has progressed or was\n             nonresponsive to available therapies, are unfit for standard chemotherapy or for which\n             no standard or available curative therapy exists;\n\n          -  ECOG score of 0, 1 or 2;\n\n          -  Adequate hematologic, hepatic, and renal function;\n\n        Expansion Phase [Inclusion]\n\n          -  Escalation Phase inclusion criteria\n\n          -  Evidence of the NTRK fusion as previously determined with prior testing from a\n             Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent certified\n             laboratory.\n\n        Exclusion (for both Escalation and Expansion)\n\n        • Current treatment with a strong cytochrome P450 (CYP) 3A4 inhibitor or inducer (EIAEDs\n        and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed)
Phase II only: at least one line of prior therapy for incurable disease
Phase II, arm 1 only: prior treatment with cetuximab
Phase I and Arm 1 of Phase II: Known human immunodeficiency virus (HIV)-positivity and on combination antiretroviral therapy; Arms 2 and 3 of Phase II: patients with HIV infection and antiretroviral therapy are not excluded
At least a single measurable lesion. Phase II patients only
Phase I (Cohorts A through S) and Phase II: Evaluable or measurable disease per RECIST version 1.1
Prior treatment with a VEGFR TKI (including pazopanib) (Phase 2 only)
adult Phase 1 Part A and Phase 2: ?16 years old at the time of screening
pediatric Phase 1 Part B: 2 to <16 years old
Be eligible for commercial receipt of therapy to be used in this study in combination with RTA 408 (i.e., ipilimumab or nivolumab in the Phase 1b portion and nivolumab only in the Phase 2 portion);
Have received prior treatment with therapy to be used in this study in combination with RTA 408 (i.e., ipilimumab or nivolumab) if enrolling in the Phase 2 portion of the study. This criterion does not apply to patients enrolling in the Phase 1b portion of the study.
All subjects in Cohort 3 or Phase 2 dose (P2D) must have a lesion accessible for FNA or core or open biopsy on day 8 of the first treatment cycle.
Dose Expansion Phase only: diagnosis of any other malignancy within 2 years prior to registration.
For institutions that have Phase 3 or Phase 4 protocols studying idelalisib (Zydelig®) ; individuals with malignancies being studied in these protocols must have failed screening in the respective idelalisib protocol
Inclusion Criteria:\n\n        Phase 1a\n\n          -  Aged 18 years or older\n\n          -  Histologically or cytologically confirmed solid tumor or hematologic malignancy\n\n          -  Life expectancy of 12 weeks or longer\n\n          -  Must have received ? 1 prior treatment regimen\n\n          -  Must not be a candidate for potentially curative or standard of care approved therapy\n\n        Phase 1b\n\n          -  Aged 18 years or older\n\n          -  Cohort A: Histologically or cytologically confirmed pancreatic adenocarcinoma,\n             triple-negative breast cancer, urothelial cancer with at least 1 measurable or\n             evaluable target lesion\n\n          -  Cohorts B, C, D, E and G: Histologically confirmed multiple myeloma and\n             measureable/evaluable disease\n\n          -  Cohort F: Confirmed acute myeloid leukemia or myelodysplastic syndrome\n\n          -  Cohort H: Individuals diagnosed with lymphoma\n\n          -  Prior therapy:\n\n               -  Cohort A: No more than 1 prior chemotherapy regimen for advanced or metastatic\n                  disease (not including neoadjuvant and/or adjuvant therapy)\n\n               -  Cohorts B, C, D, E and G: Must have relapsed from or have been refractory to ? 2\n                  prior treatment regimens\n\n               -  Cohort F: May have received any number of prior treatment regimens or be\n                  treatment-naïve\n\n               -  Cohort H: Must have relapsed from or have been refractory to available treatments\n\n        Phase 2\n\n          -  Aged 18 years or older\n\n          -  Cohorts I and J: Confirmed acute myeloid leukemia or high risk myelodysplastic\n             syndrome\n\n          -  Prior therapy:\n\n               -  Cohorts I and J: Must have failed prior therapy with a hypomethylating agent\n                  (HMA)\n\n        Exclusion Criteria:\n\n          -  Prior receipt of a JAK1 inhibitor (Phase 1a only)\n\n          -  Known active central nervous system metastases and/or carcinomatous meningitis\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status > 2\n\n          -  Any known contraindications to the use of gemcitabine, nab-paclitaxel, dexamethasone,\n             carfilzomib, bortezomib, lenalidomide, azacitidine, pomalidomide or PI3K? inhibitor\n             (Phase 1b and Phase 2 only, as appropriate to treatment cohort)\n\n          -  Known human immunodeficiency virus infection, or evidence of hepatitis B virus (HBV)\n             or hepatitis C virus (HCV) infection or risk of reactivation
Patients planning to enroll in the phase I portion of this study must first have a slot reserved in advance of the registration; all site staff will use OPEN to create a slot reservation\r\n* NOTE: Phase I is closed to accrual effective 4/1/15
KEY INCLUSION CRITERIA\n\n          -  Histological confirmation of classical Hodgkin's Lymphoma (cHL) with relapsed or\n             refractory disease who, for the lead-in phase, either have had a prior autologous or\n             allogeneic HSCT or are not eligible for HSCT, and , for the expansion phase, have had\n             a prior allogeneic HSCT. In the expansion phase there must be a documented CD3+ donor\n             chimerism of ?20%.\n\n          -  Patients must be off previous cHL therapy for at least 28 days prior to randomization\n             in the lead-in phase/first dose of study treatment in the expansion phase.\n\n          -  At least 1 fluorodeoxyglucose (FDG) PET avid (Deauville 4/5) measurable lesion >1.5 cm\n             on PET-CT scan as defined by the Response Criteria for Malignant Lymphoma (for the\n             lead-in phase) and the Lugano Classification (for the expansion phase) that has not\n             previously been irradiated.\n\n          -  Expansion phase: Required \de novo\ or \archival\ tumor biopsy, as well as required on\n             treatment biopsy\n\n          -  Estern Cooperative Oncology Group (ECOG) Performance Status 0 or 1\n\n        KEY EXCLUSION CRITERIA\n\n          -  Patients with prior allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) who\n             have had:\n\n               1. Lead-in phase: allo HSCT performed <12 months prior to randomization. Expansion\n                  phase: allo-HSCT performed ?4 months prior to the first dose of study treatment.\n                  NOTE: Patients who have had allo-HSCT performed >4 months prior to the first dose\n                  of study treatment must have discontinued all immunosuppressive therapy, and must\n                  have no clinical evidence of GVHD; or\n\n               2. Immunosuppressive treatment for acute or chronic GVHD within 3 months prior to\n                  randomization for the lead-in phase or prior to the first dose of study treatment\n                  for the expansion phase (with the exception of those patients who required 15\n                  mg/day oral prednisone or equivalent). Patients who required 15 mg/day oral\n                  prednisone or equivalent must have discontinued it within 7 days prior to first\n                  dose of study treatment; or\n\n               3. Acute Grade 3 or Grade 4 GVHD at any time in the past (as defined by the modified\n                  Seattle Glucksberg criteria (Consensus Conference on Acute GVHD Grading\n                  Criteria); or\n\n               4. Prior chronic GVHD (as defined by the NIH Consensus Development Project) that\n                  persisted for >6 months and required systemic immunosuppression (with the\n                  exception of those patients who required 15 mg/day oral prednisone or\n                  equivalent). Patients who required 15 mg/day oral prednisone or equivalent must\n                  have discontinued it within 7 days prior to the first dose of study treatment; or\n\n               5. A donor lymphocyte infusion (DLI) within 3 months prior to randomization for the\n                  lead-in phase or first dose of study treatment for the expansion phase.\n\n          -  Prior therapy with an anti PD 1 or anti PD L1 mAb.\n\n               1. Lead-in Phase: May be enrolled if patient stopped prior anti PD1 or anti-PD-L1\n                  therapy more than one year prior to randomization and had a documented prior\n                  response.\n\n               2. Expansion Phase: Prior therapy with an anti-PD-1 or anti-PD-L1 agent following\n                  allo-HSCT is prohibited unless the therapy was stopped more than one year prior\n                  to the first dose of study treatment, and the patient had a documented prior\n                  response. NOTE: Prior therapy with an anti-PD-1 or anti-PD-L1 agent prior to\n                  allo-HSCT is permitted with no time limits and irrespective of a documented\n                  response.\n\n               3. Patients with a history of ?Grade 3 anti-PD-1 or anti-PD-L1-related immune\n                  toxicity are not eligible.
For dose escalation phase (Phase Ib) distant metastatic disease or unresectable disease and not a candidate for down staging to resection.
For expansion phase (Phase II) distant metastatic disease only.
For dose escalation phase (Phase Ib) 0 or 1 prior lines of chemotherapy for advanced pancreatic cancer. Prior gemcitabine is allowed, however prior nab-paclitaxel is not allowed.
For expansion phase (Phase II) no prior therapy for pancreatic cancer is allowed except for adjuvant therapy as long as it was completed ? 6 months prior to study treatment start
Hematologic growth factors are not allowed at screening or during the first cycle of phase 1a or 1b.
Any comorbid condition that confounds the ability to interpret data from the study as judged by the Investigator or Medical Monitor. BEV-Specific Concerns (Note: These exclusion criteria apply to the Phase 2 portion of the study even though BEV is not administered so that the patient populations between Phase 1 and Phase 2 are similar):
Diagnosis of MDS, CMML, or RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ? 25,000 x 10^9/L and stable for at least 4 weeks without intervention) according to World Health Organization (WHO) criteria or French American British (FAB) classification either previously treated or previously untreated. The diagnosis must be confirmed via BM aspirate and/or biopsy within 6 weeks prior to Screening. Note: patients with RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ? 25,000 x 10^9/L and stable for at least 4 weeks without intervention) are not eligible for the Phase II Part 1 RPTD component of the study and patients with CMML will not be eligible for Phase II Part 2 Expansion of the study.
Patients with RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ? 25,000 x 10^9/L and stable for at least 4 weeks without intervention) are not eligible to participate in the Phase II Part 1 RPTD component of the study and patients with CMML will not be eligible for Phase II Part 2 of the study.
Any number of prior treatment regimens (in the phase I portion only); prior erlotinib is allowed in the dose finding phase and expansion cohort A; (only EGFR mutated patients are eligible)
Patients who currently are participating in other phase III therapeutic clinical trials and/or who have participated in other phase III therapeutic clinical trials in the previous 30 days
For participants enrolled in the expansion phase: lymphoma classified as either previously untreated Grade 1, 2, or 3a FL that requires treatment or previously untreated advanced DLBCL
Phase II expansion: biopsy proven RMHNSCC, of any primary site (including unknown primary) and RMSGC will be eligible
SECOND COURSE PHASE (RETREATMENT PERIOD FOR POST-COMPLETE RESPONSE RELAPSE ONLY)
Patients cannot have concurrent enrollment on other phase I, II, or III investigational treatment studies for the treatment of prostate cancer
For Phase 1A: no specific restriction
Phase Ib:
Phase II Group 3 (EGFRmut, T790M negative, any c-MET, 1L antineoplastic):
Phase II Group 4 (EGFRmut, any T790M, any c-MET, 1/3L antineoplastic):
For phase I, prior intolerance to imatinib at a dose of 400 mg daily
For phase II, any receipt of cytotoxic, biologic, or immune therapy aimed to treat GIST except for adjuvant imatinib systemic therapy that concluded at least 90 days prior to registration; for phase I, patients are eligible regardless of prior therapy
Only for patients entering phase Ib dose escalation and phase II cohorts:
Patients that have received prior enzalutamide in any setting will not be eligible. Exclusion criterion only for patients entering phase Ib expansion cohort:
For patients who will be entering the “expansion phase” of the trial, the patient must be able to safely delay radiation by at least 6 weeks
Histologically confirmed malignant pleural mesothelioma (MPM) (Epithelioid or biphasic subtype for Phase II patients; epithelioid subtype only for Phase III patients)
Phase II patients with sarcomatoid subtype MPM or Phase III patients with biphasic or sarcomatoid subtype MPM
Phase 2:
Previous diagnosis of accelerated phase or blast crisis
Phase 1: any DLBCL subtype.
Phase 1 patients must have at least two measurable tumor lesions ? 1.0 cm that are accessible to biopsy. Phase 2 patients must have at least one measurable lesion (per RECIST v1.1) which may be the same site that is used for the intratumoral injections.
Absolute lymphocyte count < 0.5 x 10^9/L (Phase 1 and Phase 2 Cohort A); absolute lymphocyte count < 1.0 x 10^9/L (Phase 2 Cohort B)
Be in the survival follow-up phase of a previous duvelisib study
Phase II: has had prior therapy for metastatic renal cell carcinoma.
For Phase II part:
Patients currently on the phase I trial combining perifosine + temsirolimus (Memorial Sloan-Kettering Cancer Center [MSKCC] Institutional Review Board [IRB] #09-058:  Phase I/II Trial of Temsirolimus and Perifosine for Recurrent or Progressive Malignant Gliomas; National Cancer Institute [NCI]-Cancer Therapy Evaluation Program #8249) who cannot continue treatment on the Phase I trial because of inadequate drug supply are eligible and will be continue being treated at the current dose they are receiving
FOR EXPANSION PHASE ONLY: For the expansion phase, patients must have measurable disease accessible for biopsy
FOR EXPANSION PHASE ONLY: For the expansion phase, patients must have archival specimens from the time of primary or recurrence diagnosis
FOR EXPANSION PHASE ONLY: Lack of accessible tumor for biopsy
PHASE I: Filgrastim (GCSF) is not allowed during screening or during the first cycle for phase I patients
PHASE II: GCSF is allowed during screening and therapy for all phase II patients
Participation in an investigational anti-cancer study within 3 weeks prior to day -7 (beginning of loading phase)
Patients agreeing to the optional biomarker study in the expansion phase only need to have an accessible primary tumor; (optional biomarker studies will be done in up to 18 patients in the expansion phase only)
Unlimited number of lines of endocrine therapy and up to two lines of cytotoxic chemotherapy in the metastatic setting (Phase Ib)
Unlimited number of lines of endocrine therapy and one line of cytotoxic chemotherapy in the metastatic setting (Phase II)
PHASE I: Patients may not have received > 2 prior chemotherapies for advanced disease
PHASE II: Patients must be without evidence of visceral or bone involvement with metastatic cancer on physical exam or any diagnostic study; extensive nodal involvement is allowed
PHASE I: Participants may not be receiving any other study agents within 2 weeks of initiating treatment
PHASE II: Patients with evidence of metastatic disease involvement in viscera or bone
PHASE II: Clinically significant malabsorption syndrome
PHASE II: Patients may not have received paclitaxel, doxorubicin, or cyclophosphamide as antineoplastic therapy
Confirmed diagnosis of Chronic Myeloid Leukemia in Chronic Phase or Accelerated Phase :
Blast phase CML
Phase 2 Arms 1-3: Suitable to receive a 6-week course of BCG in the adjuvant setting within 6 weeks following TURBT. Phase 2 Arm 4: Suitable for monotherapy vaccine administration post-TURBT. For Phase 1 only: Has previously received 3-6 weekly doses of BCG.
Evaluable disease in the Phase I, and measurable disease for the Phase II
Able and willing to give valid written consent for biopsy samples (subjects in the expansion phase only).
Patient has a confirmed solid tumor diagnosis according to the following: a. Phase 1: patient has a recurrent or refractory solid tumor that has progressed or did not respond to standard therapy, or for which no standard anticancer therapy exists b. Phase 2: patient has radiologically documented measurable disease by RECIST 1.1 (for neuroblastoma, evaluable disease by MIBG/Curie score is also acceptable) in one of the following tumor types and has failed up to three lines of treatment i. Group 1: neuroblastoma ii. Group 2: rhabdomyosarcoma iii. Group 3: Ewing's sarcoma Phase 1 portion or in preclinical studies
Phase 1b subject is unable to avoid alcohol or tobacco consumption for the duration of the study.
For phase Ib, any line of prior treatments is permitted including prior neratinib and capecitabine
Subjects must have an advanced hematologic malignancy including: Phase 1/ Dose escalation:
For subjects in the dose escalation phase and Part 1 Expansion, IDH2 mutation may be based on local evaluation. (Centralized testing will be performed retrospectively.)
Participants who previously received eribulin mesylate are not eligible for enrollment on the phase II portion
PHASE I AND PK EXPANSION COHORT:
PHASE II:
PHASE I and II:
PHASE I
PHASE II
PHASE I and II
Prior imatinib failure or had accelerated phase or blast crisis CML
Patients cannot have concurrent enrollment on other phase I, II, or III investigational treatment studies
Intermediate-2 and higher by International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) post polycythemia vera (PV)/essential thrombocythemia (ET) MF and primary myelofibrosis (PMF) patients either in\r\n* Chronic phase (MF-chronic phase [CP])\r\n* Accelerated phase (MF-accelerated phase [AP])
HCT recipients newly requiring systemic glucocorticoid therapy (at >= 1 mg/kg/day prednisone or equivalent) for chronic GVHD\r\n* In the phase I component of the trial, only those with overall moderate or severe global composite score are eligible\r\n* In the phase II component of the trial, patients of any global composite score are eligible, provided they have need for systemic therapy for chronic GVHD
For Phase Ib: patients with HER2 overexpressing disease must have been previously treated with trastuzumab (patients with HER2 overexpressing disease are not eligible for the Phase II trial)
In phase II study (PMLBL) patients with CNS involvement are not eligible
Received at least 1 prior line of therapy for MM (Phase 1)
Non-secretory or oligo-secretory Multiple Myeloma (Phase II only; such disease is permissible in Phase I).
Phase Ib: Patients may have had any number of prior treatments, including 0, or prior pazopanib
Patients who are unwilling to stop the use of herbal remedies while on the treatment phase of the study
Dose Expansion phase: At least 1 measurable lesion which has not been treated previously with radiotherapy. A newly arising lesion in a previously irradiated field is acceptable
Splenectomy (Phase 2 portion of the study only)
Patients cannot have concurrent enrollment on other phase I, II, or III investigational treatment studies
Patients must have CML in any phase (CP, AP, or BP of any phenotype) or Ph+ ALL
For CML blast phase (BP) patients, received chemotherapy within 14 days prior to the first dose of ponatinib.
Concurrent tumor-specific hormonal therapy or antiestrogens. (Individuals manufactured under CL-PTL 105 (Phase II Ovarian) are not subject to this exclusion).
Chronic myelogenous leukemia (CML): second chronic phase, accelerated phase or blast crises with less than 10% blasts in the bone marrow, or CR1 and resistance to Gleevec or other tyrosine kinase inhibitors
Chronic myelogenous leukemia (CML)\r\n* Chronic phase CML \r\n* Accelerated phase CML\r\n* Not eligible for myeloablative allogeneic HSCT
Chronic myelogenous leukemia (CML) second chronic phase or accelerated phase; or
Any phase of CML other than chronic phase
Diagnosis of Ph-positive or Bcr-positive CML in early chronic phase CML (i.e., time from diagnosis 12 months); except for hydroxyurea, patients must have received no or minimal prior therapy, defined as < 1 month (30 days) of prior interferon-alpha (with or without cytarabine) and/or an Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor (TKI); patients with de novo accelerated phase will be treated but analyzed separately
Patients in late chronic phase (i.e., time from diagnosis to treatment > 12 months) or blastic phase are excluded; the definitions of CML phases are as follows: \r\n* Early chronic phase: time from diagnosis to therapy < 12 months; late chronic phase: time from diagnosis to therapy > 12 months\r\n* Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow\r\n* Accelerated phase CML: presence of any of the following features:\r\n** Peripheral or marrow blasts 15% or more\r\n** Peripheral or marrow basophils 20% or more\r\n** Thrombocytopenia < 100 x 10^9/L unrelated to therapy\r\n** Documented extramedullary blastic disease outside liver or spleen due to past causes\r\n* Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome is part of accelerated phase CML; Ph chromosome variants or complex Ph chromosome translocations are not considered to indicate disease acceleration; these patients, like others with de novo accelerated phase, will be eligible, and analyzed separately
For Phase 1b individuals: absolute lymphocyte count (ALC) > 5000/?L in peripheral blood.
For Phase 2 individuals either:
Chronic myeloid leukemia (CML) failing to respond to, progressing on or not tolerating appropriate tyrosine kinase inhibitor (TKI) therapy in first chronic phase of disease; CML in accelerated phase, second chronic phase, or in complete remission (CR) after accelerated phase or blast crisis
Considered by the investigator to be an appropriate candidate for a Phase 1 clinical study;
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.
Patients with T-cell LL must have recurrent disease, documented by clinical or radiographic criteria, as well as histologic verification of the malignancy at original diagnosis. Patients with T-cell LL enrolled in the phase I dose-escalation study are not required to have measurable disease; however, patients enrolled in the phase II cohort expansion at the MTD must have measurable disease.
For participation in the Phase II portion, patients must have completed at least one line of prior therapy
For participation in the Phase I portion, patients must have completed either one or two lines of prior therapy
A core tumor biopsy obtained after progression on the last treatment must be available at study entry for the phase II portion of the study; any available archival tissue (for both phase I and II) will also be collected
Patients with ECOG performance status of 2, secondary to the underlying disease, may be enrolled in the Phase II portion of the study
Phase 1a: Have histologic or cytologic confirmation of advanced solid tumor
Phase 1b Subjects only:
No prior therapy for DLBCL, except =< 1 week of corticosteroids given on an emergent basis or as a temporizing measure (pre-phase where indicated by the treating physician)
For patients enrolled to Phase II Cohort B: Previous administration of vaccine therapy targeting NY-ESO-1.
Patients must have borderline resectable pancreatic cancer with no metastatic spread as determined by a baseline diagnostic CT scan with intravenous contrast (or MRI). CT should be performed according to a defined pancreas protocol such as triphasic cross-sectional imaging with thin slices. Optimal multi-phase technique including a non-contrast phase plus arterial, pancreatic parenchymal and portal venous phase of contrast enhancement with thin cuts (3mm) throughout the abdomen is preferred. Studies must be evaluated by a radiologist and/or surgeon and deemed borderline resectable as defined below:
For Phase 2 of the study, has a diagnosis of mixed squamous and nonsquamous (or adenosquamous) NSLC.
For Phase 2 of the study:
For Phase 1b of the study: Participants who have experienced failure of multiple lines of prior chemotherapy are eligible.
For Phase l, no more than 3 prior anticancer regimens (IL-2 or interferon do not count towards the total).
Patients must be willing to provide a screening and post-dose biopsy for biomarker analysis (extension phase only)
In the extension phase, patients must be willing to provide a screening and post-dose biopsy for biomarker analysis
Patients with advanced CML (CML-AP, CML-BP and Philadelphia chromosome-positive acute leukemia) or refractory chronic phase CML are eligible, as defined as follows: the phase I portion of the study will be conducted first in advanced phase (accelerated phase CML, blast phase CML or Philadelphia-positive acute leukemia) patients; once MTD is identified, a cohort of 6 patients with CML chronic phase who have failed prior therapy with at least two tyrosine kinase inhibitor will be treated at the MTD to determine if this dose is also acceptable for chronic phase patients; the phase II will be conducted in two treatment arms as follows: treatment Arm A (advanced phase disease) and treatment Arm B (therapy for chronic phase [CP]-CML refractory/resistant/suboptimally responding to at least two prior tyrosine kinase inhibitors [TKIs]); CML-AP is defined by the presence of one of the following: a. 15-29% blasts in peripheral blood (PB) or bone marrow (BM), b. > 20% basophils in PB or BM, c. > 30% blasts plus promyelocytes (with blasts < 30%) in PB or BM, d. < 100 x 10^9/L platelets unrelated to therapy, or clonal cytogenetics evolution (i.e., the presence of cytogenetic abnormalities other than the Philadelphia chromosome) except if only present at the time of diagnosis and not associated with other features of accelerated phase; CML-BP is defined by the presence of >= 30% blasts in the bone marrow and/or peripheral blood or the presence of extramedullary disease, with myeloid or lymphoid blast morphology; Philadelphia-chromosome acute leukemias are eligible and defined by >= 20% blasts in the peripheral blood or bone marrow at the time of diagnosis
Patients who have failed nilotinib, including those who are refractory to nilotinib at any dose or have relapsed on nilotinib at any dose will be eligible for the study; patients currently on nilotinib will continue on their prescribed dose of nilotinib and MEK-162 will be added based on the current cohort level in phase I or at the established MTD in phase II; in the instance the nilotinib dose is greater than the current cohort (in phase 1) or the MTD (in phase 2) patients will be dose reduced to the dosage as prescribed by protocol and then dose escalated as allowed in protocol at the principal investigator's (PIs) discretion
Criteria for the Phase 1b:
Cohort-specific criteria for Phase 2:
Subjects in the Phase 1b portion and in Group 1 and Group 3 of the Phase 2a portion may have received any number of prior therapies for breast cancer. Subjects in Group 2 of the Phase 2a portion may have received up to 3 lines of therapy in the metastatic setting (not including adjuvant or neoadjuvant therapy)
Patients must be considered good candidates for a phase 1 trial and the treating physician must intend to enroll the patient on a phase 1 clinical protocol, if possible; patients are not required to have progressed on their last line of therapy prior to enrollment\r\n* Other clinical trials are also acceptable; for example, an applicable phase 2 or phase 3 trial may exist for which the patient would be eligible and for which available information (inclusive of next generation sequencing [NGS]) would be relevant to such enrollment; regardless, the pertinent point is that it is the intent of the physician to use NGS data, to the degree possible, to select appropriate therapy, when selecting patients for this trial
Modified Glasgow prognostic score (mGPS) of 1 or 2 at Screening (randomized phase only)
Prior TACE < 6 months prior to screening phase in case of patients progressing from an intermediate to an advanced stage due to occurrence of PVT
Relapsed or relapse/refractory MM with at least 1 prior line of therapy for phase 1 and 1 to 5 prior lines of therapy for phase 2.
Bortezomib refractory patients are not permitted on the Phase 2 part of the study.
For Phase II, patients may have received a maximum of 1 prior line of therapy for recurrent or metastatic disease
Patients with swallowing dysfunction who are unable to swallow BYL719 whole tablets and are not using feeding tubes for study drug administration can participate in the Phase Ib Arm B. For the Phase II, these patients with swallowing dysfunction may participate if able to drink the suspension and results of Arm B confirm the use of this method. Patients with swallowing dysfunction requiring G tube (G/PEG tube) for study drug administration may participate in Phase II if Arm C confirms dispersible tablet via G tube administration is permitted if the administration of drinkable suspension of BYL719 is allowed to be used in Phase II.
Availability of a representative tumor specimen. Patients enrolled in Arm 3 of Phase II must have disease sites amenable to biopsy unless prior agreement between Novartis and the Investigator.
Previously untreated chronic phase CML, except for Anagrelide or Hydroxyurea.
Patients on the Phase II portion only must be willing to undergo pre- and post-treatment biopsies and have at least one lesion amenable to biopsy
PHASE II – GROUP B: Progressive disease must have occurred on abiraterone within the prior 12 months and patient has not received treatment with enzalutamide
Patient willingness to undergo tumor biopsy at baseline and on treatment (optional for Phase 1; mandatory for Phase 2)
Subject has been treated in the OXiGENE-sponsored Phase 2 study OX4218s
For patients in the Phase II portion of the study, must have measurable disease defined by at least 1 of the following 3 measurements:
For Phase 2 only: MET+ status
Whole brain or focal radiation therapy within 14 days prior to Cycle 1 Day 1 (C1D1) for Phase 1b or prior to randomization for Phase 2
Was enrolled on the Phase 1 clinical trial ONT-10-001 and:
PHASE II SPECIFIC:
Eligibility for phase 1 and phase 2 components:\r\n* Phase 1 – clinical T3 or T4 or N1 or M1 cancer which is untreated or previously treated with platinum based therapy with primary tumor still present in the bladder and amenable to sampling before and after treatment, as indicated\r\n* Phase 2 – clinical T2-4 N0 or N1 untreated with primary tumor still present in the bladder and amenable to sampling before and after treatment, as indicated
Patients previously randomized in any other Onyx-sponsored phase 3 trial
Measurable disease (only for the phase II portion)
No more than one prior chemotherapy regimen for recurrent or metastatic ESCC (for Phase II only).
Patients enrolled into phase Ib may be enrolled with evaluable disease only. Patients enrolled into the phase II expansion must have at least one measurable lesion as defined by RECIST 1.1 criteria for solid tumors.
Prior enrollment in the OncoGenex Phase 2 Study OGX-427-02.
Any number of prior chemotherapy regimens for recurrent disease (Phase I); =< 1 chemotherapy or other non-antiangiogenic regimen for recurrent disease (Phase II)
Last dose of bevacizumab >= 2 weeks prior to registration (Phase I); note: for the phase II study only, prior exposure to bevacizumab is not allowed
Prior hypersensitivity to bevacizumab or toxicity requiring discontinuation of bevacizumab (Phase I)
Prior hypersensitivity to triptan derivatives (Phase I and II)
The Phase II, single-arm NF Cohort (Arm G) will be required to submit tissue and pathology report for central pathology review.
Subjects are allowed to have received radiotherapy before enrollment if radiation was given to alleviate pain and/or neurologic compromise as long as there remains areas of measurable disease present; further, at the investigator’s discretion and for patients who are unstable, one cycle of rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) during the phase I portion of trial and one cycle of an anthracycline based chemotherapy in the phase II portion of the trial is allowed prior to enrollment but no more than one cycle; for purposes of this trial, prednisone or other corticosteroids used for non-lymphomatous conditions will be allowed; in addition, a prior/recent short course (=< 2 weeks) of steroids for symptom relief of lymphoma-related symptoms will be allowed
Prior temozolomide is not required for the phase 1 component; prior radiation is required for the phase 1 arm.
Patients on the phase 2 portion of the study may not have more than 2 prior regimens for recurrent disease for glioblastoma/gliosarcoma. Patients on the phase 1 portion of the study may not have had more than 3 prior regimens.
PHASE I PATIENTS:
Patients must be >= 2 weeks since any investigational agent administered as part of a phase 0 study (also referred to as an “early phase I study” or “pre-phase I study” where a sub-therapeutic dose of drug is administered) at the coordinating center PI’s discretion, and should have recovered to eligibility levels from any toxicities
Participants with measurable disease per RECIST v1.1 Additional Inclusion Criteria for Participants Who Backfill Cleared Cohorts of Phase 1a and Phase 1b:
Eligibility based on prior treatment with CIT depends on the mechanistic class of the drug and the cohort for which the participant is being considered, as described below. In addition, all criteria pertaining to adverse events attributed to prior cancer therapies must be met All Cohorts (Dose-Escalation in Phase 1a and Dose-Escalation, Backfill, and Expansion in Phase 1b):
Prior treatment with immune checkpoint inhibitors, immunomodulatory monoclonal antibody (mAbs), and/or mAb-derived therapies is allowed provided that at least 6 weeks (Phase 1a) or 3 weeks (Phase 1b) have elapsed between the last dose and the proposed Cycle 1, Day 1, with the exceptions as specified in protocol Dose-Exploration/Expansion Cohorts in Phase 1b:
Patients randomized or previously randomized in any other Onyx-Sponsored Phase 3 trial.
Life expectancy of > 3 months for the run in phase and > 6 months for the randomized phase
For patients enrolled into Stage I, they must have received at least 75% of planned radiotherapy (60 Gy) with temozolomide treatment during the concomitant phase have documentation that the patient's absolute neutrophil count (ANC) is ? 1.5 x 109/L, platelet count is ? 100 x 109/L, and there was no CTC grade 2 or above nonhematological toxicity (except for alopecia, nausea, vomiting) during the concomitant phase treatment be within ? 4 weeks but ? 6 weeks following the completion of temozolomide in the concomitant phase
For Cohort Expansion Phase (Part 2) only: Patients who are positive for the D835 mutation at Screening are excluded.
Interferon- or imatinib-refractory chronic myelogenous leukemia (CML) in first chronic phase, or CML in second or subsequent chronic phase
PHASE I: Prior systemic therapy with sorafenib is allowed
PHASE II: All patients will be required to have measurable disease
PHASE II: Prior systemic therapy with sorafenib is allowed
Phase II : Diagnosis of recurrent, metastatic or primary unresectable ATC, including ATC as part of a thyroid carcinoma of another histologic subtype
During Phase II enrollment: prior therapy with cisplatin with the exception of when given concurrently with radiation therapy (cisplatin will be allowed as prior therapy during Phase I enrollment)
Current or previous participation in the treatment phase of another interventional clinical study within 4 weeks prior to randomization. Patients may continue in the follow-up phase of another interventional clinical study, but may not have undergone any treatment on the other study within 4 weeks prior to randomization.
No prior treatment with temsirolimus or everolimus in the phase II component of the study. NOTE: Prior treatment with these agents is permitted in the phase I component of the study.
Corticosteroids initiated at the time of tumor diagnosis or recurrence for treatment of nerve compression or other symptoms is permitted during this phase of the trial, but will not be permitted during the immunotherapy phase, with the exception of a self-limited course of steroids
Participation in a Phase I lapatinib trial that has met its study objectives.
Male or female for phase I and female for phase II and any race
Prior cytotoxic chemotherapy for recurrent or metastatic breast cancer (phase II portion)
Concomitant enrollment in a Phase I study
Phase II: Have at least 1 metastatic lesion other than the primary pancreatic tumor that is evaluable per RECIST 1.1 criteria; lesions previously irradiated are not considered evaluable
Phase II: Patients that previously received systemic chemotherapy for metastatic or advanced pancreatic adenocarcinoma are not eligible
Enrollment in a Phase I trial
Patients enrolled on another clinical trial which prohibits the use of pre-phase therapy or any of its components
In phase 2, subjects are also required on accrual to be referred to palliative care
Within three days of starting the induction phase of therapy for ALL (B-cell, T-cell, or mixed phenotype)
PHASE I: Completed primary surgery, chemotherapy, and radiation
PHASE I: Currently taking AET
PHASE II: Completed primary surgery, chemotherapy, and radiation
PHASE II: Within 12 months of beginning AET
PHASE II: At least 18 months of AET recommended
Enrolled on a phase I trial
PHASE I: Any diagnosis of cancer prior to age 21
PHASE I: Off treatment
PHASE II: Any diagnosis of cancer prior to age 21
PHASE II: Off treatment for at least 6 months
PHASE I: Significant developmental delay per patient, parent, or physician report
PHASE I: Pregnant (per patient report)
PHASE II: Significant developmental delay per patient, parent, or physician report
PHASE II: Pregnant (per patient report); if participant becomes pregnant during the course of the study, she will be removed from further participation
Currently being treated in the maintenance phase of therapy for pediatric ALL or lymphoblastic lymphoma
COHORT A OVERVIEW: patients age less than 60 with untreated stage III or IV classical Hodgkin lymphoma will be eligible for cohort A; in phase I, patients may enroll onto cohort A if they have a baseline IPS ? 3 OR if their PET scan after 2 cycles of ABVD is positive (Deauville 4 or 5); enrollment onto phase I has now ceased and enrollment will begin for phase II; in phase II, patients less than 60 years of age with stage III or IV HL are eligible; patients may enroll anytime within the first 2 cycles of ABVD or after PET-2
Phase 1-Diagnosis of advanced or metastatic solid tumor; Phase 2-Diagnosis of NSCLC
PHASE 0: Ability to stand and walk unassisted
PHASE 1 & 2: Scheduled for curative surgical treatment of metastatic colorectal or peritoneal cancer at UPMC Shadyside
PHASE 1 & 2: Ability to stand and walk unassisted
PHASE 0: Not yet had surgery
PHASE 1 & 2: Identified within two weeks of surgery
Phase II: Hematologic malignancy diagnosis including any subset of lymphoma, leukemia, or myelodysplastic syndrome
Phase I: Not serving as the primary decision maker for their health-related decisions
Phase I: Having a non-hematologic malignancy reason for undergoing transplantation (e.g. aplastic anemia)
Phase II: Not completing participation in phase I of the study
Phase II: Myeloma diagnosis
Phase I: From 3–36 months post-surgical treatment
Phase II: From 3–24 months post-surgical treatment
Phase II: Not adherent to thorough SSE (i.e., did not check every area of the body at least once during the past 2 months)
Currently undergoing phase I complete decongestive therapy (CDT)
Finished with active cancer treatment within the past 4 years and are in the survivorship phase of care
PATIENTS AND PARTNERS: Prior enrollment in a couple-based mind-body intervention research study (protocols 2011-1179, 2013-0496, 2014-0036) conducted by the principal investigator including phase 1 or phase 2 of the current study
Cancer survivors will be partnered, cohabiting women with a diagnosis of non-metastatic breast cancer (stages I-III), and a body mass index (BMI) >= 30 who are healthy enough to participate in a home-based walking program (per medical provider clearance; Phase I, part B and Phase II only)
Survivors will have completed adjuvant chemotherapy and/or radiation treatment, with those participating in phase I within 5 years of completing treatment and those participating in phase II within three years (36 months) of completing treatment
Partners will be cohabiting with the cancer survivor and have a BMI >= 25, be healthy enough to participate in a home-based walking program (per medical provider clearance; Phase I, part B and Phase II only)
Interferon? or tyrosine kinase?refractory chronic myelogenous leukemia (CML) in first chronic phase, tyrosine kinase inhibitor (TKI)?intolerant CML in first chronic phase, or CML in second or subsequent chronic phase
Phase 1: Signed consent forms and completed surveys that will be returned to the study team by mail
Treatment cannot begin prior to re-registering to the crossover phase and will ideally begin =< 7 days after registration for the crossover phase
PHASE I AIM 1 (STAKEHOLDER INPUT)
PHASE I AIM 1: Malignant diagnosis in any cancer type at any stage
PHASE I AIM 1: Receiving any type of cancer treatment
PHASE I AIM 1: Current outpatient status
PHASE I AIM 1: Fluent in English
PHASE I AIM 1 (STAKEHOLDER INPUT) EXCLUSION
PHASE I AIM 1: Clinical evidence of cognitive or psychological impairment
PHASE I AIM 1: Prisoners
PHASE I AIM 1: Pregnant women
PHASE I AIM 3.1 (EVALUATION STUDY)
PHASE I AIM 3.1: Malignant diagnosis in any cancer type at any stage
PHASE I AIM 3.1: Receiving any type of cancer treatment
PHASE I AIM 3.1: Current outpatient status
PHASE I AIM 3.1: Fluent in English
PHASE I AIM 3.1 (EVALUATION STUDY) EXCLUSION
PHASE I AIM 3.1: Clinical evidence of cognitive or psychological impairment
PHASE I AIM 3.1: Prisoners
PHASE I AIM 3.1: Pregnant women
PHASE I AIM 3.2 (PILOT STUDY)
PHASE I AIM 3.2: Receiving surgery and/or chemotherapy treatment
PHASE I AIM 3.2: Current outpatient status (participation will be suspended during hospitalization)
PHASE I AIM 3.2: Fluent in English
PHASE I AIM 3.2 (PILOT STUDY) EXCLUSION
PHASE I AIM 3.2: Clinical evidence of cognitive or psychological impairment
PHASE I AIM 3.2: Prisoners
PHASE I AIM 3.2: Pregnant women
PHASE I AIM 3.2: Currently participating in other psychosocial studies
PHASE II AIM 2 (RANDOMIZED CONTROLLED TRIAL)
PHASE II AIM 2: Malignant diagnosis of breast, lung, or colorectal cancer at any stage
PHASE II AIM 2: Receiving any type of cancer treatment
PHASE II AIM 2: Life expectancy of at least six months
PHASE II AIM 2: Current medical oncology outpatient status (participation will be suspended during hospitalization)
PHASE II AIM 2: Fluent in English
PHASE II AIM 2 (RANDOMIZED CONTROLLED TRIAL) EXCLUSION
PHASE II AIM 2: Clinical evidence of cognitive or psychological impairment
PHASE II AIM 2: Prisoners
PHASE II AIM 2: Pregnant women
PHASE II AIM 2: Currently participating in other psychosocial studies
PHASE I: Speaks and reads English
PHASE II: Has a first, primary diagnosis of unilateral stage 0, 1, 2, or 3a breast cancer
PHASE II: Speaks and reads English
Patients must be enrolled in a Phase 1 clinical trial and be within 2 weeks of starting the experimental therapy or intervention
INTERVENTION PHASE: While on neurotoxic chemotherapy, has developed NCI-CTC grade 2 CIPN
INTERVENTION PHASE: Currently receiving acupuncture treatment for CIPN
PHASE 1 (DEVELOPMENT OF NARRATIVE MESSAGES)
PHASE 2 (RANDOMIZED CONTROLLED TRIAL [RCT] GROUP)
Patients enrolled on phase 1 of the study are eligible (and/or if recruited from tumor registry or clinic follow-up schedules)
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.
Dose escalation phase prior systemic treatment requirements:
For Cohort 2, Cohort 3, and the Randomized Phase, tumor must be shown to have an FGFR3 mutation or gene fusion.
Phase 2: In Phase 2, clinician participants will be the oncology clinician of record (i.e., oncologist, nurse practitioner) of the first five patients enrolled in the intervention group of the randomized trial
Phase 2: The same four groups of stakeholders from Phase 1 will become involved as research collaborators/consultants for Phase 2 of the study and will not be considered study participants (i.e., will not be registered with Quality Assurance Office for Clinical Trials [QACT])
MONITORING PHASE:
Monitoring phase:
RANDOMIZATION PHASE:
Randomization phase:
PHASE II: Did not participate in phase 1
CML patients in chronic phase receiving treatment with any Food and Drug Administration (FDA) approved TKI; or CML patients in accelerated or blastic phase who are considered to be in this phase because of thrombocytopenia or because of clonal evolution and with no other criteria for accelerated/blastic phase or patients with myelofibrosis receiving treatment with FDA approved TKI and with peripheral blood and/or bone marrow blasts =< 10%
CML patients in accelerated or blastic phase except for those who are considered to be in this phase because of thrombocytopenia or because of clonal evolution and with no other criteria for accelerated/blastic phase; or myelofibrosis patients who have transformed to acute leukemia or have >= 10% blasts in peripheral blood and/or in bone marrow
Thrombocytopenia that is considered to be unrelated to treatment with TKI or accelerated phase as defined above
EVALUATION PHASE
Caregivers will be eligible for enrollment if they identify as the person who is the caregiver of a patient enrolled in a phase I oncology clinical trial
Participants must have been informed of their eligibility for a specific phase II or III therapeutic clinical trial open for enrollment at the participating National Cancer Institute (NCI) Community Oncology Research Program (NCORP) site
Participants must not have already made a decision to participate in the phase II or III therapeutic clinical trial for which they were informed of their eligibility
Participants must not be eligible only for phase I trial
Phase I: Self-identify as Hispanic/Latino
Phase I: Prefer to receive health information in Spanish
Phase I: Previously screened or not screened
Phase II: Self-identify as Hispanic/Latino
Phase II: Prefer to receive health information in Spanish
Phase II: Only patients who are not up-to-date with screening and are attending regularly scheduled clinic visits will participate
Individuals must not currently be participating in any other clinical trial for the treatment or prevention of cancer unless they are no longer receiving the intervention and are in the follow-up phase only; patients must also agree not to join such a trial while participating in this study
PHASE I: Use of IT at least 10 times in the past year
PHASE II: Meet all the Phase 1 inclusion criteria
PHASE II: Use of IT at least 25 times in the past year
PHASE I: MGUH patients presenting for well visits, and patients' parents
PHASE II: Presenting at MGUH pediatric outpatient center in Washington DC for a well-visit exam
PHASE II: Able to complete all study assessments and procedures in English
PHASE II: Not able to complete all study assessment and procedures in English
Chronic myelogenous leukemia (CML) with one of the following criteria:\r\n* Accelerated phase, defined by any of the following:\r\n** Blasts 10-19% in peripheral blood white cells or bone marrow \r\n** Peripheral blood basophils at least 20%\r\n** Persistent thrombocytopenia (< 100 x 10^9/l) unrelated to therapy, or persistent thrombocytosis (> 1000 x 10^9/l) unresponsive to therapy \r\n** Increasing spleen size and increasing white blood cell (WBC) count unresponsive to therapy\r\n** Cytogenetic evidence of clonal evolution (i.e., the appearance of an additional genetic abnormality that was not present in the initial specimen at the time of diagnosis of chronic phase)\r\n* Chronic phase provided a complete hematologic remission was not achieved by 3 months or a complete cytogenetic remission by 18 months and the patient had received at least 2 tyrosine kinase inhibitors
Plans to move from Kansas City (KC) during the treatment and follow-up phase
Completed the 1-year phase II low-fat fish oil study
Must not participate in any other clinical trial for the treatment or prevention of cancer unless they are no longer receiving the intervention and are in the follow-up phase only. Participants must also agree not to join such a trial while participating in this study.
Women who are premenopausal, are on a stable contraceptive regimen, and are planning to continue the same regimen through surgery are eligible to participate; for women who are on hormonal contraception regimens that have a placebo phase, the following should be recorded regarding the day of baseline core biopsy and the day of surgery: the agent, whether they are in active or placebo phase, the day of the phase (e.g. day 13 of 21-day active phase or day 4 of 7-day placebo phase); this information will have to be back-calculated for the day of core biopsy, but best attempt should be made
Timing of follicular phase of menstrual cycle:\r\n* For women who are actively menstruating, at least 4 menstrual periods in past 12 months such that there is a reasonable expectation of being able to perform the aspiration in the follicular phase of the cycle (sometime between day 1 and day 10 inclusive, with day one being the first day of bleeding); very light periods and spotting count OR\r\n* Women who have not had 4 menstrual periods in the past year due to Mirena type intrauterine devices (IUDs) or endometrial ablation may be screened, but hormone levels must be assayed 2-4 weeks prior to RPFNA in order to predict when to perform RPFNA so as to be in the follicular phase; lab results and institutional normal ranges must be reviewed by the protocol chair, who will provide an acceptable time window within which to conduct the RPFNA; women who have had their uterus removed, but still have at least one functioning ovary may be screened using the same hormone level check; must be willing to have same assessment of hormones and prediction of follicular phase repeated for the off-study RPFNA
RPFNA performed within 6 months of the study entry visit and in the follicular portion (day 1-10) of the menstrual cycle; note that day 1 is defined as the first day of bleeding; for non-menstruating women, RPFNA during the follicular phase must be confirmed by hormone levels drawn on the day of RPFNA; either clinical laboratory results are sent to protocol chair for assessment of menstrual cycle phase; or an additional frozen serum aliquot is sent to University of Kansas Medical Center (KUMC) for assay of hormone levels and phase confirmation; confirmation of follicular phase will be included in the eligibility report for the potential subject
Attend classes at either Houston Community College (HCC) Central Campus or Coleman Campus (Phase 1 and Phase 2) or Spring Branch Campus (Phase 2)
Own a smartphone capable of receiving texts from the study's text messaging resource (Phase 1 and Phase 2)
Use phone text-messaging features on a regular basis (Phase 1 and Phase 2)
Provide cell phone number (Phase 1 and Phase 2)
Phase I:
Phase II:
PHASE II: Smoking history of 20 or more pack/years of cigarette smoking
For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). Previous chemotherapy for NSCLC is allowed.
Phase 2 Part: Patients who have had prior splenectomy or have had splenic irradiation within 3 months of starting study drug
Phase Ib dose expansions Arms 1, 2 and 3
Plans to move from Kansas Cancer Center (KC) during the treatment and follow-up phase
Patient scheduled for CT that includes the abdomen with a multiphasic contrast enhanced protocol (e.g. triple phase or quadruple phase liver CT)
Eligible for the trial UPCC #01615, “A Phase Ib Tissue Collection Study of Pembrolizumab (MK-3475) in Subjects with Resectable Advanced Melanoma\
Ineligible for the trial UPCC #01615, “A Phase Ib Tissue Collection Study of Pembrolizumab (MK-3475) in Subjects with Resectable Advanced Melanoma\
PHASE I:
PHASE II:
Rollover Cohort: Patients on active Hu5F9-G4 therapy on the Phase 1 AML (SCI-CD47-002) trial who are deriving clinical benefit by Investigator assessment
PHASE II: Women with a first primary ER+, HER2-, LN-, breast cancer < 3 cm immediately after their initial surgical consultation
PHASE I: Women that score > 10 on the Orientation-Memory-Concentration (OMC) test (indicative of dementia)
PHASE I: Women who do not have capacity to participate
PHASE I: Women that answer 3 or more of the questions about the benefits and risks of the study incorrectly will be excluded
PHASE I: Women with capacity to participate but mild cognitive impairment (MCI)
PHASE II: Women who do not have capacity to participate
PHASE II: women who state that there are still deciding on breast cancer treatment
AIM 2: Will consider participants from phase 1 of this study ineligible for this phase of the study
AIM 2: Will not re-screen participants who were considered ineligible for phase 1 of this study, as determined from study records
Able to provide informed consent (Pre-pilot phase, Arms 1-4, PCS study)
Be a phase 1 trial in expansion, phase 2, or 3
Phase 1 trials in dose escalation
PHASE I: Have been registered in 1209 Clinic for at least two years and assigned a primary care physician
PHASE I: Are fluent in Spanish
USABILITY PHASE: Have been registered in 1209 Clinic for at least two years and assigned a primary care physician
USABILITY PHASE: Pregnant women will be eligible to participate
PHASE II: Have been registered at a University of New Mexico (UNM) Clinic for six months and assigned a primary care provider
PHASE II: Are fluent in either English or Spanish
PHASE II: Pregnant women will be eligible to participate
Are eligible to participate in one of the phase III or IV BCCT open at the CTRC at the time of diagnosis
Inclusion Criteria:\n\n        All subjects:\n\n          -  Pathologically confirmed diagnosis of solid tumors\n\n          -  Metastatic disease\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1\n\n          -  Adequate bone marrow, hepatic and renal function\n\n          -  Normal Electrocardiogram (ECG)\n\n          -  18 years of age or above\n\n          -  Able to understand and sign informed consent\n\n        Pilot study only:\n\n        - CRC, TNBC, ER/PR Breast Cancer, NSCLC, Pancreatic Cancer, Ovarian Cancer, Gastric Cancer,\n        Gastroesophageal Junction (GEJ) adenocarcinoma, Head and Neck Cancer\n\n        Expansion Phase Additional Criteria:\n\n          -  Locally advanced or metastatic breast cancer\n\n          -  Received at least one cytotoxic therapy in the locally advanced and metastatic setting\n\n          -  Received ? 5 prior lines of chemotherapy in the metastatic setting\n\n          -  Candidate for chemotherapy\n\n        Expansion Phase Cohort 3 additional inclusion criteria:\n\n          -  Breast cancer with active brain metastasis\n\n          -  Neurologically stable\n\n        Exclusion Criteria:\n\n          -  Active Central nervous system (CNS) metastasis (applies to pilot phase and expansion\n             phase cohort 1 and 2 only)\n\n          -  Clinically significant GI disorders\n\n          -  Prior irinotecan or bevacizumab therapy within last 6 months and for Expansion Phase\n             patients, have received any prior treatment with Topol inhibitor\n\n          -  Known hypersensitivity to MM-398 or ferumoxytol\n\n          -  Inability to undergo MRI\n\n          -  Active infection\n\n          -  Pregnant or breast feeding\n\n          -  Prior chemotherapy administered within 3 weeks, or within a time interval less than at\n             least 5 half-lives of the agent, whichever is longer, prior to the first scheduled day\n             of dosing in this study\n\n          -  Received radiation therapy in the last 14 days\n\n          -  Treated with parenteral iron in the previous 4 weeks
Previous diagnosis of CML accelerated phase or blast crisis
Known second chronic phase of CML after previous progression to AP/BC
The patient has lymphoid Ph+ blast crisis or blast phase CML.
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 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
Tumor amenable to biopsy and willingness to undergo tumor biopsies before and after M6620 (VX-970) treatment during the expansion phase of the trial (biopsies optional during the escalation phase)
During the expansion phase of the protocol, patients must have disease amenable to biopsy and be willing to undergo pre- and post-treatment biopsies
For phase Ib only: Pretreated patients, and not amenable to further therapy with curative intent. This part is open to pretreated patients regardless of the number of previous treatment lines. For phase II only: Patients who received a maximum of two prior systemic regimens for recurrent and/or metastatic disease and not amenable to further therapy with curative intent.
For phase II only: Patients who received more than 2 prior systemic regimens for recurrent and/or metastatic disease (no restriction in the phase Ib part of the trial).
For phase II only: Patients who received cetuximab or another inhibitor of epidermal growth factor receptor are excluded from the phase II of the trial, except if cetuximab was given as part of a primary treatment approach, with no progressive disease for at least 4 months following the end of prior cetuximab treatment.