All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Patients must have completed study drug on arm 1 of A091401 (i.e., last dose of nivolumab) =< 12 months of re-registration to crossover dual agent therapy

Baseline serum PSA value performed with a Food and Drug Administration (FDA)-approved assay (e.g., Abbott, Hybritech) within 120 days prior to registration

NO patients receiving systemic corticosteroids (either intravenous [IV] or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human subjects research must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Participation in any investigational drug study (excluding non-oncology and/or symptom management studies) within 4 weeks prior to registration.

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

The patient must agree not to donate sperm during the study treatment and for 3 months after receiving the last dose of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Patients who are receiving any other chemotherapy or investigational agents; radiation treatment will not be permitted during study treatment; patients can receive radiation therapy (XRT) 4 weeks prior to study drug administration or 4 weeks post study completion or discontinuation; steroids equivalent to prednisone 60 mg daily are permitted prior to study drug administration, but needs to be discontinued 1 day prior to BV administration; patients receiving steroids for lymphoma symptoms should have measurable disease as mentioned above on baseline scans

Sexually active males unless they use a condom during intercourse while taking the drug and for 30 days after stopping treatment and should not father a child in this period; a condom is required to be used by vasectomized men in order to prevent delivery of the drug via seminal fluid

Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study

Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug

Use of immunosuppressant medications in the 2 weeks prior to study drug administration (Cycle 1 Day 1)

Any other radiotherapy or radionuclide require 28-day washout prior to first dose of study drug

Haemopoietic growth factors within 2 weeks prior to receiving study drug.

Patients who have had recent hemoptysis (>= 1/2 teaspoon of red blood within 8 weeks before first dose of study drug) are NOT eligible for participation

Female subjects who are lactating must discontinue nursing prior to the first dose of study drug and refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

Sexually active males unless they use a condom during intercourse while taking drug and for 3 months after stopping midostaurin medication; they should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

All institutional and Food and Drug Administration (FDA) requirements for human studies must be met

Has received treatment with any proscribed treatments within specified time frames prior to study drug administration

Female patients must agree not to breastfeed their infants while on study; patients of child fathering potential (defined as > Tanner stage 2) must use a condom during intercourse while taking the drug during treatment, for 8 weeks after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men during intercourse with a male or female partner in order to prevent delivery of the study drug via semen

Participation in other studies involving investigational drug(s) within 28 days prior to study entry.

Sexually active males must be willing to use a condom during intercourse while taking the study drug and for 150 days after stopping the study drug and should not father a child in this period; a condom is required to be used by vasectomized men in order to prevent delivery of the drug via seminal fluid

Current participation in another clinical trial of a drug or device or past participation within 4 weeks before Baseline or subject is in exclusion period from a previous clinical trial

Male participants must agree to refrain from donating sperm, to abstain or use a condom during the treatment period, and at least 60 days after last dose of study drug

Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of any study drug

Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)

Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

Sexually active males unless they use a condom during intercourse while taking the drug and for 21 days after stopping treatment and should not father a child in this period; Note: A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Prior participation in an investigational study (drug, procedure or device) within 21 days of study day 1.

History of hypersensitivity reactions to study drug or any component of the study drug formulation

Any chemotherapy within the 28 days prior to the first dose of study drug.

Tamoxifen and aromatase inhibitors within 14 days prior to the first dose of study drug.

Fulvestrant within 30 days prior to first dose of study drug.

Received any anti-cancer drug known to have anti-VEGF/VEGFR activity within a period of 5 half-lives of this drug (e.g. 100 days for bevacizumab, 75 days for ramucirumab) prior to the first scheduled dose of MM-310

Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started at least 3 months prior to study drug administration

A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at least 3 months prior to study drug administration

Female participants must not be pregnant, breastfeeding or considering becoming pregnant during the study or for at least 5 or 6 months (for monotherapy and combination therapy participants, respectively) after the last dose of study drug.

Male participants must not be considering fathering a child or donating sperm during the study or for at least 3 or 6 months (for monotherapy and combination therapy participants, respectively) after the last dose of study drug.

Male participants who are considering fathering a child or donating sperm during the study or for at least 3 or 5 months (for monotherapy and combination therapy participants, respectively) after the last dose of study drug.

Inclusion Criteria:\n\n        Phase Ib subjects must meet the following inclusion criteria:\n\n          -  Locally advanced urothelial cancer of bladder with any of the following:\n\n               1. T3-4, N0-2 M0, OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR\n                  medically unfit for surgery, OR cisplatin ineligible. T3 N0 M0 patients can be\n                  included if they are cisplatin ineligible.\n\n               2. Patients who have T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 post-neoadjuvant\n                  chemotherapy who become unresectable OR medically unfit for surgery.\n\n                  Phase II subjects must meet the following inclusion criteria:\n\n          -  Locally advanced urothelial cancer of bladder with any of the following:\n\n               1. T3-4, N0-2 M0 OR Tx N1-2 M0 OR T2 N1-2 M0: Treatment naïve, unresectable, OR\n                  medically unfit for surgery OR cisplatin ineligible. T3 N0 M0 patients can be\n                  included if they are cisplatin ineligible.\n\n               2. T3-4, N0-1 M0 OR Tx N1-2 M0 OR T2 N1-2 M0 patients post-neoadjuvant chemotherapy\n                  who become unresectable OR medically unfit for surgery.\n\n          -  T2, N0, M0 who are ineligible to get cisplatin based chemotherapy.\n\n        All subjects:\n\n          -  Written informed consent and HIPAA authorization for personal health information,\n             obtained from the subject prior to performing any protocol-related procedures,\n             including screening evaluations.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.\n\n          -  Life expectancy of >6 months per treating physician.\n\n          -  Subjects must have archival tissue available from previous TURBT (preferred) or lymph\n             node core biopsy within 8 weeks of treatment or be assessed by the treating urologist\n             to undergo maximal TURBT. The extent of TURBT may vary for each patient and will be\n             determined by the treating urologist. Further, the treating urologist will decide if\n             performing the TURBT is clinically appropriate. If the potential subject does not have\n             tumor amenable to biopsy, there is insufficient tissue for PD-L1 testing or is not\n             clinically appropriate for TURBT, enrollment must be discussed with the\n             sponsor-investigator on a case by case basis.\n\n          -  Histologically proven urothelial carcinoma of bladder with predominant transitional\n             cell component. Adenocarcinoma, squamous cell differentiation, or other atypical\n             histology (such as plasmacytoid or sarcomotoid) of the bladder will be allowed on the\n             study, provided they form <50% of the histology.\n\n          -  Females of childbearing potential must have a negative urine and serum pregnancy test\n             within 3 days of study registration.\n\n        NOTE: Female subjects are considered of child bearing potential unless they are surgically\n        sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral\n        oophorectomy) or they are ?60 years old and naturally postmenopausal for at least 12\n        consecutive months.\n\n          -  Subject is willing and able to comply with the protocol for the duration of the study\n             including undergoing treatment and scheduled visits and examinations including follow\n             up.\n\n        Exclusion Criteria:\n\n          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca\n             staff and/or staff at the study site).\n\n          -  Participation in another clinical study with an investigational product within 2 weeks\n             prior to registration.\n\n          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab.\n\n          -  Previous systemic immunotherapy. Previous use of intravesical BCG is acceptable.\n\n          -  History of another primary malignancy except for:\n\n               1. Malignancy treated with curative intent and with no known active disease ?5 years\n                  before the first dose of study drug and of low potential risk for recurrence.\n                  However adequately treated prostate cancer >3 years ago with no significant\n                  change in PSA for past 6 months can be included. Patients with a history of\n                  prostate cancer must not have any definitive radiation therapy to prostate area.\n\n               2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence\n                  of disease.\n\n               3. Adequately treated carcinoma in situ without evidence of disease e.g., cervical\n                  cancer in situ.\n\n          -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,\n             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal\n             antibodies, other investigational agent) within14 days prior to the first dose of\n             study drug (14 days prior to the first dose of study drug for subjects who have\n             received prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for\n             nitrosourea or mitomycin C).\n\n          -  Mean QT interval corrected for heart rate (QTc) ?470 ms on electrocardiogram (ECG)\n             using Frediricia's Correction.\n\n          -  Current or prior use of immunosuppressive medication within 28 days before the first\n             dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or\n             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of\n             prednisone, or an equivalent corticosteroid.\n\n          -  Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy. (Subjects\n             with irreversible toxicity that is not reasonably expected to be exacerbated by the\n             investigational product may be included (e.g., hearing loss, peripheral neuropathy).\n\n          -  Any prior Grade ?3 Immune-mediated adverse event (imAE) while receiving any previous\n             immunotherapy agent, or any unresolved imAE >Grade 1.\n\n          -  Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects\n             with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within\n             the past 2 years) are not excluded. Patients with h/o completely resolved childhood\n             asthma or atopy will not be excluded. Patients with well-controlled hypothyroidism on\n             thyroxine replacement will be eligible as well.\n\n          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,\n             ulcerative colitis).\n\n          -  History of and/or confirmed pneumonitis.\n\n          -  History of primary immunodeficiency.\n\n          -  History of allogeneic organ transplant.\n\n          -  History of hypersensitivity to durvalumab or any excipient.\n\n          -  History of hypersensitivity to the combination or radiation therapy.\n\n          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable\n             angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active\n             bleeding diatheses including any subject known to have evidence of acute or chronic\n             hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric\n             illness/social situations that would limit compliance with study requirements or\n             compromise the ability of the subject to give written informed consent.\n\n          -  Known history of previous clinical diagnosis of tuberculosis.\n\n          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within\n             30 days of starting treatment with durvalumab.\n\n        Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and\n        are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated\n        vaccines, and are not allowed.\n\n          -  Female subjects who are pregnant, breast-feeding or male or female patients of\n             reproductive potential who are not employing an effective method of birth control. For\n             this study male or female patients of reproductive potential need to employ two highly\n             effective and acceptable forms of contraception throughout their participation in the\n             study and for 90 days after last dose of study drug\n\n          -  Any condition that, in the opinion of the investigator, would interfere with\n             evaluation of study treatment or interpretation of patient safety or study results.\n\n          -  Brain metastases or history of leptomeningeal carcinomatosis.\n\n          -  Subjects with uncontrolled seizures.\n\n          -  Previous definitive radiation to pelvic area.

Subject has received small molecule therapy, radiotherapy, immunotherapy, monoclonal antibodies, investigational drug, or chemotherapy within 14 days before first dose of study drug, with the exception of hydroxyurea

Subject has an uncontrolled active infection requiring treatment and fever 38.3°C or higher 48 hours before the first dose of study drug. Controlled infections (i.e. 3 negative cultures completing antibiotics and/or stable fungal infection in therapy) are allowed provided the subject has a temperature of < 38.3°C within 48 hours of the first dose of study drug.

Inclusion criteria. Patients may be entered in the study only if they meet all of the\n        following criteria:\n\n        1. Adults at least 18 years of age. 2. Eastern Cooperative Oncology Group (ECOG)\n        performance status ?1. 3.\n\n          1. Subjects with histopathologically or cytologically confirmed diagnosis of cutaneous\n             Melanoma, RCC or NSCLC, for whom the use of nivolumab is indicated. NSCLC subjects\n             with EGFR or ALK genomic aberrations in tumor should have disease progression on\n             FDA-approved therapy for these aberrations prior to receiving nivolumab (Phase 1b).\n\n          2. Subjects with histopathologically or cytologically confirmed diagnosis of cutaneous\n             Melanoma, or NSCLC, for whom the use of nivolumab is indicated. NCSLC subjects with\n             EGFR or ALK genomic aberrations in tumor should have disease progression on\n             FDA-approved therapy for these aberrations prior to receiving nivolumab (Phase 2\n             expansion).\n\n          3. Cutaneous melanoma and NSCLC patients whose disease has progressed after achieving PR\n             or CR on previous treatment with antagonists to PD1-PD-L1 axis, or patients whose\n             disease remains stable on previous treatment with antagonists to PD1-PD-L1 axis and\n             modification to treatment is being considered. NSCLC patients with EGFR or ALK genomic\n             aberrations in tumor should have disease progression on FDA-approved therapy for these\n             aberrations prior to receiving nivolumab (Phase 2 expansion).\n\n             4. Subject must have at least one measurable target lesion as defined by Response\n             Evaluation Criteria in Solid Tumors (RECIST) v.1.1.\n\n             5. All prior systemic therapy (chemotherapy, mutation targeting therapy, immune\n             checkpoint therapy), surgical or radiation treatment must have been completed at least\n             4 weeks before study drug administration (2 weeks for palliative radiotherapy, 1 week\n             for minor surgery) pending full recovery from therapy.\n\n             6. The following laboratory results within 7 days prior to study drug administration:\n             Adequate hematopoietic, electrolyte, hepatic, and renal laboratory findings as defined\n             below: WBC ?3000/?L, Neutrophils ?1500/?L, Platelets ?100x103/?L, Hemoglobin ?9.0g/dL\n             independent of transfusion, Creatinine ?1.5mg/dL, AST and ALT ?3x ULN, Alkaline\n             phosphatase ?2.5x ULN unless bone metastases present, Bilirubin ?1.5x ULN (unless\n             known Gilbert's disease where it must be ?3x ULN) and serum albumin ?3.0g/dL.\n\n             7. Life expectancy ?12 weeks. 8. A negative serum pregnancy test at baseline for women\n             of childbearing potential.\n\n             9. Are willing to abstain from heterosexual activity or practice physical barrier\n             contraception prior to time of study entry to at least 5 months after the last day of\n             treatment.\n\n             10. Have the ability to understand and the willingness to sign a written informed\n             consent document.\n\n             Exclusion criteria. Subjects who fulfill any of the following criteria at screening\n             will not be eligible for admission into the study:\n\n               1. History of Grade 3 or above hypersensitivity reactions to other monoclonal\n                  antibodies.\n\n               2. Subjects with a history of a cardiovascular illness including: QTcF >450ms in\n                  male, and >470ms in female, congenital long QT syndrome, congestive heart failure\n                  (New York Heart Association Grade III or IV); unstable angina or myocardial\n                  infarction within the previous 6 months; or symptomatic cardiac arrhythmia\n                  despite medical management.\n\n               3. Uncontrolled hypertension, SBP >160 or DBP >100.\n\n               4. Subjects with untreated, or treated brain metastasis, unless stable for 4 weeks\n                  or more and not requiring steroids.\n\n               5. Presence of leptomeningeal disease.\n\n               6. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled\n                  peptic ulcer disease or recurrent pleural effusion requiring repetitive\n                  palliative thoracentesis within 3 months prior to study entry, except for\n                  subjects with a pleurex port. and immune-mediated toxicity leading to treatment\n                  discontinuation\n\n               7. Active, known, or suspected autoimmune disease, except for type I diabetes\n                  mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such\n                  as vitiligo, psoriasis, or alopecia).\n\n               8. Active uncontrolled bacterial, viral, or fungal infection requiring systemic\n                  therapy.\n\n               9. Known history of testing positive for human immunodeficiency virus (HIV), known\n                  acquired immunodeficiency syndrome (AIDS).\n\n              10. Active hepatitis B (serum hepatitis B surface antigen [HBV sAg] positive), or\n                  hepatitis C (HCV antibody test or serum hepatitis C RNA positive) indicating\n                  acute or chronic infection.\n\n              11. Subjects with a condition requiring systemic treatment with either\n                  corticosteroids (>10mg daily prednisone equivalents) or other immunosuppressive\n                  medications within 14 days of study drug administration. Inhaled or topical\n                  steroids are permitted.\n\n              12. Use of other investigational agent (drug not marketed for any indication) within\n                  28 days or at least 5 half-lives (whichever is longer) before study drug\n                  administration.\n\n              13. Pregnant or breast-feeding women.\n\n              14. Second malignancy unless in remission for 2 years, except for non-melanomatous\n                  skin cancer, carcinoma in situ of the cervix treated with curative intent.\n\n              15. Underlying medical conditions that, in the Investigator's opinion, will make the\n                  administration of study drug hazardous or obscure the interpretation of toxicity\n                  determination or adverse events.\n\n              16. Unwilling or unable to comply with procedures required in this protocol.

Inclusion Criteria:\n\n        Subjects must meet all of the following criteria:\n\n          1. Written and signed informed consent.\n\n          2. Age ? 18 years at the time of study entry.\n\n          3. Subjects must have received and have progressed, are refractory, or are intolerant to\n             standard therapy appropriate for the specific tumor type. Subjects should not have\n             received more than 3 prior lines of systemic therapy for recurrent or metastatic.\n\n          4. Subjects in the dose-escalation phase, must have histologic documentation of advanced\n             solid tumors, excluding primary CNS tumors and hematologic malignancies.\n\n          5. Subjects in the dose-expansion phase, must have recurrent or metastatic disease solid\n             tumors according to treatment arm as specified in the protocol.\n\n          6. Subjects who have received prior therapy with regimens containing CTLA 4, PD L1, or PD\n             1 antagonists are permitted to enroll if additional protocol criteria are met.\n\n          7. Subjects must have at least 1 lesion that is measurable using RECIST guidelines.\n\n          8. Subjects must consent to provide archived tumor specimens for correlative biomarker\n             studies. In the setting where archival material is unavailable or unsuitable for use,\n             subjects must consent and undergo fresh tumor biopsy.\n\n          9. All subjects are encouraged to consent to and provide both pretreatment and on\n             treatment tumor biopsies.\n\n         10. ECOG Performance score of 0 or 1, unless protocol exceptions are met.\n\n         11. In the opinion of the investigator likely to complete ? 8 weeks of treatment.\n\n         12. Adequate hematologic, renal and hepatic function as determined by blood laboratory\n             values.\n\n         13. At the time of Day 1 of the study, subjects with CNS metastases must have been treated\n             and must be asymptomatic and meet the following:\n\n               1. No concurrent treatment, inclusive of, but not limited to surgery, radiation,\n                  and/or corticosteroids\n\n               2. At least 42 days without progression of CNS metastases as evidenced by magnetic\n                  resonance imaging (MRI) or computed tomography (CT) after last day of treatment\n\n               3. At least 14 days since last dose of corticosteroids Note: Subjects with\n                  leptomeningeal disease or cord compression are excluded from the study.\n\n         14. Female subjects of childbearing potential who are sexually active with a\n             non-sterilized male partner must use at least 1 highly effective method of\n             contraception from screening, and must agree to continue using such precautions for\n             180 days after the final dose of investigational product.\n\n         15. Non-sterilized male subjects who are sexually active with a female partner of\n             childbearing potential must use male condom plus, if locally available, spermicide\n             from Day 1 and for 180 days after receipt of the final dose of investigational\n             product.\n\n        Exclusion Criteria:\n\n        Any of the following would exclude the subject from participation in the study:\n\n          1. Prior treatment with TNFRSF agonists\n\n          2. Prior treatment with IMT for certain disease types may be restricted per protocol.\n\n          3. History of severe allergic reactions to any unknown allergens or any components of the\n             study drug formulations\n\n          4. Active or prior documented autoimmune disease within the past 2 years.\n\n          5. Concurrent enrollment in another clinical study, unless it is an observational\n             clinical study or the follow up period of an interventional study\n\n          6. Receipt of any conventional or investigational anticancer therapy not otherwise\n             specified above within 28 days prior to the first dose\n\n          7. Any concurrent chemotherapy, IMT, or biologic or hormonal therapy for cancer\n             treatment.\n\n          8. Unresolved toxicities from prior anticancer therapy.\n\n          9. Systemic therapeutic anticoagulation or daily aspirin dose exceeding 325 mg/per day.\n\n         10. Current or prior use of immunosuppressive medication within 14 days prior to the first\n             dose of MEDI0562 with exceptions as per protocol.\n\n         11. History of primary immunodeficiency, solid organ transplantation, or tuberculosis\n\n         12. Test results indicating active infection with human immunodeficiency virus (HIV) or\n             hepatitis B or C defined by positive serologic testing and confirmatory viral nucleic\n             acid testing\n\n         13. Pregnant or breastfeeding women\n\n         14. Major surgery within 4 weeks prior to first dose of MEDI0562 or still recovering from\n             prior surgery.\n\n         15. Other invasive malignancy within 2 years with the exception of protocol specified\n             criteria\n\n         16. Any uncontrolled intercurent illness or condition that, in the opinion of the\n             investigator, would interfere with evaluation of the investigational product or\n             interpretation of subject safety or study results.

Patient has had chemotherapy within 28 days prior to first administration of study drug.

Patient has not recovered from adverse events due to chemotherapy, immunotherapy, or radiation therapy administered more than 28 days prior to first administration of study drug.

Radiotherapy within 2 weeks of first dose of study drug

Significant GI or variceal bleeding or subdural hematoma within 3 months of the first dose of study drug

Concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, or within 4 weeks prior to study registration

Sexually active males unless they use a condom during intercourse while taking the drug and for 4 months after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Administration of an investigational drug in the 28 days before the first dose of study treatment

Immunomodulating agents <28 days prior to first dose of study drug

Use of other investigational agents from 30 days prior to the Screening Visit through discontinuation of study drug.

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 PO QD or less seven (7) days prior to study drug administration are allowed.

No previous treatment with the specific assigned study drug or any other drug sharing the same target; prior treatment in monotherapy when treated in one of the combination arms in the study is allowed

Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all adverse events (AEs) have either returned to baseline or stabilized

Prior definitive radiation therapy must have been completed at least 6 weeks before study drug administration and the irradiated lesions should show evidence of progression if they are intended to be considered target lesions. Prior palliative radiotherapy must be completed at least 2 weeks before study drug administration. The radiotherapy-related side effects must have resolved before the study entry. No radiopharmaceuticals (strontium, samarium) will be allowed within 8 weeks before study drug administration.

Sexually active males, unless they use a condom during intercourse while taking the drug, and for 21 days after stopping treatment of LEE011 -- should not father a child in this period; a condom is required to be used also by vasectomized male in order to prevent delivery of the drug via seminal fluid

Prior participation in a clinical study of viagenpumatucel-L

Females who are pregnant, breast-feeding, or planning to become pregnant within 3 months after the last dose of study drug and males who plan to father a child while enrolled in this study or within 5 months after the last dose of study drug

Any cytotoxic chemotherapy within 21 days prior to initiation of study drug.

Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from clinically significant adverse events due to cancer therapeutics administered more than 4 weeks prior to the first dose of study drug

Receipt of any type of anticancer antibody (including investigational antibody) within 4 weeks before planned first dose of study drug

Use of potent inhibitor or inducer of CYP3A4/3A5 within 14 days of planned study treatment or expected requirement for use of such a drug during study

Use of a potent inhibitor or inducer of drug transporters or conjugating enzymes within 14 days prior to planned study treatment or expected requirement for use of such a drug during study

Subject has a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug

WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 10 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized

Use of any other experimental drug or therapy within 28 days of starting treatment with abatacept

Had an autologous transplant within 3 months of starting study drug treatment.

Participated in a therapeutic clinical study within 3 weeks before study drug treatment, or current participation in other therapeutic investigational procedures.

Recent (within 4 weeks of registration), current, or planned participation in another experimental drug study

Participants who have received systemic chemotherapy within 3 weeks of starting study drug

Use of any other experimental drug or therapy within 21 days prior to first dose

Completed single-agent trastuzumab emtansine or combination trastuzumab emtansine treatment in the parent study or who continue to receive single-agent trastuzumab emtansine or combination trastuzumab emtansine treatment at the time of the parent study closure and received the last study drug dose within the 6 weeks (42 days) prior to the first dose of study therapy on the extension study or Continue to receive treatment in the control arm of study BO21976/TDM4450g (NCT00679341) at the time of the parent study closure if the participant received the last dose of control arm study drug within the 6 weeks (42 days) prior to the first dose of control arm study therapy in the extension study

History of receiving any investigational treatment or other systemic therapy directed at controlling cancer (e.g., chemotherapy, trastuzumab, etc.) since the participant's last study drug dose in the parent study

Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry

Treatment with antibiotics within 14 days prior to first dose of study drug.

Unresolved or unstable, serious adverse events from prior administration of another investigational drug.

a radiographically confirmed bowel obstruction within 3 months prior to the first dose of study drug

Measureable or evaluable disease by RECIST v1.1 for solid tumors prior to the administration of study drug

Male participants must refrain from donating sperm starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication

Is pregnant or breast feeding or expecting to conceive or father starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication

Inclusion Criteria:\n\n          -  Subject has locally-advanced (unresectable) or metastatic solid tumor malignancy (no\n             limit to the number of prior treatment regimens) that is confirmed by available\n             pathology records or current biopsy as well as:\n\n               -  Subject in the escalation cohort has received all standard therapies (unless the\n                  therapy is contraindicated or intolerable) felt to provide clinical benefit for\n                  the subject's specific tumor type. OR\n\n               -  Subject in an expansion cohort has received at least one standard therapy for the\n                  subject's specific tumor type.\n\n          -  For Korea only: Subject has locally-advanced (unresectable) or metastatic solid tumor\n             malignancy (no limit to the number of prior treatment regimens) that is confirmed by\n             available pathology records or current biopsy and has received all standard therapies\n             (unless the therapy is contraindicated or intolerable) felt to provide clinical\n             benefit for the subject's specific tumor type.\n\n          -  Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or\n             2.\n\n          -  Subject's last dose of prior antineoplastic therapy, including any immunotherapy, was\n             at least 21 days prior to initiation of study drug administration. A subject with\n             epidermal growth factor receptor (EGFR) mutation-positive NSCLC is allowed to remain\n             on EGFR tyrosine kinase inhibitor (TKI) therapy until 4 days prior to the start of\n             study drug administration.\n\n          -  For Korea only: Subject's last dose of prior antineoplastic therapy, including any\n             immunotherapy, was at least 21 days prior to initiation of study drug administration.\n             For drugs with a half-life greater than or equal to 21 days, the investigator should\n             consider if this washout is sufficient. A subject with epidermal growth factor\n             receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is allowed to\n             remain on EGFR tyrosine kinase inhibitor (TKI) therapy until 7 days prior to the start\n             of study drug administration.\n\n          -  Subject has completed any radiotherapy (including stereotactic radiosurgery) at least\n             2 weeks prior to study drug administration.\n\n          -  Subject's adverse events (excluding alopecia) from prior therapy have improved to\n             grade 1 or baseline within 14 days prior to start of study treatment.\n\n          -  Subject with metastatic castration resistant prostate cancer (mCRPC) (positive bone\n             scan and/or soft tissue disease documented by computed tomography (CT) / magnetic\n             resonance imaging (MRI)) meets both of the following:\n\n               -  Subject has serum testosterone ? 50 ng/dL at screening.\n\n               -  Subject has had an orchiectomy or plans to continue androgen deprivation therapy\n                  (ADT) for the duration of study treatment.\n\n          -  Subject has adequate organ function prior to start of study treatment as indicated by\n             the following laboratory values. If a subject has received a recent blood transfusion,\n             the laboratory tests must be obtained ? 4 weeks after any blood transfusion.\n\n          -  Female subject must either:\n\n               -  Be of non-childbearing potential: Postmenopausal (defined as at least 1 year\n                  without any menses for which there is no other obvious pathological or\n                  physiological cause) prior to screening, or documented surgically sterile (e.g.,\n                  hysterectomy, bilateral salpingectomy, bilateral oophorectomy).\n\n               -  Or, if of childbearing potential, agree not to try to become pregnant during the\n                  study treatment and for 6 months after the final study drug administration, and\n                  have a negative urine or serum pregnancy test prior to study drug administration,\n                  and, if heterosexually active, agree to consistently use one form of highly\n                  effective birth control starting at screening and throughout the study treatment\n                  and 6 months after the final study drug administration.\n\n          -  Female subject must agree not to breastfeed starting at screening and throughout the\n             study treatment, and for 6 months after the final study drug administration.\n\n          -  Female subject must not donate ova starting at screening and throughout the study\n             treatment, and for 6 months after the final study drug administration.\n\n          -  A sexually active male subject with female partner(s) who are of childbearing\n             potential is eligible if:\n\n               -  Agree to use a male condom starting at screening and continue throughout the\n                  study treatment, and for 6 months after the final study drug administration.\n\n               -  If the male subject has not had a vasectomy or is not sterile as defined below\n                  the subject female partner(s) is utilizing one form of highly effective birth\n                  control starting at screening and continue throughout the study treatment and for\n                  6 months after the final study drug administration.\n\n          -  Male subject must not donate sperm starting at screening and throughout the study\n             treatment, and for 6 months after the final study drug administration.\n\n          -  Male subject with a pregnant or breastfeeding partner(s) must agree to remain\n             abstinent or use a condom for the duration of the pregnancy or time partner is\n             breastfeeding throughout the study treatment and for 6 months after the final study\n             drug administration.\n\n          -  Subject agrees not to participate in another interventional study while receiving\n             study drug (subjects who are currently in the follow-up period of an interventional\n             clinical trial are allowed).\n\n        Additional Inclusion Criteria for Subjects in the Expansion Cohorts:\n\n          -  Subject meets one of the following:\n\n               -  Subject has the tumor type for which a confirmed response was observed in a\n                  monotherapy or combination therapy dose escalation cohort; or\n\n               -  For an expansion cohort opened due to achieving predicted efficacious exposure,\n                  subject has squamous cell carcinoma of the head and neck (SCCHN).\n\n          -  Subject has at least 1 measureable lesion per Response Evaluation Criteria in Solid\n             Tumors (RECIST) 1.1. The measureable lesion must be outside the field of radiation if\n             subject had prior radiotherapy. Subjects with mCRPC who do not have measurable lesions\n             must have at least one of the following:\n\n               -  Progression with 2 or more new bone lesions; or\n\n               -  Prostate-specific antigen (PSA) progression (defined as a minimum of three rising\n                  PSA levels with an interval of ? 1 week between each determination) within 6\n                  weeks prior to study drug administration and a PSA value at the screening visit ?\n                  2 ng/mL.\n\n          -  Subject consents to provide an available tumor specimen in a tissue block or unstained\n             serial slides obtained within 56 days prior to first dose of study treatment, or\n             subject is an appropriate candidate for tumor biopsy and is amenable to undergoing a\n             tumor biopsy (core needle biopsy or excision) during the screening period.\n\n          -  Subject in a SCCHN monotherapy or combination therapy expansion cohort, is an\n             appropriate candidate for tumor biopsy and consents to undergoing a tumor biopsy (core\n             needle biopsy or excision) during the treatment period as indicated in the Schedule of\n             Assessments.\n\n        Exclusion:\n\n          -  Subject weighs < 45 kg at screening.\n\n          -  Subject has received investigational therapy (other than an investigational epidermal\n             growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in a subject with EGFR\n             activating mutations) within 21 days prior to start of study drug.\n\n          -  Subject requires or has received systemic steroid therapy or any other\n             immunosuppressive therapy within 14 days prior to study drug administration. Subjects\n             using a physiologic replacement dose of hydrocortisone or its equivalent (defined as\n             up to 30 mg per day of hydrocortisone up to 10 mg per day of prednisone) are allowed.\n\n          -  Subject has symptomatic central nervous system (CNS) metastases or subject has\n             evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans).\n             Subjects with previously treated CNS metastases are eligible, if subject is clinically\n             stable and have no evidence of CNS progression by imaging for at least 4 weeks prior\n             to start of study treatment and are not requiring immunosuppressive doses of systemic\n             steroids (> 30 mg per day of hydrocortisone or > 10 mg per day of prednisone or\n             equivalent) for longer than 2 weeks.\n\n          -  Subject has an active autoimmune disease. Subjects with type 1 diabetes mellitus,\n             endocrinopathies stably maintained on appropriate replacement therapy, or skin\n             disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment\n             are allowed.\n\n          -  Subject was discontinued from prior immunomodulatory therapy due to a grade ? 3\n             toxicity that was mechanistically related (e.g., immune related) to the agent.\n\n          -  Subject has known history of serious hypersensitivity reaction to a known ingredient\n             of ASP8374 or pembrolizumab or severe hypersensitivity reaction to treatment with\n             another monoclonal antibody.\n\n          -  Subject has a known history of Human Immunodeficiency Virus.\n\n          -  Subject with positive for Hepatitis B virus (HBV) antibodies and surface antigen\n             (including acute HBV or chronic HBV) or Hepatitis C ([HCV]; ribonucleic acid [RNA]\n             detected by qualitative assay). Hepatitis C RNA testing is not required in subjects\n             with negative Hepatitis C antibody testing.\n\n          -  Subject has received a live vaccine against infectious diseases within 28 days prior\n             to initiation of study treatment.\n\n          -  Subject has a history of drug-induced pneumonitis (interstitial lung disease) or\n             currently has pneumonitis.\n\n          -  Subject has an infection requiring systemic therapy within 14 days prior to study drug\n             treatment.\n\n          -  Subject has received a prior allogeneic bone marrow or solid organ transplant.\n\n          -  Subject is expected to require another form of antineoplastic therapy while on study\n             treatment.\n\n          -  Subject has had a myocardial infarction or unstable angina within 6 months prior to\n             the start of study treatment or currently has an uncontrolled illness including, but\n             not limited to symptomatic congestive heart failure, clinically significant cardiac\n             disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social\n             situations that would limit compliance with study requirements.\n\n          -  Any condition that makes the subject unsuitable for study participation.\n\n          -  Subject has had a major surgical procedure and has not completely recovered within 28\n             days prior to the start of study treatment.

Participant has had prior antineoplastic therapy within 14 days prior to starting study drug.

Participant that received in the 7 days prior to the administration of study drug or is currently receiving any of the following medications:

Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from sexual activity during the study period or for 28 days after study drug discontinuation.

Inclusion Criteria:\n\n          -  Disease Related\n\n               -  Patients must have documented history of histologically confirmed solid tumors\n                  (as defined by ASCO/CAP guidelines) originating in breast, pancreas, prostate,\n                  lung, colon, esophagus, liver, or ovary, and lymphomas, which are locally\n                  advanced or metastatic and who are refractory or intolerant beyond primary\n                  treatment for their malignancy, or for lymphoma patients who are not eligible for\n                  or who have refused autologous or allogenic hematopoietic stem cell transplant\n\n               -  Measurable or evaluable disease documented within one month of the planned\n                  protocol treatment (Treatment Period Cycle 1, Day 1)first dose of study drug (PK\n                  Period Day 1)\n\n               -  ECOG performance score of 0 and 1\n\n               -  Able to swallow capsules/tablets\n\n        Demographic • Male and females who are 18 years or older\n\n        Laboratory Values\n\n          -  Hemoglobin ? 9.0 g/dL\n\n          -  Absolute neutrophil count ? 1500/uL\n\n          -  Platelet count ? 100,000/uL\n\n          -  Serum creatinine ? 1.5 mg/dL or a 24-hour calculated estimated creatinine clearance of\n             ? 60 mL/min\n\n          -  Serum bilirubin ? 1.5 mg/dL\n\n          -  Serum albumin ? 3g/dL\n\n          -  AST (SGOT), ALP and ALT (SGPT) ? 2.5 times upper limit of normal (OR ? 5 times ULN in\n             the presence of known liver metastases)\n\n          -  Prothrombin time (PT)/International Normalized Ratio (INR) and partial thromboplastin\n             time (PPT) ? 1.5 times the upper limit of normal\n\n          -  Serum sodium, potassium, magnesium, calcium and phosphorous levels within\n             institutional normal limits; supplements required to maintain normal electrolyte\n             levels will be permitted\n\n        Ethical\n\n        • Before any study-specific procedure, the appropriate written informed consent must be\n        obtained\n\n        Exclusion Criteria:\n\n        Disease Related\n\n          -  Clinical or radiographical evidence of active brain metastasis\n\n          -  Patients who have not recovered to ? grade 1 toxicities except grade 2 alopecia or\n             neuropathy associated with previous chemotherapy, radiotherapy, biologic, hormone or\n             prior investigational therapies.\n\n        Medications:\n\n          -  Chemotherapy or other cancer, radiation or surgical treatments within 2 weeks or five\n             half-lives (whichever is shorter) of the first dose of study drug (PK Period Day 1)\n             planned first protocol treatment (i.e., cycle 1 day 1) or not yet recovered from\n             respective treatments\n\n          -  Patients who have had allogenic hematopoietic stem cell transplant or allogenic bone\n             marrow transplant\n\n          -  Patients who have had prior solid organ transplant\n\n          -  Patients who are on immune suppression drugs or anti-transplant rejection drugs\n\n        General:\n\n          -  History of any medical or psychiatric condition or addictive disorder, or laboratory\n             abnormality that in the opinion of the investigator, may increase the risks associated\n             with study participation or treatments that may interfere with the conduct of the\n             study or the interpretation of study results\n\n          -  Prior history of clinically significant gastrointestinal bleeding, intestinal\n             obstruction or gastrointestinal perforation within 6 months before planned initiation\n             of study treatment\n\n          -  Uncontrolled diabetes\n\n          -  History of long QT syndrome or clinically significant cardiac arrhythmia, other than\n             stable atrial fibrillation\n\n          -  Mean QTcF > 450 msec in men and mean QTcF > 470 msec in women at screening\n\n          -  Myocardial infarction within the previous 6 months before planned initiation of study\n             treatment\n\n          -  Active infection requiring intravenous antibiotics within 2 weeks of the first dose of\n             study drug (PK Period Day 1) before planned initiation of study treatment\n\n          -  Prior history or current positive tests for hepatitis B, hepatitis C or human\n             immunodeficiency virus\n\n          -  Currently enrolled in or has not yet completed at least 30 days since ending other\n             investigational device or drug study before planned date of first dose, or the patient\n             is currently receiving other investigational agent(s)\n\n          -  Pregnant, planning a pregnancy or breast feeding during the study\n\n          -  Male or female not willing to use adequate contraceptive precautions during the study\n             period\n\n          -  Unwilling or unable to comply with study requirements or not available for follow-up\n             assessments\n\n          -  Any disorder that compromises the ability of the patient to give written informed\n             consent and/or to comply with study procedures.

Has significant, ongoing, co-morbid conditions which would preclude safe delivery of the study drug.

Sexually active males unless they use a condom during intercourse while taking the drug and for 21 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Current, recent (within 4 weeks of the first dose of this study), or planned participation in an experimental drug study with an experimental agent

Non-escalating steroid requirement at the time of consent and study drug initiation for the treatment of CNS symptoms

Subjects must agree while on study drug and for 6 months following the last dose of study drug to:\r\n* Use a condom during sexual activity\r\n* Not donate sperm

Human immunodeficiency virus (HIV) positive subjects with 1 or more of the following:\r\n* Not receiving highly active antiretroviral therapy\r\n* A change in antiretroviral therapy within 6 months of the start of screening (except if, after consultation with the sponsor on exclusion criterion below; a change is made to avoid a potential drug-drug interaction with the study drug)\r\n* Receiving antiretroviral therapy that may interfere with the study drug (consult the sponsor for review of medication prior to enrollment)\r\n* CD4 count < 350 at screening\r\n* An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months of the start of screening

Inclusion Criteria (Solid Tumor Patients):\n\n          1. Patients ?18 years of age,\n\n          2. Must have progressed on all available therapies known to confer benefit for disease\n\n          3. Must have tissue source of tumor cells\n\n          4. Must have 1 measurable lesion according to RECIST Version 1.1\n\n          5. Must have objective evidence of progression of lesions that have been previously\n             irradiated\n\n          6. Must have ECOG performance status of 0-1\n\n          7. Bone Marrow Function: absolute neutrophil count (ANC) ?1500/µL; hemoglobin ?9 g/dL;\n             platelet count ?75,000/µL\n\n          8. Hepatic Function: Total serum bilirubin ?1.5 times the upper limit of normal (ULN;\n             except for patients with known Gilbert syndrome);); serum aspartate aminotransferase\n             (AST)/alanine aminotransferase (ALT), ?32.5×ULN (?5×ULN in the presence of hepatic\n             metastases)\n\n          9. Renal Function: Serum creatinine ?1.5×ULN or creatinine clearance ?50 mL/min based\n             either on urine collection or Cockcroft-Gault estimation\n\n         10. Coagulation Profile: Prothrombin time (PT) - international normalized ratio\n             (INR)/partial thromboplastin time (PTT) ?1.5xULN5×ULN.\n\n        Inclusion Criteria (Hematologic Malignancies):\n\n          1. Patients ?18 years of age, except for patients with ALL who can be ?16 years of age\n\n          2. Morphologically documented relapsed/refractory myelodysplastic syndrome (MDS), acute\n             myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic lymphocytic\n             leukemia (CLL) as defined by World Health Organization (WHO) criteria\n\n          3. Patients with relapsed/refractory MDS, AML, ALL must have progressed on least 1 prior\n             therapy and cannot be a candidate for any available therapies in patients with a\n             rationale for known to confer clinical benefit\n\n          4. For patients with MDS, AML, ALL, or CLL, must have cells obtained either by bone\n             marrow biopsy or blood collection to use for biomarkers that may enrich for DCC-3014\n             response or provide PD information\n\n          5. For CLL, must have measurable disease per International Workshop on Chronic\n             Lymphocytic Leukemia (IWCLL) criteria (Hallek criteria) to allow evaluation of\n             response\n\n          6. May have primary phagocytic malignancies including histocytoses, including Erdheim\n             Chester Disease (as diagnosed in Diamond et al 2014) and Langerhans histiocytoses are\n             eligible if refractory to or unsuitable for other therapies.\n\n          7. ECOG PS of 0-2\n\n          8. Bone Marrow Function: ANC ?1000/µL; hemoglobin ?8 g/dL; platelet count ?75,000/?L.\n\n          9. Hepatic Function: Total serum bilirubin <1.5×ULN; serum AST and ALT <2.5×ULN (?5×ULN\n             in the presence of hepatic metastases).\n\n         10. Renal Function: Serum creatinine <2xULN1.5×ULN, or glomerular filtration rate >2050\n             mL/hr as calculated by CockgroftCockroft-Gault formula.\n\n         11. Serum potassium, magnesium and calcium (corrected for albumin) that are within\n             institutional normal limits or can be corrected with supplementation.\n\n         12. Total serum bilirubin <2xULN (except for patients with known Gilbert syndrome).\n\n         13. Serum AST and ALT <5xULN.\n\n         14. Coagulation Profile: Prothrombin time (PT) - international normalized ratio\n             (INR)/partial thromboplastin time (PTT) ?1.5×ULN.\n\n        Exclusion Criteria (Solid Tumors):\n\n          1. Treatment with anticancer therapy, including investigational therapy, within 2 weeks\n             prior to the administration of study drug. For immediately prior therapies with a\n             half-life longer than 3 days, or if the half-life is not available, the interval must\n             be ?28 days prior to the first administration of study drug.\n\n          2. Unresolved toxicity according to National Cancer Institute Common Terminology Criteria\n             for Adverse Events (NCI-CTCAE), Version 4.03 (ie, >Grade 1 or baseline) from previous\n             anticancer therapy, excluding alopecia.\n\n          3. The patient has known active CNS metastases. Patients with previously treated brain\n             metastases may participate provided that:\n\n               -  They are stable (ie, without evidence of progression by magnetic resonance\n                  imaging [MRI]) for ?4 weeks prior to the first dose of study drug),\n\n               -  All neurologic symptoms have returned to baseline, and\n\n               -  Patients do not require continued steroid therapy or use of enzyme-inducing\n                  antiepileptic drugs. Patients can be switched to a non-enzyme inducing\n                  antiepileptic drug. If signs or symptoms suggest CNS metastases, a brain MRI must\n                  be performed to confirm absence of detectable CNS disease within 2 weeks prior to\n                  receiving study drug.\n\n          4. New York Heart Association class III or IV heart disease, active ischemia or any other\n             uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac\n             arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.\n\n          5. Systemic arterial thrombotic or embolic events, such as cerebrovascular accident\n             (including ischemic attacks) or hemoptysis within 6 months prior to the start of study\n             drug.\n\n          6. Systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial\n             events (eg, pulmonary embolism) within the 1 month prior to the start of study drug.\n             Patients with venous thrombotic events before the start of study drug on stable\n             anticoagulation therapy are eligible.\n\n          7. Baseline prolongation of the rate-corrected QT interval based on repeated\n             demonstration of QT interval corrected (QTc) >450 ms or history of long QTc syndrome.\n\n          8. Left ventricular ejection fraction (LVEF) <50%.\n\n          9. Concurrent treatment with proton-pump inhibitor. Other medications that increase\n             gastric pH, ie, histamine H2 receptor antagonists and antacids may be taken provided\n             they are not administered within 2 hours before or after administration of study drug.\n\n         10. Major surgery within 2 weeks of the first dose of study drug; following major\n             surgeries >2 weeks prior to the first dose of study drug, all surgical wounds must be\n             healed and free of infection or dehiscence.\n\n         11. Any other clinically significant comorbidities, such as uncontrolled pulmonary\n             disease, active infection, or any other condition, which in the judgment of the\n             Investigator, could compromise compliance with the protocol, interfere with the\n             interpretation of study results, or predispose the patient to safety risks.\n\n         12. Malabsorption syndrome or other illness that could affect oral absorption.\n\n         13. Known human immunodeficiency virus, active hepatitis B, active hepatitis C, or active\n             mycobacterium tuberculosis infection.\n\n         14. If female, the patient is pregnant or lactating.\n\n         15. Known allergy or hypersensitivity to any component of the study drug.\n\n         16. Patients with known Gilbert's disease.\n\n        Exclusion Criteria (Hematologic Malignancies):\n\n          1. Concurrent active malignancy with expected survival of less than 1 year.\n\n          2. Graft versus host disease (GVHD) that is not well-controlled on a stable treatment\n             regimen for at least 3 weeks prior to initial dose of study drug.\n\n          3. Cancer-directed therapy within 2 weeks prior to starting treatment, with the exception\n             of hydroxyurea, which is allowed to control white blood cell count.\n\n          4. History of, or current, central nervous system involvement with MDS, AML, or CLL.\n\n          5. Systemic arterial thrombotic or embolic events, such as cerebrovascular accident\n             (including ischemic attacks) or hemoptysis within 2 months prior to the start of study\n             drug.\n\n          6. Systemic venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial\n             events (eg, pulmonary embolism) within the 1 month prior to the start of study drug.\n             Patients with venous thrombotic events before the start of study drug on stable\n             anticoagulation therapy are eligible.\n\n          7. Clinically significant coagulation disorder, such as disseminated intravascular\n             coagulation.\n\n          8. New York Heart Association class III or IV heart disease, active ischemia or any other\n             uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac\n             arrhythmia requiring therapy, uncontrolled hypertension or congestive heart failure.\n\n          9. Baseline prolongation of the rate-corrected QT interval based on repeated\n             demonstration of QTc >450 ms or history of long QTc syndrome.\n\n         10. LVEF <50%.\n\n         11. Concurrent treatment with proton-pump inhibitor.\n\n         12. Major surgery within 2 weeks of the first dose of study drug; following major\n             surgeries >2 weeks prior to the first dose of study drug, all surgical wounds must be\n             healed and free of infection or dehiscence.\n\n         13. Any other clinically significant comorbidities, such as uncontrolled pulmonary\n             disease, active infection, or any other condition, which in the judgment of the\n             Investigator, could compromise compliance with the protocol, interfere with the\n             interpretation of study results, or predispose the patient to safety risks.\n\n         14. Malabsorption syndrome or other illness that could affect oral absorption.\n\n         15. Known human immunodeficiency virus, active hepatitis B, active hepatitis C, active\n             cytomegalovirus (CMV), or active mycobacterium tuberculosis infection.\n\n         16. Active infection that is not well-controlled by antibacterial or antiviral therapy.\n\n         17. If female, the patient is pregnant or lactating.\n\n         18. Known allergy or hypersensitivity to any component of the study drug.\n\n         19. Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype).\n\n         20. Unwillingness to receive infusion of blood products.\n\n         21. Patients with known Gilbert's disease.

Female subject must agree not to breastfeed at screening and throughout the study period and for 45 days after the final study drug administration. Female subject must not donate ova starting at screening and throughout the study period and for 45 days after the final study drug administration.

Male subject must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.

Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry and/or during study participation.

Enrolled in another clinical trial testing a novel therapy or drug within the past 4 weeks.

Has not fully recovered from any effects of major surgery, and is free of significant detectable infection. Surgeries that required general anesthesia must be completed >2 weeks before first study drug administration. Surgery requiring regional/epidural anesthesia must be completed >72 hours before first study drug administration and participants should be recovered.

No previous treatment with the specific assigned study drug or any other drug sharing the same target

Agree not to try to become pregnant during the study for 6 months after the final study drug administration

Female participants must agree not to breastfeed or donate ova throughout the study drug treatment period and for 6 months after the final study drug administration.

Male participants must not donate sperm throughout the study drug treatment period and for 127 days after the final study drug administration.

Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of the study drugs.

An EGFR TKI (e.g., erlotinib, gefitinib, or osimertinib) within 8 days or approximately 5 times the half-life of the specific drug, whichever is longer, of the first dose of study treatment. (If sufficient wash-out time has not occurred due to scheduling or PK properties, an alternative appropriate wash-out time based on known duration and time to reversibility of drug-related adverse events must be agreed upon by Hansoh and the Investigator).

Has had any major cardiovascular event within 6 months prior to study drug administration

Use of drugs that might pose a risk of a drug-drug interaction within 2-7 days before the start of study therapy.

Patients who have received treatment with an investigational drug within 30 days preceding the first dose of study medication

Participates or intends to participate in another drug study (other than observational studies) during the study

Neurological stability for at least 14 days prior to first dose of study drug;

Completed palliative radiotherapy within 7 days of the first dose of study drug.

Some protocol specified treatments prior to the first dose of study drug.

Significant mental illness in the 4-week period preceding drug administration.

Use of other investigational drugs within 28 days prior to study drug administration

Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study drug:

The patient has received an investigational drug within 30 days of the first dose of study drug.

Bisphosphonate therapy (osteoporosis or symptomatic hypercalcaemia) or denosumab (osteoporosis) prior to study drug

Women who are lactating/breastfeeding or who plan to breastfeed while on sudy through 1 week after receiving the last dose of study drug

Women planning to become pregnant while on study through 1 week after receiving the last dose of study drug

Principal Inclusion Criteria for All Patients\n\n          1. Male and female patients ? 18 years of age.\n\n          2. Any prior palliative radiation therapy must have been completed at least 7 days prior\n             to the start of study drugs, and patients must have recovered from any acute adverse\n             effects prior to the start of study treatment.\n\n          3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1.\n\n          4. Baseline laboratory values within 7 days of study drug(s) initiation:\n\n             ANC ? 1500/?L Haemoglobin (Hgb) ?10 g/dL without transfusion in the past 28 days\n             Platelets ? 100,000/?L Alanine aminotransferase (ALT) and aspartate aminotransferase\n             (AST) ? 3 x ULN or ? 5 x ULN if known liver metastases.\n\n             Serum bilirubin within normal limits (WNL) or ?1.5 x ULN in patients with liver\n             metastases, or total bilirubin ?3.0 x ULN with direct bilirubin WNL in patients with\n             well-documented Gilbert's Syndrome.\n\n             Serum creatinine ?1.5 x ULN and creatinine clearance (CrCl) ? 51 mL/min\n\n          5. Female patients who are not of child-bearing potential, and fertile females of\n             childbearing potential who agree to use two highly effective forms of contraception in\n             combination from 2 weeks prior to study treatment and until 1 month after study\n             treatment discontinuation, are not breastfeeding, and must have a negative serum or\n             urine pregnancy test within 28 days of study treatment and confirmed prior to the\n             start of study treatment on first day of dosing.\n\n          6. Male patients should be willing to abstain or use barrier contraception (i.e., condoms\n             with a spermicide) for the duration of the study drug exposure and for 3 months after\n             study treatment discontinuation. Female partners of male patients should also use a\n             highly effective form of contraception if they are of childbearing potential, unless\n             the male patient is abstaining from sexual intercourse.\n\n          7. Predicted life expectancy ? 12 weeks. For patients in Part C the timing of this\n             assessment is applied from the beginning of Stage 2\n\n             Inclusion criteria specific to Part A\n\n          8. Histologically confirmed refractory solid tumour for which there is no known or\n             established treatment available with curative intent, after at least one course of\n             systemic therapy for locally advanced or metastatic disease including chemotherapy,\n             targeted therapy or hormonal therapy.\n\n          9. Measurable or non-measurable disease according to RECIST v1.1\n\n             Inclusion criteria specific to Part B\n\n         10. Relapsed small-cell lung cancer (SCLC) (defined as a histologically confirmed\n             diagnosis of SCLC) with advanced disease (recurrent or metastatic).\n\n         11. Patients must have a confirmed response (either PR or CR) to first-line platinum\n             therapy and then relapsed after completing that treatment. Patients who progressed\n             whilst on platinum-containing treatment (platinum refractory) are not permitted to\n             enter the study. Prior treatment with immunotherapy is permitted..\n\n         12. Has agreed to the collection of archival tumour tissue or recent tumor biopsy sample,\n             if taken for routine clinical purposes at baseline if archival tissue is not available\n             for molecular biomarker analyses.\n\n         13. Measurable disease according to RECIST v1.1 criteria.\n\n        Principal Exclusion Criteria\n\n          1. Prior treatment with a PARP inhibitor.\n\n          2. Use of an investigational drug during the past 30 days or 5 half-lives (whichever is\n             longer) prior to 1st dose of study treatment.\n\n          3. Use of anti-cancer treatment drug ? 21 days or 5 half-lives (whichever is shorter)\n             prior to 1st dose of study treatment. For drugs for which 5 half-lives is ? 21 days, a\n             minimum of 10 days between termination of the prior treatment and administration of\n             study treatment is required.\n\n          4. Radiotherapy (except for palliative reasons) within ? 21 days prior to study\n             treatment.\n\n          5. No other anti-cancer therapy (except for palliative local radiotherapy), biological\n             therapy, or other novel agent is permitted while the patient is receiving study\n             medication.\n\n          6. Major surgical procedures ? 28 days of beginning study treatment, or minor surgical\n             procedures ? 7 days. Patients must have recovered from any of the effects of any major\n             surgery. No waiting period required following port-a-cath placement.\n\n          7. Persistent Grade >1 toxicity from prior cancer therapy (except alopecia or anorexia).\n\n          8. Patient has an inability to swallow oral medications.\n\n          9. Known malignant central nervous system (CNS) disease other than neurologically stable,\n             treated brain metastases, defined as metastasis having no evidence of progression or\n             haemorrhage for at least 2 weeks after treatment. Must be off any systemic\n             corticosteroids for the treatment of brain metastases for at least 14 days prior to\n             enrolment.\n\n         10. Patient has had prescription or non-prescription drugs or other products known to be\n             sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index,\n             or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued\n             2 weeks prior to the olaparib PK sub-study dosing and withheld throughout the study\n             until 2 weeks after the last dose of study drug.\n\n         11. The use of sensitive substrates of CYP3A4, such as atorvastatin, simvastatin and\n             lovastatin are prohibited in this study. Co-administration of aprepitant or\n             fosaprepitant during this study is prohibited.\n\n         12. Herbal preparations are not allowed throughout the study, including but not limited\n             to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone\n             (DHEA), yohimbe, saw palmetto and ginseng. Patients should stop using these herbal\n             medications 7 days prior to first dose of study treatment.\n\n         13. Any known hypersensitivity or contraindication to the components of the study drug\n             AZD1775 or olaparib.\n\n         14. Patients with either previous or current myelodysplastic syndrome/acute myeloid\n             leukaemia or features suggestive of MDS/AML.\n\n         15. Any of the following cardiac diseases currently or within the last 6 months as defined\n             by New York Heart Association (NYHA) ? Class 2.\n\n             Unstable angina pectoris Congestive heart failure Acute myocardial infarction\n             Conduction abnormality not controlled with pacemaker or medication Significant\n             ventricular or supraventricular arrhythmias (patients with chronic rate controlled\n             atrial fibrillation in the absence of other cardiac abnormalities are eligible)\n\n         16. AZD1775 should not be given to patients who have a history of Torsades des pointes\n             (TdP) unless all risk factors that contributed to TdP have been corrected.\n\n         17. Mean resting corrected QTc interval using the Fridericia formula [QTcF]) ? 470 msec\n             for female patients and ? 450 msec for male patients from 3 electrocardiograms (ECGs)\n             performed 2-5 minutes apart at study entry or congenital long QT syndrome. .\n\n         18. Pregnant or breastfeeding.\n\n         19. Serious known active infection at the time of enrolment, or another serious underlying\n             medical condition that would impair the ability of the patient to receive study\n             treatment.\n\n         20. Presence of other known active invasive cancers.\n\n         21. Psychological, familial, sociological, or geographical conditions that do not permit\n             compliance with protocol.\n\n         22. Patients considered a poor medical risk due to a serious, uncontrolled medical\n             disorder, non-malignant systemic disease or active, uncontrolled infection. Examples\n             include, but are not limited to, uncontrolled ventricular arrhythmia, recent (< 3\n             months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal\n             cord compression, superior vena cava syndrome, extensive interstitial bilateral lung\n             disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder\n             that prohibits obtaining informed consent.\n\n         23. Immunocompromised patients, e.g., patients who are known to be serologically positive\n             for human immunodeficiency virus (HIV).\n\n         24. Previous allogeneic bone marrow transplant or non-leukocyte depleted whole blood\n             transfusion within 120 days of genetic sample collection will exclude patients from\n             the pharmacogenetic portion of the study. If a patient declines to participate in the\n             optional exploratory pharmacogenetic research, there will be no penalty or loss of\n             benefit to the patient. The patient will not be excluded from other aspects of the\n             study.

Use of experimental drug within 4 weeks of treatment

Prior corticosteroids as anti-cancer therapy within a minimum of 14 days of first receipt of study drug

Last dose with any of the following agents including but not limited to: etanercept, infliximab, tacrolimus, cyclosporine, mycophenolic acid, alefacept, or efalizumab <28 days prior to first dose of study drug

Planning of any brain local treatment (including but not limited to surgery, stereotactic radiosurgery, whole brain radiation, intrathecal chemotherapy) following the administration of the first dose of study drug.

Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug

Recent infection requiring intravenous anti-infective treatment that was completed =< 14 days before the first dose of study drug

Female subjects who are breastfeeding, or intend to breastfeed during the duration of the study and for 30 days following the last dose of study drug.

Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping study drug and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Pregnant women are excluded from this study; breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 3 months following the last dose of study drug

Between days 28 and 50 post transplantation at the time of initiation of the study drug

Use of any other experimental drug or therapy within 28 days of baseline

Breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

Has received an investigational therapy within 30 days of first dose of study drug

Receiving another experimental drug within 4 weeks of initiation of conditioning (day -6) unless approved by the PI

Inclusion Criteria:\n\n        Patients must meet all of the following criteria in order to be included in the study:\n\n          1. Male or female patients, 18 years of age or older at the time of consent.\n\n          2. Provide written informed consent prior to performing any study-related procedure.\n\n          3. Histologically or cytologically confirmed patients with advanced or metastatic solid\n             tumors for both Dose Escalation and Expansion cohort.\n\n          4. Patients for whom no available treatment options are known to confer clinical benefit.\n\n          5. Measurable disease (i.e., at least one measurable lesion per Response Evaluation\n             Criteria in Solid Tumors (RECIST), version 1.1.\n\n          6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          7. At least 21 days since the last chemotherapy, immunotherapy, biological or radiation,\n             or approved tyrosine kinase inhibitor (TKI) therapy.\n\n          8. Adequate organ function defined as:\n\n               -  Hepatic:\n\n                    -  Serum alanine aminotransferase (ALT) ?3 × upper limit of normal (ULN), ?5 ×\n                       ULN in the presence of liver metastases\n\n                    -  Serum aspartate aminotransferase (AST) ?3 × ULN, ?5 × ULN in presence of\n                       liver metastases\n\n                    -  Serum bilirubin ?1.5 × ULN\n\n               -  Renal:\n\n                  - Creatinine clearance >60 mL/minute using Cockcroft Gault equation\n\n               -  Hematologic:\n\n                    -  White Blood Count (WBC) ?3,500/µL\n\n                    -  Absolute neutrophil count ?1000/µL\n\n                    -  Absolute lymphocytes ? 0.5 ×10 9/l\n\n                    -  Platelets ?75,000/µL\n\n                    -  Hemoglobin ?9 g/dL\n\n          9. Normal coagulation profile except:\n\n               -  International Normalized Ratio (INR) within 1.5 × ULN\n\n               -  Activated partial thromboplastin time (aPTT) within 1.5 × ULN\n\n         10. Patient is willing and able to comply with all protocol required assessments, visits,\n             and procedures, including pretreatment tumor biopsy. Archival tumor biopsies are\n             acceptable at baseline.\n\n         11. Females of childbearing potential must have negative serum pregnancy test prior to\n             starting study therapy, and agree to use a reliable form of contraceptive during the\n             study treatment period and for at least 120 days following the last dose of study\n             drug.\n\n             Subject not of childbearing potential (i.e., permanently sterilized, postmenopausal)\n             can be included in study. Postmenopausal is defined as 12 months with no menses\n             without an alternative medical cause.\n\n             Male patients must agree to use an adequate method of contraception during the study\n             treatment period and for at least 120 days following the last dose of study drug.\n\n         12. Cannot be breast feeding.\n\n        Exclusion Criteria:\n\n        Patients meeting any of the following criteria are ineligible to participate in this study:\n\n          1. Patients currently participating in or has participated in a study of an\n             investigational anticancer therapy received within 28 days prior to the first dose of\n             OBI-888.\n\n          2. Has undergone a major surgical procedure (as defined by the investigator) or\n             significant traumatic injury within 28 days prior to the first dose of OBI-888.\n\n          3. Presence of an active autoimmune or inflammatory disease requiring systemic treatment\n             within the past 2 months or a documented history of clinically severe autoimmune\n             disease that requires systemic steroids or other immunosuppressive medications. Local\n             steroid injections, intermittent use of topical, inhaled, ophthalmologic,\n             intra-articular, topical, or intranasal corticosteroids, or systemic corticosteroids\n             at physiologic doses not to exceed 10 mg/day of prednisone or equivalent would not be\n             excluded from the study.\n\n          4. Presence of primary immunodeficiency or receiving systemic steroids of >10 mg/day of\n             prednisone or equivalent or other immunosuppressive agents within 7 days prior to the\n             first dose of OBI 888.\n\n          5. Has active bacterial, viral, fungal, or mycobacterial infection requiring systemic\n             therapy, including known infection with human immunodeficiency virus (HIV) or active\n             infection with hepatitis B virus or hepatitis C virus.\n\n          6. Patients with a history of solid organ transplant.\n\n          7. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to\n             Grade 0 or 1 (using National Cancer Institute Common Terminology Criteria for Adverse\n             Events [NCI CTCAE] version 4.03), except for alopecia and laboratory values listed in\n             the inclusion criteria.\n\n          8. Receipt of any prior therapy targeting Globo H.\n\n          9. Prior anti cancer mAb within 3 weeks or 5 half lives prior to the first dose of OBI\n             888.\n\n         10. Known hypersensitivity to OBI 888 or its excipients.\n\n         11. Has known central nervous system metastases and/or leptomeningeal metastases.\n\n         12. Any medical co morbidity or psychiatric illness that is life threatening or, in the\n             opinion of the Investigator, renders the patient unsuitable for participation in a\n             clinical trial due to possible noncompliance, would place the patient at an\n             unacceptable risk and/or potential to affect interpretation of results of the study.\n\n         13. Unable or unwilling to complete any study procedures or discontinue any prohibited or\n             restricted medications for the duration of the study.\n\n         14. Positive serum pregnancy test.\n\n         15. Is receiving any concurrent prohibited medication

Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration; surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration

Within 14 days of the first dose of study drug: Neutrophils >= 1500/uL

Use of any other experimental drug or therapy within 28 days of baseline.

The effects of enzalutamide and CRLX101 on the developing human fetus are unknown. For this reason and because androgen receptor antagonists and topoisomerase I inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, all study subjects must agree to use a condom during the study treatment period and for 120 days following the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately.

Patient has previously taken ruxolitinib or is allergic to components of the study drug

Radionuclide treatment within 6 weeks of the first dose of study drug in this study

Treatment with therapeutic doses of metaiodobenzylguanidine (MIBG) ?6 weeks before first dose of study drug

Prior total body irradiation, total craniospinal XRT, or ?50% radiation of pelvis within 6 months of receiving first dose of study drug

Therapy with a growth factor within 7 days of starting study drug

ALLERGIES AND ADVERSE DRUG REACTION

Treatment with an investigational drug study within 28 days of before starting on study treatment

Sexually active males must use a condom during intercourse while taking the drug(s) and for 120 days after stopping study treatment and should not father a child in this period

Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug administration until 90 days after the last dose of study drug.

Non-sterile male subjects must use contraceptive methods with partner(s) prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug; male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug

Subject has received biologic agents (e.g. monoclonal antibodies) for anti-neoplastic intent within 30 days prior to first dose of study drug

Not currently pregnant during the study; participants will be informed that the use of contraceptive pills is contraindicated because it may interfere with the study drug and it may be harmful to the woman who has been diagnosed with breast cancer

Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion.

Concomitant therapy with any other experimental drug

Any cytotoxic chemotherapy or other anticancer drugs from previous treatment regimen or clinical study within 14 days of first dose of study drug

Participants who are WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) and up to 5 months post last dose of study drug(s)

Participants may not concomitantly use statins while on study; however, a patient using statins for over 3 months prior to study drug administration and in stable status without CK rise may be permitted to enroll

Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug.

Patients who have had chemotherapy within 2 weeks prior to first dose of study drug.

Patients with prior investigational drug, chemotherapy, immunotherapy or any prior radiotherapy (except for palliative bone directed therapy) within the past 28 days prior to the first drug administration except if the investigator has assessed that all residual treatment-related toxicities have resolved or are minimal and feel the patient is otherwise suitable for enrollment

CLL therapy, with the exception of ibrutinib within the following timeframes:\r\n* Chemotherapy, external beam radiation therapy, anticancer antibodies within 30 days prior to the first dose of drug on this study\r\n* Corticosteroid use >= 20mg prednisone within 1 week prior to first dose on this study\r\n* Radio- or toxin-conjugated antibody therapy within 10 weeks prior to first dose on this study\r\n* Allogeneic stem cell transplant within 6 months prior to first dose on this study

Presence of another cancer with disease manifestations or therapy that could adversely affect subject safety or longevity, create the potential for drug-drug interactions, or compromise the interpetation of study results.

Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration.

Invasive malignancy that require active systemic chemotherapy or biologics that may cause significant drug-drug interaction with either vemurafenib or obinutuzumab

Treatment with any, investigational therapy within the 4 weeks prior to the initiation of study drug administration

If of reproductive potential, agrees to use a highly effective from of contraception or avoid intercourse during and upon completion of the study and for at least 4 months after the last dose of study drug, and agrees not to retrieve, freeze or donate sperm or ova starting at Screening and throughout the study period, and at least 4 months after the final study drug administration

ADDITIONAL EXCLUSION CRITERIA for subjects on the arm of combination treatment of pembrolizumab and ramucirumab.\r\n* The subject has a known allergy or hypersensitivity to ramucirumab.\r\n* The subject is receiving chronic therapy with any of the following within 7 days prior to the first dose of trial treatment:\r\n** Nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin, ibuprofen, naproxen, or similar agents), or \r\n** Other anti-platelet agents (such as clopidogrel, ticlopidine, dipyridamole, or anagrelide). Aspirin use at doses up to 325 mg/day is permitted.\r\n* The subject received previous systemic chemotherapy with a cumulative dose of > 900 mg/m^2 of epirubicin or > 400 mg/m^2 of doxorubicin. \r\n* The subject has a significant bleeding disorder or vasculitis or had a grade >= 3 bleeding episode within 12 weeks prior to the first dose of study drug.\r\n* The subject experienced any arterial thromboembolic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to the first dose of trial treatment.\r\n* The subject experienced any grade 3 or 4 venous thromboembolic event (VTE) that is considered by the investigator to be life-threatening or that is symptomatic and not adequately treated by anticoagulation therapy, within 6 months prior to the first dose of study drug.\r\n* The subject has symptomatic congestive heart failure (CHF; New York Heart Association IIIV) or symptomatic or poorly controlled cardiac arrhythmia.\r\n* The subject has uncontrolled hypertension, as defined in Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, prior to initiating study treatment, despite antihypertensive intervention. CTCAE version 4.0 defines uncontrolled hypertension as grade > 2 hypertension; clinically, the patient continues to experience elevated blood pressure [systolic > 160 mmHg and/or diastolic > 100 mmHg] despite medications).\r\n* The subject has a history of gastrointestinal (GI) perforation or fistula within 6 months prior to the 1st dose of treatment.\r\n* The subject has an acute or subacute bowel obstruction or history of chronic diarrhea that is considered clinically significant in the opinion of the investigator.\r\n* The subject has a serious non healing: (a) wound, (b) peptic ulcer, or (c) bone fracture, within 28 days prior to the first dose of study drug.

INCLUSION CRITERIA:\n\n          1. Age: Men and women aged ? 18 years,\n\n          2. Signed written informed consent,\n\n          3. Any histologic type of locally advanced or metastatic NSCLC,\n\n          4. Life expectancy of ? 12 weeks,\n\n          5. Measurable or evaluable (cytologically or radiologically detectable disease such as\n             ascites, peritoneal deposits, or lesions which do not fulfill RECIST 1.1 criteria for\n             measurable disease) lesions according to RECIST v1.1 criteria for phase 1 portion. For\n             phase 2, all patients must have RECIST 1.1 measurable disease,\n\n          6. Physiologic function:\n\n               -  Hematologic function: Absolute neutrophil count (ANC) ? 1.5 × 109/L, platelet\n                  count ? 100 × 109/L, and hemoglobin ? 9 g/dL (may have been transfused),\n\n               -  Hepatic function: Total bilirubin level ? 1.5 × the upper limit of normal (ULN)\n                  range and aspartate aminotransferase (AST) and alanine aminotransferase (ALT)\n                  levels ? 2.5 × ULN,\n\n               -  Renal function: Estimated creatinine clearance ? 30 mL/min according to the\n                  Cockcroft-Gault formula (or local institutional standard method).\n\n          7. Pregnancy and contraception:\n\n               -  Pregnancy test: Negative serum or urine pregnancy test at screening for women of\n                  childbearing potential,\n\n               -  Contraception: Highly effective contraception for both male and female subjects\n                  throughout the study and for 90 days after last avelumab treatment administration\n                  if the risk of conception exists.\n\n          8. Ability to comply with protocol requirements,\n\n          9. Willingness to consent and ability to undergo a trucut biopsy to obtain a fresh\n             metastasis or primary tumor biopsy in case no adequate tumoral tissue is available,\n             and to undergo fibroscopy to obtain a biopsy from normal bronchial mucosa,\n\n         10. No serious or medically uncontrolled concomitant conditions that are likely to make\n             the patient unfit for SPRING combination therapy, as per investigator assessment,\n\n         11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.\n\n        EXCLUSION CRITERIA:\n\n          1. Patients with documented oncogenic aberrations at enrollment: EGFR, ALK, ROS1 when\n             available, MET exon 14 skipping when available.\n\n             Note: For Phase 1 portion, all patients with adenocarcinoma histology must have\n             documentation of results for druggable oncogenic aberrations (EGFR mutations, ALK\n             rearrangements, and ROS1 when available) prior to enrollment on the study.\n\n          2. For Phase 1 portion, >2 lines of prior therapy in the metastatic setting.\n\n          3. For the dose escalation phase of the study or until the MTD for the combination\n             regimen has been determined, patients with moderate hepatic impairment defined as AST,\n             ALT, alkaline phosphatase (ALP) >5 times ULN, which would be grade 3 or higher.\n             However patients with liver metastases with AST/ALT ? 5 x ULN can be included in the\n             study.\n\n          4. For Phase 2 portion, any prior therapy in the metastatic setting.\n\n        Clinical exclusion criteria for Phase 1 and Phase 2 studies:\n\n          1. Documented untreated central nervous system metastases (indicated by clinical\n             symptoms, cerebral edema, steroid requirement, or progressive disease in the prior\n             four weeks),\n\n          2. Participants with a history of myocardial infarction within the last 2 years or with\n             significant cardiac arrhythmias uncontrolled by medication or pacemaker,\n\n          3. Participants with any history of interstitial lung disease,\n\n          4. Prior clinically significant toxicities from anticancer agents or radiotherapy which\n             have not regressed to Grade ? 1 severity (NCI-CTCAE version 4.03) apart from\n             peripheral neuropathy and alopecia,\n\n          5. History of any second malignancy in the last two years; patients with prior history of\n             in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with a\n             history of other malignancies are eligible if they have been continuously disease-free\n             for at least two years,\n\n          6. Autoimmune condition requiring medical intervention,\n\n          7. Uncontrolled concomitant illness, active infection requiring i.v. antibiotics,\n\n          8. Participants who are at risk for, or who have a history of arterial thromboembolic\n             events within the past 12 months and/or venous thromboembolic events within the past 6\n             months, or have had any recent active gastrointestinal bleeding,\n\n          9. Prior > G3 hemoptysis, major blood vessel involvement, and/or central cavitations,\n\n         10. Known or suspected drug hypersensitivity to any drug used in the combination,\n\n         11. Difficulty swallowing, malabsorption or other chronic gastrointestinal disease, or\n             conditions that may hamper compliance and/or absorption of the oral drugs,\n\n         12. Any condition (e.g., known or suspected poor compliance, psychological instability,\n             geographical location, etc.) that, in the judgment of the investigator may affect the\n             patient's ability to sign the informed consent and undergo study procedures,\n\n         13. Taking another experimental drugs within 28 days prior to day 1 of the protocol\n             medications in this study,\n\n         14. Pregnant or breast-feeding women,\n\n         15. Both male and female patients of reproductive potential must agree to use a reliable\n             method of birth control, during the study and for 3 months following the last dose of\n             study drug,\n\n         16. Patients currently taking strong CYP3A4 inducers and inhibitors.\n\n         17. Patients currently taking proton pump inhibitors due to their impact on the\n             disposition of palbociclib during the dose escalation phase,\n\n         18. Other anticancer agents and anticoagulants are excluded (except for low doses of\n             anticoagulants used for access lines)\n\n         19. A time period of at least three weeks or five drug half-lives, whichever is shorter\n             must have elapsed from last non-investigational therapy before day 1 of treatment on\n             this study,\n\n         20. Specific exclusion criteria for administration of avelumab, in combination:\n\n               -  IMMUNOSUPRESSANTS: Current use of immunosuppressive medication, EXCEPT for the\n                  following: a. intranasal, inhaled, topical steroids, or local steroid injection\n                  (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic\n                  doses ? 10 mg/day of prednisone or equivalent; c. Steroids as premedication for\n                  hypersensitivity reactions (e.g., CT scan premedication).\n\n               -  AUTOIMMUNE DISEASE: Active autoimmune disease that might deteriorate when\n                  receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo,\n                  psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive\n                  treatment are eligible.\n\n               -  ORGAN TRANSPLANTATION: Prior organ transplantation including allogenic stem-cell\n                  transplantation.\n\n               -  INFECTIONS: Active infection requiring systemic therapy.\n\n               -  HIV/AIDS: Known history of testing positive for HIV or known acquired\n                  immunodeficiency syndrome.\n\n               -  HEPATITIS: Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at\n                  screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening\n                  test positive).\n\n               -  VACCINATION: Vaccination within 4 weeks of the first dose of avelumab and while\n                  on trials is prohibited except for administration of inactivated vaccines.\n\n               -  HYPERSENSITIVITY TO STUDY DRUG: Known prior severe hypersensitivity to\n                  investigational product or any component in its formulations, including known\n                  severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade\n                  ? 3).\n\n               -  CARDIOVASCULAR DISEASE: Clinically significant (i.e., active) cardiovascular\n                  disease: cerebral vascular accident/stroke (< 6 months prior to enrollment),\n                  myocardial infarction (< 6 months prior to enrollment), unstable angina,\n                  congestive heart failure (? New York Heart Association Classification Class II),\n                  or serious cardiac arrhythmia requiring medication.\n\n               -  OTHER PERSISTING TOXICITIES: Persisting toxicity related to prior therapy (NCI\n                  CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ? 2, or\n                  other Grade ? 2 not constituting a safety risk based on investigator's judgment\n                  are acceptable.\n\n               -  Other severe acute or chronic medical conditions including colitis, inflammatory\n                  bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions\n                  including recent (within the past year) or active suicidal ideation or behavior;\n                  or laboratory abnormalities that may increase the risk associated with study\n                  participation or study treatment administration or may interfere with the\n                  interpretation of study results and, in the judgment of the investigator, would\n                  make the patient inappropriate for entry into this study.

Received hydroxyurea therapy within 28 days (4 weeks) before the first dose of any study drug

Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug

Last dose of any prior therapy administered by the following time intervals before the first dose of study drug:

Use of any investigational drug within 14 days prior to the first dose of study drug

Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry and/or during study participation

Male Participants who are sexually active, must agree, from Study Day 1 through at least 90 days after the last dose of study drug, to practice the protocol specified contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 90 days after the last dose of study drug.

At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and

Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug

There are no prohibitions of specific medications on the basis of anticipated drug-drug interactions

Any patient receiving chronic corticosteroid administration prior to study enrollment is ineligible

Patients receiving any other anticancer or experimental drug therapy

Concomitant use of herbal medications at least 7 days prior to the first dose of study drug and throughout participation in the trial.

Must agree not to donate sperm from first dose of study drug through 3 months after the last dose of study drug

Subjects with three or more drug allergies from separate drug classes

Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of any study drug, except for hydroxyurea

Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)

Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

Subjects with three or more drug allergies from separate drug classes

Investigational therapy, defined as any drug that has not been approved for marketing for any indication in cGVHD will be restricted from the study

No investigational therapy within four weeks of the first dose of study drug.

Intolerance to immune checkpoint inhibitor therapy as defined by the occurrence of an adverse drug reaction requiring drug discontinuation (dose escalation cohorts), concurrent anticancer treatment or immunosuppressive agents.

Participation in a clinical trial in which the patient received an investigational drug or device or the off-label use of a drug or device within 3 months of enrollment

Concomitant use of potent CYP3A4/5 inhibitors during the treatment phase of the study and within 72 hours prior to starting study drug administration

Severe/unstable angina within the 6 months prior to study drug administration

Stroke, serious cardiac arrhythmia within the 6 months prior to study drug administration

Patients may not plan to receive any other approved or investigational agents to treat their glioblastoma besides temozolomide prior to the evaluation visit 10 weeks after the initiation of radiotherapy and temozolomide; Note: Exceptions may be made for non-therapeutic intervention at the discretion of the principal investigator; the recently Food and Drug Administration (FDA) approved NovoTTF electric field therapy begins after the study period and is therefore permitted

Current, recent (within 4 weeks of the administration of this study agent), or planned participation in another experimental therapeutic drug study

Current enrollment in an investigational drug or device study or participation in such a study within 30 days of cycle 1 day 1.

WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post treatment completion.

Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 90 days duration of sperm turnover for a total of 5 months post-treatment completion.

Patients must not be scheduled to receive another experimental drug while on this study.

Within 7-10 days of study drug administration: Urinalysis no greater than 1+ hematuria or proteinuria

Breastfeeding should be discontinued until 6 weeks after the last administration of study drug

Surgery within 4 weeks of study drug administration

Another investigational drug within 4 weeks of study drug administration

History of any of the following within the last 3 months before administration of the first dose of study drug:

Non-oncology vaccine therapies for prevention of infectious disease within 4 weeks of study drug administration

Subject has no significant worsening in clinical status for a minimum of 7 days prior to first dose of study drug.

Must not have received myelosuppressive chemotherapy within 21 days prior to study drug administration (42 days if prior nitrosourea).

At least 84 days must have elapsed after stem cell infusion prior to study drug administration

Females who are breastfeeding or pregnant at Screening or Baseline. A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 h before the first dose of study drug.

Phase 1: Received prior therapy with eribulin mesilate within 6 months prior to study drug administration.

Laparoscopic procedure or open biopsy within 7 days prior to study drug administration

Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 2 days prior to study drug administration.

Fine needle aspirate within 3 days prior to study drug administration.

Female subject who is of childbearing potential must agree not to breastfeed starting at screening and throughout the study and for 28 days after the final study drug administration.

Female subject who is of childbearing potential must not donate ova starting at screening and throughout the study and for 28 days after the final study drug administration.

Male subject who is of childbearing potential must not donate sperm starting at screening and throughout the study and, for 90 days after the final study drug administration.

Major surgery (including opening of the abdomen, chest, or skull) within 21 days of the first dose of study drug.

Participants must have discontinued EGFR targeted therapy prior to the first dose of study drug.

The subject has received cytotoxic chemotherapy, molecular targeted therapy, or immunotherapy within 21 days before the first dose of study drug (trametinib)

The following restrictions apply to current or prior anti-cancer treatment, prior to the first dose of study drug:\r\n* Patients who are actively receiving any other investigational agents\r\n* Any chemotherapy, external beam radiation therapy, or anti-cancer antibodies within 2 weeks prior to the first dose of study drug\r\n* Radio- or toxin-immunoconjugates within 10 weeks prior to the first dose of study drug\r\n* Previous treatment with greater than one of the study agents (i.e., venetoclax, ibrutinib, obinutuzumab or Revlimid), excluding prior prednisone or rituximab treatment\r\n* Prior allogeneic stem cell (or other organ) transplant within 6 months or any evidence of active graft-versus-host disease or requirement for immunosuppressants within 28 days prior to first dose of study drug\r\n* Not recovered (i.e., =< grade 1 or baseline) from adverse events due to previously administered anti-cancer treatment, surgery, or procedure; NOTE: exceptions to this include events not considered to place the subject at unacceptable risk of participation in the opinion of the principal investigator (PI) (e.g., alopecia)

Has received radiation therapy within 2 weeks of study drug administration

Within 14 days of the first dose of study drug: Platelets >= 100,000/·L

WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post treatment completion

Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 90 days (duration of sperm turnover) for a total of 7 months post-treatment completion

Patients must not be scheduled to receive another experimental drug while on this study

Treatment with an investigational anti-cancer study drug within 4 weeks prior to study drug administration date.

Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug

Last dose of prior therapy must be > 21 days before the first dose of study drug administration; there is no upper limit to number of prior therapies; however, the patient must have recovered from acute toxicities from the most recent therapy to grade 1 or less

Absolute neutrophil counts of >= 1500/uL (without growth factor support) results within 7 days before study drug administration

Platelet counts >=100,000/uL (without transfusion support) results within 7 days before study drug administration

Patients who have been treated with any investigational drug within 28 days prior to the first dose of study medication, or who are receiving concurrent treatment with other experimental drugs or anti-cancer therapy

Patients may not be taking any corticosteroid for any reason while on study and all corticosteroids must be stopped two weeks prior to initiation of study drug

Administration of any investigational drug within 4 weeks prior to the first dose of study treatment

Inclusion Criteria:\n\n        Disease Related\n\n          1. Subject has confirmed histologic or cytologic evidence of metastatic pancreatic cancer\n             and has no prior treatment for metastatic pancreatic cancer.\n\n          2. Subject has measurable disease using Response Evaluation Criteria in Solid Tumors\n             (RECIST) v 1.1.\n\n          3. Subject has a life expectancy of at least 3 months.\n\n          4. Subject has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.\n\n             Demographic\n\n          5. Males or females ? 18 years of age\n\n          6. Subject must be able to swallow capsules\n\n          7. Subject must have adequate venous access for intravenous (IV) infusion\n\n             Laboratory\n\n          8. Subject has hemoglobin ? 9.0 g/dL at Screening\n\n          9. Subject has absolute neutrophil count (ANC) ? 1.5 x 109/L at Screening\n\n         10. Subject has platelet count ? 100 x 109/L at Screening\n\n         11. Subject has serum creatinine ? 1.5 times the upper limit of normal (ULN) at Screening.\n             Subjects with serum creatinine levels > 1.5 times the ULN must have a 24-hour urine\n             creatinine clearance ? 60 mL/min\n\n         12. Subject has serum bilirubin ? 1.5 times the ULN (except in subjects with Gilbert's\n             Syndrome who must have serum bilirubin < 3.0 x ULN)\n\n         13. Subject has aspartate aminotransferase (AST; SGOT) and alanine aminotransferase (ALT;\n             SGPT) ? 2.5 times the ULN (OR, AST and ALT ? 5 times the ULN in the presence of known\n             liver metastases)\n\n         14. Subject has alkaline phosphatase ? 2.5 times the ULN (OR ? 5 times the ULN in the\n             presence of known liver or bone metastases)\n\n         15. Subject has normal coagulation parameters (prothrombin time [PT] and/or international\n             normalized ratio [INR], and partial thromboplastin time [PTT] within normal limits\n             [<1.2 x ULN])\n\n         16. Subject has potassium concentration within normal range, or correctable with\n             supplements.\n\n         17. Oxygen saturation by pulse oximetry ? 92% at rest.\n\n         18. For women of childbearing potential: Negative serum pregnancy test during screening\n             and negative serum or urine pregnancy test at start of study therapy (Cycle1 Day 1).\n\n             Reproductive\n\n         19. For female subjects of childbearing potential, willingness to abstain from\n             heterosexual intercourse or use a protocol-recommended method of contraception from\n             the screening visit throughout the study treatment period and for 30 days following\n             the last dose of study drug.\n\n         20. Female subjects of non-childbearing potential defined as having amenorrhea for at\n             least 24 consecutive months, a documented hysterectomy, or a documented bilateral\n             oophorectomy)\n\n         21. For fertile male subjects having intercourse with females of childbearing potential,\n             willingness to abstain from heterosexual intercourse or use a protocol-recommended\n             method of contraception from the start of study therapy throughout the study treatment\n             period and for 30 days following the last dose of study drug and to refrain from sperm\n             donation from the start of study treatment throughout the study treatment period and\n             for 30 days following the last dose of study drug.\n\n             Ethical\n\n         22. In the judgment of the investigator, participation in the protocol offers an\n             acceptable benefit-to-risk ratio when considering current disease status, medical\n             condition, and the potential benefits and risks of alternative treatments for the\n             subject's cancer.\n\n         23. Before any study-specific procedure, the appropriate written informed consent must be\n             obtained\n\n        Exclusion Criteria:\n\n        Disease Related\n\n          1. Subject has primary brain tumors or clinical evidence of active brain metastasis\n\n          2. Subject has undergone major surgery within 4 weeks of the start of study treatment.\n             Laparoscopy and central venous catheter placement are not considered major surgery\n\n             Medications\n\n          3. Subject has a history of systemic corticosteroid use within 7 days before Day 1 of\n             Cycle 1\n\n             General\n\n          4. Subject has an active infection requiring parenteral or oral antibiotics within 2\n             weeks before planned start of study therapy\n\n          5. Subject has uncontrolled diabetes as assessed by the investigator\n\n          6. Subject has a second malignancy other than curatively resected basal cell carcinoma of\n             the skin, squamous cell carcinoma of the skin, in situ carcinoma of the cervix, or\n             other cancers treated with curative intent and no known active disease within 3 years\n             before planned start of study therapy\n\n          7. Subject has an active infection of hepatitis B, hepatitis C or human immunodeficiency\n             virus\n\n          8. Female subjects who are pregnant, planning a pregnancy or breast feeding during the\n             study\n\n          9. Subject has a high cardiovascular risk, including, but not limited to, subjects with\n             congestive heart failure (New York Heart Association [NYHA] Class III or IV), cardiac\n             arrhythmia, unstable angina, coronary stenting or acute coronary syndromes within 6\n             months before planned start of study therapy or r myocardial infarction within one\n             year before planned start of study therapy\n\n         10. Subject has a history of peripheral artery disease (e.g., claudication, Leo Buerger's\n             disease).\n\n         11. Subject has a history of prior allogeneic bone marrow progenitor cell or solid organ\n             transplantation.\n\n         12. Subject has known acute or chronic pancreatitis.\n\n         13. Subject has persistent diarrhea, malabsorption, or known sub-acute bowel obstruction ?\n             NCI CTCAE Grade 2, despite medical management.\n\n         14. Subject has any disorder that may interfere with drug absorption, distribution,\n             metabolism, or excretion (including gastrointestinal surgery and bariatric surgery)\n\n         15. All acute toxic effects of any prior antitumor therapy resolved to Grade ? 1 before\n             the start of study therapy (with the exception of alopecia [Grade 1 or 2 permitted],\n             or neurotoxicity [Grade 1 or 2 permitted], or anemia [Grade 2 permitted])\n\n         16. Subject has any other medical, psychiatric, or social condition, which in the opinion\n             of the investigator, would preclude participation in the study, pose an undue medical\n             hazard, interfere with the conduct of the study, or interfere with interpretation of\n             the study results\n\n         17. Subject has a history of interstitial lung disease, slowly progressive dyspnea and\n             unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary\n             hypersensitivity pneumonitis or multiple allergies. Any lung disease that may\n             interfere with the detection or management of suspected drug-related pulmonary\n             toxicity.\n\n         18. Subject is currently enrolled in any other clinical protocol or investigational trial\n             that involves administration of experimental therapy and/or therapeutic devices, or\n             investigational drug.\n\n         19. Subject has a history of hypersensitivity to RX-3117, gemcitabine, azacytidine\n             cytosine arabinoside, paclitaxel, nab-paclitaxel, or their excipients.\n\n         20. Subject is unwilling or unable to comply with study requirements or planned\n             unavailability for follow-up assessments.

To avoid risk of drug exposure through the ejaculate (even men with vasectomies), subjects must use a condom during sexual activity while on study drug and for 3 months following the last dose of study drug. If the subject is engaged in sexual activity with a woman of childbearing potential, a condom is required along with another effective contraceptive method consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies and their partners. Donation of sperm is not allowed while on study drug and for 3 months following the last dose of study drug.

Current, recent (within 3 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study

Are not currently abstinent or do not agree to refrain from sexual activity during the study period and for 6 months after study drug discontinuation;

Use of investigational drug, other than the study medications specified by the protocol, within 30 days of transplantation

Must use a condom when having sex with a pregnant woman from the time of the first dose of study drug through 105 days after last dose of study drug. An additional highly effective form of contraception must be used from the time of the first dose of study drug through 105 days after last dose of study drug when having sex with a non pregnant female partner of childbearing potential.

Must agree not to donate sperm from the first dose of study drug to 105 days after the last dose of study drug.

Patients who have received treatment with an investigational drug within 30 days preceding the first dose of study medication

Anti-cancer therapy less than 14 days prior to the first dose of study drug (less than 28 days for bevacizumab) or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug

Anti-cancer therapy less than 6 weeks prior to the first dose of study drug (less than 28 days for bevacizumab) or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug

Sexually active males unless they use a condom during intercourse while taking drug and for 3 months after the last dose of study treatment; male patients for 3 months should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Patients scheduled for definitive cancer surgical resection less than 7 days from beginning of study drug administration or greater than 6 weeks from beginning of study drug administration

Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration; surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration

Male participants who are sexually active, must agree, from Study Day 1 through at least 180 days after the last dose of study drug, to practice protocol specified methods of contraception. Male subjects must agree to refrain from sperm donation from initial study drug administration through at least 180 days after the last dose of study drug.

At Screening with a serum sample obtained within 14 days prior to the first study drug administration, and

Anti-cancer therapy less than 14 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug

Use of herbal supplements unless discontinued >= 7 days prior to initiation of study drug

Consumption of grapefruit and related fruits within 7 days prior to initiation of study drug

Have known contraindications or sensitivities to the study drug

Patients who have received systemic corticosteroids within 28 days prior to the first dose of study drug

Patients who have received systemic nonsteroidal antiinflammatory drug (NSAID) therapy within 14 days prior to the first dose of study drug

Patients being treated with medications with drug-drug interactions with study agents will require evaluation by to determine if full doses of all study treatments can be given safely; significant drug-drug interactions will need to be addressed prior to enrollment; alternatively, the patient will not be eligible

Patients receiving anti-retroviral therapy or other agents that are contra-indicated with nelfinavir due to drug-drug interactions

Prior somatostatin analogue therapy; (patients should receive the first dose of study drug no sooner than 4 weeks from the last dose of somatostatin analogue)

Subject has started treatment with denosumab < 1 month prior to study entry; subjects are allowed to be on bisphosphonates or denosumab provided they are on a stable dose for >= 4 weeks before administration of study drug

Received investigational drugs within the 14 days before 1st dose of study drug

Chemotherapy, biochemotherapy, radiation or immunotherapy or any investigational treatment within 30 days prior to receiving any study drug.

Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first dose of study drug, or having hypervitaminosis A.

Use of experimental drug therapy for myelofibrosis, or any other standard drug (eg, danazol, hydroxyurea, etc) with the exception of ruxolitinib within 6 months of starting study (combination) therapy and/or lack of recovery from all toxicities from previous therapy (except ruxolitinib) to Grade 1 or better

Inclusion Criteria:\n\n        Patients with NSCLC:\n\n          1. Has histologically- or pathologically-confirmed recurrent/metastatic NSCLC.\n\n          2. If has adenocarcinoma, required to have previously been tested for anaplastic lymphoma\n             kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutations,\n             with results available for collection in this study, and, if positive, has been\n             treated with prior EGFR or ALK therapy.\n\n          3. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and\n             experienced documented, unequivocal progressive disease by either RECIST 1.1 or\n             clinical assessment.\n\n          4. Patients with NSCLC enrolled in Cohort 1 of the Expansion Phase should not have been\n             previously treated with a PD-1/PD-L1-blocking antibody\n\n             Patients in Expansion Phase, Cohorts 2 and 3\n\n          5. Previously treated with a PD-1/PD-L1-blocking antibody and experienced experienced\n             documented, unequivocal radiographic progression of disease by irRECIST, or similar\n             criteria during or within 12 weeks after last dose of such treatment. Patients must\n             have received at least 6 weeks of PD-1/PD-L1 therapy for Cohort 3.\n\n             Patients with Melanoma:\n\n          6. In addition to having been previously treated with a PD-1/PD-L1-blocking antibody\n             (inclusion #5), has a histologically- or cytologically-confirmed diagnosis of\n             unresectable or metastatic melanoma and experienced unequivocal progressive disease\n             during treatment with a BRAF inhibitor if BRAF V600 mutation-positive. Treatment with\n             BRAF inhibitor may occur AFTER treatment with the checkpoint inhibitor.\n\n             Patients in Expansion Phase, Cohort 4 (Colorectal Cancer)\n\n          7. Received at least 1 chemotherapeutic regimen in the advanced/metastatic setting and\n             experienced documented, unequivocal progressive disease by either RECIST 1.1 or\n             clinical assessment. Must have documented mismatch repair-proficient colon cancer as\n             determined by either immunohistochemistry for mismatch repair proteins or PCR-based\n             functional microsatellite instability. Patients with colorectal cancer enrolled in\n             Cohort 4 should not have been previously treated with a PD-1/PD-L1-blocking antibody\n             (i.e., pembrolizumab, nivolumab, MEDI36MEDI4376, or GNE PDL1 [MPDL3280A])\n\n             All Patients\n\n          8. Aged 18 years or older on the day written informed consent is given.\n\n          9. If has brain metastases, must have stable neurologic status following local therapy\n             for at least 4 weeks without the use of steroids or on stable or decreasing dose of\n             ?10 mg daily prednisone (or equivalent), and must be without neurologic dysfunction\n             that would confound the evaluation of neurologic and other AEs.\n\n         10. Evidence of locally recurrent or metastatic disease based on imaging studies within 28\n             days before the first study drug dose:\n\n               -  At least 1 measurable lesion ?20 mm by conventional techniques or ?10 mm by\n                  spiral CT scan or MRI, with the last imaging performed within 28 days before the\n                  first study drug dose. If there is only 1 measurable lesion and it is located in\n                  previously irradiated field, it must have demonstrated unequivocal progression\n                  according to RECIST, version 1.1.\n\n         11. If receiving radiation therapy, has a 2-week washout period following completion of\n             the treatment prior to receiving the first study drug dose and continues to have at\n             least 1 measureable lesion, per above criterion.\n\n         12. ECOG performance status of 0 or 1.\n\n         13. Has acceptable, applicable laboratory parameters.\n\n         14. Female subjects must not be pregnant.\n\n         15. If male, agrees to use an adequate method of contraception\n\n        15. Experienced resolution of toxic effect(s) of the most recent prior chemotherapy to\n        Grade 1 or less (except alopecia). If patient underwent major surgery or radiation therapy\n        of >30 Gy, they must have recovered from the toxicity and/or complications from the\n        intervention.\n\n        17. Willing to have fresh tumor samples collected during screening and at other time points\n        designated as mandatory, per the Schedule of Study Assessments.\n\n        18. Able to understand and give written informed consent and comply with study procedures.\n\n        Exclusion Criteria:\n\n        Patients meeting any of the following criteria are not eligible for study participation:\n\n          1. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form\n             of immunosuppressive therapy within 7 days prior to the first dose of study drug. The\n             use of physiologic doses of corticosteroids may be approved after consultation with\n             the Sponsor.\n\n          2. Active autoimmune disease that has required systemic treatment in past 2 years (i.e.,\n             with disease modifying agents, corticosteroids, or immunosuppressive drugs).\n             Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid\n             replacement therapy for adrenal or pituitary insufficiency) is not considered a form\n             of systemic treatment.\n\n          3. History of interstitial lung disease (ILD).\n\n          4. Allergy to benzamide or inactive components of entinostat.\n\n          5. History of allergies to any active or inactive ingredients of pembrolizumab or severe\n             hypersensitivity (>= Grade 3) to pembroluzumab.\n\n          6. History or current evidence of any condition, therapy, or laboratory abnormality that\n             might confound the results of the study, interfere with the patient's participation\n             for the full duration of the study, or is not in the best interest of the patient to\n             participate, in the opinion of the treating Investigator, including, but not limited\n             to:\n\n               -  Myocardial infarction or arterial thromboembolic events within 6 months prior to\n                  baseline or severe or unstable angina, New York Heart Association (NYHA) Class\n                  III or IV disease, or a QTc interval > 470 msec.\n\n               -  Uncontrolled heart failure or hypertension, uncontrolled diabetes mellitus, or\n                  uncontrolled systemic infection.\n\n               -  Another known additional malignancy that is progressing or requires active\n                  treatment (excluding adequately treated basal cell carcinoma, squamous cell of\n                  the skin, cervical intraepithelial neoplasia [CIN]/cervical carcinoma in situ or\n                  melanoma in situ, or ductal carinoma in situ of the breast). Prior history of\n                  other cancer is allowed, as long as there is no active disease within the prior 5\n                  years.\n\n               -  Has a history of (non-infectious) pneumonitis that required steroids or current\n                  pneumonitis.\n\n               -  Active infection requiring systemic therapy.\n\n               -  Known active central nervous system (CNS) metastases and/or carcinomatous\n                  meningitis.\n\n             Note: Patients with previously treated brain metastases may participate provided they\n             are stable (without evidence of progression by imaging [using the identical imaging\n             modality for each assessment, either MRI or CT scan] for at least 4 weeks prior to the\n             first dose of study drug and any neurologic symptoms have returned to baseline), have\n             no evidence of new or enlarging brain metastases, and are not using steroids for at\n             least 2 weeks prior to the first dose of study drug or are on stable or decreasing\n             dose of ?10 mg daily prednisone (or equivalent). This exception does not include\n             carcinomatous meningitis which is excluded regardless of clinical stability.\n\n          7. Known psychiatric or substance abuse disorders that would interfere with cooperation\n             with the requirements of the study.\n\n          8. Currently participating and receiving study therapy or has participated in a study of\n             an investigational agent and received study therapy or used an investigational device\n             within 4 weeks of the first dose of treatment.\n\n          9. Received a live virus vaccination within 30 days of the first dose of treatment.\n\n         10. Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to baseline or who\n             has not recovered (i.e., ?Grade 1 or at baseline) from AEs due to agents administered\n             more than 4 weeks earlier.\n\n         11. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2\n             weeks prior to study baseline or who has not recovered (i.e., ?Grade 1 or at baseline)\n             from AEs due to a previously administered agent.\n\n             Note: Patients with ?Grade 2 neuropathy or ?Grade 2 alopecia are an exception to this\n             criterion and may qualify for the study.\n\n             Note: If patient underwent major surgery, they must have recovered adequately from the\n             toxicity and/or complications from the intervention prior to starting therapy.\n\n         12. Received transfusion of blood products (including platelets or red blood cells) or\n             administration of colony stimulating factors (including granulocyte-colony stimulating\n             factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF], or\n             recombinant erythropoietin) within 4 weeks prior to the first dose of study drug.\n\n         13. Currently receiving treatment with any other agent listed on the prohibited medication\n             list such as valproic acid, or other systemic cancer agents within 14 days of the\n             first dose of treatment.\n\n         14. If female, is pregnant, breastfeeding, or expecting to conceive, or if male, expect to\n             father children within the projected duration of the study, starting with the\n             screening visit through 120 days after the last dose of study drug.\n\n         15. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).\n\n         16. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C\n             (e.g., hepatitis C virus ribonucleic acid [qualitative]).\n\n         17. For CRC expansion cohort, no prior history of malignant bowel obstruction requiring\n             hospitalization in the 6 months prior to enrollment\n\n         18. For the CRC expansion cohort, no history of uncontrolled ascites, defined as\n             symptomatic ascites and/or repeated paracenteses for symptom control in the past 3\n             months

Known hypersensitivity to study drug and/or drug class

Use of proton-pump inhibitors within 4 days prior to the first dose of study drug. Other medications that increase gastric pH, ie, histamine H2 receptor antagonists and antacids may be taken provided they are not administered within 2 hours before or after administration of study drug.

Major surgeries (eg, abdominal laparotomy) within 4 weeks of the first dose of study drug. Following major surgeries, >4 weeks prior to the first dose of study drug, all surgical wounds must be healed and free of infection or dehiscence.

Participants who are taking proton pump inhibitors (PPIs) within 7 days of the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug.

History of any of the following within the last 6 months before administration of the first dose of study drug:

Agree not to try to become pregnant during the study and for 6 months after the final study drug administration

Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study drug administration.

Female subject must not donate ova starting at Screening and throughout the study period, and for 6 months after the final study drug administration.

Has used any investigational drug (including marketed drugs not approved for this indication) ? 14 days of C1D1. No time limit applies to the use of marketed drugs approved for this indication provided that the subject has progressed on the treatment and all toxicities attributable to the drug have resolved, returned to baseline or stabilized.

Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 21 days after completion of study medication; this includes condom use: a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Patients receiving corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug

Patients must not be scheduled to receive another experimental drug while on this study

Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug, except for hydroxyurea

Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)

Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

Willing to use adequate contraception throughout the study and for 3 weeks after study drug discontinuation

Serum creatinine < 1.5 mg/dl within 7 days prior to starting the study drug or creatinine clearance rate (CCr) ? 50 mL/min within 7 days prior to starting the study drug determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = [(140 - age) x (wt in kg)]/[(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CrCl male)

Patients receiving systemic corticosteroids (either intravenous [IV] or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug

Patients who are taking proton pump inhibitor (PPI) within 7 days before receiving the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug

Exposure to any investigational drug within 4 weeks of study drug administration

Subjects must not have had any prior investigational agents or devices within 4 weeks of beginning study drug

Patients must avoid grapefruit, grapefruit juice, supplements containing grapefruit juice, star fruit, and Seville oranges during the entire study, starting 7 days prior to the first dose of study drug

Receipt of anticancer chemotherapy within 4 weeks before the administration of study drug

Previous immunotherapy or investigational agents within 6 months of first administration of study drug

Currently receiving or has received systemic corticosteroids within 4 weeks prior to starting study drug for management of brain metastases, or who have not fully recovered from side effects of such treatment; steroids for endocrine replacement or receipt of short-course of steroids during the preceding 4 week period as supportive medication such as for drug allergy, anti-emetic, etc. is allowed)

Receipt of anticancer chemotherapy within 4 weeks before the first administration of study drug

Previous immunotherapy or investigational agents within 6 months of first administration of study drug

Has untreated active hepatitis B; Note: to qualify for enrollment, antiviral therapy for HBV must be given for at least 3 months prior to first dose of study drug, and HBV viral load must be less than 100 IU/mL prior to first dose of study drug; those on active HBV therapy with viral loads under 100 IU/mL should stay on the same therapy throughout study treatment; those subjects who are anti-HBc (+) and negative for HBsAg, Anti-HBs, and HBV viral load do not require HBV prophylaxis, but need close monitoring for reactivation

Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, pommelos, or exotic citrus fruits, from 1 day prior to the first dose of study treatment(s) until the last dose of study drug

Inclusion Criteria:\n\n        Dose Escalation and Dose Expansion Cohorts\n\n        Patients must meet all of the following criteria to be eligible for participation in the\n        study:\n\n          1. Female patients, ? 18 years of age at the time of obtaining informed consent.\n\n          2. Patients with a documented (histologically- or cytologically-proven) breast cancer\n             that is locally advanced or metastatic.\n\n          3. Patients with a malignancy that is either relapsed/refractory to standard therapy or\n             for which no standard therapy is available.\n\n          4. Patients with a malignancy that is currently not amenable to surgical intervention due\n             to either medical contraindications or non-resectability of the tumor.\n\n          5. Patients with measurable or non-measurable disease according to the Response\n             Evaluation Criteria In Solid Tumor (RECIST, v1.1).\n\n          6. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of\n             0 or 1 (see APPENDIX B: Performance Status Evaluation).\n\n          7. Life expectancy of greater than or equal to 3 months.\n\n          8. Resolution of all chemotherapy-related or radiation-related toxicities to Grade 1\n             severity or lower, except for stable sensory neuropathy (less than or equal to Grade\n             2).\n\n          9. Patients who are either not of childbearing potential or who agree to use a medically\n             effective method of contraception during the study and during 3 months after the last\n             dose of study drug. (See Appendix H: Forms of contraception).\n\n         10. Patients with the ability to understand and give written informed consent for\n             participation in this trial, including all evaluations and procedures as specified by\n             this protocol.\n\n        Dose expansion Cohort - TNBC\n\n          1. Patients with conditions as follows:\n\n               -  ER <10%, PR <10% by IHC assay; And\n\n               -  HER2 negative based on ASCO CAP guideline\n\n          2. Patients with measurable disease according to the response evaluation criteria in TNBC\n             (RECIST, v1.1)\n\n          3. Patients with measurable disease that can be easily accessed for biopsy.\n\n          4. Relapsed (recurrence or disease progression after achieving a documented clinical\n             response to first- or second-line treatment) or refractory (disease progression while\n             receiving first line or second line treatment). In the case of TNBC, prior initial\n             therapy with at least one known active regimen for TNBC including, but not limited to,\n             any combination of anthracyclines, taxanes, platinum agents, Ixabepilone, and/or\n             cyclophosphamide is required.\n\n        Exclusion Criteria:\n\n        Dose Escalation and Dose Expansion Cohorts Patients meeting any of the following criteria\n        are ineligible for participation in the study.\n\n          1. Women who are pregnant or lactating. Women of child-bearing potential (WOCBP) not\n             using adequate birth control see Appendix H: Forms of contraception.\n\n          2. Patients with known central nervous system (CNS) or leptomeningeal metastases not\n             controlled by prior surgery, radiotherapy or requiring corticosteroids to control\n             symptoms, or patients with symptoms suggesting CNS involvement for which treatment is\n             required.\n\n          3. Patients with primary brain tumors.\n\n          4. Patients with any hematologic malignancy. This includes leukemia (any form), lymphoma,\n             and multiple myeloma.\n\n          5. Patients with any of the following hematologic abnormalities at baseline. (Patients\n             may have received a red blood cell product transfusion prior to study, if clinically\n             warranted.):\n\n               -  Absolute neutrophil count (ANC) < 1,500 per mm3\n\n               -  Platelet count < 100,000 per mm3\n\n               -  Hemoglobin < 8.0 gm/dL\n\n          6. Patients with any of the following serum chemistry abnormalities at baseline:\n\n               -  Total bilirubin ? 1.5 × the ULN for the institution value\n\n               -  AST or ALT ? 3 × the ULN for the institution value (? 5 × if due to hepatic\n                  involvement by tumor)\n\n               -  Creatinine ? 1.5 × ULN for the institution value (or a calculated creatinine\n                  clearance < 60 mL/min/1.73 m2* )\n\n          7. Patients with a significant active cardiovascular disease or condition, including:\n\n               -  Congestive heart failure (CHF)requiring therapy\n\n               -  Need for antiarrhythmic medical therapy for a ventricular arrhythmia\n\n               -  Severe conduction disturbance\n\n               -  Unstable angina pectoris requiring therapy\n\n               -  QTc interval > 450 msec (males) or > 470 msec (females)\n\n               -  QTc interval ? 300 msec\n\n               -  History of congenital long QT syndrome or congenital short QT syndrome\n\n               -  LVEF < 50% as measured by echocardiography or MUGA scan\n\n               -  Uncontrolled hypertension (per the Investigator's discretion)\n\n               -  Class III or IV cardiovascular disease according to the New York Heart\n                  Association's (NYHA) Functional Criteria (see APPENDIX C: New York Heart\n                  Association's Functional Criteria).\n\n               -  Myocardial infarction (MI) within 6 months prior to first study drug\n                  administration\n\n          8. Patients with a known or suspected hypersensitivity to any of the components of\n             OTS167.\n\n          9. Patients with a known history of human immunodeficiency virus (HIV) or active\n             infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).\n\n         10. Patients with any other serious/active/uncontrolled infection, any infection requiring\n             parenteral antibiotics, or unexplained fever > 38ºC within 1 week prior to first study\n             drug administration.\n\n         11. Patients with inadequate recovery from any prior surgical procedure, or patients\n             having undergone any major surgical procedure within 4 weeks prior to first study drug\n             administration.\n\n         12. Patients with any other life-threatening illness, significant organ system\n             dysfunction, or clinically significant laboratory abnormality, which, in the opinion\n             of the Investigator, would either compromise the patient's safety or interfere with\n             evaluation of the safety of the study drug.\n\n         13. Patients with a psychiatric disorder or altered mental status that would preclude\n             understanding of the informed consent process and/or completion of the necessary\n             studies.\n\n         14. Patients with the inability or with foreseeable incapacity, in the opinion of the\n             Investigator, to comply with the protocol requirements.\n\n         15. Any anti-neoplastic agent or monoclonal antibody therapy for the primary malignancy\n             (standard or experimental) within 2 weeks prior to first study drug administration.\n\n         16. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a\n             limited field of radiation for palliation within 1 week of the first dose of study\n             treatment. If acute symptoms of radiation have fully resolved, the extent and timing\n             of radiotherapy for eligibility can be discussed between Investigator and Sponsor.\n\n         17. Patients requiring surgery for the primary or metastatic primary malignancy.\n\n         18. Herbal preparations or related over the counter (OTC) preparations/supplements\n             containing herbal ingredients within 1 week prior to first study drug administration\n             and during study.\n\n         19. Systemic hormonal therapy which is not related to breast cancer treatment (standard or\n             experimental) within 1 week prior to first study drug administration and during study.\n             The following therapies are allowed:\n\n               -  Hormonal therapy (e.g., Megace) for appetite stimulation\n\n               -  Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations\n\n               -  Oral replacement glucocorticoid therapy for adrenal insufficiency\n\n               -  Low-dose maintenance steroid therapy for other conditions (excluding steroid\n                  tapers for brain edema/metastases/radiation)\n\n               -  Hormonal contraceptive therapy (for WOCBP must be combined with non-hormonal\n                  contraceptive equivalent to a double-barrier method)\n\n         20. Any other investigational treatments during study. This includes participation in any\n             medical device or therapeutic intervention clinical trials.\n\n             Dose expansion Cohort - TNBC\n\n         21. Patients with only lesions that cannot be accessed for biopsy.

Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug (25 days) plus 30 days (duration of ovulatory cycle) for a total of 155 days post-treatment completion

Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of the study drug plus 90 days (duration of sperm turnover) for a total of 215 days post-treatment completion; in addition, male subjects must be willing to refrain from sperm donation during this time

Male subjects must be willing to refrain from sperm donation during the entire study and for 5 half-lives of study drug plus 90 days (duration of sperm turnover) after dosing has been completed

Patients scheduled for definitive cancer surgical resection less than 7 days from beginning of study drug administration or greater than 5 weeks from beginning study drug administration

Treatment with any of the following within the specified time frame prior to the study drug administration:

Radiation therapy within 14 days of the first dose of study drug

Platelets ? 100 K/mm^3 (transfusion to achieve this level is not permitted within 2 weeks of first study drug administration)

Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry or used an investigational device within 4 weeks of the first dose of treatment

Prior definitive radiation therapy must have been completed at least 4 weeks before study drug administration; prior palliative radiotherapy should be completed at least 2 weeks before study drug administration; whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) and focal radiation to the sites of pain or bronchial obstruction will be considered palliative; no radiopharmaceuticals (strontium, samarium) within 8 weeks before study drug administration

Prior major surgery must be completed at least 4 weeks before study drug administration; prior minor surgery must be completed at least 1 week before study drug administration and subjects should be recovered; percutaneous biopsies should be completed at least 10 days prior to study drug administration

Anticipated need for concomitant administration of any other experimental drug, or a concomitant chemotherapy, anticancer hormonal therapy, radiotherapy, or immunotherapy during study participation.

Females who are pregnant, breastfeeding, or planning a pregnancy during the treatment period or within 12 months after the last infusion of study drug.

PART 2 GROUP 1 EXCLUSION CRITERIA: Sexually active males unless they use a condom during intercourse while on protocol therapy and for 3 months after study drug discontinuation and thus do not attempt to father a child in this period

PART 2 GROUP 2A EXCLUSION CRITERIA: Sexually active males unless they use a condom during intercourse while on protocol therapy and for 3 months after study drug discontinuation and thus do not attempt to father a child in this period

PART 2 GROUP 3 EXCLUSION CRITERIA: Sexually active males unless they use a condom during intercourse while on protocol therapy and for 3 months after study drug discontinuation and thus do not attempt to father a child in this period

All patients must discontinue anti-platelet agents or anticoagulants 7 days prior to initiation of study drug

Patients requiring hydroxyurea to bring WBC below 10,000/uL prior to study enrollment will require a 48-hour washout prior to starting the study drug

Use of any other experimental drug or therapy within 21 days of baseline

Recent infection requiring intravenous anti-infective treatment that was completed =< 14 days before the first dose of study drug

Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment

Sexually active males must agree to use a condom during intercourse while receiving and for 3 months after the last dose of study treatment; male patients should not father a child for 3 months after the last dose of study treatment; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug

Enrolled on another clinical trial testing a novel therapy or drug

Sexually active males unless they use a condom during intercourse while taking drug and for 3 months after the last dose of the study drug and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Performed 28 days prior to study registration up to the first dose of study drug: platelets >= 100,000 /mcL

Pregnant or lactating patients; patients of childbearing potential must agree to avoid pregnancy during study treatment and for at least two weeks after the last dose of the study drug

Male patients must agree to use condoms during intercourse throughout study drug therapy and the following 12 months.

Exposure to another CD37 targeting drug.

Sexually active males must use a condom during intercourse while taking drug and for three months after the last dose of the study drug; they should not father a child during this period; men who have undergone vasectomy are also required to use a condom during intercourse

Use of any other experimental drug or therapy =< 28 days prior to registration on this study; NOTE: Patients on low dose prednisone (=< 10 mg) for treatment of conditions other than CLL are eligible

Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug

Experimental therapy within 4 weeks prior to first dose of study drug treatment on Study Day 1 of Period A

Disease progression or intolerance to at least two prior Food and Drug Administration (FDA)-approved therapeutic regimens

Allergies and adverse drug reaction

CAPMATINIB EXCLUSION CRITERIA: Sexually active males unless:\r\n* A condom is used during intercourse while taking drug and 7 days after the last dose of entrectinib; male patients should not father a child in the 7 days after the last dose of the study treatment\r\n* Male sterilization has taken place, with appropriate postvasectomy documentation of the absence of sperm in the ejaculate; condom use is also required in vasectomized men in order to prevent delivery of the drug via seminal fluid

CERITINIB EXCLUSION CRITERIA: Sexually active males unless:\r\n* A condom is used during intercourse while taking drug and 7 days after the last dose of entrectinib; male patients should not father a child in the 7 days after the last dose of the study treatment\r\n* Male sterilization has taken place, with appropriate postvasectomy documentation of the absence of sperm in the ejaculate; condom use is also required in vasectomized men in order to prevent delivery of the drug via seminal fluid

REGORAFENIB EXCLUSION CRITERIA: Sexually active males unless:\r\n* A condom is used during intercourse while taking drug and for 3 months after the last dose of entrectinib; male patients should not father a child in the 3 months after the last dose of the study treatment\r\n* Male sterilization has taken place, with appropriate post-vasectomy documentation of the absence of sperm in the ejaculate; condom use is also required in vasectomized men in order to prevent delivery of the drug via seminal fluid

Participants receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy within 30 days from first receipt of study drug

Pharmacologic therapy with agents reported to produce adverse drug-drug interactions. (Table 2)

Radical radiotherapy to the thorax with curative intent within 28 days of initiation of study drug treatment; palliative radiotherapy for bone lesions outside of the thorax or brain within 14 days of the first dose of study treatment; palliative radiotherapy to the brain or thorax within 28 days of the first dose of study drug treatment

Administration of agents with potential QT interval prolonging effects within 14 days prior to the first administration of study drug and while on treatment

Have received NO anti-cancer therapy within 28 days prior to receiving study drug

Have received NO radiotherapy within 14 days prior to receiving study drug

Sexually active males unless they agree to use a condom during intercourse while taking drug and agree to continue for 3 months after the last dose of study treatment; male patients for 3 months should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Male patients should be asked to avoid unprotected sex with all sexual partners but use condoms plus spermicide during the study, and for a washout period of 90 days after the last dose of study drug; where a sexual partner of a male participant is a woman of child-bearing potential, patients should avoid procreation for 90 days after completion of study drug treatment; patients should refrain from donating sperm from the start of dosing until 90 days after discontinuing study treatment; if male patients wish to father children they should be advised to arrange for freezing of sperm samples prior to the start of study treatment

Participation in other studies involving investigational drug(s) (phases 1-4) within 2 weeks before randomization in the current study

Prior participation in this study

Is not breastfeeding at screening and will not breastfeed throughout the study period and for at least 3 months after final drug administration

Inclusion Criteria (Escalation and Expansion Phases)\n\n        Patients must meet the following criteria to be eligible to enroll in the study:\n\n          1. Patients must have histologically confirmed solid tumors or hematologic malignancies.\n             Eligible patients include the following:\n\n             a) GIST patients must have a KIT and PDGFRA mutation and must have progressed on or\n             had an intolerability to at least 1 line of systemic anticancer therapy: i. Patients\n             with a pre-existing resistance mutation to an approved line of therapy are eligible.\n             For example, imatinib resistant mutations including KIT Exon 17 and PDGFRA D842V.\n\n             b) SM patients must have a confirmed diagnosis (confirmed by a central independent\n             pathologist) of advanced SM according to 2016 World Health Organization (WHO) criteria\n             for SM and must have documented KIT mutant disease. SM patients must also have a\n             normal karyotype.\n\n             Advanced SM includes: ASM, SM-AHN, wherein the AHN does not require immediate\n             alternative therapy, such as acute myeloid leukemia. AHNs that are eligible include:\n             low grade myelodysplastic syndrome (MDS) with a high SM burden who require treatment\n             for SM only, myeloproliferative neoplasms (MPNs), MDS/MPN, and HES/CEL], and MCL i.\n             Patients with advanced SM must present with at least 1 eligible C-Finding (organ\n             damage) as outlined in Table 3 of the 2013 International Working\n             Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European\n             Competence Network on Mastocytosis (ECNM) consensus response criteria (Appendix 10.5);\n             please see below for MCL exception) (#iii).\n\n             ii. Patients with imatinib-sensitive KIT mutations must have progressed on or were\n             intolerant to a tryosine kinase inhibitor.\n\n             iii. Patients with histopathologically-confirmed MCL without a C-finding are eligible.\n\n             iv. Patients with symptomatic SSM are eligible. By definition, SSM patients must have\n             at least 2 B-findings, and clinically significant symptom burden (eg, flushing,\n             diarrhea, etc.) despite maximal treatment with approved agents to treat mediator\n             symptoms, such as antihistamines and cromolyn sodium. Patients must have a normal\n             karyotype.\n\n             v. Patients with hematologic malignancies featuring clonal expansion of eosinophils\n             driven by genomic alterations of KIT or PDGFR (eg, HES or CEL) must have a diagnosis\n             confirmed by a central independent pathologist and are eligible if they have\n             progressed on or are intolerant of imatinib therapy. Patients with de novo imatinib\n             resistant mutations, such as but not limited to KIT D816V or PDGFRA D842V, are\n             eligible without prior imatinib therapy.\n\n             c) Malignant glioma patients with genomic alterations potentially conferring\n             sensitivity to DCC-2618 including, but not limited to, amplification and/or mutations\n             of PDGFRA and/or KIT.\n\n             i. Patients must not require use of enzyme-inducing antiepileptic drugs. ii. Patients\n             that require steroids must be on a stable dose for 2 weeks prior to the first dose of\n             study drug.\n\n             d) Other solid tumor patients that have alterations in genes encoding kinases that are\n             targets of DCC-2618. This includes KIT, PDGFR (A or B), TIE2, CSF1R, and VEGFR2.\n             Patients must have received approved treatments known to provide clinical benefit\n             prior to study entry.\n\n             e) If signs or symptoms suggest CNS metastases, a brain MRI must be performed to\n             confirm absence of CNS disease within 1 week prior to receiving study drug.\n\n          2. Patients with known CNS metastases may participate provided that:\n\n               1. they are stable (ie, without evidence of progression by magnetic resonance\n                  imaging [MRI]) for at least 4 weeks prior to the first dose study drug (patients\n                  with active disease may be eligible following discussion between the Investigator\n                  and the Sponsor),\n\n               2. all neurologic symptoms have been stable for 2 weeks prior to the first dose of\n                  study drug,\n\n               3. patients must not require use of enzyme-inducing antiepileptic drugs,\n\n               4. patients that require steroids must be on a stable dose for 2 weeks prior to the\n                  first dose of study drug.\n\n          3. Patients with solid tumors (with the exception of glial tumors and tumors that are\n             anatomically inaccessible) must have an archival tumor biopsy sample as long as no\n             anticancer therapy was administered since the sample was collected; otherwise, a\n             current biopsy is required. In the case of glial tumors and anatomically inaccessible\n             tumors, the most recent archival tissue is required.\n\n          4. Male or female patients ?18 years of age.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of ?2.\n\n          6. Female patients of childbearing potential must have a negative serum beta?human\n             chorionic gonadotropin (?-hCG) pregnancy test within 28 days prior to the start of\n             study drug. For clinical sites in the UK, pregnancy testing must occur within 7 days\n             prior to the start of study drug.\n\n          7. Patients of reproductive potential must agree to follow the contraception requirements\n             outlined in Section 6.8.11.\n\n          8. The patient is capable of understanding and complying with the protocol and has signed\n             the informed consent document. A signed informed consent form must be obtained before\n             any study?specific procedures are performed. Standard procedures performed as part of\n             the practice of medicine prior to consent (eg, imaging, physical exam) can be used to\n             determine eligibility if completed within 28 days prior to the initial dose of study\n             drug.\n\n          9. Patients with solid tumors must have at least 1 measurable lesion according to RECIST\n             Version 1.1 (non-nodal lesions must be ?1.0 cm in the long axis or ?double the slice\n             thickness in the long axis; nodal lesions must be ?1.5 cm in the short axis) or\n             Response Assessment in Neuro-Oncology Criteria (RANO).\n\n             a) A non-brain lesion in a previously irradiated area is eligible to be considered as\n             measurable disease as long as there is objective evidence of progression of the lesion\n             before study enrollment.\n\n         10. Adequate organ function and bone marrow function as indicated by the following central\n             laboratory screening assessments performed within 14 days prior to the first dose of\n             study drug. Local laboratory values obtained after screening and prior to Cycle 1 Day\n             1 dosing that do not meet the criteria below must be discussed with the Sponsor:\n\n               1. Solid Tumor Patients: Bone Marrow Function: Absolute neutrophil count (ANC)\n                  ?1500/?L; hemoglobin ?9 g/dL; platelet count ?75,000/?L.\n\n               2. All Patients:\n\n             i. Hepatic Function: Serum direct bilirubin ?1.5 times the upper limit of normal (ULN)\n             (?3 × ULN if this elevation is solely due to ASM/MCL); aspartate transaminase\n             (AST)/alanine transaminase (ALT), ?3 × ULN (?5 × ULN in the presence of hepatic\n             metastases or if this elevation is solely due to ASM/MCL).\n\n             ii. Renal Function: Serum creatinine ?2.0 × ULN or creatinine clearance ?50 mL/min\n             based either on urine collection or Cockcroft Gault estimation.\n\n             iii. Coagulation Profile: Prothrombin time (PT) - international normalized ratio\n             (INR)/partial thromboplastin time (PTT) ?1.5 × ULN. Patients on a stable, maintenance\n             regimen of anticoagulant therapy for at least 30 days prior to study drug\n             administration may have PT/INR measurements >1.5 × ULN if, in the opinion of the\n             Investigator, the patient is suitable for the study. An adequate rationale must be\n             provided to the Sponsor prior to enrollment.\n\n             c) SM patients with one or more inadequate organ function laboratory value may be\n             eligible if both the Investigator and Sponsor deem it to be disease-related and the\n             abnormality qualifies as a C-Finding (see Appendix 10.5).\n\n         11. Resolution of all toxicities from prior therapy to ?Grade 1 (or baseline) within 1\n             week prior to the first dose of study drug (excluding alopecia and ?Grade 3 clinically\n             asymptomatic lipase, amylase, and creatine phosphokinase laboratory abnormalities).\n\n        Exclusion Criteria (Escalation and Expansion Phases)\n\n        Patients meeting any of the following criteria will be excluded from the study:\n\n          1. GIST patients with wild type or unknown KIT or PDGFRA status.\n\n          2. Patients with SM or other hematologic malignancies will be excluded if the following\n             apply:\n\n               1. SM patients with wild type KIT mutational status.\n\n               2. SM patients with neutropenia accompanied by fever or infection, or\n                  thrombocytopenia associated with clinically significant bleeding.\n\n                    -  Patients with an infection that is well controlled with antibiotics are\n                       eligible if there is an immediate need for treatment\n\n               3. SM-AHN patients diagnosed with:\n\n             i. SM with MDS (SM-MDS) who require treatment for MDS. ii. Patients requiring\n             immediate treatment for AHN. d) Patients with leukemias, with the exception of MCL and\n             CEL, that have progressed after imatinib.\n\n             e) Eosinophilic myeloproliferative neoplasm patients: i. Lacking a mutation that is a\n             known target of DCC-2618. This includes, but is not limited to, fusions/mutations of\n             FGFR1, JAK2, and ABL.\n\n          3. Has a known additional malignancy that is progressing or required active treatment\n             within 3 years of the first dose of study treatment. Exceptions include basal cell\n             carcinoma of the skin, squamous cell carcinoma of the skin that has undergone\n             potentially curative therapy, or other in situ cancers.\n\n          4. Treatment with anticancer therapy, including investigational therapy, within 2 weeks\n             prior to the administration of study drug, with the exception of hydroxyurea that is\n             allowed to control white blood cell count. For prior therapies with a half-life longer\n             than 3 days, the interval must be at least 28 days prior to the first administration\n             of study drug.\n\n          5. New York Heart Association class III and IV heart disease, active ischemia or any\n             other uncontrolled cardiac condition such as angina pectoris, clinically significant\n             cardiac arrhythmia requiring therapy, uncontrolled hypertension or congestive heart\n             failure.\n\n          6. Arterial thrombotic or embolic events such as cerebrovascular accident (including\n             ischemic attacks) or hemoptysis within 6 months before start of study drug.\n\n          7. Venous thrombotic events (eg, deep vein thrombosis) or pulmonary arterial events (eg,\n             pulmonary embolism) within the 3 months before start of study drug. Patients with\n             venous thrombotic events ?3 months before start of study drug on stable\n             anticoagulation therapy are eligible.\n\n          8. Baseline prolongation of the rate-corrected QT interval based on repeated\n             demonstration of QT interval corrected by Fridericia's formula (QTcF) >450 ms in males\n             or >470 ms in females or history of long QT interval corrected (QTc) syndrome.\n\n          9. LVEF <50% or below the lower limit of normal (whichever is higher).\n\n         10. Major surgery within 4 weeks of the first dose of study drug; following major\n             surgeries >4 weeks prior to the first dose of study drug, all surgical wounds must be\n             healed and free of infection or dehiscence.\n\n         11. Any other clinically significant comorbidities, such as uncontrolled pulmonary\n             disease, active infection, or any other condition, which in the judgment of the\n             Investigator, could compromise compliance with the protocol, interfere with the\n             interpretation of study results, or predispose the patient to safety risks.\n\n         12. Malabsorption syndrome or other illness that could affect oral absorption.\n\n         13. Known human immunodeficiency virus or active hepatitis C infection only if the patient\n             is taking medications that are described in Section 5.8.2.2, active hepatitis B, or\n             active hepatitis C infection.\n\n         14. If female, the patient is pregnant or lactating.\n\n         15. Known allergy or hypersensitivity to any component of the investigational drug\n             product.

Participants who have received any of the following prior to the first dose of study drug:

Radiation therapy within four weeks prior to administration of the first dose of study drug • To be eligible for study treatment, radiation therapy-related toxicity must recover to Grade ? 1 prior to administration of the first dose of study drug. Concurrent palliative radiotherapy for local pain-control may be allowed, provided the subject does not meet criteria of progressive disease and treated lesions will not be included in the target/non-target lesion assessment.

Any of the following within 6 months prior to study drug administration:

Performed within 28 days prior to study registration up to the first dose of study drug: Platelets >= 100,000 /mcL

Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 3 weeks prior to the first dose of study drug.

Current, recent (within 4 weeks of the first infusion of this study), or planned participation in any other experimental drug study

Received any investigational compound within 28 days prior to the first dose of study drug or planned during the treatment period or follow-up

Patients who are on warfarin and cannot have a drug substitution or who decline the drug substitution

Male subjects must not donate sperm from initial study drug administration, until 90 days after drug discontinuation.

Patient has completed participation in one of the ONC201 protocol, has not shown tumor progression while on study treatment, and has tolerated the study drug without unacceptable toxicities

Sexually active males unless they use a condom during intercourse while taking drug and for 31 weeks after the last dose of study treatment.

Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are not permitted during the study.

Participated in a therapeutic clinical study within 3 weeks before study drug treatment, or current participation in other therapeutic investigational procedures.

Use of any other experimental drug or therapy within 14 days of baseline

Sexually active males unless they agree to use a condom during intercourse while taking drug and agree to continue for 3 months after the last dose of study treatment; male patients for 3 months should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Subjects on any immunomodulatory drug

Subject considered by the investigator as unsuitable candidate for receipt of an investigational drug, or unstable to be followed up throughout the entire duration of the study

Patients who have received the last administration of nitrosourea or mitomycin-C =< 6 weeks prior to starting study drug

WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment completion

Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 90 days duration of sperm turnover for a total of 31 weeks post-treatment completion

Patients must not be scheduled to receive another experimental drug while on this study

Current, or recent (within 4 weeks of the first treatment of this study) cytotoxic chemotherapy (e.g. cisplatin, taxol) or experimental drug therapy, or planned participation in an experimental drug study

Patients who are taking proton pump inhibitor (PPI) within 7 days before receiving the first dose of study drug or who require treatment with PPIs throughout the trial or those who are taking H2 receptor antagonists within 24 hours of the first dose of study drug

Patients who have taken part in an experimental drug study within 4 weeks of initiating study treatment with sonidegib

Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study

Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping study drug and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Patients who have taken part in an experimental drug study =< 4 weeks prior to registration

Subject has a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug

Baseline serum PSA value performed with an Food and Drug Administration (FDA)-approved assay (e.g., Abbott, Hybritech) within 12 weeks (90 days) prior to registration

Women who:\r\n* Are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after cessation of study drug, or\r\n* Have a positive pregnancy test at baseline, or\r\n* Are pregnant or breastfeeding

Sexually active males unless they use a condom during intercourse while taking the drug and for 15 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Participation in an investigational drug or device study within 14 days of the first day of dosing on this study

Prior illicit drug addiction

Patient is simultaneously participating in another investigational drug or device study

Patients who are unable to refrain from the use of any nonsteroidal anti-inflammatory drug (NSAID) or full-dose acetylsalicylic acid (ASA)-containing NSAID while taking study drug

Patient is currently participating in a Novartis Oncology sponsored study receiving pasireotide (LAR and/or s.c.) and has fulfilled all required assessments in the parent study (unless the study is being terminated) and patients that are benefiting from the study drug have no other alternatives

Sexually active males unless they use a condom during intercourse while taking drug and for 1 months after pasireotide s.c. last dose and 3 months after pasireotide LAR last dose and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid If a study patient or partner becomes pregnant or suspects being pregnant during the study or within 1 month after the final dose of pasireotide s.c. or 3 months after the final dose of pasireotide LAR, the Study Doctor needs to be informed immediately and ongoing study treatment with pasireotide has to be stopped immediately For patients taking pasireotide LAR, the future dose injections will be cancelled.

For the MF and MDS/MPN-U arms (arms 1 & 2), use of any other standard drug (except hydroxyurea, anagrelide, growth factors, Revlimid, clofarabine, etc) or experimental drug or therapy within 14 days of starting study therapy

Prior illicit drug addiction

Use of any other experimental drug or therapy within 21 days of study-related drug therapy

Less than or equal to (</=) 96 hours between onset of ILI and first dose of study drug

Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or prior anti-cancer treatment

Previous enrollment on another study involving the investigation of veliparib (ABT-888), with the exception of receiving a single dose of study drug

Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug

Use of any other experimental drug or therapy within 28 days of baseline

Must not donate sperm starting at screening throughout the study period and for 90 days after the final study drug administration.

Received radiotherapy ?14 days prior to the first dose of AP32788 of study drug.

Receipt of anticancer medications, anticancer therapies, or investigational drugs within the defined interval before the first administration of study drug.

Receipt of anticancer medications or investigational drugs within a defined interval before the first administration of study drug.

Participants in Study Part C must have HR+ breast cancer, NSCLC, or melanoma with brain lesions clinically indicated for surgical resection as well as consent to provide tissue for drug concentration determination after 5 to 14 days of study drug dosing.

All Institutional, Food and Drug Administration (FDA) and National Cancer Institute (NCI) requirements for human studies must be met

Patients receiving any other anticancer or experimental drug therapy

Planned participation in any other experimental drug study

Baseline serum PSA value performed with a Food and Drug Administration (FDA)-approved assay (e.g., Abbott, Hybritech) within 60 days prior to registration

All institutional and Food and Drug Administration (FDA) requirements for human studies must be met

Use of any other experimental drug or therapy =< 28 days prior to registration

Use of any other experimental drug or therapy within 28 days of baseline.

Food and Drug Administration (FDA) approval to receive compassionate use of TheraSphere

agree not to try to become pregnant during the study and for 6 months after the final study treatment administration,

Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study treatment administration.

Female subject must not donate ova starting at Screening and throughout the study period, and for 6 months after the final study drug administration.

Agree to use a male condom starting at screening and continue throughout study treatment and for 6 months after the final study drug administration.

Male subject must not donate sperm starting at Screening and throughout the study period and for 6 months after the final study drug administration.

Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or for the time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.

An oral contraceptive (must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks before dosing with study drug and for the duration of the study and for 6 months after study drug discontinuation); or

Males who have not had a successful vasectomy (confirmed azoospermia) or if they and their female partners do not meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period or for 28 days after study drug discontinuation). No sperm donation is allowed during the study period or for 28 days after study drug discontinuation.

Laparoscopic procedure or open biopsy within 7 days prior to study drug administration

Central line placement or subcutaneous port placement is not considered major surgery but must be placed at least 2 days prior to study drug administration

Fine needle aspirate within 3 days prior to study drug administration

INCLUSION CRITERIA:\n\n        Each patient (male or female) must meet all of the following criteria to be enrolled in\n        this study:\n\n          1. Capable of understanding the written informed consent, provides signed and witnessed\n             written informed consent, and agrees to comply with protocol requirements.\n\n          2. Age 18 years or older (US sites) or 21 years or older (Singapore site) at Baseline.\n\n          3. Bone marrow (BM) cytogenetic analysis with at least 20 metaphase cells, confirmed\n             advanced haematologic malignancies in any of the 4 following disease populations at\n             Screening:\n\n               -  CML-AP, Ph+\n\n               -  CML-BC, Ph+\n\n               -  Ph+ ALL\n\n               -  Ph- ALL with relapsed and refractory disease who have exhausted all available\n                  therapy (for patients who develop T315I mutation related resistance, the\n                  definition requires failure of ponatinib treatment if drug is accessible).\n\n          4. Meets definition for one of the following study subgroups:\n\n             CML-AP:\n\n               -  ? 15% and < 30% blast in peripheral blood or bone marrow, or\n\n               -  ? 20% basophils in peripheral blood or bone marrow or\n\n               -  ? 30% blasts + promyelocytes in peripheral blood or bone marrow (but < 30%\n                  blasts) or\n\n               -  < 100 x 10^9 platelets/L in peripheral blood unrelated to therapy or\n\n               -  Cytogenetic, genetic evidence of clonal evolution and\n\n               -  No extramedullary disease.\n\n             CML-BC:\n\n               -  ? 30% blasts in peripheral blood or bone marrow, or\n\n               -  extramedullary disease other than hepatosplenomegaly.\n\n             Ph+ ALL:\n\n               -  ? 30% blasts in blood or bone marrow and\n\n               -  no prior history of CML.\n\n             Ph- ALL:\n\n               -  ? 10% blasts in bone marrow.\n\n          5. ECOG performance status of 0 to 2 at Baseline.\n\n          6. Life expectancy of at least 3 months at Baseline.\n\n          7. Adequate organ function at Baseline, including the following (noting that repeated\n             tests at Baseline should not be performed unless there are sufficient reasons to\n             assume the patient would meet the inclusion criteria with re testing):\n\n               1. Total bilirubin ? 1.5 x upper limit of normal (ULN), unless resulting from\n                  haemolysis or documented Gilbert syndrome.\n\n               2. Transaminases [aspartate aminotransferase (AST) and/or alanine aminotransferase\n                  (ALT) ? 2.5 x ULN]. [< 5 x ULN if liver infiltration with tumour present]\n\n               3. Prothrombin time (PT) < 1.5 ULN.\n\n               4. Calculated creatinine clearance ? 60 mL/min (Cockcroft and Gault formula).\n\n               5. No clinically relevant abnormalities in the urinalysis results.\n\n               6. Haematology:\n\n                    -  Haemoglobin > 10 g/dL (transfusion allowed to reach the level)\n\n                    -  Neutrophils > 1,000/µL\n\n                    -  Platelets > 75,000/µL.\n\n               7. Pancreatic status:\n\n                    -  Lipase ? 1.5 x ULN\n\n                    -  Amylase ? 1.5 x ULN.\n\n          8. Capable of taking oral medication and following direction regarding taking study drug\n             (either by himself/herself or by caregiver).\n\n          9. Negative serum pregnancy test at Baseline plus a negative urine pregnancy test on Day\n             1, Cycle 1 prior to treatment (applies to females of childbearing potential only).\n\n         10. A minimum of 2 weeks (14 days), or 5 half-lives (whichever is shorter) since last\n             receipt of any anti-cancer therapy (except dasatinib, hydroxyurea, anagrelide or\n             steroids), or 4 weeks from radiation or major surgery to the first administration of\n             the study drug.\n\n         11. All non-haematological AEs of any prior anti-cancer therapy, surgery, or radiotherapy\n             have to be resolved to NCI CTCAE Grade ? 1 (except alopecia) within 2 weeks prior to\n             starting study drug.\n\n         12. Willing to submit the blood samples and bone marrow samples for PK and pharmacodynamic\n             (PD) analyses.\n\n        CML-AP Ph+, CML-BC Ph+, Ph- ALL, and Ph+ ALL patients with relapsed and refractory disease\n        who have exhausted all available therapy.\n\n        Subgroup-specific intolerance definition: [Intolerance to tyrosine kinase inhibitors (TKIs)\n        or other approved treatments for CML-AP, CML-BC and Ph+ ALL; to approved treatments for Ph-\n        ALL] defined as:\n\n          -  Non-haematologic intolerance:\n\n        Patients with Grade 3 or 4 toxicity while on therapy, or with persistent Grade 2 toxicity,\n        unresponsive to optimal management, including dose adjustments (unless a dose reduction is\n        not considered in the best interest of the patient if response is already suboptimal) in\n        absence of: major haematologic response (MaHR) for accelerated phase (AP), blast crisis\n        (BC) or Ph+ ALL patients; complete remission (CR) or complete haematological response with\n        partial haematologic recovery of peripheral blood count (CRh) for Ph- ALL.\n\n          -  Haematologic intolerance:\n\n        Patients with Grade 3 or 4 toxicity [absolute neutrophil count (ANC) or platelets] while on\n        therapy that is recurrent after dose reduction to the lowest dose recommended by drug\n        manufacturers in the absence of: MaHR for AP, BC or Ph+ ALL patients; CR or CRh for Ph-\n        ALL.\n\n        NOTE: For dasatinib, non-haematologic and haematologic intolerance is defined as: CTCAE\n        Grade > 2 requiring discontinuation.\n\n        EXCLUSION CRITERIA:\n\n        Patients meeting any of the following criteria will be excluded from the study:\n\n          1. Is a male patient with sexual partner(s) of childbearing potential who is unwilling to\n             use a highly effective method of contraception, one of which includes a condom.\n             Sexually active male patients must use a condom during intercourse throughout the\n             study and for 12 weeks after the end of treatment and should not father a child in\n             this period. A condom is required to be used also by vasectomised males in order to\n             prevent potential delivery of the study drug via seminal fluid. Female partners of\n             male patients must be advised to also use one of the following contraception methods:\n\n               -  intrauterine device or intrauterine system;\n\n               -  prior sterilisation; or\n\n               -  total abstinence from male/female intercourse.\n\n          2. Is a female patient of childbearing potential, defined as a female physiologically\n             capable of becoming pregnant (including a female whose career, lifestyle, or sexual\n             orientation precludes intercourse with a male partner, and females whose partners have\n             been sterilised by vasectomy or other means), unless they are using a highly effective\n             method for birth control throughout the study and for 12 weeks after the end of\n             treatment. Highly effective methods for birth control include the following:\n\n               -  Total abstinence: This is an acceptable method when this is consistent with the\n                  preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,\n                  calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are\n                  not acceptable methods of contraception.\n\n               -  Female sterilisation: The patient has had a surgical bilateral oophorectomy (with\n                  or without hysterectomy) or tubal ligation at least 6 weeks prior to taking study\n                  drug. In case of an oophorectomy alone, the reproductive status of the patient\n                  must have been confirmed by follow-up hormone level assessment.\n\n               -  Male partner sterilisation: The patient has the appropriate post-vasectomy\n                  documentation of the absence of sperm in the ejaculate. (For female patients on\n                  the study, the vasectomised male partner should be the sole partner for that\n                  patient.) These patients must also agree to the use an intrauterine device or\n                  intrauterine system AND a barrier method of contraception: condom or occlusive\n                  cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, or\n                  cream, or vaginal suppository. Reliable contraception must be maintained\n                  throughout the study and for 12 weeks after study drug discontinuation.\n\n               -  Females considered post-menopausal and not of childbearing potential: The\n                  definition applies to females who have had 12 months of natural (spontaneous)\n                  amenorrhoea with an appropriate clinical profile (e.g., age appropriate, history\n                  of vasomotor symptoms) or 6 months of spontaneous amenorrhoea with serum\n                  follicle-stimulating hormone (FSH) levels > 40 million international units per\n                  milliliter (mIU/mL) (for US only: and estradiol < 20 pg/mL) or have had surgical\n                  bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior to\n                  starting treatment. In the case of oophorectomy alone, only when the reproductive\n                  status of the patient has been confirmed by follow-up hormone level assessment is\n                  she considered not of childbearing potential.\n\n          3. Is a pregnant or nursing (lactating) female, where pregnancy is defined as the state\n             of a female after conception and until the termination of gestation, confirmed by a\n             positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL).\n\n          4. Has dasatinib intolerance (haematologic and non-haematologic). Defined as: CTCAE Grade\n             >2\n\n          5. Has received anti-cancer therapy within 2 weeks or 5 half-lives, whichever is shorter\n             (except for hydroxyurea, steroids, allopurinol, febuxostat, rasburicase, and\n             intravenous hydration), prior to starting study drug or the side effects of such\n             therapy have not resolved to Grade ?1 within 2 weeks prior to starting study drug.\n\n          6. Is receiving concomitant anti-cancer therapy (except for hydroxyurea, steroids,\n             anagrelide, allopurinol, febuxostat, rasburicase, and intravenous hydration during the\n             first week of the study drug[s] administration, or corticosteroids when appropriate).\n\n          7. Has used other investigational drugs within 2 weeks or 5 half-lives (whichever is\n             shorter) prior to the first dose of study drug.\n\n          8. Has undergone autologous or allogenic stem cell transplantation < 60 days prior to the\n             first dose of study drug;\n\n          9. Has any evidence of on-going graft-versus-host disease (GVHD).\n\n         10. Has evidence of another malignancy not in remission or history of such a malignancy\n             within the last 3 years (except for treated basal or squamous cell carcinoma of the\n             skin, or in situ cancer of the cervix).\n\n         11. Has central nervous system (CNS) metastases.\n\n         12. Has significant bleeding disorder unrelated to the disease.\n\n         13. Has a history of long QT syndrome or prolonged QT interval corrected based on\n             Fridericia's method (QTcF) > 450 ms.\n\n         14. Has ECG evidence of complete left bundle branch block, or ventricular pacing.\n\n         15. Has abnormalities in the 12-lead ECG that in the opinion of the Investigator increase\n             the risk of participating in the study (e.g., sinus rhythm with PR interval > 240 ms\n             or second degree or higher atrioventricular (AV) block confirmed by a repeat ECG).\n\n         16. Has blood pressure and heart rate (HR) higher than 160/100 mmHg and 100 beats per\n             minute (bpm), respectively, or lower than 80/50 mm Hg and 45 bpm, respectively,\n             confirmed by a repeat assessment.\n\n         17. Is receiving treatment with drugs known to be associated with Torsade de Pointes.\n\n         18. Has ophthalmic signs or symptoms, such as flashes and colour perception changes.\n\n         19. Has evidence of electrolyte imbalance such as hypokalaemia, hypocalcaemia, and\n             hypomagnesaemia of NCI-CTCAE Grade ? 2 (NCI CTCAE version 4.03).\n\n         20. Has symptomatic chronic heart failure; unstable angina pectoris, cardiac arrhythmia.\n\n         21. Has cardiac left ventricular ejection fraction (LVEF) < 40% (assessed by transthoracic\n             echocardiography).\n\n         22. Has a history of myocardial infarction and/or thromboembolism in the past 6 months.\n\n         23. Has uncontrolled diabetes mellitus, neurologic or psychiatric condition, an ongoing\n             systemic (including opportunistic) clinically significant infections or any other\n             significant or unstable concurrent medical illness that in the opinion of the\n             Investigator would preclude protocol therapy.\n\n         24. Has a known history of human immunodeficiency virus (HIV) sero positivity and/or is\n             receiving combination anti retroviral therapy.\n\n         25. Has a history of gastric bypass surgery or with pre-existing gastrointestinal\n             disorders that may interfere with proper absorption of the drug, as per Investigator's\n             judgement.\n\n         26. Has history of seizure disorders or CNS leukaemia.\n\n         27. Is receiving cytochrome P450 3A4 (CYP3A4) inhibitors within 7 days prior to the first\n             dose of ETC-1907206 or receiving CYP3A4 inducers within 14 days prior to the first\n             dose of ETC-1907206 and dasatinib.\n\n         28. Cannot start treatment with dasatinib 140 mg daily, oral.\n\n         29. Is unwilling or unable to comply with the protocol

Main criteria for inclusion:\n\n        PK Phase:\n\n        To be considered eligible to participate in this study, all of the following requirements\n        must be met:\n\n          -  Patients with histologically or cytologically confirmed diagnosis of metastatic or\n             locally advanced solid tumors that have failed to respond to standard therapy, has\n             progressed despite standard therapy, or for which no standard therapy exists, and who\n             may benefit from treatment with a PARP inhibitor as assessed by the Investigator.\n\n          -  ECOG performance status of 0 to 2.\n\n          -  Adequate organ function as defined below:\n\n               -  Absolute neutrophil count ? 1,500/?L\n\n               -  Platelets ? 100,000/?L\n\n               -  Hemoglobin ? 9 g/dL (5.6 mM)\n\n               -  Serum creatinine ? 1.5 × the upper limit of normal (ULN) or a calculated\n                  creatinine clearance ? 60 mL/min using the Cockcroft-Gault equation or 24-hour\n                  urine creatinine clearance.\n\n               -  Total bilirubin ? 1.5 × ULN except in patients with Gilbert's syndrome. Patients\n                  with Gilbert's syndrome may enroll if direct bilirubin ? 1.5 × ULN of the direct\n                  bilirubin.\n\n               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 2.5 × ULN\n                  unless liver metastases are present, in which case, they must be ? 5 × ULN\n\n          -  Patient has recovered to Grade 1 toxicity from prior cancer therapy (a patient with\n             Grade 2 neuropathy or Grade 2 alopecia is an exception to this criterion and may\n             qualify for this study).\n\n          -  Female Patient of childbearing potential is not breastfeeding, has a negative serum\n             pregnancy test within 72 hours prior to taking study drug and agrees to abstain from\n             activities that could result in pregnancy from Screening through 180 days after the\n             last dose of study drug,\n\n          -  Male patient agrees to use an adequate method of contraception and not donate sperm\n             starting with the first dose of study drug through 90 days after the last dose of\n             study drug\n\n        Key Exclusion, PK Phase:\n\n          -  Known diagnosis of immunodeficiency\n\n          -  Symptomatic uncontrolled brain or leptomeningeal metastases.\n\n          -  Major surgery within 3 weeks of starting the study or patient has not recovered from\n             any effects of any major surgery.\n\n          -  Patient is considered a poor medical risk due to a serious, uncontrolled medical\n             disorder; nonmalignant systemic disease; or active, uncontrolled infection.\n\n          -  Known history of myelodysplastic syndrome or acute myeloid leukemia.\n\n          -  Patient is currently receiving a sensitive cytochrome P450 (CYP) 1A2 substrates with a\n             narrow therapeutic index (e.g., tizanidine and theophylline) (Does not apply for\n             Extension Phase).\n\n          -  Patient is currently taking any of the following P-glycoprotein (P-gp) inhibitors:\n             amiodarone, azithromycin, captopril, carvedilol, clarithromycin, conivaptan,\n             cyclosporine, diltiazem, dronedarone, erythromycin, felodipine, itraconazole,\n             ketoconazole, lopinavir and ritonavir, quercetin, quinidine, ranolazine, ticagrelor,\n             and verapamil (Does not apply for Extension Phase).\n\n          -  Patient taking proton pump inhibitors, antacids, or histamine 2 blockers within 48\n             hours prior to study drug administration, and/or within 6 hours after study drug\n             administration (Does not apply for Extension Phase).\n\n          -  Patient has gastric, gastro-esophageal or esophageal cancer; patient is unable to\n             swallow orally administered medication; or patient has gastrointestinal disorders or\n             significant gastrointestinal resection likely to interfere with the absorption of\n             niraparib.\n\n          -  Patient has known active hepatic disease\n\n          -  Patient has a past or current history of chronic alcohol use.\n\n          -  Patient has significant pleural effusion or ascites that is expected to require\n             drainage during the PK Phase (Does not apply for Extension Phase).\n\n        Key Inclusion, Extension Phase:\n\n          -  ECOG performance status of 0 to 2.\n\n          -  Adequate organ function as defined below\n\n               -  Absolute neutrophil count ? 1,500/?L\n\n               -  Platelets ? 100,000/?L\n\n               -  Hemoglobin ? 9 g/dL (5.6 mM)\n\n               -  Serum creatinine ? 1.5 × the ULN or a calculated creatinine clearance ? 60 mL/min\n                  using the Cockcroft-Gault equation or 24-hour urine creatinine clearance\n\n               -  Total bilirubin ? 1.5 × ULN except in patients with Gilbert's syndrome. Patients\n                  with Gilbert's syndrome may enroll if direct bilirubin ? 1.5 × ULN of the direct\n                  bilirubin.\n\n               -  AST and ALT ? 2.5 × ULN unless liver metastases are present, in which case, they\n                  must be ?5 × ULN\n\n          -  Female patient of childbearing potential is not breastfeeding, has a negative serum\n             pregnancy test within 72 hours prior to taking study drug and agrees to abstain from\n             activities that could result in pregnancy from Screening through 180 days after the\n             last dose of study drug.\n\n          -  Male patient agrees to use an adequate method of contraception and not donate sperm\n             starting with the first dose of study drug through 90 days after the last dose of\n             study drug.

Received study contraindicated medications prior to study drug administration including but not limited to those listed in the Full Prescribing Information Sheet for ledipasvir/sofosbuvir (Harvoni®).

Is not expected to be available to receive study drug within 16 weeks from the time of baseline biopsy for any reason

Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 14 days before the first dose of any study drug, except for hydroxyurea

Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)

Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

Previous treatment with radiotherapy, or immunotherapeutic agents, or receipt of live vaccines in the 4 weeks prior to study drug administration;

Must be willing to implement contraception throughout study and for 120 days after receiving the study drug.

Subjects must have completed chemotherapy, targeted therapy, investigational therapy, other immunotherapy, prior radiotherapy, or major surgery (requiring general anesthesia) at least 28 days before administration of the first dose of study drug(s). Subjects undergoing minor surgical procedures and biopsies that do not require general anesthesia may begin receiving study therapy if sufficiently recovered as determined by the treating investigator. Clinically significant toxicity experienced during any prior therapy must be resolved or stabilized before the first dose of study drug(s).

Radiotherapy within the past 2 weeks prior to date of first administration of study drug

Treatment with any drug(s) known to be an inhibitor or inducer of cytochrome P450 (CYP)2C19, CYP3A4, CYP2C8, and CYP2E1, within 14 days of the date of first administration of study drug

Active drug addiction including alcohol, cocaine or intravenous drug use defined as occurring within the 6 months preceding diagnosis

Inclusion Criteria:\n\n          -  Study Participants must be 18 years or older.\n\n          -  Study Participants must have 2 sites of cutaneous metastatic melanoma that can not be\n             removed with surgery.\n\n          -  Study Participants may have been previously treated with chemotherapy or immunotherapy\n             but not with in 4 weeks of first dose of study treatment.

Previous cytotoxic drug therapy, non-cytotoxic drug therapy, or experimental drug therapy directed against the brain tumor. Subjects who received Gliadel wafers will be excluded.

No investigational therapy within 4 weeks of first dose of study drug

Have completed a patisiran study (i.e., completed the last efficacy visit in the parent study) and, in the opinion of the investigator, tolerated study drug

Participation in other studies involving investigational drug(s) within 28 days prior to study entry and/or during study participation;

Systemic anti-myeloma therapy within <14 days, or plasmapheresis within 7 days prior to the first dose of study drug.

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

219 Females who are lactating/breastfeeding or who plan to breastfeed while on study through 110 days after receiving the last dose of study drug.

221 Females planning to become pregnant while on study through 110 days after receiving the last dose of study drug.

222 Males who are unwilling to abstain from sperm donation while on study through 170 days after receiving the last dose of study drug.

Receipt of anticancer medications, anticancer therapies, or investigational drugs within protocol-defined intervals before the first administration of study drug.

Male subjects must agree to refrain from sperm donation throughout the duration of the study and for 90 days following the last dose of study drug;

Systemic anti-myeloma therapy (including systemic steroids) within 14 days, or plasmapheresis within 7 days prior to the first dose of study drug.

Active hemoptysis (bright red blood of at least 0.5 teaspoon) or tumor bleeding within 3 weeks prior to the first dose of study drug

Within 14 days of first dose of study drug: Platelets > 100 x 10^9/L

Willingness to receive all outpatient treatment, all laboratory monitoring, and all radiological evaluations at the institution that administers study drug for the entire study

Treatment with prior chemotherapy, monoclonal antibodies, other protein or peptide therapeutics or anticancer immunotherapy within 21 days of the first dose of study drug

Appropriate for single agent study drug therapy as prescribed by this protocol;

Women of child bearing potential who are unwilling to use effective contraception for the duration of the study drug administration and 6 months after final dose of drug is administered;

Pregnant women are excluded from this study; breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 3 months following the last dose of study drug

Pregnant women are excluded; breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 3 months following the last dose of study drug

Within 14 days of study drug(s) initiation: Platelets >= 100,000/·L.

Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)

Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

Patient has had any systemic therapy within 2 weeks prior to initiating study drug.

Patient has participated in a prior investigational study within 3 weeks prior to initiating study drug.

Patients who are on warfarin and cannot have a drug substitution or who decline the drug substitution

Subjects receiving investigational study drug for any indication or immunological-based treatment for any reason (Filgrastim may be used for prevention of severe neutropenia).

Concurrent Therapy \r\n* Patients who are receiving any other anticancer or investigational drug therapy\r\n* Patients requiring systemic treatment with either corticosteroids (greater than dexamethasone 0.75 mg/m^2/day or the equivalent dose of other steroids) or other immunosuppressive medications within 14 days of study drug administration will be excluded; however, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study

Sexually active men must use a condom during intercourse while taking study drug and for 60 days after study drug discontinuation; a condom is required for vasectomized men to prevent delivery of study drug via seminal fluid

Patient has any of the following within 14 days prior to the first dose of study drug:

Participants taking an enzyme-inducing anti-epileptic drug (EIAED): phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, and felbamate; participants must be off any EIAEDs for at least 14 days prior to starting study drug

Participants taking a drug known to be a strong inhibitor or inducer of isoenzyme CYP3A; participant must be off CYP3A inhibitors and inducers for at least 14 days prior to starting study drug; NOTE: participants must avoid consumption of Seville oranges (and juice), grapefruits or grapefruit juice, grapefruit hybrids, pomelos and exotic citrus fruits from 7 days prior to the first dose of study drug and during the entire study treatment period

Treated with any investigational drug within 2 weeks of the first dose of study treatment.

Subject is receiving or is less than 14 days since ending other experimental drug (no marketing authorization for any indication)

Women who are lactating/breast feeding or who plan to breastfeed while on study through 1 week after receiving the last dose of study drug

Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) study therapy plus 5 half-lives of the study drug study therapy up to 25 days plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion

Male participants must be willing to refrain from sperm donation during the entire study and for 5 half-lives of study drug plus 90 days (duration of sperm turnover)

Subject has received small molecule therapy, radiotherapy, immunotherapy, monoclonal antibodies, investigational drug, or chemotherapy within 14 days before first dose of study drug, with the exception of hydroxyurea

Subject has an uncontrolled active infection requiring treatment and fever 38.3°C or higher 48 hours before the first dose of study drug. Controlled infections (i.e. 3 negative cultures completing antibiotics and/or stable fungal infection in therapy are allowed provided the subject has a temperature of <38.3°C within 48 hours of the first dose of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

TREATMENT: Breastfeeding should be discontinued while the patient is on this trial and for 30 days following last dose of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [FDA]-approved indication and in the context of a research investigation) or any other treatment specifically for treating the current malignancy

Women may have been taking tamoxifen or raloxifene as a preventive agent prior to study entry but must have discontinued the drug for at least 21 days prior to study enrollment

Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug

Patients enrolled to the prior treatment arm of the dose escalation cohort must not have received anti-cancer therapy less than 14 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug

Obtained within 14 days (or as stipulated) prior to study drug (treatment) administration: total bilirubin ? 2.0 mg/dL or > 3.0 x ULN for subjects with hereditary benign hyperbilirubinemia

Both female and male patients of reproductive potential must agree to avoid pregnancy or impregnating a partner (respectively) while receiving drug and for 120 days after last dose of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Stable systemic cGVHD medication regimen for seven days prior to study enrollment; dose modifications to maintain therapeutic drug levels of immunosuppressants (i.e. tacrolimus and sirolimus) for the month prior and during the study intervention period are allowed and do not constitute a trial violation

4 weeks from prior experimental drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug

Had involvement in the planning and/or conduct of the study by association with the sponsor, study drug supplier(s) or study center or was previously enrolled in the present study

Patients must have successfully completed therapy with sipuleucel-T within 3-7 days of planned CYT107 study drug treatment

Allergy/sensitivity to any study drug (gemcitabine, cisplatin, enzalutamide), or drugs chemically related to study drug, or excipients

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Hypersensitive or intolerant to any component of the study drug(s) formulation

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6)

Ability to be off prednisone and other immunosuppressive drugs for at least 14 days before first dose of study drug

Prior treatment with any investigational drug within the preceding 4 weeks prior to starting study drug

Current, recent (within 4 weeks of the first treatment of this study), or planned participation in an experimental drug study (prevention trials are permitted if the trial is not testing a novel experimental agent)

Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all adverse events have either returned to baseline or stabilized

Prior systemic radiation therapy must have been completed at least 4 weeks before study drug administration; prior focal radiotherapy completed at least 2 weeks before study drug administration; no radiopharmaceuticals (strontium, samarium) within 8 weeks before study drug administration

Completed nitrosourea treatment at least 6 weeks before administration of any study drug

Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration; surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and subjects should be recovered

Females of childbearing potential must:\r\n* Agree to using a reliable form of contraception (eg, oral contraceptives, intrauterine device, double barrier method of condom and spermicidal) for at least 28 days prior to the first dose of any study drug, during the treatment period (and treatment/follow-up if receiving study drug), and for at least 70 days after the last dose of any study drug\r\n* Have a negative serum beta-human chorionic gonadotropin (beta-HCG) at screening

Prior systemic radiation therapy must have been completed at least 4 weeks before study drug administration\r\n* Prior focal radiotherapy completed at least 2 weeks before study drug administration\r\n* No radiopharmaceuticals (strontium, samarium) within 8 weeks before study drug administration

Completed nitrosourea treatment at least 6 weeks before administration of any study drug

Prior surgery that required general anesthesia must be completed at least 2 weeks before study drug administration\r\n* Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and subjects should be recovered

Females of childbearing potential must:\r\n* Agree to use using a reliable form of contraception (e.g., oral contraceptives, intrauterine device, double barrier method of condom and spermicidal) for at least 28 days prior to the first dose of any study drug, during the treatment period (and treatment/follow-up if receiving study drug), and for at least 70 days after the last dose of any study drug\r\n* Have a negative serum beta (B)-human chorionic gonadotropin (B-HCG) at screening

Patient is currently participating or has participated in a study with an investigational compound or devise within 30 days of initial dosing with study drug(s)

Subject is suitable for oral administration of study drug.

Agree not to try to become pregnant during the study and for 180 days after the final study administration

Female subject must agree not to breastfeed at Screening and throughout the study period and for 60 days after the final study drug administration.

Female subject must not donate ova starting at Screening and throughout the study period and for 180 days after the final study drug administration.

Male subject must not donate sperm starting at Screening and throughout the study period and 120 days after the final study drug administration.

Multiple bone metastases within 12 weeks prior to study drug

Participation in another clinical trial/investigation within 28 days prior to study drug

Immunostimulants within 4 weeks or immunosuppressants within 14 days prior to study drug

Female Subjects must agree to not breastfeed from the time of Screening and throughout the study period, and for 25 days after the final study drug administration.

Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.

Last dose of any prior therapy administered by the following time intervals before the first dose of study drug:

Has received sorafenib within 14 days of first dose of study drug.

Has had minor surgery (i.e., simple excision, tooth extraction) <7 days prior to the first dose of study drug (Cycle 1, Day 1).

Subjects who have completed sipuleucel-T (Provenge ®) treatment within 28 days of study drug initiation.

Therapeutic or experimental monoclonal antibodies within 28 day or prior radiation therapy within 14 days of the first dose of study drug.

Completion of, if applicable, radiotherapy, chemotherapy, antibodies and immunoconjugates including brentuximab vedotin and/or another investigational drug which could interact with this trial not less than 4 weeks (or 5 half-lives of the drug, whichever occurs later) prior to first dose of study drug. Cessation of small molecule tyrosine kinase inhibitors must be at least 7 days prior to first dose of study drug.

Patients who received systemic anticancer therapy or radiotherapy <21 days prior to their first day of study drug administration

Sexually active males should use a condom during intercourse while taking drug and for 8 weeks after the final dose of study treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Treatment with any other test drug or participation in another clinical trial within 28 days of enrollment.

Subject participating in any other study involving an investigational (unapproved) drug or device within the past 60 days.

Received any chemotherapy, external beam radiation therapy, anticancer antibodies, or investigational drug within 30 days before first dose of study drug.

Receipt of anticancer medications or investigational drugs within protocol-defined intervals before the first administration of study drug.

Receipt of anticancer medications or investigational drugs within a defined interval before the first administration of study drug.

Are currently totally abstinent (as their preferred and usual lifestyle), and who do not agree to be totally abstinent during the study period and for 30 days after study drug discontinuation.

Known intolerance to the study drug or any of the excipients.

Has had certain other recent treatment e.g. major surgery, anticancer therapy, extended field radiation, received investigational agent within the specified time frames prior to study drug administration.

Inclusion Criteria:\n\n        All Treatment Arms:\n\n          1. Male or female participants 18 years or older.\n\n          2. Participants who, in the opinion of the treating physician, have failed standard\n             therapies and for whom a phase 1 trial is an appropriate option.\n\n          3. Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be\n             measurable and of the protocol specified genetic mutational status, where applicable.\n\n          4. Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects\n             (except alopecia) of prior therapy.\n\n          5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.\n\n          6. Expected survival time of at least 3 months in the opinion of the investigator.\n\n          7. Block of banked tumor tissue and/or greater than or equal to (>=) 10 unstained slides.\n             Participants who satisfy all other eligibility criteria but do not have banked\n             tissue/slides may be asked to consent to baseline biopsy.\n\n          8. Suitable vein access for the study-required blood sampling.\n\n          9. Thyroid function tests consistent with stable thyroid function. Note: Participants on\n             a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks\n             before Cycle 1, Day 1 are eligible.\n\n         10. Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by\n             echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before\n             the first dose of MLN2480\n\n         11. Female participants who are post menopausal for at least 1 year, surgically sterile,\n             or agree to practice 2 effective methods of contraception through 120 days (4 months)\n             after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6\n             months for participants in Arms 3 and 4, or agree to practice true abstinence.\n\n         12. Male participants who, even if surgically sterilized, agree to practice effective\n             barrier contraception through 120 days (4 months) after the last dose of study drug\n             for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3,\n             and 4, or agree to practice true abstinence.\n\n         13. Additional inclusion criteria for arm 3 expansion only (MLN2480 + paclitaxel):\n\n             a. Participants with KRAS exon 2 or BRAF non-V600 mutation-positive non small cell\n             lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior\n             cytotoxic-approved regimens.\n\n         14. Additional inclusion criteria for arms 4 and 5 expansion only (MLN2480 + cetuximab;\n             MLN2480 + irinotecan):\n\n               1. Participants with CRC who have received a minimum of 1 but not more than 2 prior\n                  cytotoxic-approved regimens.\n\n        Exclusion Criteria:\n\n        All treatment arms:\n\n          1. Female participants who are pregnant or currently breastfeeding.\n\n          2. History of any serious medical or psychiatric illness that could, in the\n             investigator's opinion, potentially interfere with safe protocol completion.\n\n          3. History of uncontrolled brain metastasis unless: previously treated with surgery,\n             whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days\n             without steroid use (or stable steroid dose established for >= 28 days before the\n             first dose of MLN2480).\n\n          4. Ongoing seizure disorder or a requirement for antieplieptics.\n\n          5. Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4\n             half lives, whichever occurs first, before administration of study drug;\n             immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or\n             radiation therapy <= 3 weeks before administration of study drug.\n\n          6. Chronic therapeutic corticosteroid use with the exception of replacement therapy for\n             adrenal insufficiency or corticosteroid inhalers.\n\n          7. Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C;\n             Prior allogeneic bone marrow or organ transplantation, or active condition of chronic\n             immune suppression is not allowed.\n\n          8. Concomitant use, or administration <= 14 days before first dose of study drug(s), of\n             clinically significant enzyme inducers.\n\n          9. Treatment with gemfibrozil (strong Cytochrome P4502C8 [CYP2C8] inhibitor) within 14\n             days before the first dose of MLN2480.\n\n         10. History of or current illicit drug use, drug abuse, or alcohol abuse.\n\n         11. Major surgery within 14 days before the first dose of study drug.\n\n         12. Inability to comply with study requirements.\n\n         13. Other unspecified reasons that, in the opinion of the investigator or Millennium, make\n             the participant unsuitable for enrollment.\n\n         14. Additional exclusion criteria for arms 3, 5, and 6 expansion only (MLN2480 +\n             paclitaxel; MLN2480 + irinotecan; MLN2480 monotherapy):\n\n             a. Prior treatment with rapidly accelerated fibrosarcoma (RAF), extracellular\n             signal-regulated kinases (MEK), or other inhibitors of the mitogen-activated protein\n             kinase (MAPK) pathway.\n\n         15. Additional exclusion criteria for arm 2 only (MLN2480 + alisertib):\n\n             a. History of uncontrolled sleep apnea syndrome and other conditions that could result\n             in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.\n\n         16. Additional exclusion criteria for arm 3 only (MLN2480 + paclitaxel):\n\n             a. Known hypersensitivity to paclitaxel or its components or other drugs formulated in\n             Cremophor® EL (polyoxyethylated castor oil).\n\n         17. Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan):\n\n               1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the\n                  first dose of irinotecan.

No prior G-CSF, GM-CSF or plerixafor within 14 days of study drug dosing

Use of any investigational drug within 14 days prior to the first dose of study drug

Participated in any other study in which receipt of an investigational new drug or investigational device occurred within 28 days of first dose of study drug

Time required between the last dose of the latest therapy and the first dose of study drug:

At least 12 weeks for craniospinal, ?50% radiation of pelvis, or total body irradiation prior to first dose of study drug

Women planning to become pregnant or who are lactating/breastfeeding while on study through 4 months after receiving the last dose of study drug.

Treatment with high-dose chemotherapy and hematopoietic stem-cell rescue within 3 months prior to initiation of study drug

Treatment with a long-acting hematopoietic growth factor within 2 weeks prior to initiation of study drug or a short-acting hematopoietic growth factor within 1 week prior to initiation of study drug

Treatment with herbal cancer therapy within 1 week prior to initiation of study drug

Inclusion Criteria\n\n        PART 1\n\n          -  Has locally advanced or metastatic ccRCC and has progressed during treatment with at\n             least one prior therapeutic regimen\n\n          -  Is of age ? 18 years\n\n          -  Has a life expectancy of ? 3 months\n\n          -  Has adequate organ function\n\n          -  If a female patient, must be surgically sterile, post-menopausal, or must agree to use\n             physician-approved method of birth control during the study and for a minimum of 30\n             days after the last study drug administration, or if a male patient with a female\n             partner, must agree to use physician-approved method of birth control during the study\n             and for a minimum of 30 days after the last study drug administration\n\n          -  Able to swallow oral medications\n\n        PART 2 - In addition to PART 1\n\n          -  Received no more than three prior systemic treatment regimens in the advanced or\n             metastatic setting\n\n          -  Must have received at least one but not more than two prior anti-angiogenic therapy\n             regimens\n\n        PART 3 - In addition to PART 1\n\n        • Must have received at least one vascular endothelial growth factor receptor (VEGFR)\n        targeting tyrosine kinase inhibitor\n\n        Exclusion Criteria\n\n        PART 1\n\n          -  Has a history of untreated brain metastasis or history of leptomeningeal disease or\n             spinal cord compression\n\n          -  Has failed to recover from the reversible effects of prior anticancer therapy\n\n          -  Has uncontrolled or poorly controlled hypertension\n\n          -  Is receiving warfarin anticoagulant therapy or expected to require warfarin\n\n          -  Has had any major cardiovascular event within 6 months prior to study drug\n             administration\n\n          -  Has any other clinically significant cardiac, respiratory, or other medical or\n             psychiatric condition that might interfere with participation in the trial or\n             interfere with the interpretation of trial results\n\n          -  Has had major surgery within 4 weeks before first study drug administration\n\n          -  Has known HIV\n\n          -  Has an active infection requiring systemic treatment\n\n          -  Is participating in another therapeutic clinical trial\n\n        PART 2 - In addition to PART 1\n\n          -  Has received prior immunotherapy\n\n          -  Has any active or recent history of a known or suspected autoimmune disease\n\n        PART 3 - In addition to PART 1\n\n          -  Gastrointestinal (GI) disorders\n\n          -  Any history of congenital long QT syndrome

Inclusion\n\n          -  Has read and understands the informed consent form (ICF) and has given written IC\n             prior to any study specific procedures.\n\n          -  Histologic or cytologic diagnosis of epithelial ovarian, fallopian tube, or primary\n             peritoneal cancer.\n\n          -  Progressed within 6 months of completing at least 4 cycles of a first-line\n             platinum-containing regimen for Stage III/IV disease. Patients with refractory disease\n             (progression during platinum-containing therapy) are ineligible.\n\n          -  No more than 2-4 prior treatment regimens for Stage III/IV disease, defined as\n             investigational, chemotherapy, hormonal, biologic, or targeted therapy.\n\n          -  Prior doxorubicin (or other anthracycline) at a cumulative dose of ? 360 mg/m² or\n             cumulative epirubicin dose of ? 720 mg/m² (calculated using doxorubicin equivalent\n             doses: 1 mg of doxorubicin = 1 mg PLD = 0.3 mg mitoxantrone = 0.25 mg idarubicin).\n             Subjects without any prior anthracycline exposure can also be included. Applies to Arm\n             D only.\n\n          -  At least 1 measurable lesion according to RECIST v1.1.\n\n          -  Any prior palliative radiation therapy must be completed at least 7 days prior to\n             start of study treatment and patients must have recovered from any acute adverse\n             effects prior to start of study treatment.\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 - 1.\n\n          -  Baseline Laboratory Values:\n\n               1. ANC ?1500/?L\n\n               2. HgB ? 9 g/dL with no blood transfusions in the past 28 days\n\n               3. Platelets ? 100,000/?L\n\n               4. ALT & AST ?3 x ULN or ?5 x ULN if known hepatic metastases\n\n               5. Serum bilirubin within normal limits (WNL) or ?1.5 x the ULN in patients with\n                  liver metastases; or total bilirubin ?3.0 x ULN with direct bilirubin WNL in\n                  patients with well documented Gilbert's Syndrome.\n\n               6. Serum creatinine ?1.5 x the ULN and a calculated creatinine clearance (CrCl) ?45\n                  mL/min by the Cockcroft-Gault method.\n\n          -  Left ventricular ejection fraction (LVEF) WNL of the institution as determined by\n             multiple uptake gated acquisition (MUGA) or echocardiography (ECHO) (applies to Arm D\n             only).\n\n          -  Female patients, ?18, (not of childbearing potential and fertile female patients of\n             childbearing potential) who agree to use adequate contraceptive measures from 2 weeks\n             prior to the study and until 1 month after study treatment discontinuation, who are\n             not breastfeeding, and who have a negative serum or urine pregnancy test within 72\n             hours prior to start.\n\n          -  Predicted life expectancy ? 12 weeks\n\n        Exclusion\n\n          -  Use of a study drug (approved or investigational drug therapy) ?21 days or 5\n             half-lives (whichever is shorter) prior to the first dose of study treatment. For\n             study drugs for which 5 half-lives is ?21 days, a minimum of 10 days between\n             termination of the study drug and administration of study treatment is required.\n\n          -  Major surgical procedures ? 28 days of beginning study, or minor surgical procedures ?\n             7 days. No waiting period following port-a-cath placement, or any other central venous\n             access placement.\n\n          -  Grade >1 toxicity from prior therapy (except alopecia or anorexia).\n\n          -  Known malignant CNS disease other than neurologically stable, treated brain\n             metastases, defined as metastasis having no evidence of progression or haemorrhage\n             after treatment for at least 2 weeks (including brain radiotherapy). Must be off any\n             systemic corticosteroids for the treatment of brain metastases for at least 14 days\n             prior to enrolment.\n\n          -  Patient has had prescription or non-prescription drugs or other products (i.e.\n             grapefruit juice) known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a\n             narrow therapeutic index, or to be moderate to strong inhibitors or inducers of CYP3A4\n             which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout\n             the study until 2 weeks after last dose of study drug.\n\n          -  Caution should be exercised when inhibitors or substrates of P-gP, substrates of\n             CYP1A2 with a narrow therapeutic range, sensitive substrates of CYP2C19 or CYP2C19\n             substrates with a narrow therapeutic range are administered with AZD1775.\n\n          -  Herbal medications should be discontinued 7 days prior to the first dose of study\n             treatment.\n\n          -  Any of the following cardiac diseases currently or within the last 6 months as defined\n             by New York Heart Association (NYHA) ? Class 2:\n\n               1. Unstable angina pectoris\n\n               2. Congestive heart failure\n\n               3. Acute myocardial infarction\n\n               4. Conduction abnormality not controlled with pacemaker or medication\n\n               5. Significant ventricular or supraventricular arrhythmias (patients with chronic\n                  rate controlled atrial fibrillation in the absence of other cardiac abnormalities\n                  are eligible).\n\n          -  AZD1775 should not be given to patients who have a history of Torsades de pointes\n             unless all risk factors that contributed to Torsades have been corrected. AZD1775 has\n             not been studied in patients with ventricular arrhythmias or recent myocardial\n             infarction.\n\n          -  Corrected QT interval (QTc) >470 msec at study entry or congenital long QT syndrome.\n\n          -  Pregnant or lactating.\n\n          -  Serious active infection at the time of enrolment, or another serious underlying\n             medical condition that would impair the patient's ability to receive study treatment.\n\n          -  Presence of other active cancers, or history of treatment for invasive cancer within 3\n             years. Patients with Stage I cancer who have received definitive local treatment\n             within 3 years, and whom are considered unlikely to recur, are eligible. Patients with\n             previously treated in-situ carcinoma (i.e., non-invasive) are eligible, as are\n             patients with prior non-melanoma skin cancers.

Investigational drug within 30 days of first trilaciclib (G1T28) dose

Received anti-neoplastic monoclonal antibodies within 30 days of the first dose of study drug.

Subject must currently be participating in an Astellas sponsored, single agent ASP2215 trial, receiving ASP2215 and have not met any discontinuation criteria of the parent study and can enroll into this rollover study without interruption of study drug, or with no more than 2 weeks interruption in study drug.

Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 60 days after the final study drug administration.

Female subject must not donate ova starting at Screening and throughout the study period, and for 180 days after the final study drug administration.

Male subject must not donate sperm starting at Screening and throughout the study period and, for 120 days after the final study drug administration.

Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug

At least four weeks must have elapsed between the last dose of any MF- directed drug treatments for myelofibrosis (including investigational therapies) and study enrollment;

Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping study drug and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Use of any other experimental drug or therapy within 28 days of baseline

All institutional, Food and Drug Administration (FDA), and NCI requirements for human studies must be met

Pleurodesis within 14 days prior to first dose of study drug

Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all adverse events have either returned to baseline or stabilized

Prior systemic radiation therapy must have been completed at least 4 weeks before study drug administration; prior focal radiotherapy completed at least 2 weeks before study drug administration; no radiopharmaceuticals (strontium, samarium) within 8 weeks before study drug administration

Completed nitrosourea treatment at least 6 weeks before administration of any study drug

Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration; surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and subjects should be recovered

Current or recent treatment with another investigational drug within 30 days of first study treatment dosing or earlier participation in this study

Inclusion Criteria:\n\n        All Subjects:\n\n          1. Provide signed and dated informed consent prior to study-specific screening procedures\n\n          2. ? 18 years old\n\n          3. Karnofsky performance status (KPS) ? 70\n\n          4. Must have adequate bone marrow and renal/hepatic function within protocol specified\n             limits\n\n          5. Disease-free period of > 2 years from any other previous malignancies, excluding\n             curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or\n             carcinoma in situ of the cervix. Subjects with prostate cancer Stage 1 that do not\n             require treatment may also be included\n\n          6. Women and men must use protocol approved methods of contraception\n\n          7. Must be able and willing to comply with the study visit schedule and study procedures\n\n          8. Must have available archived tumor tissue and willing and able to provide consent for\n             study access to such tissue\n\n             For Phase 1 Subjects Only:\n\n          9. Histologically or cytologically documented diagnosis of solid tumor for which no\n             standard therapy is recognized or have failed or intolerant to the standard-of-care\n             treatment\n\n         10. Inoperable metastatic or locally advanced, unresectable disease\n\n         11. Subjects may have either evaluable or measurable disease\n\n         12. Subjects with treated (surgically excised or irradiated) and stable brain metastases\n             are eligible as long as the subject has adequately recovered from treatment and the\n             treatment was ? 28 days prior to initiation of study drug(s) and baseline brain\n             computed tomography (CT) with contrast or magnetic resonance imaging (MRI) ? 14 days\n             of initiation of study drug is negative for new brain metastases\n\n             For Phase 2 Subjects Only:\n\n         13. Histologically confirmed diagnosis of GBM\n\n         14. Subjects must have documented recurrence after first-line treatment\n\n         15. Prior first-line treatment must have included radiation and temozolomide\n\n         16. Subject is suitable for re-resection, per Investigator discretion, as a component of\n             their clinical care\n\n         17. No more than one prior resection (Note: biopsy does not count as prior resection)\n\n        Exclusion Criteria:\n\n        All Subjects\n\n          1. Subjects who have had recent systemic anticancer therapies, interventional device\n             treatment and/or radiotherapy either within 14 days prior to first dose of study\n             drug(s) or have not recovered (to grade ? 1) from all clinically significant\n             toxicities related to prior therapies\n\n          2. Subjects who have had any major surgery (not including re-resection surgery required\n             in Phase 2) within 28 days prior to first dose of study drug(s), or minor surgery\n             within 14 days prior to first day of study drug(s)\n\n          3. Subjects taking any protocol prohibited medications within 14 days prior to initiating\n             study drug(s) treatment\n\n          4. Subjects who have been treated with an investigational agent or investigational\n             interventional device within 21 days prior to the first dose of study drug(s)\n\n          5. History of significant cardiac disease\n\n          6. Pregnant or breastfeeding\n\n          7. Any other significant co-morbid conditions that in the opinion of the Investigator\n             would impair study participation or cooperation\n\n             For Phase 1 Subjects Only:\n\n          8. Subjects with lymphoma as primary cancer\n\n             For Phase 2 Subjects Only:\n\n          9. Subjects unable or unwilling to consent to the provision of resected tissue after\n             surgery

Agree not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug.

History of any of the following within the last 6 months before administration of the first dose of study drug

For Cohort 1: has received sorafenib within 14 days of first dose of study drug

Active hemoptysis (bright red blood of at least 2.5 mL ie, half teaspoon) within 3 weeks prior to the first dose of study drug.

are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from sexual activity during the study period and for 28 days after study drug discontinuation,

For CMML participants: WBC count <20,000/mcL before administration of the first dose of study drug on Cycle 1 Day 1; participants must have been off hydroxyurea for at least 1 week prior to WBC count assessment.

Systemic antineoplastic therapy or radiotherapy for other malignant conditions within 12 months before the first dose of any study drug, except for hydroxyurea.

Female participants who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s).

Male participants who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s).

Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to starting study drug Ribociclib:

Any anti-cancer therapy within 3 weeks of study drug

Signs/symptoms of infection, or use of antibiotics within 2 weeks of study drug

Breastfeeding should be discontinued until 6 weeks after the last administration of study drug

Surgery within 4 weeks of study drug administration

Another investigational drug within 4 weeks of study drug administration

Use of any investigational, non-United States Food and Drug Administration (US FDA) approved drug

Patients who have received any investigational agent, chemotherapy, interferon-alpha, or 2-chlorodeoxyadenosine (2-CdA, cladribine) within 30 days prior to day 1; or monoclonal antibody =< 6 weeks prior to first administration of study treatment (patients with an AHNMD with progressive leukocytosis who require control of their counts are permitted to be given hydroxyurea); EXCEPTION: midostaurin can be used up to 10 days before the start of the study drug (study day 1)

Are currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study

current or prior IV drug users,

current or prior IV drug users,

Participation in any investigational drug study within 4 weeks preceding the start of study treatment; patients are not permitted to participate in another investigational drug study while being treated on this protocol

Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, pommelos, or exotic citrus fruits, from 1 day prior to the first dose of study treatment(s) until the last dose of study drug.

Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a nonmyelosuppressive or myelosuppressive agent, respectively.

Received prior systemic cytotoxic chemotherapy, biological therapy, major surgery within 3 weeks of first dose of study drug; received thoracic radiation therapy of > 30 gray (Gy) within 6 months of first dose of study drug

Recipient of any drug with potential QT interval prolonging effects within 14 days prior to the first dose for all participants and while on treatment through the end of the study for crizotinib-treated participants only

Currently receiving or has received any intensive chemotherapy within the 14 days prior to the first dose of study drug (day -7) (Hydrea or other non-intensive regimens such as decitabine may be used but must stop at least one day prior to the first dose of study drug)

Radiotherapy within 14 days before first dose of study drug; if the involved field is small, 7 days will be considered a sufficient interval between treatment and study initiation

Exposure to any investigational drug within 4 weeks of study drug administration

Has had certain other recent treatment e.g. major surgery, anticancer therapy, extended field radiation, received investigational agent, within the specified time frames prior to study drug administration.

Acceptable laboratory assessment obtained within 14 days prior to the first dose of study drug:

Splenic irradiation within 3 months prior to the first dose of study drug

Prior systemic cytotoxic chemotherapy, antineoplastic biological therapy (e.g., cetuximab), major surgery within 3 weeks of the first dose of study drug; received thoracic radiation therapy of >30 Gy within 6 months of the first dose of study drug; received prior tyrosine kinase inhibitor therapy or completed palliative radiotherapy within 7 days of the first dose of study drug

Survival expectation of 12 weeks or longer after starting study drug

Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first does of study drug.

Current participation in another clinical investigation of a medical device or a drug or has participated in such a study within 30 days prior to study enrollment

Participation in a therapeutic research study or receipt of an investigational drug within 4 weeks of leukapheresis

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Receipt of anticancer medications or investigational drugs within the Protocol-defined intervals before the first administration of study drug.

Women who are lactating/breast feeding or who plan to breastfeed while on study through 1 week after receiving the last dose of study drug

Radiotherapy within 2 weeks of the first dose of study drug

Subject is suitable for oral administration of study drug.

Agree not to try to become pregnant during the study and for 180 days after the final study drug administration

Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 60 days after the final study drug administration.

Female subject must not donate ova starting at screening and throughout the study period, and for 180 days after the final study drug administration.

Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after the final study drug administration.

Monoclonal antibody, radioimmunoconjugate, antibody-drug conjugate, chemotherapy, or other investigational anti-cancer agent within 4 weeks prior to study drug

Treatment with systemic cancer therapy or investigational therapy within 4 weeks of first study drug administration; radiation within 2 weeks; corticosteroids (greater than or equal to 10 mg prednisone or equivalent per day) or other immune suppressive drugs within 2 weeks of first study drug administration

Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications within 21 days or 5 half-lives before first dose of study drug

Whole brain radiation within 28 days or other radiotherapy within 14 days prior to first administration of study drug after crossing over

Participation in any other clinical investigation within 4 weeks of receiving the first dose of study drug

Treatment with any additional Food and Drug Administration (FDA)-approved biologic agent (i.e. bevacizumab, cetuximab, or panitumumab) is allowed according to standard practice

Patient must be willing to practice two forms of contraception, one of which must be a barrier method, from study entry until at least 35 days after the last dose of the study drug.

Female subject must not be breastfeeding at Screening or during the study period and for 3 months after final study drug administration.

Subject must agree not to donate sperm or ova from first dose of study drug through 3 months after the last dose of study drug.

Treatment with non-Food and Drug Administration (FDA) approved drug within 21 days of start of this trial

Treatment with a non-Food and Drug Administration (FDA) approved drug in the previous 4 weeks

Any non-study related significant surgical procedures within the past 28 days prior to the first administration of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Subject has received other investigational drugs within 14 days prior to first dose of study drug.

Use of any standard/experimental anti-lymphoma drug therapy, including steroids (dexamethasone dose >= 4 mg/day or prednisone >= 20 mg/day), within 3 weeks of initiation of the study or use of any experimental non-drug therapy (e.g., donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug treatment; hydroxyurea is permitted up to 24 hours before the first dose of study drug in patients with rapidly-proliferating disease

Sexually active males unless they use a condom during intercourse while taking the drug and for 21 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Current, recent (within 4 weeks of the administration of this study agent), or planned participation in an experimental drug study

Inclusion Criteria - Cohort 1:\n\n          -  Received and progressed on ?2 prior chemotherapy regimens for their advanced disease;\n             prior regimen must have included a cisplatin and a fluoropyridine\n\n          -  Human epidermal growth factor receptor 2 (HER-2/neu) negative, or, if HER2/neu\n             positive, must have previously received treatment with trastuzumab\n\n        Inclusion Criteria - Cohort 2 or 3:\n\n          -  HER2/neu negative\n\n          -  Has not received prior systemic anti-cancer therapy for their advanced carcinoma\n             (systemic therapy received in the neoadjuvant and adjuvant setting does not count)\n\n        Inclusion Criteria - All Participants:\n\n          -  Histologically- or cytologically-confirmed recurrent or metastatic gastric or\n             gastroesophageal junction adenocarcinoma that is considered incurable by local\n             therapies\n\n          -  Willing to provide tissue for PD-L1 biomarker analysis from newly-obtained and/or\n             archival tissue\n\n          -  Measurable disease based on Response Evaluation Criteria in Solid Tumors version 1.1\n             (RECIST 1.1)\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 3 days\n             prior to first dose of study drug\n\n          -  Life expectancy of >=3 months\n\n          -  Female participants of childbearing potential should have a negative pregnancy test\n             and be willing to use 2 methods of birth control or be surgically sterile, or abstain\n             from heterosexual activity for the course of the study through 120 days after the last\n             dose of study drug (180 days for participants receiving cisplatin + 5FU)\n\n          -  Male participants should agree to use an adequate method of contraception starting\n             with the first dose through 120 days after the last dose of study drug (180 days for\n             participants receiving cisplatin + 5FU)\n\n          -  Adequate organ function\n\n        Exclusion Criteria - All Participants:\n\n          -  Currently participating and receiving study therapy or participated in a study of an\n             investigational agent and received study therapy or used an investigation device\n             within 4 weeks of the first dose of study drug\n\n          -  Active autoimmune disease that has required systemic treatment in past 2 years\n\n          -  Immunodeficiency or receiving systemic steroid therapy or any other form of\n             immunosuppressive therapy within 7 days prior to the first dose of study drug\n\n          -  Weight loss >10% over 2 months prior to first dose of study drug\n\n          -  Clinical evidence of ascites by physical exam\n\n          -  Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not\n             recovered from AEs due to agents administered more than 4 weeks earlier\n\n          -  Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2\n             weeks prior to study Day 1 or who has not recovered from AEs due to a previously\n             administered agent\n\n          -  Known additional malignancy that is progressing or requires active treatment excepting\n             basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has\n             undergone potentially curative therapy or in situ cervical cancer\n\n          -  Known active central nervous system (CNS) metastases and/or carcinomatous meningitis\n\n          -  Known history of, or any evidence of active, non-infectious pneumonitis\n\n          -  Active infection requiring systemic therapy\n\n          -  Psychiatric or substance abuse disorders that would interfere with cooperation with\n             the requirements of the study\n\n          -  Pregnant or breastfeeding, or expecting to conceive or father children within the\n             projected duration of the study, starting with the screening visit through 120 days\n             after the last dose of study drug (180 days for participants receiving cisplatin +\n             5FU)\n\n          -  Prior therapy with an anti-programmed death-1 (PD-1), anti-PD-L1, or anti-PD-L2 agent\n\n          -  Human immunodeficiency virus (HIV)\n\n          -  Hepatitis B or C\n\n          -  Received live vaccine within 30 days of planned start of study drug

Patient is capable of swallowing study drug capsules whole.

Pregnant or lactating, or intending to become pregnant during the study: Women who are not postmenopausal (>=12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug

Patient is taking an enzyme inducing anti-epileptic drug (EIAED), including phenobarbital, phenytoin, fosphenytoin, primidone, carbamazepine, oxcarbazepine, eslicarbazepine, rufinamide, and felbamate; participates must be off of any EIAED for a least two weeks prior to starting the study drug

Group C: progression following ceritinib is required and the last dose of ceritinib must be no more than 60 days prior to the first dose of study drug.

Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 180 days after the last dose of study drug.

Use of any standard/experimental anti-lymphoma drug therapy, including steroids, within 3 weeks of initiation of the study or use of any experimental non-drug therapy (e.g., donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug treatment

Male and female subjects who are not surgically sterile or post-menopausal must agree to use reliable methods of birth control for the duration of the study and for 90 days after the last dose of study drug administration; male partners of female subjects should use condoms for the duration of the study, and for 90 days after the last dose of study drug administration

Skin lesion involvement of at least 2% of BSA accessible for topical application of study drug

Treatment with any investigational products within 14 days before the first dose of study drug and systemic anticancer therapy within 28 days before the first dose of study drug.

Systemic corticosteroid (inhalers are allowed) within 7 days before the first dose of study drug.

Radiotherapy within 14 days before the first dose of study drug.

Hematologic function, as follows (no platelet transfusion within 2 weeks and no RBC transfusion within 4 days before the first dose of study drug)

Radioimmunotherapy within 4 weeks before first dose of study drug

Use of any investigational drug (including marketed drugs not approved for this indication) within 14 days prior to the first dose of study drug

Platelet transfusion within 2 weeks and RBC transfusion within 4 days before the first dose of study drug

Subjects receiving systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.) within 28 days of the first dose of study drug are not eligible

Negative serum pregnancy test done =< 7 days prior to registration/randomization, for women of childbearing potential only\r\n* Note:\r\n** Females: adequate contraception must be used by both patient and partner while receiving study drug and for 12 weeks after the last dose of study drug\r\n** Males: adequate contraception must be used by both patient and partner while receiving study drug; men who have a partner of childbearing age should also avoid fathering a child for 6 months after the last dose of study drug

Any immunotherapy within 4 weeks of first dose of study drug.

For subjects with recent chemotherapy or experimental therapy the first dose of study drug must occur after 5 times the half-life of the agent(s).

Are currently receiving an investigational drug in a clinical trial or participating in any other type of medical research judged not to be scientifically or medically compatible with this study

At least 12 weeks must have elapsed from the use of strontium-89, radium-223 or any investigational or approved immunotherapy (e.g., Provenge) prior to starting study drug

Subjects who received systemic anticancer therapy or radiotherapy <21 days prior to their first day of study drug administration.

Patient must not be on any other systemic immunosuppressant therapy other than corticosteroids within 28 days of the first dose of study drug

Inclusion Criteria:\n\n        Each participant with newly diagnosed multiple myeloma (NDMM) must meet all of the\n        following inclusion criteria to be enrolled in the study:\n\n          1. Adult male or female participants 18 years of age or older with a confirmed diagnosis\n             of symptomatic multiple myeloma (MM) according to standard criteria.\n\n          2. Participants for whom cyclophosphamide and dexamethasone treatment is appropriate and\n             who are considered not eligible for high-dose therapy (HDT)-stem cell transplantation\n             (SCT) for 1 or more of the following reasons:\n\n               -  The participant is 65 years of age or older.\n\n               -  The participant is less than 65 years of age but has significant comorbid\n                  condition(s) that are, in the opinion of the investigator, likely to have a\n                  negative impact on tolerability of HDT-SCT.\n\n        Each participant with relapsed and/or refractory multiple myeloma (RRMM) must meet all of\n        the following inclusion criteria to be enrolled in the study:\n\n          1. Adult male or female participants 18 years or older with a confirmed diagnosis of\n             symptomatic MM either currently or at the time of initial diagnosis, according to\n             standard criteria, and relapsed and/or refractory disease after 1 to 3 lines of prior\n             therapy. A participant is considered to have refractory disease if disease progression\n             occurred during the treatment period or within 60 days of receiving the last dose of a\n             given therapy. A line of therapy is defined as 1 or more cycles of a single-agent or\n             combination therapy or a sequence of planned treatments such as induction therapy\n             followed by autologous stem cell transplantation (ASCT) and then maintenance therapy.\n\n          2. No evidence of graft-versus-host disease for participants who have undergone prior\n             allogeneic stem cell transplantation.\n\n        In addition, all participants (NDMM and RRMM) must meet all of the remaining criteria:\n\n          1. Participants must have measurable disease defined by at least 1 of the following 3\n             measurements:\n\n               -  Serum M-protein ? 1 g/dL (? 10 g/L).\n\n               -  Urine M-protein ? 200 mg/24 hours.\n\n               -  Serum free light chain assay: involved free light chain level ? 10 mg/dL (? 100\n                  mg/L), provided that the serum free light chain ratio is abnormal.\n\n          2. Participants must meet all of the following clinical laboratory criteria:\n\n               -  Absolute neutrophil count (ANC) ? 1000/mm^3 and platelet count ? 75,000/mm^3.\n                  Platelet transfusions to help participants meet eligibility criteria are not\n                  allowed within 3 days prior to administration of the study drug.\n\n               -  Total bilirubin ? 1.5 x the upper limit of the normal range (ULN).\n\n               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ? 3 x ULN.\n\n               -  Calculated creatinine clearance (CrCL) ? 30 mL/min.\n\n          3. Eastern Cooperative Oncology Group performance status of 0, 1, or 2.\n\n          4. Female participants who:\n\n               -  are postmenopausal for at least 1 year before the screening visit, or\n\n               -  are surgically sterile, or\n\n               -  If they are of childbearing potential, agree to practice 2 effective methods of\n                  contraception, at the same time, from the time of signing the informed consent\n                  through 90 days after the last dose of study drug, or\n\n               -  agree to practice true abstinence over the period previously described, when this\n                  is in line with the preferred and usual lifestyle of the participant. (Periodic\n                  abstinence [ie, calendar, ovulation, symptothermal, postovulation methods] and\n                  withdrawal are not acceptable methods of contraception.), and\n\n               -  adhere to any treatment-specific pregnancy prevention guidelines for\n                  cyclophosphamide and dexamethasone.\n\n          5. Male participants, even if surgically sterilized (ie, status post-vasectomy), who:\n\n               -  agree to practice effective barrier contraception during the entire study\n                  treatment period and through 90 days after the last dose of study drug, or\n\n               -  agree to practice true abstinence over the period previously described, when this\n                  is in line with the preferred and usual lifestyle of the participant. (Periodic\n                  abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the\n                  female partner] and withdrawal are not acceptable methods of contraception.), and\n\n               -  adhere to any treatment-specific pregnancy prevention guidelines for\n                  cyclophosphamide and dexamethasone.\n\n          6. Voluntary written consent must be given before performance of any study-related\n             procedure not part of standard medical care, with the understanding that consent may\n             be withdrawn by the participant at any time without prejudice to future medical care.\n\n          7. Suitable venous access for the study-required blood sampling.\n\n          8. Is willing and able to adhere to the study visit schedule and other protocol\n             requirements.\n\n        Exclusion Criteria:\n\n          1. Prior treatment for multiple myeloma with either standard of care treatment or\n             investigational regimen (for participants with NDMM only).\n\n             NOTE: Prior treatment with corticosteroids (maximum dose of corticosteroids should not\n             exceed the equivalent of 160 mg of dexamethasone over 14 days. Localized radiation is\n             permitted as long as it is below a therapeutic level and administered at least 14 days\n             prior to the first dose of study treatment.\n\n          2. Diagnosis of smoldering MM, Waldenström's macroglobulinemia, POEMS (polyneuropathy,\n             organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome,\n             plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or\n             myeloproliferative syndrome.\n\n          3. Central nervous system involvement.\n\n          4. Diagnosed or treated for another malignancy within 2 years before the first dose or\n             previously diagnosed with another malignancy and have any evidence of residual\n             disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type\n             are not excluded if they have undergone complete resection.\n\n          5. Peripheral neuropathy Grade 1 with pain or Grade 2 or higher peripheral neuropathy of\n             any cause on clinical examination during the Screening period.\n\n          6. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral\n             absorption or tolerance of study drug, including difficulty swallowing.\n\n          7. Infection requiring intravenous (IV) antibiotic therapy or other serious infection\n             within 14 days before the first dose of study drug.\n\n          8. Ongoing or active infection, known human immunodeficiency virus (HIV) positive, active\n             hepatitis B or C infection.\n\n          9. Systemic treatment with strong inhibitors of CYP1A2 (fluvoxamine, enoxacin,\n             ciprofloxacin), strong inhibitors of CYP3A (clarithromycin, telithromycin,\n             itraconazole, voriconazole, ketoconazole, nefazodone, posaconazole) or strong CYP3A\n             inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital),\n             or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of\n             study treatment.\n\n         10. Known allergy to any of the study medications, their analogues, or excipients in the\n             various formulations.\n\n         11. Major surgery within 14 days before the first dose of study drug. (Note: kyphoplasty\n             or vertebroplasty is not considered major surgery.)\n\n         12. Female participants who are lactating and breastfeeding or have a positive serum\n             pregnancy test during the Screening period.\n\n         13. Any serious medical or psychiatric illness that could, in the investigator's opinion,\n             potentially interfere with the completion of treatment according to this protocol.\n\n         14. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment\n             of the investigator, would make the participant inappropriate for entry into this\n             study or interfere significantly with the proper assessment of safety and toxicity of\n             the prescribed regimens.\n\n         15. Treatment with any investigational products for reasons other than MM within 30 days\n             before the first dose of study drug.

Agreement to use contraception during the study and for 90 days after the last dose of study drug if sexually active and able to bear children.

Any immunotherapy within 4 weeks of first dose of study drug.

For subjects with recent chemotherapy or experimental therapy the first dose of study drug must occur after 5 times the half-life of the agent(s).

Current enrollment in an investigational drug or device study or participation in such a study within 4 weeks of cycle 1, day 1

COHORT A: Concomitant therapy with any other experimental drug

COHORT B: Concomitant therapy with any other experimental drug

Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug

Male subject must not donate sperm starting at Screening and throughout the study period and for at least 3 months after final drug administration.

FOCBP must have a negative pregnancy test within 7 days prior to registration on study\r\n* Note: female patients who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

Recent hemoptysis (>= 1/2 teaspoon [2.5 mL]) of red blood within 8 weeks before first dose of study drug

Administration of any non-oncologic investigational drug within 28 days prior to receiving the first dose of therapy

Patients who received systemic anti-cancer treatment prior to the first dose of study drug within the following time frames:

Subject is suitable for oral administration of study drug.

must agree not to try to become pregnant during the study and for 180 days after the final study drug administration, and

Female subject must not be breastfeeding at Screening or during the study period, and for 60 days after the final study drug administration.

Female subject must not donate ova starting at Screening and throughout the study period, and for 180 days after the final study drug administration.

Male subject must not donate sperm starting at Screening and throughout the study period and for 120 days after the final study drug administration.

Patients must have the ability to swallow the study drug whole as a tablet or capsule

Participation in any other investigational drug study within 4 weeks of study enrollment

Patient who has had chemotherapy, or biological cancer therapy within 2 weeks prior to the first dose of study drug; patient who has had radiation within 2 weeks prior to the first dose of study drug

Participation in other studies involving investigational drug(s) within 4 weeks prior to study participation and/or during study participation.

Female patients who intend to donate eggs (ova) during the course of this study or 4 months after receiving their last dose of study drug(s)

Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g. cyclosporine A, tacrolimus, etc) within 28 days of the first dose of study drug

Current enrollment in an investigational drug or device study or participation in such a study within 30 days of enrollment

Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug

Female subjects of child-bearing potential must agree to undergo medically supervised pregnancy test prior to starting study drug. The first pregnancy test will be performed at screening (within 7 days prior to first study drug administration), and on the day of the first study drug administration and confirmed negative prior to dosing and Day 1 before dosing all subsequent cycles.

Use of an investigational anti-cancer drug within 28 days preceding the first dose of dabrafenib

Enrolled on another clinical trial testing a novel therapy or drug

Have received systemic corticosteroid (inhalers are allowed) within 7 days before the first administration of study drug

Patients must have acceptable organ and marrow function, which should be present independent of growth factor or transfusion support for at least 7 days prior to first dose of study drug, with the exception of pegylated G-CSF (pegfilgrastim) and darbopoeitin which require a 14-day period between dosing and first dose of study drug

Chemotherapy =< 21 days prior to first administration of study treatment and/or monoclonal antibody =< 6 weeks prior to first administration of study treatment; immunotherapy, radiotherapy or experimental therapy within 28 days of first day of study drug dosing, or within six weeks of first day of study drug dosing in the event that nitrosoureas or mitomycin were used; concurrent systemic immunosuppressant therapy other than corticosteroids (e.g. cyclosporine A, tacrolimus, etc) must be discontinued within 28 days of the first dose of study drug

Prior chemotherapy, cancer immunosuppressive therapy, or other investigational agents within 4 weeks before first dose of study drug.

Survival expectation of 12 weeks or longer after starting study drug.

Subjects who have received any anticancer therapy (including surgery, locoregional, biological, immunotherapy, hormonal, or radiotherapy) within 21 days before the first dose of study drug (28 days for investigational therapies).

Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks before the first dose of study drug.

Men must agree to not donate sperm during and after the study for 12 months after the last dose of rituximab or 3 months after the last dose of study drug, whichever is later

Sexually active males unless they use a condom during intercourse while taking drug and for 5 months after stopping midostaurin medication; they should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Prior illicit drug addiction

Recent hemoptysis (>= ½ teaspoon of red blood within 8 weeks before first dose of study drug)

Treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry

Administration of an investigational therapeutic drug within 30 Days of Cycle 1 Day 1

Prior treatment with pemetrexed < 6 months prior to starting study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Inclusion Criteria: Subjects eligible for enrolment in this study must meet all of the\n        following criteria\n\n          -  Provided written informed consent,\n\n          -  Male or female >=18 years of age and able to swallow and retain orally administered\n             study treatment and does not have any clinically significant gastrointestinal (GI)\n             abnormalities that may alter absorption such as malabsorption syndrome or major\n             resection of the stomach and/or bowels.\n\n          -  Part 1 and Part 2: Histologically- or cytologically-confirmed diagnosis of advanced or\n             metastatic BRAF V600E mutation positive CRC\n\n          -  Part 4A and 4B ONLY: Histologically- or cytologically-confirmed diagnosis of advanced\n             or metastatic CRC that either harbours the BRAF V600E -mutation, as determined by\n             relevant genetic testing OR has developed secondary resistance to anti-EGFR therapy,\n             defined as patients that derived benefit (disease control based on investigator\n             assessment for >6 months OR partial response [confirmed or unconfirmed] based on\n             RECIST 1.1) from prior anti-EGFR-containing therapy (as defined below) and then\n             subsequently progressed on therapy. The anti-EGFR therapy must have been the most\n             recent therapy and the patient must have progressed based on investigator assessment\n             within 3 months of screening. Acceptable prior anti-EGFR-containing therapies include:\n             a. Monotherapy anti-EGFR, including cetuximab or panitumumab OR b.\n             irinotecan/anti-EGFR combo after previously having disease progression (based on\n             investigator assessment) on an irinotecan-containing regimen\n\n          -  Part 3: Histologically- or cytologically-confirmed diagnosis of BRAFV600E mutation\n             positive advanced or metastatic colorectal cancer (CRC who are eligible to receive\n             fluoropyrimidine-containing chemotherapy regimen that have experienced documented\n             radiographic progression on one prior line of fluoropyrimidine-containing chemotherapy\n             (previous anti-EGFR therapy is excluded), Second-line for advanced/metastatic disease,\n             having failed or been intolerant to at least one regimen of\n             fluoropyrimidine-containing chemotherapy including irinotecan or oxaliplatin in the\n             advanced/metastatic setting. Enrollment in Part 3 may only occur following\n             confirmation of KRAS wild-type cancer.\n\n          -  Archival tissue is required; if archival tissue is not available or found to not\n             contain tumor tissue, a fresh biopsy is required.\n\n          -  Measurable disease per RECIST version 1.1.\n\n          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.\n\n          -  Men with a female partner of childbearing potential must have either had a prior\n             vasectomy or agree to use one of the contraception methods listed in protocol.\n\n          -  Female subjects are eligible if: Non-childbearing potential defined as pre-menopausal\n             females with a documented tubal ligation or hysterectomy; or post-menopausal female\n             defined as 12 months of spontaneous amenorrhea to be verified with a\n             follicle-stimulating hormone (FSH) level >40 Milli-international units per milliliter\n             (MIU/mL) and estradiol level <40 picogram per milliliter (pg/mL). Child-bearing\n             potential and agrees to use one of the contraceptive methods listed in protocol.\n\n          -  Female subjects must agree to use contraception from 7 days prior to the first dose of\n             study drug(s) until 6 months after the last dose of panitumumab, until 4 months after\n             the last dose of trametinib, or 4 weeks after the last dose of dabrafenib, whichever\n             is longer. Additionally, women of childbearing potential must have had a negative\n             serum pregnancy test within 7 days prior to the first dose of study drug(s).\n\n          -  Adequate organ system function as defined in absolute neutrophil count greater than or\n             equal to 1.2X10^9/Liter (L), hemoglobin greater than or equal to 9 grams per deciliter\n             (g/dL) or 5.6 millimoles per litre (mmol/L), platelets greater than or equal to 75 ×\n             10^9/L, Prothrombin Time / International Normalized Ratio (PT/INR) and Partial\n             Thromboplastin Time (PTT) less than or equal to 1.5X upper limit of normal (ULN);\n             serum magnesium greater than or equal to the lower limit of normal (LLN); albumin\n             greater than or equal to 2.5 g/dL or 25 grams per liter (g/L), total bilirubin less\n             than or equal to 1.5XULN, and Aspartate aminotransferase (AST) and Alanine\n             aminotransferase (ALT) less than or equal to 2.5X ULN; creatinine less than or equal\n             to 1.5XULN or calculated creatinine clearance greater than or equal to 50mL/min; left\n             ventricular ejection fraction (LVEF) greater than or equal to the LLN by\n             echocardiography (ECHO) or multigated acquisition scan (MUGA).\n\n          -  Subjects enrolled in France or Italy: In France or Italy, a subject will be eligible\n             for inclusion in this study only if either affiliated to, or a beneficiary of, a\n             social security category.\n\n        Exclusion Criteria: Subjects meeting any of the following criteria must not be enrolled in\n        the study\n\n          -  History of prior malignancy, other than colorectal cancer.\n\n          -  Any serious and/or unstable pre-existing medical, psychiatric disorder or other\n             conditions that could interfere with subject's safety, obtaining informed consent or\n             compliance to the study procedures.\n\n          -  Current active liver or biliary disease (with the exception of Gilbert's syndrome or\n             asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease\n             per investigator's assessment).\n\n          -  History of sensitivity to heparin or heparin-induced thrombocytopenia.\n\n          -  Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy or\n             biologic therapy).\n\n          -  Prior exposure to a MEK inhibitor.\n\n          -  Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Prior exposure to a BRAF\n             inhibitor.\n\n          -  Part 1, Part 2 and BRAF-mutant patients in Part 4 ONLY: Known presence of\n             KRAS-mutation based on previous KRAS-testing. Note: Propsective KRAS testing is not\n             required. However, if the results of previous KRAS testing are known, they must be\n             used in assessing eligibility. KRAS testing will be performed retrospectively for all\n             patients.\n\n          -  Part 3: Prior exposure to EGFR inhibitors or an anti-EGFR antibody\n\n          -  Received an investigational or approved anti-cancer drug within 4 weeks, or within 5\n             half-lives (whichever is shorter) of the first dose of study drug(s). At least 14 days\n             must have passed between the last dose of prior investigational agent and the first\n             dose of study drug(s).\n\n          -  Part 3: Received more than one prior anti-cancer therapy in the metastatic setting,\n             exclusive of previous adjuvant regimens. Previous investigational anti-cancer therapy\n             in the metastatic setting is prohibited.\n\n          -  Current use of a prohibited medication or requirement to dose with any of these\n             medications during treatment with study drug(s).\n\n          -  Known Hepatitis B, or Hepatitis C infection.\n\n          -  Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first\n             dose of study drug(s). Limited radiotherapy with in the 2 weeks prior to first dose of\n             study drug(s).\n\n          -  Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose of\n             study drug(s). Chemotherapy regimens given continuously or on a weekly basis with\n             limited potential for delayed toxicity within 2 weeks prior to first dose of study\n             drug(s).\n\n          -  Unresolved toxicity greater than National Cancer Institute Common Terminology Criteria\n             for Adverse Events (NCI-CTCAE) version 4 Grade 1 from previous anti-cancer therapy,\n             with the exception of Grade 2 alopecia, Grade 2 neuropathy, or laboratory values that\n             are allowed per inclusion criteria.\n\n          -  History of retinal vein occlusion (RVO).\n\n          -  Presence of active gastrointestinal disease or other condition that will interfere\n             significantly with the absorption, distribution, metabolism or excretion of drugs.\n             Previous colectomy is acceptable.\n\n          -  Subjects with brain metastases are excluded, unless: All known lesions must be\n             previously treated with surgery or stereotactic radio-surgery, and Brain lesion(s), if\n             present, must be confirmed stable (i.e., no increase in lesion size) for >=90 days\n             prior to first dose of study drug(s). This must be documented with two consecutive MRI\n             or CT scans using contrast, and Asymptomatic with no corticosteroids requirement for\n             >=30 days prior to first dose of study drug(s), and No enzyme-inducing anticonvulsants\n             for >=14 days prior to first dose of study drug(s). In addition, for subjects that had\n             brain metastases but currently have no evidence of disease (NED), NED for >=12 weeks\n             is required and must be confirmed by two consecutive MRI or CT scans (using contrast)\n             separated by >=6 weeks, prior to randomization. Enrollment of a subject with brain\n             metastases who meet the above criteria requires approval of a GlaxoSmithKline (GSK)\n             Medical Monitor.\n\n          -  Psychological, familial, sociological or geographical conditions that do not permit\n             compliance with the protocol.\n\n          -  History or evidence of cardiovascular risk including any of the following: LVEF<LLN; A\n             QT interval corrected for heart rate using the Bazett's formula (QTcB;) ? 480\n             milliseconds (msec);.History or evidence of current clinically significant\n             uncontrolled arrhythmias. Exception: Subjects with controlled atrial fibrillation for\n             >30 days prior to randomization are eligible. History of acute coronary syndromes\n             (including myocardial infarction and unstable angina), coronary angioplasty, or\n             stenting within 6 months prior to randomization. History or evidence of current >=\n             Class II congestive heart failure as defined by New York Heart Association (NYHA).\n             Treatment refractory hypertension defined as a blood pressure of systolic> 140\n             millimeter of mercury (mm Hg) and/or diastolic > 90 mm Hg which cannot be controlled\n             by anti-hypertensive therapy; Subjects with intra-cardiac defibrillators or permanent\n             pacemakers; Known cardiac metastases\n\n          -  Unstable pulmonary embolism, deep vein thrombosis, or other significant\n             arterial/venous thromboembolic event <=30 days before randomization. If on\n             anticoagulation, subject must be on stable therapeutic dose prior to randomization.\n\n          -  Subjects with a history of pneumonitis or interstitial lung disease (ILD).\n\n          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs\n             chemically related to the study drug(s) or their excipients.\n\n          -  Pregnant or lactating female.\n\n          -  Unwillingness or inability to follow the procedures outlined in the protocol.\n\n          -  Uncontrolled diabetes or other medical condition that may interfere with assessment of\n             toxicity.

Use of any standard/experimental anti-lymphoma drug therapy, including steroids, within 3 weeks of initiation of the study or use of any experimental non-drug therapy (e.g., donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug treatment; prior allogeneic stem cell transplant (SCT) within 16 weeks or autologous SCT within 8 weeks of initiation of therapy

Use of any other experimental drug or therapy within 28 days of baseline

Treatment with any investigational drug within 2 weeks before first administration of present trial drug.

Neutrophil count >= 1000/mm^3; (no growth factors within 5 days prior to first dose of the study drug)

At the time of trial enrollment, participants may be receiving one or two other immunosuppressive therapies in addition to glucocorticoids; immunosuppressant doses must be stable for 14 days prior to starting study drug; monoclonal T or B cell antibodies must be discontinued at least 28 days before starting study drug

Have taken certain medications or had grapefruit juice within 7 days of initial dose of study drug, as levels of the study drug may be affected.

Must be willing to use contraception during the study, and for 30 days following the last dose of study drug

A woman who is pregnant or breast feeding, or a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug

Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Any prior therapy for castrate disease is acceptable except prior abiraterone, which is excluded; a minimum washout of 28 days for any other anticancer therapy prior to first dose of study drug is required\r\n* Any other radiotherapy or radionuclide require 28-day washout prior to first dose of study drug\r\n* Denosumab or zoledronic acid are allowed

Concomitant therapy with any other experimental drug

Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study

Inclusion Criteria:\n\n          1. At least 18 years of age.\n\n          2. Ability to understand the purposes and risks of the study and has signed a written\n             informed consent form approved by the investigator's IRB/Ethics Committee.\n\n          3. Relapsed/refractory multiple myeloma for which no standard therapy options are\n             anticipated to result in a durable remission.\n\n          4. Receipt of at least two prior therapies as indicated by protocol\n\n          5. Subjects with measurable disease\n\n          6. ECOG performance status of less than or equal to 2\n\n          7. Acceptable liver function\n\n          8. Acceptable renal function\n\n          9. Acceptable hematologic status\n\n         10. For Part A, B, C subjects: Women of childbearing potential must have a negative serum\n             pregnancy test and women and men subjects must agree to use effective means of\n             contraception with their partner as indicated by protocol For Part D subjects: a\n             negative serum pregnancy test is required within 10- 14 days prior to initiating with\n             pomalidomide, AND a negative serum pregnancy test within 24 hours of starting\n             pomalidomide and must either commit to continued abstinence from heterosexual\n             intercourse or begin two acceptable methods of birth control at least 28 days before\n             she starts taking pomalidomide.\n\n             Women of childbearing potential must enroll into and follow all requirements of the\n             POMALYST REMS program, which includes adhering to the scheduled pregnancy testing.\n\n             Men must agree to use a latex or synthetic condom during sexual contact with women of\n             child bearing potential even if they have had a vasectomy.\n\n             All subjects must be counseled at a minimum of every 28 days about pregnancy\n             precautions and risks of fetal exposure, or when a female patient misses her period or\n             if there is any abnormality in her menstrual bleeding.\n\n         11. Subjects must adhere to the study visit schedule and other protocol requirements and\n             receive outpatient therapy and laboratory monitoring at the institute that administers\n             the study drug.\n\n        Exclusion Criteria\n\n        Subjects who meet any of the following exclusion criteria are not eligible to be enrolled\n        in this study:\n\n          1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy\n             and skin changes.)\n\n          2. Waldenstrom's macroglobulinemia\n\n          3. Localized radiation therapy to only measurable disease site(s) within 2 weeks of\n             treatment\n\n          4. New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial\n             infarction within 6 months prior to Day 1, or unstable arrhythmia\n\n          5. Significant neuropathy (Grade 3 or 4, or Grade 2 with pain) at the time of enrollment\n             or within 14 days before enrollment\n\n          6. Symptomatic brain metastases (unless previously treated and well controlled for a\n             period of ? 3 months)\n\n          7. Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the\n             investigator any physiological state leading to hypoxemia\n\n          8. Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without\n             complete recovery\n\n          9. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic\n             therapy within 14 days prior to the first dose\n\n         10. Previously treated malignancies, except for adequately treated non-melanoma skin\n             cancer (basal cell or squamous cell), in situ cancer, or other cancer from which the\n             subject has been disease-free for at least 5 years\n\n         11. Subjects who participated in an investigational drug or device study within 2 weeks\n             prior to study entry\n\n         12. Known or suspected active infection with HIV, hepatitis A, hepatitis B, or hepatitis C\n\n         13. Subjects who have exhibited allergic reactions to a similar structural compound,\n             biological agent, or formulation similar to TH-302, bortezomib (for subjects enrolled\n             in Part C only), pomalidomide (Part D), dexamethasone or pimonidazole\n\n         14. Females who are pregnant or breast-feeding\n\n         15. Concomitant psychiatric disease or medical condition that could interfere with the\n             conduct of the study, or that would, in the opinion of the investigator, pose an\n             unacceptable risk to the subject in this study\n\n         16. Unwillingness or inability to comply with the study protocol for any reason\n\n         17. Previous cytotoxic therapies for multiple myeloma within 3 weeks prior to study entry\n             (2 weeks for biologic, novel therapy or corticosteroids)\n\n         18. Subjects who have been on hormone replacement less than 2 months (subjects on hormone\n             replacement for at least 2 months will not be excluded provided the HRT regimen\n             remains unchanged during the conduct of the study).\n\n         19. Prior peripheral stem cell transplant within 12 weeks of the start of study\n\n         20. Epilepsy or other convulsive disorder requiring active management\n\n         21. Prior therapy with a pomalidomide-containing regimen\n\n         22. Subjects on strong inducers or strong inhibitors of cytochrome P450 CYP3A4 or CYP1A2\n\n         23. Any other medical condition that in opinion of investigator would place patient at\n             increased risk for toxicity during pomalidomide treatment (i.e. history of recurrent\n             or serious thromboembolic events)

Use of any other experimental drug or therapy within 28 days of baseline

Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study

Treatment with other FAP directed drug therapy (including sulindac or celecoxib, fish oil) within 12 weeks of study enrollment.

Use of any other experimental drug or therapy within 28 days of baseline.

Current, recent (within 2 weeks of enrollment of this study), or planned participation in an experimental drug study

History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to first dose of study drug

Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a nonmyelosuppressive or myelosuppressive agent, respectively

For Dose Confirmation (Parts B, D, E, F and G): Have CNS metastasis that is radiographically or clinically unstable less than 14 days prior to receiving study drug, regardless of whether they are receiving corticosteroids

For Dose Confirmation (Part C): Have glioblastoma multiforme that is radiographically or clinically unstable less than 14 days prior to receiving study drug, regardless of whether they are receiving corticosteroids

Any unresolved toxicity that meets the study treatment discontinuation or study withdrawal criteria from the parent study at the time of transition to this study.

Unable or unwilling to discontinue use of prohibited medications for at least 7 days prior to the first dose of study drug and for the duration of the study

Subject has received a monoclonal antibody for anti-neoplastic intent within 8 weeks prior to the first dose of study drug.

Are currently enrolled in, or discontinued within the last 28 days from a clinical trial involving an investigational drug or device or not approved use of a drug or device (other than the study drug used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study

Has demonstrated compliance with study drug(s), treatment visit schedules, and the requirements and restrictions listed in the consent form

A FCBP must have two negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to starting study drug; the first pregnancy test must be performed within 10-14 days prior to the start of study drug and the second pregnancy test must be performed within 24 hours prior to prescribing the study drug; the subject may not receive study drug until the investigator has verified that the results of these pregnancy tests are negative

Use of any other experimental drug or therapy within 28 days of baseline

Hemoptysis within 6 weeks of first dose of study drug

EXPANSION COHORT ONLY: Hemoptysis within 6 weeks of first dose of study drug

Patients receiving any other anticancer or experimental drug therapy

Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study

Use of any other experimental anti-cancer drug or therapy within 28 days of initiation of the study drug

Ability to receive study drug therapy by enteral administration

A man who is sexually active with a woman of childbearing potential must agree to use a barrier method of birth control during the study and for 4 weeks after receiving the last dose of study drug. All men must also not donate sperm during the study and for 90 days after receiving the last dose of study drug.

Plan to father a child while enrolled in this study or within 90 days after the last dose of study drug.

complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of study agent and 6 months after the last dose of study agent; or

Radiotherapy within 14 days prior to the first dose of study drug; if the involved field is small, 7 days will be considered a sufficient interval between treatment and administration of the first dose of the study medications

Patients who are currently participating or planning to participate in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study or who are receiving other investigational agents.

Have received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug

Known treatment with systemic corticosteroid within one week prior to the first administration of study drug

WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug

Either commit to continued abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.

Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.

Have an understanding that the study drug could have a potential teratogenic risk.

Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy. • Agree not to share study medication with another person.

Participation in other studies involving investigational drug(s) (Phases 1-4) within 4 weeks of registering for the current study and/or during study participation.

Female subject must not be breastfeeding at Screening or during the study period, and for 28 days after the final study drug administration.

Female subject must not donate ova starting at Screening and throughout the study period, and for 28 days after the final study drug administration.

Male subject must not donate sperm starting at Screening and throughout the study period and for 90 days after the final study drug administration.

Subject has received intervening anticancer treatment or previous treatment with chemotherapy for metastatic disease other than palliative local radiation to painful bone metastases completed at least 1 week prior to the first dose of study drug. The administration of neoadjuvant or adjuvant chemotherapy is allowed as long as it has finalized ? 6 months before the first dose of study drug.

Subject has symptomatic central nervous system (CNS) metastasis. Subject with previously treated brain or CNS metastases are eligible provided that the subject has recovered from any acute effects of radiotherapy, does not have brain metastasis related symptoms, is not requiring systemic steroids for at least 2 weeks prior to study drug administration, and any whole brain radiation therapy was completed at least 4 weeks prior to study drug administration, or any stereotactic radiosurgery (SRS) was completed at least 2 weeks prior to study drug administration. Steroid inhaler use or ointment treatment for other concomitant medical disease is permitted.

Subject has received blood transfusions or hematopoietic factor therapy within 14 days prior to the first dose of study drug.

Subject has received potent CYP 3A4 inhibitors within 7 days prior to first dose of study drug or proton pump inhibitors such as omeprazole within 14 days prior to first dose of study drug.

Antileukemia or experimental treatment within 4 weeks of study drug (other than hydroxyurea or 6-mercaptopurine)

Prior exposure to a pyrrolobenzodiazepine or indolinobenzodiazepine based drug.

Must be willing to implement contraception throughout study and for the 8 weeks following last study drug administration.

Use of drugs that might pose a risk of a drug-drug interaction within 4-7 days before the start of study therapy.

Agree not to share either study drug with another person.

Non-study related surgical procedures less than or equal to 7 days prior to administration of study drug. In all cases, the patient must be sufficiently recovered and stable before treatment administration.

Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, pommelos, or exotic citrus fruits, from 1 day prior to the first dose of study treatment(s) until the last dose of study drug.

Received last dose of study drug on another therapeutic clinical trial within 30 days prior to randomization

Participation in other studies involving investigational drug(s) (Phases 1-4) before the current study begins and/or during study participation.

Subject agrees not to participate in another interventional study while receiving study drug and participating in the present study.

Agree not to try to become pregnant during the study and for 28 days after the final study drug administration

Female subject must agree not to breastfeed at screening and throughout the study period, and for 28 days after the final study drug administration.

Female subject must not donate ova starting at screening and throughout the study period, and for 28 days after the final study drug administration.

Agrees to use a male condom starting at screening and continue throughout study treatment and for 90 days after the final study drug administration. If the male subject has not had a vasectomy or is not sterile as defined below their female partner(s) is utilizing 1 form of highly effective birth control*starting at screening and continue throughout study treatment and for 90 days after the male subject receives their final study drug administration.

Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 90 days after the final study drug administration

Male subject must not donate sperm starting at screening and throughout the study period, and for 90 days after the final study drug administration.

Subject has any of the following within 14 days prior to the first dose of study drug:

Subject has received the following within 14 days prior to the first dose of study drug:

Sexually active males unwilling to use a condom during intercourse while taking drug and for 45 days after stopping investigational medication. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Male patients should not father a child in this period.

Use of investigational drug, other than the study medications specified by the protocol, within 30 days of transplantation

Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 28 days prior to the first administration of study drug and agree to use highly effective physician-approved contraception from 30 days prior to the first study drug administration to 90 days following the last study drug administration

Male subjects must be surgically sterile or must agree to use highly effective physician-approved contraception from 30 days prior to the first study drug administration to 90 days following the last study drug administration

Received any of the following within the specified time frame prior to the first administration of study drug:

Inclusion Criteria:\n\n        Part 1 and Part 2\n\n          1. Is male or female aged 18 years or older at the time of consent.\n\n          2. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14\n             days before enrollment.\n\n          3. Has adequate organ and hematologic function as evidenced by the following laboratory\n             values within 14 days before enrollment:\n\n               -  Absolute neutrophil count (ANC) ?1.5x10^9/L.\n\n               -  Platelet count ?100x10^9/L.\n\n               -  Hemoglobin ?9 g/dL (Transfusions are allowed to reach this hemoglobin level).\n\n               -  Serum creatinine ?1.5 times the upper limit of the normal range (ULN) or\n                  creatinine clearance ?50 mL/min either as estimated by the Cockcroft-Gault\n                  equation or based on urine collection (12 or 24 hours).\n\n               -  Total bilirubin ?1.5×ULN.\n\n               -  Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ?2.5×ULN.\n\n          4. Female participants who:\n\n               -  Are postmenopausal for at least 1 year before the screening visit, OR\n\n               -  Are surgically sterile, OR\n\n               -  If they are of childbearing potential, agree to practice 1 highly effective\n                  method and 1 additional effective (barrier) method of contraception at the same\n                  time, from the time of signing the informed consent form through 30 days after\n                  the last dose of study drug (with the exception of those participants assigned to\n                  TAK-659, for whom the duration required is 180 days), or for as long as mandated\n                  by local labeling for docetaxel and paclitaxel, OR\n\n               -  Agree to practice true abstinence, when this is in line with the preferred and\n                  usual lifestyle of the participant, from the time of signing the informed consent\n                  form through 30 days after the last dose of study drug (with the exception of\n                  those participants assigned to TAK-659, for whom the duration required is 180\n                  days), or for as long as mandated by local labeling for docetaxel and paclitaxel.\n                  (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation\n                  methods], withdrawal, spermicides only, and lactational amenorrhea are not\n                  acceptable methods of contraception. Female and male condoms should not be used\n                  together.)\n\n             Male participants, even if surgically sterilized (ie, status postvasectomy), who:\n\n               -  Agree to practice effective barrier contraception during the entire study\n                  treatment period and through 120 days after the last dose of study drug (with the\n                  exception of those participants assigned to TAK-659, for whom the duration\n                  required is 180 days), or for as long as mandated by local labeling for docetaxel\n                  and paclitaxel, OR\n\n               -  Agree to practice true abstinence, when this is in line with the preferred and\n                  usual lifestyle of the participant during the entire study treatment period and\n                  through 120 days after the last dose of study drug (with the exception of those\n                  participants assigned to TAK-659, for whom the duration required is 180 days) or\n                  for as long as mandated by local labeling for docetaxel and paclitaxel. (Periodic\n                  abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the\n                  female partner] and withdrawal are not acceptable methods of contraception.)\n\n          5. Voluntary written consent must be given before performance of any study-related\n             procedure not part of standard medical care, with the understanding that consent may\n             be withdrawn by the participant at any time without prejudice to future medical care.\n\n          6. Has suitable venous access for the study-required blood sampling (ie, pharmacokinetic\n             (PK) sampling, circulating tumor deoxyribonucleic acid [DNA]).\n\n        Part 1 only\n\n          1. Has a histologically confirmed diagnosis of advanced solid tumor, including but not\n             limited to gastric or gastroesophageal junction adenocarcinoma.\n\n          2. Has radiographically or clinically evaluable disease. Measurable disease as defined by\n             Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1 is not required.\n\n          3. Is relapsed or refractory with no effective therapeutic options available.\n\n        Part 2 only\n\n          1. Has a histologically confirmed diagnosis of metastatic or locally advanced\n             adenocarcinoma of the stomach or gastroesophageal junction (Stage IIIb or IV according\n             to International Union Against Cancer [UICC] tumor, node, metastases [TNM]\n             classification, 7th edition).\n\n          2. Has at least 1 measurable tumor lesion per RECIST Version 1.1 by radiographic\n             techniques (computed tomography [CT] or magnetic resonance imaging [MRI]).\n\n          3. Has receipt of 1 prior systemic chemotherapy regimen for advanced or metastatic\n             adenocarcinoma of the stomach or gastroesophageal junction with documented progressive\n             disease (PD).\n\n          4. Has archived or fresh tumor biopsy samples obtained during screening sufficient for\n             Epstein-Barr virus (EBV) testing and genotyping.\n\n        Exclusion Criteria:\n\n        Part 1 and Part 2\n\n          1. Has received prior systemic anticancer therapies or other investigational agents\n             within 2 weeks before the first administration of study drug or has failed to recover\n             from the adverse drug effects of prior therapies (to ?Grade 1 or to a level meeting\n             inclusion criteria). For prior therapies with a half-life longer than 3 days, the\n             interval must equal minimally 28 days before the first administration of study drug\n             and the participant must have documented PD.\n\n          2. Has radiotherapy within 14 days before enrollment.\n\n          3. Has fasting glucose ?130 mg/dL. Poorly controlled diabetes mellitus (glycosylated\n             hemoglobin [HbA1c] >7.0%). Participants with a history of transient glucose\n             intolerance due to corticosteroid administration are allowed.\n\n          4. Has received strong cytochrome P-450 (CYP) 3A4 inducers/inhibitors within 7 days\n             before the first administration of study drug or has conditions that require the\n             concomitant use of CYP3A4 inducers/inhibitors during the course of the study.\n\n          5. For TAK-659 (Cohort A) only: Is receiving treatment with medications that are known to\n             be inhibitors or inducers of P-glycoprotein (P-gp). Baseline lipase >ULN. Participants\n             not fulfilling these exclusion criteria can be enrolled in other cohorts (Part 1\n             only).\n\n          6. Has taken proton pump inhibitors within 7 days before the first administration of\n             study drug or has conditions that require the concomitant use of proton pump\n             inhibitors during the course of the study.\n\n          7. Has signs of peripheral neuropathy ? National Cancer Institute Common Terminology\n             Criteria for Adverse Events (NCI CTCAE) Grade 2.\n\n          8. Has symptomatic brain metastases or brain metastases with a stable neurologic status\n             for <2 weeks after completion of the definitive therapy and steroids.\n\n          9. Has systemic infection requiring intravenous (IV) antibiotic therapy or other serious\n             infection within 14 days before the first dose of study drug.\n\n         10. Has known or suspected human immunodeficiency virus (HIV) positive or hepatitis B\n             surface antigen-positive status, or known or suspected active hepatitis C infection.\n             Testing for these agents is not required in the absence of clinical findings or\n             suspicion.\n\n         11. Has known gastrointestinal (GI) disease or GI procedure that could interfere with the\n             oral absorption or tolerability of orally administered study drug, including\n             difficulty swallowing tablets; diarrhea >Grade 1 despite supportive therapy; or prior\n             total gastrectomy.\n\n         12. Has clinically significant comorbidities, such as uncontrolled pulmonary disease,\n             known impaired cardiac function or clinically significant cardiac disease, active\n             central nervous system disease, or any other condition that could compromise the\n             participant's participation in the study.\n\n             • Known impaired cardiac function or clinically significant cardiac disease includes:\n             evidence of currently uncontrolled cardiovascular conditions (including arrhythmias,\n             angina, pulmonary hypertension, acute ischemia or active conduction system\n             abnormalities); current history of New York Heart Association Class III or IV heart\n             failure; acute myocardial infarction within 6 months before starting study drug;\n             baseline QT interval corrected for heart rate (QTc) ?Grade 1 according to NCI CTCAE\n             Version 4.03 criteria; or abnormalities on baseline 12-lead ECG that are considered\n             clinically significant per the investigator.\n\n         13. Female participants who are lactating and breastfeeding or have a positive serum\n             pregnancy test during the screening period or a positive urine pregnancy test on Day 1\n             before the first dose of study drug.\n\n         14. Participants with bilirubin >ULN, or AST and/or ALT >1.5 X ULN concomitant with\n             alkaline phosphatase >2.5 X ULN cannot be allocated to Cohort D (MLN1117+docetaxel) in\n             Part 1 and are not eligible for Part 2 if they are also EBV negative.\n\n        Part 2 only\n\n        1. Has prior treatment with any of the following:\n\n          -  An Aurora A-targeted agent (not eligible for randomization in Cohorts B, C, or D, but\n             eligible for Cohort A if EBV positive).\n\n          -  A docetaxel- or paclitaxel-containing chemotherapy regimen (not eligible for\n             randomization in Cohorts B, C, or D, but eligible for Cohort A if EBV positive).\n\n          -  A spleen tyrosine kinase (SYK) inhibitor (MLN1117+TAK-659 arm only).\n\n          -  A phosphoinositide 3-kinase (PI3K) or serine/threonine kinase, also known as protein\n             kinase B or PKB (AKT) inhibitor.

Agree not to try to become pregnant during the study and for 45 days after the final study drug administration

Subject has received blood transfusions or hematopoietic growth factor therapy within 14 days prior to the first dose of study drug.

Any stereotactic radiosurgery (SRS) was completed at least 1 week prior to the first dose of study drug.

Subject does not require steroids or does not require escalating doses of steroids for at least 2 weeks prior to the first dose of study drug.

Subject has history of gastrointestinal ulcer within 28 days prior to the first dose of study drug.

Must not donate sperm from screening through 3 months after final study drug administration.

Treatment with any known non-marketed drug substance or experimental therapy within 4 weeks prior to enrollment, or currently participating in any other interventional clinical study for NHL or any other illness (except observational and registry trials)

Prior cancer therapy or other investigational therapy within 2 weeks before the first administration of study drug or failed to recover from the reversible effects of prior anticancer therapies. For prior therapies with a half-life longer than 3 days, the interval must be at least 28 days before the first administration of study drug, and the participant must have documented progressive disease.

Has taken histamine-H2 receptor antagonists and/or neutralizing antacids within 24 hours before the first administration of study drug.

Has taken proton pump inhibitors within 7 days before the first administration of study drug.

Use of any strong CYP3A4 inhibitor such as ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir, or saquinavir (see Table 6 6) 14 days before the first dose of study drug or during the study

Subject has received a monoclonal antibody for anticancer intent within 8 weeks prior to the first dose of study drug.

Poor venous access for study drug administration; in this case, patients would require a peripheral or central indwelling catheter for study drug administration; study drug administration via indwelling catheters is prohibited at this time unless silicone based catheters are used; anything other than catheters made from silicone are not allowed with ganetespib therapy

Inclusion Criteria:\n\n          1. Male or female patients, > 18 years of age (in Singapore > 21 years or > 18 years with\n             consent of guardian).\n\n          2. Patients with documented (histologically- or cytologically-proven) HCC, with at least\n             1 measureable lesion > 10 mm (excluding bone metastases). If the measurable lesion(s)\n             is in the liver, it either should not have been treated previously with loco-regional\n             therapy, or there must be demonstrated progression of the lesion following previous\n             loco-regional therapy.\n\n          3. Patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C HCC not amenable to\n             surgical intervention due to either medical contraindications or non-resectability of\n             the tumor.\n\n          4. Patients who are either refractory to or intolerant of sorafenib despite dose\n             reduction and best supportive care, or patients who do not have access to sorafenib or\n             other suitable therapy for HCC.\n\n          5. Patients with underlying hepatic cirrhosis must have a current cirrhosis status of\n             Child-Pugh Class A (i.e., score of 5-6) without encephalopathy.\n\n          6. Phase 1b MTD Biopsy Cohort: Patients with primary or metastatic tumor site(s)\n             considered safely accessible for biopsy and consenting to undergo pre- and post-dosing\n             tumor biopsies.\n\n          7. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or\n             1, and an anticipated life expectancy of ? 3 months.\n\n          8. Patients, both male and female, who are either not of childbearing potential or who\n             agree to use a medically effective method of contraception during the study and for 3\n             months after the last dose of study drug.\n\n          9. Patients with the ability to understand and give written informed consent for\n             participation in this trial, including all evaluations and procedures as specified by\n             this protocol.\n\n        Exclusion Criteria (Patients):\n\n          1. Women who are pregnant or lactating; women of child-bearing potential (WOCBP), and\n             fertile men with a WOCBP-partner not using and not willing to use a medically\n             effective method of contraception.\n\n          2. Patients with known central nervous system (CNS) or leptomeningeal metastases not\n             controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS\n             involvement for which treatment is required.\n\n          3. Patients with mixed histology cholangiocarcinoma and HCC, or fibrolamellar variant\n             HCC.\n\n          4. Patients with any of the following hematologic abnormalities at baseline:\n\n               -  Hemoglobin < 8.5 g/dL\n\n               -  Absolute neutrophil count < 1,500 per mm3\n\n               -  Platelet count < 75,000 per mm\n\n          5. Patients with any of the following serum chemistry abnormalities at baseline:\n\n               -  Total bilirubin > 1.5 × the upper limit of normal (ULN) for the institution\n\n               -  AST or ALT > 5 × the ULN for the institution\n\n               -  Serum creatinine > 1.5 × the ULN for the institution\n\n          6. Patients with the following coagulation parameter abnormality at baseline:\n\n               -  INR > 1.7 × ULN for the institution\n\n          7. Patients with:\n\n               -  A history of deep vein thrombosis (DVT) or pulmonary embolism (PE), within 6\n                  months prior to first study drug administration; patients receiving systemic\n                  anti-coagulation for prophylactic or therapeutic reasons\n\n               -  Active uncontrolled bleeding or a known bleeding diathesis\n\n          8. Patients with:\n\n               -  Esophageal or gastric variceal bleeding within 2 months prior to first study drug\n                  administration; patients with a history of variceal bleeding between 2 and 12\n                  months prior to first study drug administration should have undergone adequate\n                  treatment and be considered clinically stable in the opinion of the investigator\n\n               -  A history of symptomatic ascites requiring paracentesis within the past 3 months\n                  or any encephalopathy requiring hospitalization or medication within the past 3\n                  months\n\n               -  Portal-caval shunts\n\n          9. Patients with a significant cardiovascular disease or condition, including:\n\n               -  Congestive heart failure currently requiring therapy\n\n               -  Need for antiarrhythmic medical therapy for a ventricular arrhythmia\n\n               -  Severe conduction disturbance (i.e., 3rd degree heart block)\n\n               -  Angina pectoris requiring therapy\n\n               -  Known left ventricular ejection fraction (LVEF) < 50% by MUGA or echocardiogram\n\n               -  QTc interval > 450 msec in males, or > 470 msec in females\n\n               -  Uncontrolled systemic hypertension (per the Investigator's discretion)\n\n               -  Class III or IV cardiovascular disease according to the New York Heart\n                  Association (NYHA) Functional Criteria\n\n               -  Myocardial infarction within 6 months prior to first study drug administration\n\n         10. Patients with a known or suspected hypersensitivity to any of the components of lipid\n             nanoparticle-formulated DCR-MYC; patients with a known sensitivity to cremophor (found\n             with paclitaxel and other formulations).\n\n         11. Patients with an estimated daily alcohol intake greater than 80 g/day.\n\n         12. Patients having undergone previous organ transplantation (e.g., liver transplantation)\n             requiring immunosuppression; patients on long-term immunosuppressive therapy.\n\n         13. Patients with a known history of human immunodeficiency virus (HIV) seropositivity.\n\n         14. Patients with any other serious/active/uncontrolled infection, with the exception of\n             chronic hepatitis B virus (HBV) or chronic hepatitis C virus (HCV) infection; any\n             infection requiring parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks\n             prior to first study drug administration.\n\n         15. Patients with inadequate recovery from an acute toxicity associated with any prior\n             antineoplastic therapy.\n\n         16. Patients with inadequate recovery from any previous surgical procedure, or patients\n             having undergone any major surgical procedure within 4 weeks prior to first study drug\n             administration.\n\n         17. Patients with an active second malignancy or history of another malignancy within the\n             last 3 years, with the exception of:\n\n               -  Treated, non-melanoma skin cancers\n\n               -  Treated CIS of the breast or cervix\n\n               -  Controlled, superficial carcinoma of the bladder\n\n               -  T1a or b carcinoma of the prostate treated according to local standard of care,\n                  with prostate specific antigen (PSA) within normal limits (wnl)\n\n         18. Patients with any other life-threatening illness, significant organ system\n             dysfunction, or clinically significant laboratory abnormality, which, in the opinion\n             of the Investigator, would either compromise the patient's safety or interfere with\n             evaluation of the safety of the study drug.\n\n         19. Patients with a psychiatric disorder or altered mental status that would preclude\n             understanding of the informed consent process and/or completion of the necessary\n             study-related evaluations.\n\n         20. Patients with the inability or with foreseeable incapacity, in the opinion of the\n             Investigator, to comply with the protocol requirements, including the ability to\n             attend all visits and undergo all assessments.\n\n        Exclusion Criteria (Treatments):\n\n          1. Phase 1b: Greater than 3 prior systemic anti-cancer chemotherapies or targeted agents\n             for HCC; prior loco-regional treatment, including transcatheter arterial\n             chemo-embolization (TACE), is allowed.\n\n          2. Phase 2: greater than 1 prior systemic anti-cancer chemotherapy or targeted agent for\n             HCC; prior loco-regional treatment, including TACE, is allowed.\n\n          3. Sorafenib therapy within 2 weeks prior to first study drug administration and during\n             study.\n\n          4. Any other antineoplastic agent (standard or experimental) within 4 weeks; monoclonal\n             antibody therapy, nitrosoureas, and nitrogen mustard within 6 weeks prior to first\n             study drug administration and during study.\n\n          5. Loco-regional therapy including TACE or radioembolization within 6 weeks prior to\n             first study drug administration and during study.\n\n          6. Radiotherapy within 4 weeks prior to first study drug administration and during study.\n\n          7. Therapy with sofosbuvir for HCV within 6 weeks prior to first study drug\n             administration and during study.\n\n          8. Herbal preparations, or related non-prescription preparations/supplements containing\n             herbal ingredients, aimed at treating the underlying malignancy within 2 weeks prior\n             to first study drug administration and during study.\n\n          9. Systemic hormonal therapy within 2 weeks prior to first study drug administration and\n             during study.\n\n         10. Any other investigational treatments during study. This includes participation in any\n             medical device or therapeutic intervention clinical trial.\n\n         11. Prophylactic use of hematopoietic growth factors within 1 week prior to first study\n             drug administration and during Cycle 1 of study; thereafter prophylactic use of growth\n             factors is allowed as clinically indicated.

Inclusion Criteria -\n\n          1. Between the ages of greater or equal to (?) 6 months and less than (<) 18 years of age\n\n          2. Must have histologically proven B-cell acute lymphoblastic leukemia (ALL) or B-cell\n             lymphoblastic lymphoma with marrow involvement\n\n          3. All participants (both ALL and participants with lymphoblastic lymphoma) must have M2\n             or M3 bone marrow classification\n\n          4. Disease status: a) Participants must have relapsed or refractory disease b) In the\n             event of relapse after prior allogeneic hematopoietic stem cell transplant (HSCT),\n             participants must be at least 3 months post-transplant and have no evidence of active\n             graft-vs-host disease, and must have been off immunosuppression for at least 4 weeks,\n             c) Must have resolution of the acute toxic effects to less than or equal to (?) Grade\n             2 from prior chemotherapy before entry, in the opinion of the investigator\n\n          5. Participants with the following central nervous system (CNS) 1 or 2 status are\n             eligible only in the absence of neurologic symptoms\n\n          6. Female participants of childbearing potential and post-pubertal male participants must\n             use an approved method of contraception for the study.\n\n        Exclusion Criteria\n\n          1. Concurrent enrollment in another clinical study for cancer treatment, unless the\n             subject is in the follow-up period from a previous study.\n\n          2. Isolated testicular or CNS ALL\n\n          3. Participants with mixed-lineage leukemia (MLL) gene rearrangement\n\n          4. Inadequate Hepatic function\n\n          5. Inadequate Renal function\n\n          6. Radiologically-detected CNS lymphoma\n\n          7. Participants with clear laboratory or clinical evidence of disseminated intravascular\n             coagulation (DIC)\n\n          8. Hyperleukocytosis or rapidly progressive disease that would compromise ability to\n             complete study therapy\n\n          9. QT interval corrected using Fridericia's formula (QTcF) greater than or equal to a\n             Grade 2, confirmed by 2 additional seperate electrocardiographs (ECG's) within 28 days\n             prior to starting study drug. The initial screening ECG need not be repeated for\n             confirmation if the QTcF interval is <481 milliseconds.\n\n         10. Pregnant or breast-feeding females\n\n         11. Prior treatment with CAT-3888 (BL22), moxetumomab pasudotox, or any\n             pseudomonas-exotoxin-containing compound\n\n         12. Prior treatment with any anticancer biologic therapy within 2 weeks prior to starting\n             study drug, including but not limited to therapeutic monoclonal antibodies or\n             antibody-drug conjugates\n\n         13. Systemic chemotherapy ? 2 weeks (6 weeks for nitrosoureas) and radiation therapy ? 3\n             weeks prior to starting study drug\n\n         14. Clinically significant ophthalmologic findings (evidence of retinal damage or injury)\n             during the screening\n\n         15. Presence of a second invasive malignancy\n\n         16. Uncontrolled pulmonary infection, presence of pulmonary edema\n\n         17. Serum albumin < 2 gram per deciliter (g/dL). Albumin infusions for correction of\n             hypoalbuminemia are allowed, but cannot have administered within 7 days prior to start\n             of study drug\n\n         18. Radioimmunotherapy within 2 years prior to study start of study drug\n\n         19. Participants with prior history of thrombotic microangiopathy or hemolytic uremic\n             syndrome (HUS)\n\n         20. T-cell ALL or T-cell lymphoblastic lymphoma\n\n         21. Participants currently receiving high-dose estrogen therapy defined as >0.625\n             milligram per day (mg/day) of an estrogen compound or within 2 weeks prior to starting\n             study drug.

Current participation in another drug trial

French subjects: the French subject has participated in any study using an investigational drug during the previous 30 days

Therapy with samarium-153, strontium-89, or radium-223 within 8 weeks prior to first dose of study drug.

Participation in clinical drug trials within 4 weeks

Current, recent (within 2 weeks of enrollment of this study), or planned participation in an experimental drug study

Chemotherapy or investigational drug therapy for cancer up to 21 days prior to day-1 of study.

Inclusion Criteria:\n\n          1. Male or female patients, > 18 years of age at the time of obtaining informed consent.\n\n          2. Patients with a documented solid tumor malignancy that is locally advanced or\n             metastatic; patients with documented multiple myeloma or non-Hodgkin's lymphoma.\n\n          3. Patients with a malignancy that is either refractory to standard therapy or for which\n             no standard therapy is available.\n\n          4. Patients with a malignancy that is currently not amenable to surgical intervention due\n             to either medical contraindications or non-resectability of the tumor.\n\n          5. Dose escalation portion of study: Patients with measurable or non-measurable disease\n             according to standard response criteria .\n\n          6. MTD Biopsy Cohort ONLY: Patients with measurable disease with primary or metastatic\n             tumor site(s) considered safely accessible for biopsy; patients must consent to\n             undergo 2 tumor biopsies.\n\n          7. MTD PNET Cohort ONLY: Patients with advanced (unresectable or metastatic),\n             histologically-confirmed low or intermediate grade PNET according to the World Health\n             Organization (WHO) 2010 classification. Patients with neuroendocrine tumors (e.g.,\n             gastrinoma, VIPoma) in whom a pancreatic or peripancreatic primary is strongly\n             suspected are also eligible. Patients must also have:\n\n               -  A Ki-67 proliferation index < 20%\n\n               -  Demonstrated radiological evidence of disease progression during or following the\n                  last treatment regimen (based on CT, MRI, or Octreoscan®)\n\n               -  Measurable disease according to RECIST v1.1 (determined by CT or MRI). Any\n                  lesions which have been subjected to percutaneous therapies or radiotherapy\n                  should not be considered measureable, unless the lesion has clearly progressed\n                  (per RECIST v1.1) since the procedure.\n\n               -  Received < 2 prior systemic treatments for PNET, at least one of which must have\n                  been an FDA-approved targeted therapy for PNET (i.e., sunitinib [Sutent®] or\n                  everolimus [Afinitor®]). Treatment with a somatostatin analog (SSA) will not be\n                  considered as a systemic treatment for the purposes of eligibility.\n\n          8. Patients with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2,\n             and an anticipated life expectancy of ? 3 months.\n\n          9. Patients, both male and female, who are either not of childbearing potential or who\n             agree to use a medically effective method of contraception during the study and for 3\n             months after the last dose of study drug.\n\n         10. Patients with the ability to understand and give written informed consent for\n             participation in this trial, including all evaluations and procedures as specified by\n             this protocol.\n\n        Exclusion Criteria-Patients:\n\n          1. Women who are pregnant or lactating. Women of child-bearing potential (WOCBP), and\n             fertile men with a WOCBP-partner not using and not willing to use a medically\n             effective method of contraception.\n\n          2. Patients with known central nervous system (CNS) or leptomeningeal metastases not\n             controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS\n             involvement for which treatment is required.\n\n          3. Patients with leukemia (any form) or myelodysplastic syndromes.\n\n          4. MTD PNET Cohort ONLY: Patients with poorly differentiated, high grade (grade 3)\n             neuroendocrine carcinoma, as well as patients with adenocarcinoid, goblet cell\n             carcinoid, or small cell carcinoma, or PNET patients with a Ki-67 proliferation index\n             > 20 %.\n\n          5. Patients with any of the following hematologic abnormalities at baseline:\n\n               -  Absolute neutrophil count < 1,500 per mm3\n\n               -  Platelet count < 100,000 per mm3\n\n          6. Patients with any of the following serum chemistry abnormalities at baseline:\n\n               -  Total bilirubin > 1.5 × the ULN for the institution\n\n               -  AST or ALT > 3 × the ULN for the institution (> 5 × if due to hepatic involvement\n                  by tumor)\n\n               -  Creatinine > 1.5 × ULN for the institution\n\n          7. Patients with any of the following coagulation parameter abnormalities at baseline:\n\n               -  PT (INR) > 1.5 × ULN for the institution\n\n               -  PTT > 1.5 × ULN for the institution\n\n          8. Patients with:\n\n               -  Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism,\n                  within 6 months prior to first study drug administration; patients receiving\n                  systemic anti-coagulation for prophylactic or therapeutic reasons\n\n               -  Active uncontrolled bleeding or a known bleeding diathesis\n\n          9. Patients with a significant cardiovascular disease or condition, including:\n\n               -  Congestive heart failure currently requiring therapy\n\n               -  Need for antiarrhythmic medical therapy for a ventricular arrhythmia\n\n               -  Severe conduction disturbance (e.g., 3rd degree heart block)\n\n               -  Angina pectoris requiring therapy\n\n               -  Known left ventricular ejection fraction < 50% by MUGA or echocardiogram\n\n               -  QTc interval > 450 msec in males, or > 470 msec in females\n\n               -  Uncontrolled hypertension (per the Investigator's discretion)\n\n               -  Class III or IV cardiovascular disease according to the New York Heart\n                  Association's Functional Criteria.\n\n               -  Myocardial infarction within 6 months prior to first study drug administration\n\n         10. Patients with a known or suspected hypersensitivity to any of the components of lipid\n             nanoparticle-formulated DCR-MYC.\n\n         11. Patients with a known history of human immunodeficiency virus or active infection with\n             hepatitis B virus or hepatitis C virus.\n\n         12. Patients with any other serious/active/uncontrolled infection, any infection requiring\n             parenteral antibiotics, or unexplained fever > 38ºC within 2 weeks prior to first\n             study drug administration.\n\n         13. Patients with inadequate recovery from an acute toxicity associated with any prior\n             antineoplastic therapy.\n\n         14. Patients with inadequate recovery from any prior surgical procedure, or patients\n             having undergone any major surgical procedure within 4 weeks prior to first study drug\n             administration.\n\n         15. Patients with any other life-threatening illness, significant organ system\n             dysfunction, or clinically significant laboratory abnormality, which, in the opinion\n             of the Investigator, would either compromise the patient's safety or interfere with\n             evaluation of the safety of the study drug.\n\n         16. Patients with a psychiatric disorder or altered mental status that would preclude\n             understanding of the informed consent process and/or completion of the necessary\n             study-related evaluations.\n\n         17. Patients with the inability or with foreseeable incapacity, in the opinion of the\n             Investigator, to comply with the protocol requirements.\n\n        Exclusion Criteria-Treatments:\n\n          1. MTD PNET Cohort ONLY: Greater than 2 prior systemic treatments for the underlying\n             malignancy\n\n          2. Any antineoplastic agent for the primary malignancy (standard or experimental) within\n             4 weeks prior to first study drug administration with the exception of monoclonal\n             antibody therapy, nitrosoureas, and nitrogen mustard for the primary malignancy within\n             6 weeks prior to first study drug administration\n\n          3. Radiotherapy for the primary malignancy within 4 weeks prior to first study drug\n             administration and during study.\n\n          4. Herbal preparations or related over-the-counter preparations/supplements containing\n             herbal ingredients within 2 weeks prior to first study drug administration and during\n             study.\n\n          5. Systemic hormonal therapy within 2 weeks prior to first study drug administration and\n             during study.\n\n          6. Any other investigational treatments during study. This includes participation in any\n             medical device or therapeutic intervention clinical trials.\n\n          7. Prophylactic use of hematopoietic growth factors within 1 week prior to first study\n             drug administration and during Cycle 1 of study; thereafter prophylactic use of growth\n             factors is allowed as clinically indicated.

Participated in another drug study within 90 days before this one

Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks prior to first dose of study drug

Sexually active males unless they use a condom during intercourse while taking the drug and for 30 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

4 weeks from prior experimental drug

Received last dose of study drug on another therapeutic clinical trial within 30 days prior to enrollment

Males must agree to use a condom with spermicide every time they have sex during the study and for 3 months after the last dose of study drug; they also must agree to not donate sperm during the study and for 3 months after the last dose of study drug

Use of any standard/experimental anti-lymphoma drug therapy, including steroids, within 3 weeks of initiation of the study or use of any experimental non-drug therapy (e.g. donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug treatment; prior allogeneic stem cell transplant (SCT) within 16 weeks or autologous SCT within 8 weeks of initiation of therapy

Initiation of anti-tumor therapy including chemotherapy or investigational drug treatment within 30 days before beginning study

Currently enrolled in (or completed within 30 days before study drug administration)another investigational drug study.

Received investigational drug within 30 days prior to study dosing. Patients may participate in non-interventional or observational clinical studies, including the 10PLK13 PROCLAIM registry study.

Corticosteroid monotherapy for lymphoma within 1 week of the first dose of study drug

Hemoptysis of red blood in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.

Patients taking substrates of CYP2C9 should be encouraged to switch to alternative drugs whenever possible, given the potential for drug-drug interactions with the study drugs

Gastro-intestinal abnormalities that could affect the absorption of study drug.

Initiation of a new drug therapy within the past 30 days prior to study commencement

Participation in a therapeutic research study or receipt of an investigational drug within 30 days of T-cell infusion

NON-PROGRESSED DIPG (STRATUM 2): Patients who are receiving any other anticancer or investigational drug therapy

Has had within the 4 weeks prior to initiation of study drug, or is expected to have during the study period, surgery requiring general anesthesia.

Receipt of anticancer medications or investigational drugs within a defined interval before the first administration of study drug.

A male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study (and for up to 12 weeks after the last dose of study drug) to minimize the risk of pregnancy; if the partner is pregnant or breastfeeding, the subject must use a condom; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Patients with conditions that would prevent absorption of the study drug

Males who have had a successful vasectomy (confirmed azoospermia) or they and their female partners meet the criteria above (that is, not of childbearing potential or practicing highly effective contraception throughout the study period or for 120 days after study drug discontinuation). No sperm donation is allowed during the study period or for 120 days after study drug discontinuation.

Current enrollment in another interventional clinical study or used any investigational drug or device within the past 28 days preceding informed consent.

Inclusion Criteria- Group A:\n\n          -  Age ? 18 years.\n\n          -  Phase 1-Dose Escalation: Patients with histologically confirmed advanced solid tumors\n             who are refractory to, relapsed after, or intolerant to standard therapy or for whom\n             no standard therapy exists.\n\n          -  Phase 2a-RP2D Confirmation (Formulation 2) and Phase 2a-Dose Extension: Patients with\n             a history of histologically confirmed solid tumors with a BRAF mutation.\n\n               -  Phase 2a-Dose Extension—Cohort 1\n\n                    1. Patients with solid tumors driven by a BRAF-V600 mutation\n\n                    2. Patients with no prior exposure to BRAF-directed therapy and for whom no\n                       standard therapy exists.\n\n               -  Phase 2a-Dose Extension—Cohort 2\n\n                    1. Patients with solid tumors driven by BRAF non-V600 mutation.\n\n                    2. Patients with no prior exposure to BRAF-directed therapy and for whom no\n                       standard therapy exists.\n\n          -  Measurable disease by RECIST 1.1.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.\n\n          -  Adequate hematologic, hepatic, and renal function.\n\n          -  Women of child-bearing potential must have a negative pregnancy test and must agree to\n             use an effective form of contraception from the time of the negative pregnancy test up\n             to 3 months after the last dose of study drug. Women of non-child-bearing potential\n             may be included if they are either surgically sterile or have been postmenopausal for\n             ? 1 year.\n\n          -  Fertile men must agree to use an effective method of birth control during the study\n             and for up to 3 months after the last dose of study drug.\n\n          -  Completion of previous anti-cancer therapy at least 2 weeks before study drug\n             initiation.\n\n        Exclusion Criteria- Group A:\n\n          -  Phase 1 and Phase 2a RP2D confirmation-Dose Escalation: Investigational drug use\n             within 28 days (or 5 half-lives, whichever is shorter) of the first dose of PLX8394.\n\n          -  Major surgical procedure, open biopsy (excluding skin cancer resection), or\n             significant traumatic injury within 14 days of initiating study drug or anticipation\n             of the need for major surgery during the study.\n\n          -  Uncontrolled intercurrent illness.\n\n          -  Active secondary malignancy unless the malignancy is not expected to interfere with\n             the evaluation of safety and is approved by the Medical Monitor. Patients with a\n             completely treated prior malignancy and no evidence of disease for ? 2 years are\n             eligible.\n\n          -  Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant\n             bowel resection that would preclude adequate absorption.\n\n          -  Clinically significant cardiac disease.\n\n          -  Known infection with HIV, HBV, or HCV or a known carrier of HBV or HCV.\n\n        Inclusion Criteria — Group B:\n\n          -  Age (all criteria are required):\n\n               -  ?3 and <18 years;\n\n               -  Ability to swallow and retain study drug;\n\n               -  A minimum BSA that allows for adequate dosing with PLX8394.\n\n               -  Patients with a history of activating BRAF mutation, such patients include those\n                  with the following:\n\n                    1. Diagnosis of pediatric brain tumor (e.g., pilocytic astrocytoma, pleomorphic\n                       xanthoastrocytoma, ganglioglioma, astrocytoma, papillary craniopharyngioma,\n                       glioblastoma) with an activating BRAF mutation.\n\n                    2. LCH (Langerhans cell histiocytosis) i.) Patients with either high-risk\n                       disease are eligible. ii) Patients with overlap histiocytic disorders (e.g.,\n                       LCH/juvenile xanthogranuloma, LCH/Erdheim-Chester disease, or\n                       LCH/Rosai-Dorfman disease) are eligible.\n\n                    3. Diagnosis of LCH-associated neurodegenerative disease (LCH-ND).\n\n                    4. Other advanced malignancy with an activating BRAF mutation.\n\n          -  ECOG performance status of 0-2.\n\n          -  Adequate hematologic, hepatic, and renal function.\n\n          -  Females of child-bearing potential must have a negative pregnancy test and must agree\n             to use an effective form of contraception from the time of the negative pregnancy test\n             and for 3 months after the last dose of study drug. Females of non-child-bearing\n             potential may be included if they are either surgically sterile, have been\n             postmenopausal for ?1 year, or are premenopausal.\n\n          -  Fertile male patients must agree to use an effective method of birth control during\n             the study and for 3 months after the last dose of study drug.\n\n          -  Completion of previous anti-cancer therapy at least 2 weeks before study drug\n             initiation.\n\n          -  All patients or their legal guardians (if the patient is <18 years old) must sign an\n             IRB-approved document of informed consent to demonstrate their understanding of the\n             investigational nature and the risks of this study before any protocol-related\n             procedures are performed. When appropriate, pediatric subjects will be included in all\n             discussions.\n\n        Exclusion Criteria — Group B:\n\n          -  Major surgical procedure, open biopsy (excluding skin cancer resection), or\n             significant traumatic injury within 14 days of initiating the study drug or\n             anticipation of the need for major surgery during the study.\n\n          -  Dose Escalation and Dose Extension — Investigational drug use within 28 days (or 5\n             half-lives, whichever is shorter) of the first dose of PLX8394.\n\n          -  Uncontrolled intercurrent illness.\n\n          -  Active secondary malignancy, unless the malignancy is not expected to interfere with\n             the evaluation of safety and is approved by the Medical Monitor.\n\n          -  Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant\n             bowel resection that would preclude adequate absorption.\n\n          -  Clinically significant cardiac disease.\n\n          -  Known infection with HIV, HBV, or HCV or a known carrier of HBV or HCV.

No radiation, major surgery, chemotherapy or biologic therapy within 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C); >= 2 weeks since any prior administration of study drug in an exploratory investigational new drug (IND)/phase 0 study (also referred to as an “early phase I study” or “pre-phase I study” where a subtherapeutic dose of drug is administered) at the principal investigator (PI)’s discretion; patients must have recovered to at least eligibility levels due to adverse events and/or toxicity of prior chemotherapy or biologic therapy

Evidence of measurable disease based on imaging studies within 28 days before the first dose of study drug

Currently enrolled in (or completed) another investigational drug study within 30 days prior to study drug administration

Antineoplastic therapy, radiotherapy, or any other investigational drug within 30 days prior to first study drug administration

Unable to return at the regular required intervals for reassessment, or study drug administration

Patients who have taken herbal medications and certain fruits within 7 days prior to starting study drug, see section 11.1.2.7.

Receipt of anticancer medications or investigational drugs within the following interval before the first administration of study drug:

Participant who were treated with other investigational drug or medical device within 4 weeks prior to the planned first day of study drug dosing.

Treatment with any investigational drug within 6 weeks of first dose of mirvetuximab soravtansine

Able to swallow the study drug, have no known intolerance to the study drug or excipients, and comply with study requirements.

Male and female patients must agree not to donate sperm or eggs, respectively, from the first dose of study drug through 105 days and 45 days after the last dose of study drug, respectively.

Female patients may not be breastfeeding at screening and must not breastfeed during study participation through 45 days after the last dose of study drug.

Patient taking enzyme-inducing anti-epileptic drug (EIAED) < 7 days of the first dose of PQR309.

Previous radiotherapy (unless brachytherapy), endocrine therapy, chemotherapy, or exposure to investigational medicinal products during the 4 weeks (6 weeks for nitrosoureas and Mitomycin-C) or 4 drug half-lives before the planned administration of the first dose of study drug, whichever is greater. Previous immunotherapy during the 4 weeks before the planned administration of the first dose of study drug.

Male subjects with pregnant or lactating partners or partners who plan to become pregnant while on study or within 6 months after the planned administration of the last dose of study drug

Have received treatment within 28 days of the initial dose of study drug with an investigational product or non-approved use of a drug or device (other than the study drug/device used in this study) or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Experimental therapy within 4 weeks prior to first dose of study-drug treatment in Cycle 1

Anti-cancer therapy within 28 days prior to the first dose of study-drug treatment in Cycle 1

Systemic investigational drug of any kind within 6 weeks of AVB-620 administration

Women of childbearing potential and men must agree to use adequate contraception from 28 days prior to the first dose of the study drug, during the entire Treatment Period, and for at least 28 days after the last dose of the study drug

Allergies to excipients in the study drug.

Inclusion Criteria:\n\n        Subjects must meet all of the following major inclusion criteria to be eligible for the\n        study:\n\n          1. 18 years of age or older\n\n          2. Histologically or cytologically documented stage IV ductal adenocarcinoma of the\n             pancreas.\n\n          3. Performance Status (ECOG) 0 or 1\n\n          4. FFPE tumor tissue from metastatic site(s\n\n          5. Adequate organ function\n\n          6. Written consent on an IRB/IEC-approved Informed Consent Form prior to any\n             study-specific evaluation.\n\n          7. For women of child-bearing potential, negative serum pregnancy test at screening and\n             use of physician-approved method of birth control from 30 days prior to the first\n             study drug administration to 30 days following the last study drug administration.\n\n          8. Male subjects must be surgically sterile or must agree to use physician-approved\n             contraception from 30 days prior to the first study drug administration to 30 days\n             following the last study drug administration.\n\n        Exclusion Criteria:\n\n        Subjects who meet any of the following major exclusion criteria will not be eligible for\n        participation in the study:\n\n          1. Neuroendocrine tumors (i.e., carcinoid, islet cell cancer) of the pancreas.\n\n          2. Known brain metastases.\n\n          3. Prior therapy, including systemic therapy, surgical resection or radiation for newly\n             diagnosed stage IV pancreatic cancer.\n\n          4. Presence of any serious or unstable concomitant systemic disorder incompatible with\n             the clinical study (e.g., substance abuse, uncontrolled intercurrent illness including\n             active infection, arterial thrombosis, symptomatic pulmonary embolism).\n\n          5. Any disorder that would significantly compromise protocol compliance.\n\n          6. Prior non-pancreatic malignancy treated with chemotherapy. Prior malignancies treated\n             with surgery and/or radiotherapy alone must be in remission ?3 years. The following\n             prior malignancies are allowable irrespective of when they occurred: in situ carcinoma\n             of the cervix, in situ ductal breast cancer, low-grade local bladder cancer, and\n             nonmelanotic skin cancer.\n\n          7. Known human immunodeficiency virus (HIV) infection.\n\n          8. Females who are pregnant or breastfeeding.

Treatment with any investigational anticancer drug within 21 days of the first study\n             treatment administration

Patient has an infection and has had a body temperature of > 38.3?C within 48 hours prior to planned first dose of study drug.

surgery, radiation, or immunosuppressants within 28 days prior to planned first dose of study drug,

investigational drug within the 28 days prior to planned first dose of study drug, or

mitomycin-C or nitrosoureas within 42 days prior to planned first dose of study drug. Note: Patients receiving LHRH agonists or antagonists or antiestrogens or aromatase inhibitors started and at a stable dose for at least 90 days prior to planned first dose of study drug are eligible. Patients are permitted one 28 day cycle of concurrent treatment with hydroxyurea during the study.

Patient has had previous treatment with the study drug or other WT1-related vaccine therapy.

Use of any other experimental drug or therapy within 14 days of baseline

Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration.

Administration of any investigational drug within 28 days prior to receipt of enzalutamide, abiraterone, prednisone or denosumab

Radiation therapy within 2 weeks of first administration of study drug

Required screening laboratory data (within 2 weeks prior to administration of study drug) as shown in study protocol.

Or, if of childbearing potential: agree not to try to become pregnant during the study and for 60 days after the final study drug administration and have a negative serum or urine pregnancy test at screening, and if heterosexually active, agree to consistently use 2 forms of birth control (at least one of which must be a barrier method) starting at screening and throughout the study period and for 60 days after final study drug administration.

Female subject must not be breastfeeding at screening or during the study period, and for 60 days after the final study drug administration.

Female subject must not donate ova starting at screening and throughout the study period and for 60 days after final study drug administration.

Male subject must not donate sperm starting at screening and throughout the study period and for 120 days after final study drug administration.

Subject has had any of the following within 14 days prior to the first dose of study drug:

agree not to try to become pregnant during the study and for 90 days after the final study drug administration;

Received any chemotherapeutic or targeted agent for metastatic colorectal cancer within two weeks of initiation of study drug

Drug induced thrombocytopenia

Received systemic anticancer therapy or radiotherapy <21 days prior to their first day of study drug administration

Exposure to nitrosoureas or mitomycin C within 42 days before the first dose of study drug.

Radiotherapy within 14 days before the first dose of study drug.

Serious infection within 14 days before the first dose of study drug. Participant must have recovered from infection before first dose.

Radiotherapy within 14 days before the first dose of either study drug except localized radiation therapy for lytic bone lesions and plasmacytomas

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Had an autologous transplant within 3 months of starting study drug treatment.

Significant neurotoxicity/neuropathy (Grade 3 or higher) within 14 days prior to the first dose of study drug

Poor venous access for study drug administration\r\n* Study drug administration via indwelling catheters is allowed only if the catheter is made of silicone material

Inclusion Criteria\n\n        Each patient must meet all of the following inclusion criteria to be enrolled in the study:\n\n          1. Male or female patients 18 years or older.\n\n          2. Patients must have a histologically confirmed diagnosis of an advanced, metastatic\n             malignant solid tumor and must have failed or exhausted standard therapies or for\n             which no standard therapy is available.\n\n          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.\n\n          4. Patients with adequate hematologic and organ function\n\n          5. All patients must have radiographically detectable tumors; however, measurable disease\n             as defined by RECIST (version 1.1) is not required for participation in the dose\n             escalation part of this study.\n\n          6. Patients undergoing a biopsy procedure must have accessible lesions which are safe to\n             biopsy.\n\n          7. Recovered (ie, ? Grade 1 toxicity) from the reversible effects of prior antineoplastic\n             therapy, except alopecia.\n\n          8. Female patients who are postmenopausal for at least 1 year before the screening visit,\n             surgically sterile, or agree to practice 2 effective methods of contraception, at the\n             same time, from the time of signing the informed consent form through 4 months after\n             the last dose of study drug, or agree to practice true abstinence.\n\n             Male patients who agree to practice effective barrier contraception during the entire\n             study treatment period through 4 months after the last dose of study drug or agree to\n             practice true abstinence.\n\n          9. Suitable venous access for the study-required blood sampling including PK sampling.\n\n        Exclusion Criteria\n\n        Patients meeting any of the following exclusion criteria are not to be enrolled in the\n        study:\n\n          1. Patients with clinically significant pre-existing cardiac impairment.\n\n          2. Patients with known active CNS lesions are excluded. Systemic antineoplastic therapy\n             or investigational agents within 21 days before the first dose of study drug.\n\n          3. Radiotherapy within 14 days before the first dose of study drug is not allowed except\n             for limited field radiotherapy for palliative bone pain.\n\n          4. For patients where tumor biopsies are required or requested:\n\n               -  Any known coagulation abnormalities that would contraindicate the tumor biopsy\n                  procedure.\n\n               -  Ongoing therapy with any anticoagulant or antiplatelet agents (eg, aspirin,\n                  clopidogrel [Plavix®], heparin, or warfarin).\n\n          5. Major surgery within 28 days before the first dose of MLN7243.\n\n          6. Life-threatening illness unrelated to cancer.\n\n          7. Any evidence of active infection or antibiotic therapy within 14 days before the first\n             dose of MLN7243.\n\n          8. Known human immunodeficiency virus (HIV) positivity or AIDS-related illness, hepatitis\n             B virus, and hepatitis C virus.\n\n          9. Patients whose weight is <40 kg.\n\n         10. History of uncontrolled sleep apnea syndrome and other conditions that could result in\n             excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.\n\n         11. Female patients who are lactating and breastfeeding or have a positive serum pregnancy\n             test during the Screening period or a positive urine pregnancy test on Day 1 before\n             first dose of study drug.\n\n        For the exhaustive list, please contact the study central contact.

Use of investigational drug, other than the study medications specified by the protocol, within 30 days of transplantation

Any chemotherapy, anticancer antibodies, or other systemic anticancer therapy within 21 days of the first dose of study drug

Recent infection requiring IV anti-infective treatment that was completed ?14 days before the first dose of study drug

Patient is currently receiving an enzyme-inducing anti-epileptic drug (EIAED). The patient must have discontinued EIAED therapy for at least two weeks prior to starting study drug.

Has had certain other recent treatment e.g. major surgery, extended field radiation, anticancer therapy, received investigational agent, within the specified time frames prior to study drug administration

High-dose chemotherapy within 4 weeks of study drug

Antileukemia treatment within 14 days of study drug (other than hydroxyurea or 6-mercaptopurine)

Systemic antineoplastic therapy within 21 days before the first dose of study drug

Inclusion Criteria:\n\n        Subjects must meet all of the following criteria to be eligible for the study:\n\n          1. Histologically or cytologically documented extensive stage small cell lung cancer.\n\n          2. Adults of 18 years of age or older.\n\n          3. Performance Status (ECOG) of 0 or 1.\n\n          4. FFPE tumor tissue.\n\n          5. Adequate organ function:\n\n               1. Adequate hematologic function (absolute neutrophil count [ANC] ? 1,500 cells/?L;\n                  hemoglobin ? 9 g/dL, platelets ? 100,000/?L).\n\n               2. Adequate renal function (serum creatinine ? 1.5 mg/dL or calculated creatinine\n                  clearance ? 60 mL/min using Cockcroft-Gault formula).\n\n               3. Adequate hepatic function (alanine aminotransferase [ALT] ? 3 x upper limit of\n                  normal [ULN], ALT may be ? 5 x ULN if due to liver metastases but cannot be\n                  associated with concurrent elevated bilirubin >1.5xULN unless it is approved by\n                  the Sponsor's Medical Monitor).\n\n               4. Prothrombin Time (PT)/International Normalized Ration (INR) ?1.5 × ULN, activated\n                  partial thromboplastin time (aPTT) ?1.5 × ULN.\n\n          6. Written consent on an IRB/IEC-approved Informed Consent Form prior to any\n             study-specific evaluation.\n\n          7. For women of child-bearing potential, negative serum pregnancy test at screening and\n             use of physician-approved method of birth control from 30 days prior to the first\n             study drug administration to 30 days following the last study drug administration or\n             the last EP in the study, whichever is discontinued last.\n\n          8. Male subjects must be surgically sterile or must agree to use physician-approved\n             contraception during the study and for 30 days following the last study drug\n             administration or the last EP in the study, whichever is discontinued last.\n\n        Exclusion Criteria:\n\n        Subjects who meet any of the following criteria will not be eligible for participation in\n        the study:\n\n          1. Limited stage small cell lung cancer appropriate for radical treatment with\n             chemoradiation.\n\n          2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed\n             extensive stage small cell lung cancer.\n\n          3. Presence of any serious or uncontrolled illness including, but not limited to: ongoing\n             or active infection, symptomatic congestive heart failure unstable angina pectoris,\n             uncontrolled cardiac arrhythmia, uncontrolled arterial thrombosis, symptomatic\n             pulmonary embolism, and psychiatric illness that would limit compliance with study\n             requirement.\n\n          4. History of myocardial infarction, acute coronary syndromes (including unstable\n             angina), coronary angioplasty and/or stenting within 6 months prior to the first\n             administration of study drug.\n\n          5. A history of malignancy with the exception of:\n\n               1. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or\n                  in situ cervical cancer\n\n               2. Adequately treated stage I cancer from which the subject is currently in\n                  remission, or\n\n               3. Any other cancer from which the subject has been disease-free for ? 3 years\n\n          6. Known human immunodeficiency virus (HIV) infection.\n\n          7. Females who are pregnant or breastfeeding.\n\n          8. Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg\n             daily for port catheter is allowed)

Completion of last anti-cancer therapy must be at least 28 days prior to study drug administration.

hormonal contraceptives (oral, parenteral or transdermal) for at least 3 months prior to study drug administration;

Subject who requires parenteral nutrition, tube feeding or has evidence of partial bowel obstruction or perforation within 28 days prior to study drug administration.

Consumption of food or beverages containing grapefruit juice within 7 days of study drug dosing

Use of a first-generation anti-androgen such as bicalutamide within 6 weeks of study drug dosing, or flutamide within 4 weeks of study dosing

Dexamethasone (or equivalent systemic steroid) higher than the physiologic dosing with 7 days before study drug administration

Subject has received a biologic agent for anti-neoplastic intent within 30 days prior to the first dose of study drug

Subject has received aspirin or warfarin within 7 days prior to the first dose of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Participating in another investigational drug or device trial that has not completed the follow-up period

Recent (i.e., within the past 28 days prior to randomization) or current participation in another experimental drug study

Systemic antineoplastic therapy or radiotherapy within 14 days before the first dose of study drug, except for hydroxyurea

Patients who are unwilling or unable to refrain from using hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) starting 5 days before the initial study drug administration and throughout the study will not be permitted to enroll

Treatment with an experimental drug within 28 days of first dose

Angina pectoris ? 3 months prior to starting study drug

Inclusion Criteria:\n\n        Subjects must meet all of the following criteria to be eligible for the study:\n\n          1. Age >18 years\n\n          2. ECOG performance status <2 (see Appendix B)\n\n          3. Solid tumor malignancy for which there is no remaining standard therapy or either\n             refuse or are not considered to be candidates for any remaining standard therapy.\n\n          4. Must have a tumor that is measurable or evaluable per RECIST v1.1 in the dose\n             escalation phase. In the expansion cohort(s), subjects must have measurable disease.\n\n          5. Subjects must have Formalin-Fixed, Paraffin-Embedded (FFPE) tissue available either\n             archived or fresh core or punch needle biopsied at study entry (two fresh\n             cores/punches preferred whenever possible) for determination of Notch1 pathway\n             activation status.\n\n          6. Must have received their last chemotherapy, biologic, radiotherapy, or investigational\n             therapy at least 4 weeks prior to enrollment; 6 weeks if the last regimen included\n             BCNU or mitomycin C.\n\n          7. Subjects must have normal organ and marrow function as defined below:\n\n               -  Absolute neutrophil count >1500/mL without growth factor support in the past 7\n                  days\n\n               -  Platelets >100,000/mL without transfusions in the past 7 days\n\n               -  Total bilirubin <1.5 X institutional upper limit of normal (ULN) (<2X ULN for\n                  subjects with Gilbert's syndrome)\n\n               -  AST (SGOT) and ALT (SGPT) <3 X institutional ULN (for subjects with hepatic\n                  involvement <5 X institutional ULN but cannot be associated with elevated\n                  bilirubin)\n\n               -  PT/INR and aPTT within 1.5 X institutional ULN\n\n               -  Creatinine <1.5 X institutional ULN OR\n\n               -  Creatinine clearance >60 mL/min/1.73 m2 for subjects with creatinine levels above\n                  institutional normal\n\n               -  Normal Ejection Fraction (>50%) on ECHO scan or MUGA\n\n          8. Women of childbearing potential must have had a prior hysterectomy or have a negative\n             serum pregnancy test and be using adequate contraception prior to study entry and must\n             agree to use adequate contraception from study entry through at least 6 months after\n             discontinuation of study drug. Men must also agree to use adequate contraception\n             (hormonal or barrier method of birth control; abstinence) prior to study entry and\n             from study entry through at least 6 months after discontinuation of study drug. Should\n             a woman enrolled in the study or a female partner of a man enrolled in the study\n             become pregnant or suspect she is pregnant while participating in this study or within\n             6 months after discontinuation of study, she should inform the Investigator\n             immediately.\n\n          9. Ability to understand and the willingness to sign a written informed consent document\n\n        Exclusion Criteria:\n\n        Subjects who meet any of the following criteria will not be eligible for participation in\n        the study:\n\n          1. Currently receiving any therapeutic treatment for their malignancy including other\n             investigational agents\n\n          2. Prior treatment with gamma secretase inhibitors or other Notch 1 inhibitors\n\n          3. Uncontrolled seizure disorder, active neurologic disease, or active CNS involvement\n             except for individuals who have previously-treated CNS metastases, are asymptomatic,\n             and have no requirement for higher doses of corticosteroids (> prednisone 10mg orally\n             per day) or anti-seizure medication for at least 4 weeks prior to first dose of study\n             drug.\n\n          4. History of a Grade 4 allergic reaction attributed to humanized or human monoclonal\n             antibody therapy\n\n          5. Significant intercurrent illness including, but not limited to, ongoing or active\n             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac\n             arrhythmia, or psychiatric illness/social situations that would limit compliance with\n             study requirements\n\n          6. Pregnant women or nursing women\n\n          7. Ongoing malignancies or malignancies in remission <3 years other than the malignancies\n             included in this trial. Patients with history of known squamous cell skin cancers\n             within the past 3 years will not be included in this trial. The following prior\n             malignancies are allowable irrespective of when they occurred: in situ carcinoma of\n             the cervix, in situ ductal breast cancer, and low-grade local bladder cancer.\n\n          8. Subjects with known HIV infection\n\n          9. Known bleeding disorder or coagulopathy\n\n         10. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.\n\n         11. Hemoptysis in excess of 2.5 mL(or one-half teaspoon) within 8 weeks of first dose of\n             study drug.\n\n         12. Subjects receiving heparin, warfarin, or other similar anticoagulants, except for\n             subjects on low molecular weight heparin for DVT/PE prophylaxis. Note: Subjects may be\n             receiving low-dose aspirin and/or non-steroidal anti-inflammatory agents.\n\n         13. New York Heart Association Classification II, III, or IV (see Appendix D)\n\n         14. Subjects with poorly controlled blood pressure (defined as systolic blood pressure\n             ?140 mmHg or diastolic blood pressure ?90 mmHg) that is not responsive to medical\n             therapy. Subjects taking antihypertensive medications must be taking ?2 medications to\n             obtain this level of blood pressure control.\n\n             NOTE: Initiation or adjustment of antihypertensive medication(s) is permitted prior to\n             study entry.\n\n         15. Subjects with ECG evidence of ischemia or ?Grade 2 ventricular arrhythmia, subjects\n             who have a history of acute myocardial infarction within 6 months, or subjects with\n             unstable angina.\n\n         16. Subjects with known clinically significant gastrointestinal disease including, but not\n             limited to:\n\n               -  inflammatory bowel disease\n\n               -  active peptic ulcer disease\n\n               -  known intraluminal metastatic lesion(s) with risk of bleeding\n\n               -  history of abdominal fistula, GI perforation, or intra-abdominal abscess within\n                  28 days prior to beginning study treatment\n\n         17. Subjects with diarrhea at time of enrollment or have an ongoing requirement for anti\n             diarrheal therapy

Participants receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy within 14 days of first receipt of study drug, with the exception of hydroxyurea as defined in protocol

Use of any other experimental drug or therapy within 21 days of baseline

Treatment with an investigational drug within 3 weeks prior to the first dose of study drug

WCBP must agree to have pregnancy tests monthly (every 14 days for women with irregular cycles) while on study drug and 4 weeks after the last dose of study drug

Vomited in the 24 hours prior study drug administration (Cycle 1)

Received or will receive radiation therapy to the abdomen or pelvis in the week prior to study drug administration and/or during the course of the study

Participated in any previous study of aprepitant or fosaprepitant, or taken an investigational drug within 4 weeks prior to study participation

Participants who have stopped study drug dosing for greater than 56 days

Off study use of ketorolac or other NSAIDs prior to study administration

Participation in a study of an investigational drug within 4 weeks prior to the planned first day of study drug administration

Treatment with molecularly targeted agents within the past 3 weeks prior to planned first study drug administration. Patients who were receiving standard chemotherapy or experimental therapies must wait 4 weeks from their last dose prior to the planned first study drug administration. Patients treated with nitrosoureas or mitomycin C must wait 6 weeks from their last dose prior to the planned first study drug administration.

Herbal supplements are prohibited 1 week prior to the planned first study drug administration, during the clinical study, and up to the time that the patient is discharged from the study

Candidate for at least one comparator drug:

Treatment with any known non-marketed drug substance or experimental therapy within 4 weeks prior to enrollment, or currently participating in any other interventional clinical study for NHL or any other illness (except observational, prevention, and/or registry trials)

Participation in another clinical trial in which they received active therapy within 4 weeks prior to the first dose of study drug.

Administration of an investigational study treatment within 30 days preceding the first dose of study treatment(s) in this study.

Bilirubin =< 1.5 x ULN, within 14 days prior to initiation of study drug

INTRATUMORAL DRUG DISTRIBUTION STUDY PATIENTS:

Sexually active males, who do not agree to abstinence, must be willing to use a condom during intercourse while taking the study drug, and for 16 weeks after stopping treatment and should not father a child in this period.

Patient is pregnant, breastfeeding, or expecting to conceive children while receiving study drug or for 180 days after the last dose of study drug.

Receipt of anticancer medications or investigational drugs within protocol-defined intervals before the first administration of study drug.

Participants who have received any of the following within the listed time frame, prior to the first dose of study drug

Participants who have received the following within 7 days prior to the first dose of study drug:

Patients who have taken part in an experimental drug study within 4 weeks of initiating treatment with LDE225

Sexually active males must use a condom during intercourse while taking the drug for 6 months after stopping treatment and should not father a child in this period; a condom is required to be use also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Active severe personality disorders (defined according to DSM-IV). Note: for patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug.

Patient is currently receiving an enzyme inducing anti-epileptic drug. The patient must have discontinued EIAED therapy for at least two weeks prior to starting study drug. Non-enzyme inducing anti-epileptic medication is allowed, except those listed in the protocol

Allergies and Adverse Drug Reaction

For women of child-bearing potential, negative serum pregnancy test within 14 days prior to the first study drug administration and use of physician-approved method of birth control from 30 days prior to the first study drug administration to 30 days following the last study drug administration

Received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug;

Have received a systemic corticosteroid within one week prior to the first administration of study drug;

In the absence of rapidly progressing disease, the interval from prior treatment to time of study drug administration should be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents. If a patient is on hydroxyurea to control peripheral blood leukemic cell counts, the patient must have discontinued hydroxyurea for at least 24 hours before initiation of treatment with study drug. Persistent clinically significant toxicities from prior chemotherapy must not be greater than grade 1

Therapy with anticoagulant or antithrombotic agents (including aspirin) within 7 days prior to study drug administration

Uncontrolled infection requiring systematic antibiotics within 14 days before the first dose of study drug

Investigational drug use within 28 days of the first dose of PLX3397

Hemoptysis in excess of 2.5 mL within 8 weeks of first dose of study drug.

Females of childbearing potential (FCBP) must not become pregnant for 28 days prior to initiation of study drug, during the study, and for 28 days after discontinuation

Females must agree to abstain from breastfeeding during study participation and 28 days after study drug discontinuation

Patients may not be receiving any agents not approved by the Food and Drug Administration (FDA) within the past 4 weeks

Key Inclusion Criteria (Part 1 and Part 2):\n\n          -  Confirmed relapsed or refractory MM (measurable disease) or PCL.\n\n          -  Prior treatment regimens for Part 1: Patients should have received at least 2 prior\n             treatment regimens. Prior treatment must have included at least one full cycle of a\n             proteasome inhibitor (e.g., bortezomib or carfilzomib) and at least one full cycle of\n             an IMiD (e.g., thalidomide, lenalidomide or pomalidomide).\n\n          -  Prior treatment regimens for Part 2: Patients should have received 1 to 3 prior\n             treatment regimens. Prior treatment could have included bortezomib only if the disease\n             was not refractory to treatment with bortezomib (refractory defined as documented\n             progression on therapy or within 60 days of completing treatment with bortezomib).\n\n          -  The disease should have progressed per IMWG criteria during or after the last prior\n             treatment regimen.\n\n          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.\n\n          -  Adequate hematology laboratory values without transfusion support and without\n             hematological growth factor support within 2 weeks of screening.\n\n          -  Adequate liver and renal function.\n\n          -  Additional criteria exist.\n\n        Key Exclusion Criteria (Part 1 and Part 2):\n\n          -  Primary amyloidosis.\n\n          -  Peripheral neuropathy ? Grade 2 or neuropathy with pain, regardless of grade.\n\n          -  Concomitant malignancies or previous malignancies with less than a 3-year disease free\n             interval at the time of enrollment (patients with adequately resected basal or\n             squamous cell carcinoma of the skin, carcinoma in situ of the cervix or Stage A low\n             grade prostate cancer may enroll irrespective of the time of diagnosis).\n\n          -  Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to\n             first dose of study drug.\n\n          -  Treatment with an investigational medicinal product or device within 28 days prior to\n             first dose of study drug.\n\n          -  Cytotoxic therapy or monoclonal antibodies within 21 days prior to first dose of study\n             drug.\n\n          -  Radiotherapy within 21 days prior to first dose of study drug (if the radiation portal\n             covered ? 5% of the bone marrow reserve, the patient may be enrolled irrespective of\n             the end date of radiotherapy).\n\n          -  Major surgery within 14 days and minor surgery within 7 days prior to first dose of\n             study drug.\n\n          -  Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to\n             first dose of study drug.\n\n          -  Known positive serology for the human immunodeficiency virus (HIV), hepatitis B and/or\n             active hepatitis C.\n\n          -  Additional criteria exist.

Participation in an investigational therapeutic study within 14 days of initiation of study drug treatment

Angina pectoris ? 3 months prior to dosing with study drug

Acute MI ? 3 months prior to dosing with study drug

Are currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

Use of any other experimental drug or therapy within 28 days of baseline

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

Pregnant or lactating female; female subjects who are lactating are eligible if they discontinue nursing prior to the first dose of study drug and refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

Hemoptysis within 6 weeks of first dose of study drug

Radiation therapy within 28 days of the first dose of study drug

patients who received dasatinib within 3 days of starting study drug

patients who received imatinib within 5 days of starting study drug

patients who received hematopoietic growth factors within 7 days of starting study drug or Pegfilgrastim (Neulasta®) within 14 days of starting study drug

Received an investigational anti-cancer drug within 4 weeks or 5 half-lives (whichever is shorter) of study drug administration--- at least 14 days must have passed between the last dose of prior investigational anti-cancer drug and the first dose of study drug.

The patient has received any investigational or non-registered medicinal product other than the study treat-ment within 30 days preceding the first dose of study treatment or plans to receive such a drug during the study period.

Use of any other experimental drug or therapy within 28 days prior to randomization

The subject has active infection or fever > 38.5 degrees Celsius (C) within 3 days prior to first dose of study drug

The patient has received any investigational or non-registered medicinal product other than the study medi-cation within 30 days preceding the first dose of study medication or plans to receive such a drug during the study period.

Must commit to either continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use and be able to comply with effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including during periods of dose interruptions), and for 28 days after discontinuation of study therapy.

Must agree to not donate semen during study drug therapy and for a period after end of study drug therapy.

Have an understanding that the study drug could have a potential teratogenic risk.

Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy.

Allergic to diphtheria toxin a component of the study drug A-dmDT390-bisFv(UCHT1).

Anticoagulant drug therapy,

Subject must be receiving a stable dose of ASP8273 for 14 days minimum and is able to enroll into this rollover study without treatment interruption of study drug, or with no more than 21 consecutive days of treatment interruption in study drug within the parent study.

To avoid risk of drug exposure through the ejaculate (even men with vasectomies), subjects must use a condom during sexual activity while on study drug and for 3 months following the last dose of study drug; if the subject is engaged in sexual activity with a woman of childbearing potential, a condom is required along with another effective contraceptive method consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies and their partners; donation of sperm is not allowed while on study drug and for 3 months following the last dose of study drug

Agree not to try to become pregnant during the study and for 28 days after the final study drug administration,

Female subject must not be breastfeeding at screening or during the study period, and for 28 days after the final study drug administration.

Female subject must not donate ova starting at screening and throughout the study period, and for 28 days after the final study drug administration.

Male subject must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration. *Acceptable forms of birth control include:

Subject has received a prior EGFR inhibitor within 6 days prior to the first dose of study drug.

Subject has had any of the following within 14 days prior to the first dose of study drug:

Sexually active males must use a condom during intercourse while taking the drug and for 90 days after stopping treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Sexually active males unless they use a condom during intercourse during and for 3 months after the last dose of the study treatment and should not father a child in this period; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid

Recent hemoptysis (>= ½ teaspoon of red blood within 8 weeks before first dose of study drug)

Administration of any non-oncologic investigational drug within 30 days prior to receiving the first dose of topotecan/pazopanib

Recent hemoptysis (>= half teaspoon of red blood within 8 weeks before first dose of study drug)

Experimental therapy within 4 weeks prior to first dose of study drug

Prior anti-cancer therapy within 28 days before the first dose of study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Participating in any other investigational study for either drug or device which could influence collection of valid data under this study

Planned administration of an investigational study drug or agent that either can interact with pamidronate or have an independent effect on bone mineral density within the 4 weeks prior to randomization (day 90) or planned use during study participation (day 90 through day 360)

Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug plus 5 half-lives of study drug plus 90 days (duration of sperm turnover) for a total of 31 weeks posttreatment completion

Male patients must agree to use a condom when having sex with a pregnant woman or with a non-pregnant female partner of childbearing potential, from 21 days before the first dose of study drug through 105 days after last dose of study drug.

Female patients must not be breastfeeding at screening nor during the study participation until 45 days after the last dose of the study drug.

Male patients must agree to use a condom when having sex with a pregnant woman or with a non-pregnant female partner of childbearing potential, from 21 days before the first dose of study drug through 105 days after last dose of study drug.

Female patients must not be breastfeeding at screening nor during the study participation until 45 days after the last dose of study drug.

Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are not permitted during the study.

Seville oranges within 5 days before the first dose of study drugs and during the study.

Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from being sexually active during the study period or for 28 days after study drug discontinuation

Males who have not had a successful vasectomy (confirmed azoospermia) or they and their female partners do not meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period or for 28 days after study drug discontinuation). No sperm donation is allowed during the study period and for 28 days after study drug discontinuation.

Currently enrolled in another interventional clinical study or used any investigational drug or device within the past 28 days preceding informed consent

Subjects with gastrointestinal conditions which might result in malabsorption of the study drug

Treatment with any Food and Drug Administration (FDA) non-approved study medication within the past four weeks; off label treatment with FDA approved medication is allowed

Patient is a woman with a positive urine or serum pregnancy test within 3 days prior to study drug administration, is breast-feeding, or is planning to conceive children within the projected duration of the study treatment

Able to tolerate enteral drug administration

If on medication for anxiety, stable dose of medications for management of anxiety symptoms for at least six weeks prior to enrollment with no plans to change meditations in the subsequent four weeks. Increases or decreases allowed within drug class, but changing drug class will make patient in-evaluable

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study

Radiation therapy within 2 weeks of the first administration of study drug

Anticancer chemotherapy or immunotherapy during the study or within 4 weeks prior to the first dose of study drug

Treatment with systemic cancer therapy or investigational therapy within 4 weeks of first study drug administration; radiation within 2 weeks; corticosteroids (greater than or equal to 10 mg prednisone or equivalent per day) or other immune suppressive drugs within 2 weeks of first study drug administration

Neutrophils >= 1000/uL, obtained within 14 days of the first dose of study drug

Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug

Consumption of grapefruit or grapefruit juice is not permitted during the study; patients should not consume food or beverages containing the fruit or juice of grapefruits or Seville oranges within 7 days before the first dose of study drug and throughout the study

Prior participation, i.e., receipt of study medication, in this study;

Enrolled in a clinical trial involving an investigational product or nonapproved use of a drug or in medical research judged not to be scientifically or medically compatible with this study.

Treatment with an investigational anti-cancer study drug within 3 weeks prior to study drug administration date

Prior corticosteroids as anti-cancer therapy within a minimum of 14 days of first receipt of study drug

Patient has received external beam radiation therapy to the CNS within 21 days of the first dose of the study drug

The patient has been treated with radio- or toxin-immunoconjugates within 70 days of the first dose of the study drug

Patient is allergic to components of the study drug; for arms A and B only, patient has perviously taken ibrutinib

Subject is receiving or is less than 30 days since ending other experimental device or drug (no marketing authorization for any indication)

Use of any other experimental drug or therapy within 28 days of baseline

Participation in another clinical study within 28 days of the day chemotherapy is initiated, in which the study drug or device may influence hematopoiesis. Co-enrollment in another study is allowed in cases where the investigational therapy under study is a version of an acceptable chemotherapy regimen for this study per the inclusion criteria.

Subject has participated in an investigational drug or device research study within 30 days of enrollment that would interfere with this study.

Participating in another investigational drug or device study in which patient has not completed the follow-up phase for the primary endpoint at least 30 days prior to enrollment

Tuberculosis requiring treatment within the past 3 years; all patients must have a negative quantiferon test within 4 weeks prior to starting study drug

All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Any investigational drug being administered during the study

Patient who experienced any vomiting, retching, or nausea within 24 h prior to the administration of the study drug

Patient who received palonosetron within 1 week prior to administration of study drug.

Patient who has been started on systemic corticosteroid therapy within 72 h prior to study drug administration or is planned to receive a corticosteroid as part of the chemotherapy regimen

Individuals who have used photosensitizing drugs within the last 30 days prior to study enrollment, or who will be using a photosensitizing drug during the time of the study, will not be eligible

Use of any systemic antifungal therapy for > 72 hours during the week prior to study drug initiation

Use of an investigational drug in the 3 months prior to screening and must agree to not participate in any drug or device study while enrolled in this study

Women must not be breastfeeding, WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) apixaban plus 5 half-lives of study drug apixaban (2.5 days) plus 30 days (duration of ovulatory cycle) for a total of 32.5 days post-treatment completion

Subject considered by the investigator as unsuitable candidate for receipt of an investigational drug, or unstable to be followed up throughout the entire duration of the study

Patients who are participating in another experimental protocol during the study period (last intake of investigational drug within 6 months prior to first study drug injection)

Women who are pregnant or lactating, or planning pregnancy while enrolled in the study or for 7 months after the last dose of the study drug

Significant neurotoxicity/neuropathy (Grade 3 or higher) within 14 days of first dose of study drug

Systemic anti-tumor therapy within 14 days, or plasmapheresis within 7 days prior to the first dose of study drug

Use of enzyme-inducing anti-epileptic drugs (EIAED) within 7 days prior to the first dose of study drug.

Participants who have previously enrolled and received study drugs on arm 1 of this study cannot re-enroll onto arm 1 after being removed from this study, but if they were removed from arm 1 for disease progression, they are eligible to re-register onto this study in order to enroll onto arm 2 of this study if they otherwise meet all of the eligibility criteria for this study; all participants who received an investigational product on a clinical trial, including arm 1 of this study, must wait 21 days prior to course 1 day 1 (C1D1) of this study

Current participation in another clinical investigation of a medical device or a drug or has participated in such a study within 30 days prior to study enrollment.

Have received any investigational new drug within the past 30 days or planning to receive such during the study period

Willing to receive anti-epileptic prophylaxis for the duration of study drug administration.

Willing to receive anti-epileptic prophylaxis for the duration of study drug administration

Administration of chemotherapy or any investigational drug in the 28 days prior to receiving the first dose of treatment.

Subject has concurrent participation in any interventional studies within 14 days of first dose of study drug.

Use of enzyme-inducing antiepileptic drugs (EIAEDs) within 7 days prior to the first dose of study drug

Has a preexisting functional central venous catheter available for study drug administration

Is male OR is female who is not of reproductive potential OR is female who is of reproductive potential and agrees to avoid becoming pregnant in the 28 days prior to receiving study drug, while receiving study drug and for at least 30 days after last dose of study drug

Has started on systemic corticosteroid therapy within 72 hours prior to study drug administration or is expected to receive a corticosteroid as part of the chemotherapy regimen

Has ever participated in a previous study of aprepitant or fosaprepitant or has taken an investigational drug with the last 4 weeks.

Is pregnant or expecting to conceive, is breastfeeding, or plans to breastfeed from the time of consent through 90 days after the last dose of study drug

Is expecting to donate eggs or sperm from the time of consent through 90 days after the last dose of study drug

Has participated in a study with an unapproved investigational compound (monoclonal antibodies are excepted) or device within 28 days of the first dose of study drug

Prior treatment with Food and Drug Administration (FDA)-approved or investigational biologics or novel molecularly target therapies, including oral or IV formulations, are permitted; patients must be off prior targeted therapy for at least 14 days prior to study biopsy

The patient has participated in another investigational drug study within 30 days of scheduled surgery

Patients who have received an investigational drug in the 30 days before study drug administration, or will receive one within 72 hours (h) after their final CEUS exam

Subjects with three or more drug allergies from separate drug classes

Received an investigational drug within 30 days prior to first dose of panitumumab-IRDye800

Received an investigational drug within 30 days prior to first dose of panitumumab-IRDye800

Patients who have received an investigational drug in the 30 days before study drug administration, or will receive one within 72 hours (h) afterwards

Subjects with three or more drug allergies from separate drug classes

Willingness to use adequate contraception throughout study and for a period of 90 days last dose of study drug

HEALTHY VOLUNTEER: Participation in an investigational drug study within the period starting 1 month before study drug administration

Subjects will receive the standard Food and Drug Administration (FDA)-approved dose and schedule of 5-azacytidine; this dose is 75 mg/m^2 SC or intravenously (IV) daily for seven days with cycles repeated every 28 days

Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug

Patient must not have hemoptysis within 6 weeks of first dose of study drug

Subjects with three or more drug allergies from separate drug classes

Patient has participated in a clinical study of an investigational drug or device within 3 months prior to screening CDU that may have an impact on clinical outcomes; and,

Patient is < 18 years old at the time of the drug administration

Received an investigational drug within 30 days prior to first dose of panitumumab IRDye800

Received an investigational drug within 30 days prior to first dose of cetuximab IRDye800

Received an investigational drug within 30 days prior to first dose of cetuximab-IRDye800

Evidence for clonal T-cell receptor gene rearrangement (obtained within 1 year prior to study drug administration). CTCL-Specific:

History of allergies and adverse drug reaction to study drug components

Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications within 28 days before first dose of study drug; subjects must have recovered from AEs due to previously administered therapies.

Participants with prior exposure to a pyrrolobenzodiazepine or indolinobenzodiazepine based drug.

Inclusion Criteria:\n\n          -  In order to be eligible for participation in this trial, the subject must meet all the\n             following:\n\n               1. Pathologically documented unresectable melanoma, AJCC Stage III or IV. Subjects\n                  must have histological or cytological confirmed diagnosis of unresectable\n                  melanoma with progressive locally advanced or metastatic disease.\n\n               2. Subjects must be refractory to anti-PD-1 monoclonal antibodies (pembrolizumab or\n                  nivolumab either as monotherapy or in combination with other approved checkpoint\n                  inhibitors or targeted therapies according to their approved label) and subjects\n                  must meet all of the following criteria:\n\n                    1. Received at least 4 doses of anti-PD1 mAb (minimum dose of 2 mg/kg or fixed\n                       dose of 200 mg given Q3W for pembrolizumab; minimum dose of 240 mg given Q2W\n                       for nivolumab in monotherapy; minimum dose of 1 mg/kg given Q3W for\n                       nivolumab in combination with ipilimumab)\n\n                    2. Progressive disease after anti-PD1 mAb will be defined according to RECIST\n                       v1.1.\n\n                    3. Documented disease progression within 24 weeks of the last dose of anti-PD1\n                       mAb.\n\n               3. Resolution/improvement of anti-PD1 mAb-related AEs\n\n                    1. No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs\n                       from anti-PD1 mAb.\n\n                    2. No history of CTCAE Grade 3 requiring steroid treatment (>10 mg/day\n                       prednisone or equivalent dose) for >12 weeks or CTCAE Grade 2 pneumonitis\n                       regardless of steroid treatment.\n\n                    3. Minimum of 4 weeks (washout period) from the last dose of anti PD1 mAb.\n\n               4. Prior treatment with an approved BRAF inhibitor if BRAF V600 mutation-positive.\n\n               5. Age ? 18 years of age on day of signing informed consent.\n\n               6. Has a performance status of 0 or 1 on the ECOG Performance Scale.\n\n               7. Have measurable disease based on RECIST v1.1, with at least one anatomically\n                  distinct lesion. Lesion or lesions must meet all the following baseline criteria:\n\n                    1. Accessible for electroporation,\n\n                    2. Must be accurately measured in at least one dimension (longest diameter in\n                       the plane of measurement is to be recorded)\n\n               8. Demonstrate adequate organ function as defined below. All screening laboratories\n                  should be performed within 10 days of treatment initiation.\n\n                  System Laboratory Value Hematological Absolute neutrophil count (ANC) ?1.5 ×\n                  109/L Platelets ?100 × 109/L Hemoglobin ?9 g/dL or ?5.6 mmol/L* Renal Creatinine\n                  OR ?1.5 × the upper limit of normal (ULN) OR Measured or calculated** creatinine\n                  clearance (CrCl) Glomerular filtration rate (GFR) can also be used instead of\n                  creatinine or CrCl ? 30 mL/min for patient with creatinine levels >1.5 ×\n                  institutional ULN Hepatic Total bilirubin ?1.5 × ULN OR direct bilirubin ?ULN for\n                  patients with total bilirubin levels > 1.5× ULN Aspartate aminotransferase (AST)\n                  and alanine aminotransferase (ALT) ?2.5 × ULN OR ?5 × ULN for patients with liver\n                  metastases Coagulation International Normalized Ratio (INR) or Prothrombin Time\n                  (PT) ?1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT\n                  or PTT is within therapeutic range of intended use of anticoagulants Activated\n                  Partial Thromboplastin Time (aPTT)\n\n                  * Criteria must be met without erythropoietin dependency and without packed red\n                  blood cell (pRBC) transfusion within last 2 weeks\n\n                  ** Creatinine clearance should be calculated per institutional standard.\n\n               9. Women of childbearing potential must have negative serum or urine pregnancy test\n                  within 72 hours prior to receiving the first study drug administration.\n\n              10. For women of childbearing potential, must be willing to use an adequate method of\n                  contraception from 30 days prior to the first study drug administration and 120\n                  days following last day study drug administration. Spermicide alone is not\n                  considered sufficient in Canada and will not be accepted.\n\n              11. Male patients must be surgically sterile, or must agree to use adequate method of\n                  contraception during the study and at least 120 days following the last day of\n                  study drug administration.\n\n              12. Able and willing to provide written informed consent and to follow study\n                  instructions.\n\n        Exclusion Criteria:\n\n        The subject must be excluded from participating in the trial if meet any of the following:\n\n          1. Subject has disease that is suitable for local therapy administered with curative\n             intent.\n\n          2. Subject with a diagnosis of uveal melanoma.\n\n          3. Subject has a known additional malignancy that is progressing or requires active\n             treatment within the past 3 years. Exceptions include basal cell carcinoma of the\n             skin, squamous cell carcinoma of the skin that has undergone potentially curative\n             therapy or in situ cervical cancer.\n\n          4. Clinically active CNS metastases or non-measurable bone-only metastases. Subjects with\n             previously treated brain metastases may participate provided they are radiologically\n             stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging,\n             clinically stable and without requirement of steroid treatment for at least 14 days\n             prior to first dose of study drug.\n\n          5. Greater than 3 visceral sites of metastases. Liver lesions must meet RECIST v1.1\n             criteria for SD for at least 1 month prior to enrolment.\n\n          6. Subjects with electronic pacemakers or defibrillators.\n\n          7. Subjects who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2\n             antibodies).\n\n          8. Subjects who have known active Hepatitis B (defined as HBsAg reactive) or Hepatitis C\n             virus infection (defined as HCV RNA [qualitative] is detected)\n\n          9. Subject has a diagnosis of immunodeficiency or is receiving chronic systemic steroid\n             therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form\n             of immunosuppressive therapy within 7 days prior to the first dose of study drug. The\n             use of physiologic doses of corticosteroids may be approved after consultation with\n             the Sponsor.\n\n         10. Subjects who have received a live-virus vaccination within 30 days of the first dose\n             of treatment. Seasonal flu vaccines that do not contain live virus are permitted.\n\n         11. Subject has severe hypersensitivity (?Grade 3) to pembrolizumab and/or any of its\n             excipients.\n\n         12. Subject who have received transfusion of blood products (including platelets or red\n             blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF\n             or recombinant erythropoietin) within 4 weeks prior to study Cycle 1, Day 1\n             (baseline).\n\n         13. Subject has a history of (non-infectious) pneumonitis that required steroids or\n             current pneumonitis.\n\n         14. Subject has a history of interstitial lung disease.\n\n         15. Subject has an active infection requiring systemic therapy.\n\n         16. Subject has a history or current evidence of any condition, therapy, or laboratory\n             abnormality that might confound the results of the trial, interfere with the subject's\n             participation for the full duration of the study, or is not in the best interest of\n             the subject to participate, in the opinion of the treating Investigator.\n\n         17. Subject has not recovered (i.e., ? Grade 1 or at baseline) from adverse events due to\n             a previously administered agent.\n\n         18. Participation in another clinical study of an investigational agent or has used an\n             investigational device within 30 days of screening.\n\n         19. Subjects who have had any targeted small molecule therapy or any immunotherapy after\n             their confirmed progression on anti-PD-1 therapy.\n\n         20. Subject has known psychiatric or substance abuse disorders that would interfere with\n             cooperation with the requirements of the study.\n\n         21. Subjects who are pregnant or breastfeeding, or expecting to conceive or father\n             children within the projected duration of the study, starting with the screening visit\n             through 120 days after the last dose of studytreatment.

Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc.) within 28 days of the first dose of study drug

Male subject who is considering fathering a child or donating sperm during the study or for approximately 90 days after the last dose of study drugs

Investigational drug use within 28 days of the first dose of avelumab

Has received treatment with any prescribed treatments within specified time frames prior to study drug administration

Subject is suitable for oral administration of study drug.

Agree not to try to become pregnant during the study and for 6 months after the final study drug administration

Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.

Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.

Male subject must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration.

Subjects with three or more drug allergies from separate drug classes

Received an investigational drug within 30 days prior to first dose of cetuximab IRDye800

Be using more than one antihypertensive drug

The subject has participated in another investigational drug study within 30 days of scheduled surgery.

Currently taking imperative medications with significant drug-drug interaction with ciprofloxacin

Prior chemotherapy, monoclonal antibody or immunotherapy (eg, tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all AEs have either returned to baseline or resolved to Grade 0 or 1

Participants taking any drug that is a strong inhibitor or inducer of the CYP3A4 enzyme within at least 2 weeks before the start of study drug and during the conduct of the study unless there is an emergent or life-threatening medical condition that requires it

Participants taking any drug known to prolong QTc interval within at least 2 weeks before the start of the study drug and during the conduct of the study

Off study use of ketorolac or other NSAIDs prior to study administration within the perioperative window (7 days before surgery and up to the time of planned study administration)

Allergy/sensitivity to any study drug (degarelix, enzalutamide, trametinib, dasatinib), or drugs chemically related to study drug, or excipients or to dimethylsulfoxide

Have received treatment within 28 days prior to the initial dose of study drug with an investigational product or non-approved use of a drug or device (other than the study drug/device used in this study) for non-cancer indications or are concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.

Are enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study within 28 days of the initial dose of study drug.

Patients must not be on enzalutamide within five half-lives before the first planned dose of the study drug or anticipating to start enzalutamide within the next 3 months of the first planned dose of study drug

Treatment with anticancer chemotherapy or biologic therapy or with an experimental anticancer agent within 28 days of the initial dose of study drug.

Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for 90 days after study entry (withdrawal of dasatinib), at restart of study drug (dasatinib) and for the duration of treatment with study drug (dasatinib) plus 90 days (duration of sperm turnover) for a total of 90 days post-treatment completion

The patient has received an investigational drug within 30 days of the first dose of study drug.

Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug. (Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval)

Experimental therapy within 4 weeks prior to first dose of study drug treatment in Cycle 1

Food or beverages containing grapefruit within 5 days before the first dose of study drug. Note that food and beverages containing grapefruit are not permitted during the study.

Receipt of anticancer medications or investigational drugs within the protocol-defined intervals before the first administration of study drug.

Grapefruit-containing food or beverages within 5 days before the first dose of study drug. Note that grapefruit-containing food and beverages are prohibited during the study.

Use of an investigational drug within 21 days prior to the first dose of study drug. Note that to be eligible, any drug-related toxicity should have recovered to Grade 1 or less, with the exception of alopecia.

Off dexamethasone treatment for ?4 weeks before the first dose of study drug.

Inclusion Criteria:\n\n        Locally advanced or metastatic NSCLC that has been cytologically or histologically\n        confirmed\n\n        ALK rearrangement based on FDA approved test (e.g. Vysis breakapart FISH or IHC using\n        Ventana)\n\n        ECOG PS ?2\n\n        Age of ? 18 years\n\n        Brain lesions may be used as target lesions if progressing, ?10mm in longest diameter and\n        if they were not previously treated with any of the following:\n\n          -  Whole brain radiation therapy (WBRT) within 3 months\n\n          -  Stereotactic radiosurgery (SRS)\n\n          -  Surgical resection Availability of core biopsy of progressive lesion taken within 60\n             days prior to D1 of treatment under study therapy or willing to undergo tumor biopsy:\n             NOTE:. All subjects must consent to provide tumor blocks or slides.\n\n          -  If archival tissue is not available and biopsies to obtain fresh tumor tissue cannot\n             be performed with minimal risk to the subject, subjects may be permitted to enroll on\n             the study with prior approval of the Study PI.\n\n          -  In the situation the patient undergoes biopsy within 60 days prior to D1. and there is\n             insufficient tumor tissue subjects for the correlative science part of the protocol\n             patient will be permitted to enroll on the study with prior approval of the study PI\n\n          -  In the situation the patient undergoes molecular testing or next-generation sequencing\n             as part of standard care there must be sufficient tumor sample available for\n             participation in the study (i.e. a next generation sequencing report is not sufficient\n             for enrollment)\n\n        Recovered from toxicities related to prior anticancer treatment to ?Grade 2 or baseline\n        with the exception of alopecia\n\n        Have normal QT interval on ECG evaluation QT corrected Fridericia (QTcF) of ? 450 ms in\n        males or ? 470 ms in females\n\n        Adequate organ function defined as:\n\n        Absolute neutrophil count (ANC) ?1500/µL Platelets ?75,000/µL Hemoglobin? 10g/dL AST /ALT ?\n        2.5 x upper limit of normal (ULN); ? 5 x ULN if liver metastasis Total serum bilirubin ?\n        1.5 x ULN Serum creatinine ? 1.5 x UNL Serum amylase ? 1.5 x UNL\n\n        At least 1 measurable lesion per RECIST version 1.1\n\n        Negative serum pregnancy test within 7 days of D1 of treatment in women of child bearing\n        potential (WOCBP)\n\n        If fertile, willing to use highly effective form of contraception (defined as a combination\n        of at least two of the following methods: condom or other barrier methods, oral\n        contraceptives, implantable contraceptives, intrauterine devices) during the dosing period\n        and for at least 4 months after\n\n        Ability to provide signed informed consent and willing and able to comply with all study\n        requirements\n\n        Inclusion criteria for cohort assignment:\n\n        Cohort A: Progressive disease on any next generation ALK inhibitor except first line\n        alectinib or brigatinib (any line)\n\n        Cohort B: Progressive disease on first-line therapy with alectinib, and no other ALK\n        inhibitors\n\n        Cohort C: Previous treatment brigatinib at 180 mg daily for ?4 weeks without > grade 2\n        drug-related toxicities and with radiographic evidence of progressive disease and no\n        intervening systemic therapies such as chemotherapy, immunotherapy or another ALK inhibitor\n        (radiation therapy allowed as intervening therapy). Patients who are treated on cohorts A\n        and B will be allowed to enroll in cohort C if the meet the inclusion and exclusion\n        criteria\n\n        Exclusion Criteria for cohorts A, B, and C:\n\n        Patients meeting any of the following exclusion criteria will not be able to participate in\n        this study:\n\n        History or the presence of pulmonary interstitial disease, drug-related or immune-related\n        pneumonitis, or radiation pneumonitis requiring medical management within 6 months of trial\n        enrollment\n\n        Prior treatment with brigatinib for cohorts A and B\n\n        History of or active significant gastrointestinal (GI) bleeding within 3 months\n\n        Malabsorption syndrome or other GI illness that could affect oral absorption of the study\n        drug\n\n        Received cytotoxic chemotherapy, investigational agents or radiation within 7 days prior to\n        D1 of study treatment\n\n        Received prior ALK TKI therapy within 7 days prior to D1 of treatment under study drug. 7\n        day wash out period is required after prior ALK inhibitor treatment.\n\n        Have significant, uncontrolled, or active cardiovascular disease, specifically including,\n        but not restricted to:\n\n          -  Myocardial infarction (MI) within 6 months of trial enrollment\n\n          -  Unstable angina within 6 months of trial enrollment\n\n          -  Congestive heart failure (CHF) with 6 months prior to trial enrollment\n\n          -  Any history of ventricular arrhythmia\n\n          -  Cerebrovascular accident or transient ischemic attack within 6 months of D1 of study\n             treatment\n\n          -  Clinically significant atrial arrhythmia or severe baseline bradycardia defined as\n             resting heart rate < 60 beat per minute\n\n          -  Uncontrolled hypertension defined as baseline SBP> 160 and DBP > 100 on 3 separate\n             clinic visits or past history of hypertensive urgency, emergency or encephalopathy\n\n        Have been diagnosed with another primary malignancy within the past 3 years (except for\n        adequately treated non-melanoma skin cancer, cervical cancer in situ, or prostate cancer,\n        which are allowed within 3 years)\n\n        Have symptomatic CNS metastases which require an increasing dose of corticosteroids within\n        the last 2 weeks to remain asymptomatic.\n\n        Have active infection requiring intravenous antibiotics\n\n        Pregnant or breastfeeding\n\n        Have any condition or illness that, in the opinion of the investigator, would compromise\n        patient safety or interfere with evaluation of the study drug.

Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.

Known intolerance to study drug (or any of the excipients).

Receipt of anticancer medications or investigational drugs within protocol-defined intervals before the first administration of study drug

Male participants of childbearing potential must be willing to use an adequate method of contraception starting with the first dose of study drug through 120 days (for participants receiving pembrolizumab) or 180 days (for participants receiving BV) after the last dose of study drug.

Receipt of systemic anticancer therapy, including investigational agents, within 28 days of starting study treatment. If anticancer therapy was given within 28 days of starting study treatment, patients may be included if 5 times the elimination half-life of the drug has passed

CLL therapy, with the exception of ibrutinib within the following timeframes:\r\n* Chemotherapy, external beam radiation therapy, anticancer antibodies within 30 days prior to the first dose of drug on this study\r\n* Corticosteroid use >= 20 mg prednisone within 1 week prior to first dose on this study\r\n* Radio- or toxin-conjugated antibody therapy within 10 weeks prior to first dose on this study\r\n* Allogeneic stem cell transplant within 6 months prior to first dose on this study