• Ductal carcinoma in situ (DCIS) or invasive epithelial (ductal, medullary, papillary, mucinous (colloid), or tubular histologies
• Willing and able to provide consent
• Age >=18 years.
• Performance status Eastern Cooperative Oncology Group (ECOG) 0-2
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Appropriate staging studies identifying as American Joint Committee on Cancer (AJCC) stage 0, I, or II breast cancer. If stage II, the tumor size must be 3 cm or less.
• Surgical treatment of the breast with lumpectomy Clinical Target Volume (CTV) margin up to 5 cm in maximum dimension with histologically confirmed margins free of tumor (negative margins defined as no tumor on ink in all directions). Re-excision of surgical margins is permitted.
• Gross disease within the breast must be unifocal. (Patients with microscopic multifocality are eligible as long as the total extent of tumor, gross and microscopic, occupies a volume with greatest dimension 3 cm or less)
• Patients with invasive disease are required to have axillary staging including: sentinel node biopsy alone if sentinel node is negative, sentinel node biopsy followed by axillary dissection with a minimum of 6 axillary nodes sampled if sentinel node is positive, or axillary dissection alone (with a minimum of 6 axillary nodes). Patients with DCIS are not required to have axillary staging.
• Patients with a history of non-breast invasive malignancies are eligible if they have been disease-free for 3 or more years prior to entry into the study
• T2 (>3.0 cm), T3, stage III, or stage IV breast cancer
• More than 3 histologically positive axillary lymph nodes or axillary lymph nodes with microscopic or macroscopic extracapsular extension.
• Positive non-axillary sentinel nodes or evidence of suspicious supraclavicular, infraclavicular, or internal mammary nodes by imaging or physical exam, unless biopsied and found to be negative for tumor.
• Evidence by physical examination or mammography of other suspicious masses, densities, or microcalcifications in either breast, unless biopsied and found to be benign.
• Non epithelial breast malignancies such as sarcoma or lymphoma.
• Multicentric gross breast carcinoma (either DCIS or invasive cancer) or microscopic breast carcinoma occupying a volume with maximum dimensions of more than 3 centimeters.
• Synchronous bilateral invasive or non-invasive breast cancer.
• Paget's disease of the nipple.
• Previous breast radiation on ipsilateral side or thoracic radiation on the ipsilateral side.
• Treatment plan that includes regional nodal irradiation.
• Any prior treatment with radiation therapy or chemotherapy for the currently diagnosed breast cancer prior to registration. Endocrine therapy may be given but not within 28 days prior to study entry and must be stopped if the patient will be receiving chemotherapy until completion of chemotherapy. Patients must discontinue any hormonal agents such as raloxifene, tamoxifen, or other selective estrogen receptor modulators prior to registration.
• Patients with collagen vascular disease, specifically dermatomyositis with a Creatine phosphokinase (CPK) level above normal or active skin rash, systemic lupus erythematosis, or scleroderma.
• Pregnancy or lactation at the time of registration. For women of childbearing age, they must agree to use effective contraceptive methods such as condom/diaphragm and spermicidal foam, intrauterine device, or prescription birth control pills.
• Patients with severe co-extensive comorbidities or significant psychiatric illness.

• ELIGIBILITY CRITERIA FOR SCREENING AND MOLECULAR PROFILING (STEP 0)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 2 weeks prior to screening
• Female and male patients must have histologically confirmed invasive breast cancer that meets the following criteria:
• Clinical stage II-III (American Joint Committee on Cancer [AJCC] 7th edition) at diagnosis, based on initial evaluation by clinical examination and/or breast imaging; no metastatic disease allowed
• ER- and PR- should meet one of the following criteria:
• =< 10% cells stain positive, with weak intensity score (equivalent to Allred score =< 3)
• =< 1% cells stain positive, with weak or intermediate intensity score (equivalent to Allred score =< 3)
• HER2 negative (not eligible for anti-HER2 therapy) will be defined as:
• Immunohistochemistry (IHC) 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR
• IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells OR
• ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells without IHC
• NOTE: Patients that originally present with synchronous bilateral tumors are eligible provided both tumors are TNBC, and at least one of them fulfills the remainder eligibility criteria of the protocol; multifocal or multicentric breast cancers are eligible as long as all tumors fulfill eligibility criteria
• NOTE: Patients that have a discrepancy in ER/PR/HER2 status between original diagnosis and surgical specimen (if ER/PR/HER2 status were repeated) are not eligible for study participation (i.e. ER/PR/HER2 has to fulfill above criteria in both scenarios)
• Patients must have completed neoadjuvant taxane +/- anthracycline; patients must NOT have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant therapy regimen
• NOTE: Patients who received preoperative therapy as part of a clinical trial may enroll
• NOTE: Patients that were not able to complete their planned neoadjuvant chemotherapy for any reason (i.e. toxicities, etc.) are eligible to participate as long as no further systemic standard of care therapy is planned by the treating physician
• Must have completed definitive resection of primary tumor
• Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS) are eligible
• Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable
• Sentinel node biopsy either pre or post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) are allowed; axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory
• Post neoadjuvant chemotherapy, patients must be found to have residual invasive cancer in the breast at the time of definitive surgery; residual cancer is defined as a contiguous focus of residual invasive cancer, in the breast, measuring >= 1 cm in diameter, and with more than minimal cellularity, as per local pathologist determination; this is required due to constraints in deoxyribonucleic acid (DNA) extraction for PAM50 analysis
• NOTE: The presence of ductal carcinoma in situ (DCIS) without invasion does not qualify as residual invasive disease in the breast
• NOTE: Despite lymph node involvement if residual invasive cancer in the breast is < 1 cm in diameter patients are not eligible for participation
• Radiotherapy may be given before or after protocol treatment per standard of care guidelines; when radiotherapy is planned prior to protocol treatment administration, patients may be registered and screened while receiving radiation
• Post-mastectomy radiotherapy is required for all patients with the following:
• Primary tumor >= 5 cm (prior to neoadjuvant chemotherapy [clinically] or at the time of definitive surgery) or involvement of 4 or more lymph nodes at the time of definitive surgery
• For patients with primary tumors < 5 cm or with < 4 involved lymph nodes prior to neoadjuvant chemotherapy and at the time of definitive surgery, provision of post-mastectomy radiotherapy is at the discretion of the treating physician
• Radiation of regional nodal basins is at the discretion of the treating radiation oncologist
• NOTE: Breast radiotherapy (whole breast or partial) is required for patients who underwent breast-conserving therapy, including lumpectomy or partial mastectomy
• Hemoglobin (Hgb) > 9.0 g/dL
• Platelets > 100,000 mm^3
• Absolute neutrophil count (ANC) > 1500 mm^3
• Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula
• Bilirubin =< 1.5 x ULN upper limit of normal (except in patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL)
• Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x upper limit of normal (ULN)
• Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• No history of TNBC invasive breast cancer within 5 years of enrollment, no concurrent malignancies of any sort
• No clinically significant infections as judged by the treating investigator
• Patients with active >= Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 grade 2 neuropathy are ineligible
• Adjuvant chemotherapy after surgery other than that specified in this protocol is not allowed; luteinizing hormone-releasing hormone (LHRH) agonists and adjuvant bisphosphonate or denosumab use is allowed
• Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the residual disease on the definitive surgical specimen available for PAM50 analysis for stratification
• Tumor tissue specimen from the definitive surgery has been collected and is ready to ship to the ECOG-American College of Radiology Imaging Network (ACRIN) Central Biorepository and Pathology Facility (CBPF) within 21 weeks post-surgery
• The Molecular Diagnostics Laboratory (MDL) at MD Anderson Cancer Center will perform the PAM50 analysis and notify the ECOG-American College of Radiology Imaging Network (ACRIN) operations office within three (3) weeks of receipt of the tumor tissue specimen via secure electronic messaging to the ECOG-ACRIN database; results will not be reported to the submitting institution
• NOTE: Tissue must be submitted any time during screening period, even if patient is getting radiation
• NOTE: Every effort should be made to submit the tumor tissue specimen to the ECOG-ACRIN CBPF immediately
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): No specific timeframe between registration and randomization needs to be observed, as long as:
• Patients randomized to the chemotherapy arms have their cycle 1/ day 1 (platinum based or capecitabine) start within 3 weeks (15 working days) following randomization date
• Randomization occurs no more than 24 weeks from surgery date
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Must have PAM50 analysis by digital mRNA quantitation on the formalin-fixed paraffin-embedded tumor tissue specimen (FFPE) of the residual disease in the breast or axilla resected at the time of definitive surgery completed
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): ECOG performance status 0 or 1 within 2 weeks prior to randomization
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Radiotherapy may be given before or after protocol treatment. when radiotherapy is planned prior to protocol treatment administration, patients must have completed adjuvant radiotherapy >= 2 weeks prior to randomization for protocol therapy, if applicable
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must have completed treatment with any investigational agent >= 30 days prior to randomization for protocol therapy, if applicable
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must be randomized within 24 weeks from surgery
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Hemoglobin (Hgb) > 9.0 g/dL
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Platelets > 100,000 mm^3
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Absolute neutrophil count (ANC) > 1500 mm^3
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): International normalized ratio (INR) =< 3 (to be done/tested only for subjects on warfarin)
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Bilirubin =< 1.5 x ULN (except in patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL)
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Aspartate aminotransferase (AST, SGOT) =< 2.5 x ULN
• ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Alanine aminotransferase (ALT, SGPT) =< 2.5 x ULN

• diagnosis of neuroblastoma either by histologic verification and/or demonstration of tumor cells in the bone marrow with increased urinary catecholamines.
• must have high risk neuroblastoma with one of the following: 1) recurrent/progressive disease at any time, 2) refractory disease, 3) persistent disease after at least a partial response to frontline therapy, or 4) Second or greater complete remission after definitive disease progression.
• must have at least one of the following sites of disease: 1) measurable tumor on MRI, CT scan, or X-Ray; 2)MIBG scan with positive uptake in at least one site; 3) bone marrow with tumor cells seen on routine morphology.
• must have an ECOG performance status of 0, 1, or 2
• must have a life expectancy of greater than or equal to 8 weeks
• must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy
• hemoglobin greater than or equal to 8.0 (may transfuse to achieve this level)
• ANC greater than or equal to 500 (must be at least 7 days after last dose of growth factor)
• platelet count greater than or equal to 50,000 (must be transfusion independent, defined as at least 1 week since last platelet transfusion)
• age-adjusted serum creatinine less than or equal to 1.5 times normal for age
• normal cardiac function documented by: ejection fraction (greater than or equal to 55%) documented by echocardiogram or radionuclide MUGA evaluation OR fractional shortening (greater than or equal to 27%) documented by echocardiogram AND EKG must demonstrate no abnormality severe enough to justify cardiac medications AND baseline QTc interval greater than or equal to 450 msecs
• total bilirubin less than or equal to 1.5 times normal for age
• ALT and AST less than or equal to 3 times normal for age (for this study, the upper limit of normal of ALT is defined as 45 U/L)
• normal prothrombin time (PT) for age
• baseline hepatitis titers without evidence of acute/active hepatitis. Patients will need to have a negative Hep B Surface Antigen (HBsAg), Hep B e Antigen (HBeAg), Anti-Hep B core Antibody IgM (Anti-HBc IgM), Anti-HAV IgM, and Anti-HCV IgM.
• Patients with CNS parenchymal or meningeal-based lesions are eligible. Patients with prior history of CNS irradiation are study eligible.
• Patients with a seizure disorder are eligible if seizures are controlled on anticonvulsants and if the specific anticonvulsant(s) is not contraindicated.
• Normal lung function as manifested by no dyspnea at rest and no oxygen requirement.
• Due to the potential teratogenic effects of retinoids, negative serum beta-HCG in females, and use of effective contraception in males and females of child-bearing potential, is required.
• skin toxicity no greater than grade 1 per CTCAE v4
• Serum triglycerides < 300mg/dL fasting or on a random plasma test.
• Serum calcium < 11.6mg/dL
• No hematuria and/or proteinuria greater than 1+ on urinalysis.
• Patients with known genetic metabolic conditions, or other ongoing serious medical issues, must be approved by the Study Chair prior to registration.
• Pregnancy or breast feeding. Due to the potential teratogenic effects of retinoids, pregnant women are NOT eligible. Breast milk feeding by study patient is NOT allowed.
• Patients with history of organ and allogeneic stem cell transplantation.
• Patients with a known history of allergy to soy products.
• Patients with a known history of a severe allergy or sensitivity of wheat gluten.
• Patients requiring anti-arrhythmia cardiac medications are NOT eligible.
• Prior therapy with fenretinide, or fenretinide + ketoconazole, if DLT's were experienced.
• A known history of intolerance of ketoconazole.
• Patients on other essential medications for which an interaction with ketoconazole can be expected and for which dose reductions to other essential medications cannot be made in a manner adequate to ensure patient safety.
• Patients who, in the opinion of the investigator, may not be able to comply with safety monitoring requirements of the study.
• Active hepatitis.
• Baseline cardiac QTc interval >450 msecs.
• Eligible for enrollment on other national or regional treatment protocols employing fenretinide/LXS oral power that are reasonably accessible to the patient.
• Patient must NOT receive other anti-cancer agents while on Study.
• Ceftriaxone (Rocephin®) is NOT permitted for 24 hours prior to the start of the oral fenretinide course, during the course, and for 24 hours after the completion of seven day fenretinide course due to concerns of possible adverse effects on the hepatic clearance of fenretinide. Alternative antibiotics should be used. Other cephalosporins are permitted.
• Acetaminophen (Tylenol®) is NOT permitted for 24 hours prior the start of the oral fenretinide course, during the course, and for 48 hours following the completion of the seven day fenretinide course due to concerns of possible hepatic interactions. Ibuprofen (Motrin®) should be used for antipyretic control during this time period.
• Palliative radiation is allowed.
• Patients should NOT receive supplemental Vitamin A, C, or E except as contained in routine total parenteral nutrition vitamin supplements, or in a single daily standard dose oral multivitamin supplement, because of possible interference with antitumor 4-HPR-induced, reactive oxygen species and/or ceramide, and due to the unknown effects of these drugs on retinol levels
• Patients must NOT take any drugs suspected of causing pseudotumor cerebri, which include tetracycline, nalidixic acid, nitrofurantoin, phenytoin, sulfonamides (Dapsone permitted), lithium, amiodarone, or vitamin A (except as part of routine TPN supplements or as part of a single daily standard dose oral multivitamin supplement).
• Concomitant use of herbal supplements or other alternative therapy medications IS CONTRAINDICATED due to potential adverse metabolic interactions of such supplements with fenretinide.
• Patients should NOT concurrently take medications that may potentially act as modulators of intracellular ceramide levels or ceramide cytotoxicity, sphingolipid transport, or p-glycoprotein (MDR1) or MRP1 drug/lipid transporters, such as: cyclosporine A or analogue; verapamil; tamoxifen or analogue; chlorpromazine; RU486; indomethacin; or sulfinpyrazone. Patients should NOT concurrently take medications that are known P450 inhibitors. Contact Study Chair if there are questions regarding the suitability of any medication.
• As corticosteroids may impact sphingolipid metabolism, systemic corticosteroids should NOT be used for emesis control during the course of the study. Systemic corticosteroids for asthma control are permissible but should be minimized. Inhaled corticosteroids for asthma control are allowed. Steroids for routine metabolic deficiency states are allowed. Steroids for CNS lesions are allowed.
• Because gastric acidity is necessary for the maximal dissolution and absorption of ketoconazole, when actively taking ketoconazole, patients should avoid/minimize concurrent medications that decrease gastric acid output (such as ranitidine) or increase gastric pH (such as Tums).
• Concomitant medication that may prolong cardiac QT interval, especially those with known interaction with ketoconazole (See Appendices IV, V and VI). A LIST OF THESE MEDICATIONS SHOULD BE PROVIDED TO THE PATIENT AND FAMILY
•PLEASE SEE APPENDICES IV, V and VI FOR A LIST OF MEDICATIONS THAT SHOULD NOT BE USED WITH CONCURRENT KETOCONAZOLE OR THAT SHOULD BE USED WITH CAUTION. Please SEE APPENDIX IV for a partial list of medications potentially prolonging QT interval. Patients may NOT receive therapy with the medications listed as PROHIBITED in Appendix IV and V. Medications in Appendix VI may be used with cautions as noted. Regulatory:
• Patients and/or their parents or legal guardians must sign a written informed consent (or assent.)
• All institutional, FDA, and NCI requirements for human studies must be met.

1. Be willing and able to provide written informed consent for the trial. 2. Histologically or cytologically confirmed diagnosis of anaplastic thyroid cancer or undifferentiated thyroid cancer. A diagnosis of possible ATC/UTC will be allowed if the clinical presentation is consistent with anaplastic or undifferentiated thyroid cancer. 3. Be ≥ 18 years of age on day of signing informed consent. 4. Have measurable disease based on RECIST 1.1. 5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived sample. 6. Have a performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. 7. Demonstrate adequate organ function as defined in the protocol. , 8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 9. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. 10. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. 1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 3. Has a known history of active TB (Bacillus Tuberculosis). 4. Hypersensitivity to pembrolizumab or any of its excipients. 5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 10. Has known history of, or any evidence of active, non-infectious pneumonitis. 11. Has an active infection requiring systemic therapy. 12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). 18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

1. Female, >/= 50 years old or less than 75 years old. 2. Postmenopausal (>/= 12 months amenorrhea). 3. Have at least one ovary. 4. Cancer-free and have not received any chemotherapy or radiation therapy for >/=12 months prior to enrolling on this study. 5. Willingness to return for CA 125 blood tests annually or earlier if indicated. 6. Willingness to return to undergo transvaginal ultrasound if indicated. 7. Women need to provide the name of a gynecologist or qualified healthcare professional willing to provide appropriate follow-up care if indicated 1. Female: Less than 50 years old or older than 75 years at the time of enrollment. 2. Psychiatric or psychological or other conditions which prevent a fully informed consent. 3. Prior removal of both ovaries. 4. Active non-ovarian malignancy. 5. Women who have a history of non-ovarian malignancy will be eligible if they have no persistent or recurrent disease and have not received treatment for >12 months. If they are on SERMS (i.e. tamoxifen or aromatase inhibitors) they will not be excluded. Women maybe undergoing or have had treatment <12 months prior to study entry for basal cell carcinoma only. 6. High risk for ovarian cancer due to familial predisposition as defined by the following: a. Known mutation in BRCA1 of BRCA2. b. Two 1st or 2nd degree relatives of same lineage who have: two ovarian cancers; one ovarian cancer & one pre-menopausal breast cancer; two pre-menopausal breast cancers; one pre-menopausal & one post-menopausal breast cancer. (These conditions can also be met using the patient and one 1st or 2nd degree female relative.) c. Ashkenazi Jewish descent with one 1st degree or two 2nd degree relatives with pre-menopausal breast or ovarian cancer or participant has had pre-menopausal breast cancer. d. 1st or 2nd degree male relative with breast cancer diagnosed at any age. (First degree relative defined as children, siblings and parents. Second degree relative defined as half-siblings, aunts, uncles, nieces, nephews, grandparents, and grandchildren.) 7. Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome: known genetic mutation, presumed HNPCC carrier, Amsterdam criteria.

• Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, or osteosarcoma
• Disease progression after prior therapy in locally advanced or metastatic setting
• Measurable or evaluable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria
• Age 12 months to <21 years
• Adequate bone marrow reserves, hepatic function, and renal function
• Recovered from effects of any prior surgery or cancer therapy
• Patients 18 years or older will provide written consent. A parent or legal guardian of a patient <18 years of age will provide informed consent and patients 11 to 18 years of age will provide written assent or as per participating institutional policy.
• Clinically significant gastrointestinal disorders
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled blood pressure
• Active infection or unexplained fever
• Known hypersensitivity to any of the components of MM-398 or other liposomal products
• Recent Investigational therapy
• Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment

• Patients must be over 18 years old and capable and willing to provide informed consent.
• Patients of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to PET/CT imaging per institution's standard of care;
• A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria;
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).
• Medically stable as judged by patient's physician.
• Life expectancy must be estimated at > 6 months.
• Patients must have an ECOG performance status of 0-3 (restricted to ECOG PS 0-2 if age >70 years).
• Patients with known allergic or hypersensitivity reactions to previously administered radiopharmaceuticals of similar chemical or biologic composition to FES are NOT eligible.
• Patients with liver failure are NOT eligible.
• Patient must NOT be breast-feeding.
• Histologically confirmed ER+ breast cancer either from a metastatic biopsy or from a primary breast tumor with imaging evidence of metastatic disease. The pathology report and either (1) tumor tissue (blocks or unstained slides) or (2) a photomicrograph of the ER IHC slide from at least one site of metastatic disease
• No prior endocrine therapy for metastatic disease is allowed (i.e. must be first-line endocrine therapy for metastatic disease). However, a history of adjuvant endocrine therapy is allowed, as long as the date of diagnosis of metastatic disease is > 2 years following initiation of adjuvant endocrine therapy. Patients who develop metastatic disease while still receiving adjuvant endocrine therapy must have a change in the type of endocrine agent used for subsequent metastatic disease treatment. Patients on blocking adjuvant therapy (with a blocking agent such as toremifene or tamoxifen) must be off the agents for a minimum of 60 days to allow for adequate uptake of FES
• Patients with human epidermal growth factor-2 positive (HER2+) metastatic tumors are NOT eligible
• Postmenopausal women, men, or premenopausal women for whom endocrine therapy (tamoxifen, aromatase inhibitor (AI) with or without ovarian suppression or fulvestrant), with or without a CDK4/6 inhibitor is planned after FES-PET/CT is completed
• Disease may be measurable (by RECIST 1.1 criteria) or non-measurable but must be present in at least one non-liver site, 1.5 cm or greater and visualized on PET/CT with [18F]-fluorodeoxyglucose (FDG). Patients with effusion only disease or disease only in the liver are not eligible for the study
• Patient must be able to lie still for a 20 to 30 minute PET/CT scan. . Patients not meeting the inclusion criteria.

1. Has morphologically confirmed diagnosis of myelodysplastic syndromes (MDS) or CMML (i.e., with white blood cell [WBC] <13,000/μL) or low-blast acute myelogenous leukemia (AML). 2. Has MDS or CMML and must also have one of the following Prognostic Risk Categories, based on the Revised International Prognostic Scoring System (IPSS-R):
• Very high (>6 points).
• High (>4.5-6 points).
• Intermediate (>3-4.5 points): a participant determined to be in the Intermediate Prognostic Risk Category is only allowable in the setting of >=5% bone marrow myeloblasts. 3. Eastern Cooperative Oncology Group (ECOG) status of 0, 1, or 2. 4. Participants with AML (20%-30% blasts) must have a treatment-related mortality (TRM) score >=4 for intensive, induction chemotherapy as calculated using the simplified model described by Walter and coworkers. Calculation of TRM score:
• 0 for (age <61 years), +2 for (age 61-70 years), +4 for (age >71 years).
• + 0 for (PS=0), +2 for (PS=1), +4 for (PS >1).
• + 0 for (platelets <50), +1 for (platelets >50). 1. Has previous treatment for HR MDS or CMML or low-blast AML with chemotherapy or other antineoplastic agents including hypomethylating agent (HMAs) such as decitabine or azacitidine. Previous treatment is permitted with hydroxyurea and with lenalidomide, except that lenalidomide may not be given within 8 weeks before the first dose of study drug. 2. Has acute promyelocytic leukemia as diagnosed by morphologic examination of bone marrow, by fluorescent in situ hybridization or cytogenetics of peripheral blood or bone marrow, or by other accepted analysis. 3. Participants with AML with a WBC count >50,000/ microliter (mcL).. Participants who are cytoreduced with leukapheresis or with hydroxyurea may be enrolled if they meet the eligibility criteria. 4. Is eligible for intensive chemotherapy and/or allogeneic stem cell transplantation. The reason a participant is not eligible for intensive chemotherapy and/or allogeneic stem cell transplantation may consist of one or more of the following factors:
• Age >75.
• Comorbidities.
• Inability to tolerate intensive chemotherapy (e.g., participants with AML with 20%-30% blasts and TRM >=4).
• Physician decision (e.g., lack of available stem cell donor).
• The reason a participant is not eligible should be documented in the electronic case report form (eCRF). 5. Has either clinical evidence of or history of central nervous system involvement by AML. 6. Has active uncontrolled infection or severe infectious disease, such as severe pneumonia, meningitis, or septicemia. 7. Is diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. 8. Has nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone resection. 9. Has prothrombin time (PT) or aPTT >1.5× upper limit of normal (ULN) or active uncontrolled coagulopathy or bleeding disorder. Participants therapeutically anticoagulated with warfarin, direct thrombin inhibitors, direct factor Xa inhibitors, or heparin are excluded from enrollment. 10. Has known human immunodeficiency virus (HIV) seropositive. 11. Has known hepatitis B surface antigen seropositive, or known or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. 12. Has known hepatic cirrhosis or severe preexisting hepatic impairment. 13. Has known cardiopulmonary disease defined as unstable angina, clinically significant arrhythmia, congestive heart failure (New York Heart Association Class III or IV), and/or myocardial infarction within 6 months before first dose, or severe pulmonary hypertension. 14. Has treatment with strong cytochrome P 3A (CYP3A) inducers within 14 days before the first dose of pevonedistat.

• Patients must have a locally advanced and unresectable or metastatic gastroenteropancreatic neuroendocrine carcinoma that is either known or suspected to be of gastrointestinal (GI) origin; primary tumors arising from the lung, gynecologic organs or prostate are not permitted
• Patients must have pathologically/histologically confirmed tumor of non-small cell histology
• Patients must have a Ki-67 proliferative index of 20-100% OR at least 10 mitotic figures per 10 high powered fields
• Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria; baseline measurements and evaluations of all sites of disease must be obtained within 4 weeks prior to randomization and must be acquired by multiphasic computed tomography (CT) or contrast magnetic resonance imaging (MRI)
• NOTE: positron emission tomography (PET)-CT scans are allowed provided the CT portion of the exam is equivalent to a diagnostic CT scan and includes both oral and IV contrast
• Patients may not have had any prior systemic treatment for this malignancy (for example chemotherapy or somatostatin analogues); prior palliative radiation is permitted but radiated lesions may not be used for measurement
• Patients may not have received any of the protocol agents within 5 years prior to randomization
• Any prior surgeries must have been completed at least 4 weeks prior to randomization
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Patients may not be receiving any other investigational agents while on study treatment
• Patients may not be receiving Coumadin while on treatment; other anticoagulants are allowed
• Leukocytes >= 3,000/mm^3
• Absolute neutrophil count >= 1,500/mm^3
• Hemoglobin >= 9 g/dL
• Platelets >= 100,000/mm^3
• Total bilirubin =< institutional upper limit of normal (ULN) or =< 1.5 X institutional ULN (if the patient has liver metastases)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN or (=< 5 X institutional ULN if the patient has liver metastases)
• Serum creatinine =< 1.5 X institutional ULN and creatinine clearance >= 60 ml/min
• NOTE: creatinine clearance must be calculated using the Cockcroft-Gault equation
• Patients must have a life expectancy of >= 12 weeks as determined clinically by the treating physician
• Patients with brain metastases (either remote or current) or presence of carcinomatous meningitis are not eligible
• Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency will be excluded
• Patients must NOT have active or uncontrolled infection, symptomatic heart failure, unstable angina pectoris, cardiac arrhythmia or a serious psychiatric illness/social situation that would limit compliance with study requirements
• Patients with impaired decision making capacity may participate in the study if a legal authorized representative is available to consent
• Patients must NOT have a history of allergic reactions attributed to compounds of similar chemical or biochemical composition to cisplatin, carboplatin, etoposide, temozolomide or capecitabine
• Patients must NOT have absorption issues that would limit the ability to absorb study agents
• Patients with a history of the following within =< 12 months of study entry are not eligible:
• Arterial thromboembolic events
• Unstable angina
• Myocardial Infarction
• Patients with symptomatic peripheral vascular disease are not eligible
• Patients must NOT have previous or concurrent malignancy; exceptions are made for patients who meet any of the following conditions:
• Non-melanoma skin cancer, in situ cervical cancer, superficial bladder cancer, or breast cancer in situ OR
• Prior malignancy completely excised or removed and patient has been continuously disease free for > 5 years OR
• Prior malignancy cured by non-surgical modalities and patient has been continuously disease free for > 5 years
• Women must not be pregnant or breast-feeding
• All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy
• A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study
• Patients must be able to swallow pills
• Patients must be able to tolerate CT or magnetic resonance (MR) imaging including contrast agents as required for the treatment and the protocol
• Patients who are known to have human immunodeficiency virus (HIV) or are on combination antiretroviral therapy are ineligible

• Subject has sufficient venous access to permit administration of study drug (for the IV cohorts), collection of pharmacokinetic samples and monitoring of safety laboratories.
• Female subject must either:
• Be of non-childbearing potential: Clearly premenarchal or documented surgically sterile
• Or, if of childbearing potential: Agree not to try to become pregnant during the study and for 28 days after the final study drug administration; and have a negative urine or serum pregnancy test at screening; and, if heterosexually active, agree to consistently use 2 forms of highly effective birth control (at least one of which must be a barrier method) 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 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 and their female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least one of which must be a barrier method) starting at screening and continue throughout the study, and for 90 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.
• Subject and subject's parent(s) or legal guardian agree that the subject will not participate in another interventional study while on treatment.
• For oral cohorts: subject is able to swallow the oral capsule medication.
• Subject has familial short QT syndrome, is receiving medications that are known to shorten the QT interval, or has a clinically significant abnormal electrocardiogram (ECG).
• Subject has evidence of hepatic dysfunction defined as:
• Total bilirubin ≥ 3 times the upper limit of normal (ULN)
• Alanine transaminase or aspartate transaminase ≥ 5 times the ULN
• Known cirrhosis or chronic hepatic failure
• Subject has used strong cytochrome P450 (CYP) 3A4 inhibitors or inducers such as ketoconazole, rifampin/rifampicin, long acting barbiturates, carbamazepine and St. John's wort in the 5 days prior to the first administration of study drug.
• Subject has known history of allergy, hypersensitivity, or any serious reaction to any of the azole class antifungals.
• Subject has any condition which makes the subject unsuitable for study participation.
• Subject is unlikely to survive 30 days.
• Subject has received investigational therapy, with the exception of oncology drug trials, within 28 days or 5 half-lives, whichever is longer, prior to screening.
• For oral cohorts: The subject has gastrointestinal disease or has had a procedure that is expected to interfere with the oral absorption or tolerance of the study drug (e.g., functionally relevant gastrointestinal obstruction, mucositis/stomatitis, or frequent vomiting).
• Subject previously dosed with isavuconazonium sulfate.

• Feasibility Phase: Patients must be < 21 years of age at the time of enrollment; please note: the feasibility phase is complete, effective with amendment #1
• Efficacy Phase: Patients must be =< 40 years of age at the time of enrollment
• Patients with newly diagnosed RMS of any subtype, except adult-type pleomorphic, based upon institutional histopathologic classification, are eligible to enroll on the study based upon stage, group, and age, as below
• RMS types included under embryonal rhabdomyosarcoma (ERMS) include those classified in the 1995 International Classification of Rhabdomyosarcoma (ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified in the 2013 World Health Organization (WHO) classification as ERMS (classic, dense and botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical spindle cell ERMS variant and the newly recognized sclerosing RMS variant); classification of alveolar rhabdomyosarcoma (ARMS) in the 2013 WHO classification is the same as in the ICR and includes classic and solid variants
• ERMS
• Stage 1, group III (non-orbit)
• Stage 3, group I/II
• Stage 2/3, group III
• Stage 4, group IV, < 10 years old
• ARMS:
• Stages 1-3, groups I-III
• Specimen Submission: Patients must have sufficient tissue available for the required biology study
• Lansky performance status score >= 50 for patients =< 16 years of age; Karnofsky performance status score >= 50 for patients > 16 years of age
• Peripheral absolute neutrophil count (ANC) >= 750/uL
• Platelet count >= 75,000/uL
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:
• 1 month to < 6 months old: 0.4 mg/dl (male), 0.4 mg/dl (female)
• 6 months to < 1 year old: 0.5 mg/dl (male), 0.5 mg/dl (female)
• 1 to < 2 years old: 0.6 mg/dl (male), 0.6 mg/dl (female)
• 2 to < 6 years old: 0.8 mg/dl (male), 0.8 mg/dl (female)
• 6 to < 10 years old: 1 mg/dl (male), 1 mg/dl (female)
• 10 to < 13 years old: 1.2 mg/dl (male), 1.2 mg/dl (female)
• 13 to < 16 years old: 1.5 mg/dl (male), 1.4 mg/dl (female)
• >= 16 years old: 1.7 mg/dl (male), 1.4 mg/dl (female)
• Patients with an elevated serum creatinine due to obstructive hydronephrosis secondary to tumor are still eligible; however, patients with urinary tract obstruction by tumor must have unimpeded urinary flow established via diversion (i.e. percutaneous nephrostomies or ureteric stents) of the urinary tract
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
• All patients and/or their parents or legal guardians must sign a written informed consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
• Patients who have previously received temsirolimus, another mTOR inhibitor, or any other investigational agent
• Patients who have received any chemotherapy (excluding steroids) and/or RT prior to this enrollment
• Patients with uncontrolled hyperglycemia
• Patients with uncontrolled hyperlipidemia
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for at least 3 months after treatment is completed
• Female patients who are pregnant are not eligible; Note: a pregnancy test is required for female patients of childbearing potential prior to study entry
• Lactating females who plan to breastfeed their infants are not eligible

Inclusion Criteria-Part A: Subject must meet all of the following applicable inclusion criteria to participate in this study:
• Patients must have histologically confirmed advanced RCC (any histology). Collecting duct tumors and tumors originating from the renal pelvis or upper urinary tract are considered of urothelial origin and are excluded from this protocol.
• Patients must have at least one measurable site of disease, per RECIST 1.1, that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.
• ECOG performance status 0-2
• Have signed the current approved informed consent form Patients must have adequate organ function within 14 days prior to study entry as evidenced by screening laboratory values that must meet the following criteria: Hematological:
• White blood cell (WBC) ≥ 2000/µL
• Absolute Neutrophil Count (ANC) ≥ 1500/μL
• Platelets (Plt) ≥ 100 x103/μL
• Hemoglobin (Hgb) > 9.0 g/dL (with or without transfusion) Renal:
• Serum Creatinine ≤ 1.5 x ULN; if creatinine > 1.5, subject must demonstrate CrCl as outlined below.
• Calculated creatinine clearance ≥ 40 mL/min using Cockcroft-Gault formula Hepatic:
• Bilirubin ≤ 1.5× upper limit of normal (ULN); Except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL
• Aspartate aminotransferase (AST) ≤ 3 × ULN
• Alanine aminotransferase (ALT) ≤ 3 × ULN
• Archival tissue is mandatory (a tumor biopsy- core or excisional) of a metastatic lesion obtained within 1 year prior to study registration (within 4 weeks preferred). Tumor tissue from nephrectomy and site of metastasis will be required. If archival tissue of a metastatic lesion obtained within the preceding year is not available, patients must have at least one site of disease (not including bone metastases) accessible for core needle or excisional biopsy. If archival tissue of a metastatic lesion is not available and biopsy of a new lesion is not feasible, the subject is not eligible for the study.
• Patients should not have received prior systemic therapy for metastatic RCC. Prior radiotherapy must have been completed at least 2 weeks prior to the administration of study drug. Patients must be 2 weeks from prior major surgery and 1 week from pre-treatment biopsy. Prior systemic adjuvant therapy (excluding with PD1 or CTLA4 pathway blockers) is allowed if treatment completed > 12 months previously.
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks
• Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) during screening for registration purposes. This pregnancy test should be repeated within 24 hours prior to the start of nivolumab.
• Women must not be breastfeeding
• 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 a period of 31 weeks after the last dose of investigational product Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception.
• Be willing and able to comply with this protocol.
• Patients are excluded if they have active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for 2 weeks of more after treatment is complete and within 28 days prior to the first dose of nivolumab administration. There must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration.
• Patients with controlled brain metastases are allowed on protocol if they had solitary brain metastases that was surgically resected without recurrence or treated with SRS without progression x 4 weeks.
• Patients should be excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen
• Active infection requiring systemic therapy
• Has any other medical or personal condition that, in the opinion of the site investigator, may potentially compromise the safety or compliance of the patient, or may preclude the patient's successful completion of the clinical trial
• Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and Adverse Drug Reaction
• History of allergy to study drug components
• History of severe hypersensitivity reaction to any monoclonal antibody
• Known additional malignancies within the past 3 years (excluding basal of squamous cell skin cancers, CIS or localized prostate cancer that has been treated or is being observed) Inclusion/Exclusion Criteria- Part B
• Must meet eligibility criteria for initiation of Part A with the exception of being allowed to have prior nivolumab in Part A of this protocol
• Must have evidence of either RECIST 1.1 defined Disease Progression or Stable Disease 1 year after initiating nivolumab therapy
• Must undergo repeat tumor biopsy for acquisition of resistant tumor tissue
• Must not have had a Grade ≥ 3 irAE on nivolumab monotherapy
• Must not have untreated brain metastases
• Must not have had major surgery or radiation therapy within 14 days of starting study treatment
• Must not have active autoimmune disease
• Must not have a concurrent medical condition requiring use of systemic corticosteroids with prednisone >10 mg per day
• Must not have had prior systemic therapy for Stage IV RCC (except for nivolumab as part of part A of this protocol)
• Prior solid organ or stem cell transplant

• Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up
• Women of childbearing potential and men who are sexually active should be willing and able to use medically acceptable forms of contraception during the trial and for up to 180 days after completion of all treatment to prevent pregnancy or fathering a child.
• Pathologically proven diagnosis of NSCLC, with metastases (stage IV disease) present prior to registration; this includes patients newly diagnosed with metastatic disease or those initially diagnosed and treated for stage I-III NSCLC who ultimately develop metastases
• Appropriate stage for study entry based on the following diagnostic workup:
• History/physical examination within 30 days prior to registration
• Imaging proof of limited metastatic disease and response to therapy/stable disease, by at least CT chest through the adrenals or PET/CT within 30 days prior to registration
• Zubrod performance status 0, 1, or 2 within 30 days prior to registration
• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with metastatic liver disease
• Total bilirubin ≤ 1.5 × ULN
• Absolute neutrophil count (ANC) ≥ 500 cells/mm^3
• Creatinine clearance ≥ 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Platelets ≥ 50,000 cells/mm^3
• Negative serum pregnancy test within one week prior to registration for females of childbearing potential
• Patients must have received first-line/induction chemotherapy (4 cycles) and achieved stable disease or a partial response
• Prior systemic chemotherapy as part of concurrent treatment approach for previously diagnosed stage III NSCLC, as adjuvant therapy for previously resected NSCLC, or for other previous cancers is permitted
• Prior radiotherapy for patients with brain metastases prior to enrollment is acceptable
• Patients must have measurable disease at baseline and 3 or fewer discrete, extracranial metastatic disease sites that are technically amenable to SBRT
• For de novo stage IV NSCLC patients (patients with metastatic disease at first presentation), primary disease must be treatable with local therapy in the form of SBRT or hypofractionated radiation; if the primary disease is found in the peripheral or central lung parenchyma without nodal disease for instance, SBRT may be employed; if primary disease is more advanced with involvement of the mediastinum (T4 tumor, N1-N3 disease, etc.), these volumes should be technically treatable with hypofractionated radiation
• If primary disease in the thoracic cavity was previously treated with local therapy in the form of surgery, any local/regional disease recurrence should be technically treatable with SBRT or hypofractionated radiation after induction systemic therapy
• Patients must be registered within 35 days of administration of the last dose of first-line/induction systemic therapy
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• Patients with brain metastases are eligible if these lesions have been previously treated and the patients have no clinical or radiographic evidence of progression prior to enrollment
• Clinical or radiologic evidence of untreated and/or progressive brain metastases
• Cutaneous metastasis of NSCLC
• Metastatic disease invading the esophagus, stomach, intestines, or mesenteric lymph nodes if not a candidate for surgery for these lesions
• Prior invasive malignancy (except non-melanomatous skin cancer, low or intermediate risk prostate cancer, or in situ carcinoma of breast, oral cavity, skin, or cervix) unless disease free for a minimum of one year
• Metastases located within 3 cm of previously irradiated (< 3Gy per fraction) structures if if not a candidate for surgery for these lesions and if:
• Spinal cord previously irradiated to > 40 Gy
• Brachial plexus previously irradiated to > 50 Gy
• Small intestine, large intestine, or stomach previously irradiated to > 45 Gy
• Brainstem previously irradiated to > 50 Gy
• Lung previously irradiated with prior V20 Gy > 35%
• Patients receiving targeted therapy (non-cytotoxic systemic therapy) for NSCLC in the first-line setting
• If a patient has progressed in previous areas of primary disease that received definitive doses of radiation, these patients would require re-irradiation in previous high dose anatomic areas and are not eligible for this study
• Patients with malignant pleural effusions that do not resolve after first-line systemic therapy; patients with pleural effusions that have become too small for thoracentesis at the time of registration would be permitted on study, indicating a significant response to first-line chemotherapy
• Patients with more than 3 discrete locations of extra-cranial metastatic disease after first-line systemic therapy requiring more than 3 SBRT plans to cover these distinct metastatic disease entities
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
• Patients who are pregnant or nursing
• Participation in any investigational drug study (excluding non-oncology and/or symptom management studies) within 4 weeks prior to registration
• Known human immunodeficiency virus (HIV) positive with cluster of differentiation 4 (CD4) count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol
• Patients who received prior non-induction pembrolizumab, patients on chronic steroids or who have active autoimmune disease for which they received systemic treatment in the previous 2 years with corticosteroids, disease modifying agents, or immunosuppressive drugs. Replacement therapy (thyroxine, insulin or physiological corticosteroid replacement for adrenal or pituitary insufficiency) is allowed. Patients with active interstitial lung disease or who have a history of pneumonitis for which they had received glucocorticoids are not eligible
• Prior bevacizumab therapy

• Patients must have a pathologically confirmed adenocarcinoma of the biliary tract (intra-hepatic, extra-hepatic (hilar, distal) or gall bladder) that is not eligible for curative resection, transplantation, or ablative therapies. Tumors of mixed histology are excluded.
• Patients may have received prior radiation, chemoembolization, radioembolization or other local ablative therapies or hepatic resection if completed ≥ 4 weeks prior to registration AND if patient has recovered to <= grade 1 toxicity. Extrahepatic palliative radiation is permitted if completed ≥ 2 weeks prior to enrollment AND if patient has recovered to ≤ grade 1 toxicity.
• Patients must have radiographically measurable disease in at least one site not previously treated with radiation or liver directed therapy (including bland, chemo- or radio-embolization, or ablation) either within the liver or in a metastatic site.
• Must be ≥18 years of age
• Must have a Child-Pugh score of A (prognosis in chronic liver disease and cirrhosis)
• Must have an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1
• Ability to understand and willingness to sign IRB-approved informed consent
• Willing to provide archived tissue, if available, from a previous diagnostic biopsy
• Must be able to tolerate CT (computerized tomography) and/or MRI (magnetic resonance imaging) with contrast
• Must have adequate organ function obtained ≤ 2 weeks prior to registration
• Patients may not have received prior systemic treatment (chemotherapy or targeted therapy) for advanced BTC (biliary tract cancer). Prior adjuvant chemotherapy is permitted provided it was completed > 6 months from registration.
• Must not have a diagnosis of immunodeficiency, or have received systemic steroid therapy, or any other form of immunosuppressive therapy within 7 days prior to trial treatment.
• Must not have known Hepatitis B, Hepatitis C, or HIV seropositivity. Testing is not required in absence of clinical suspicion.
• Must not have prior history of organ transplantation or brain metastasis.
• Must not have undergone a major surgical procedure < 4 weeks prior to registration.
• Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ. Patients with history of malignancy are eligible provided primary treatment of that cancer was completed > 1 year prior to registration and the patient is free of clinical or radiologic evidence of recurrent or progressive malignancy.
• Must have no ongoing active, uncontrolled infections
• Must not have received a live vaccine within 30 days of planned start of the study therapy.
• Must not have a psychiatric illness, other significant medical illness, or social situation which, in the investigator's opinion, would limit compliance or ability to comply with study requirements.
• Women must not be pregnant or breastfeeding since study drugs may harm the fetus or child.
• Women of child-bearing potential and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation and for 5 months (for women) and 7 months (for men) following completion of study therapy.
• Participants with an active, known or suspected autoimmune disease which may affect vital organ function, or has/may require systemic immunosuppressive therapy for management are excluded. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 7 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.

• Pure seminoma after orchiectomy presenting with isolated retropreritoneal lymphadenopathy OR stage I pure seminoma with isolated retroperitoneal relapse. Relapse should be within 3 years
• Lymphadenopathy in the retroperitoneum: at least one lymph node 1-3 cm in greatest dimension, no lymph node > 3 cm in greatest dimension, no more than 2 lymph nodes 1-3 cm in greatest dimension
• Axial imaging of lymphadenopathy within 6 weeks of the date of RPLND
• Retroperitoneal lymphadenopathy must be within the RPLND template
• If there is borderline lymphadenopathy, defined as the largest retroperitoneal lymph node measuring 0.90
•0.99 cm in the greatest dimension, an abdominal computed tomography (CT) scan should be repeated (recommend interval of 6
•8 weeks); the same lymph node must demonstrate growth to >= 1.0 cm in the greatest dimension
• Biopsy is not required, though if biopsy of the retroperitoneal node(s) was obtained, pathology must be consistent with pure seminoma
• Chest imaging (x-ray, CT or magnetic resonance imaging [MRI]) negative for metastasis no more than 6 weeks prior to the date of RPLND
• Primary tumor excised by radical inguinal orchiectomy and pathology consistent with pure seminoma
• Serum alpha fetoprotein (AFP) not more than 1.5 times upper limit of normal, beta-human chorionic gonadotropin (HCG), lactate dehydrogenase (LDH) (per the local laboratory assay) within 14 days of RPLND
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Ability to understand and the willingness to sign a written informed consent
• Serum coagulation studies (INR/PTT) and platelet counts suitable for surgery per surgeon discretion.
• Second primary malignancy
• History of receiving chemotherapy or radiotherapy
• Patients receiving any other investigational agent (s)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Age: ≥12 months to <18 years old at the time of informed consent
• Diagnosis: Histologically confirmed rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) (Grade 2 or 3), or Ewing sarcoma (EWS) which is relapsed or refractory (failed front line therapy)
• The presence of measurable disease meeting the following criteria:
• At least 1 lesion of ≥1.0 centimeter (cm) in the longest diameter for a non-lymph node or ≥1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI).
• Lesions that have had radiotherapy must show subsequent radiographic evidence of increase in size by at least 20% to be deemed a target lesion.
• Therapeutic options: Participant's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life.
• Performance level: Performance score ≥50%. Karnofsky (for participants >16 years of age) or Lansky (for participants ≤16 years of age). Participants who are unable to walk because of paralysis and/or previous surgeries, but who are in a wheelchair, will be considered ambulatory for the purpose of assessing performance score.
• Participants must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer directed therapy prior to study drug administration. If, after the required time frame, the numerical eligibility criteria are met, eg, blood count criteria, the participant is considered to have recovered adequately:
• Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea).
• Anticancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil count [ANC] counts): ≥7 days after the last dose of agent.
• Monoclonal antibodies ≥ 3 half-lives must have elapsed from infusion of last dose of antibody (including checkpoint inhibitors), and toxicity related to prior antibody therapy must be recovered to Grade ≤1.
• Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth factor (eg, Neulasta) or 7 days for a short-acting growth factor. For agents that have known adverse events (AEs) occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the sponsor.
• Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥21 days after the completion of interleukins, interferons, or cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total body irradiation [TBI]): ≥84 days
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion or boost infusion: ≥84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: ≥42 days
• Cellular therapy: ≥42 days after the completion of any type of cellular therapy (eg, modified T-cells, natural killer cells, dendritic cells, etc)
• Radiation therapy (XRT)/External Beam Irradiation including Protons: ≥14 days after local XRT; ≥150 days after TBI, craniospinal XRT or if radiation to ≥50% of the pelvis; ≥42 days if other substantial BM radiation
• Radiopharmaceutical therapy (eg, radiolabeled antibody, 131I-metaiodobenzylguanidine): ≥42 days after systemically administered radiopharmaceutical therapy.
• Adequate bone marrow function, defined as:
• ANC ≥1.0 × 10^9/Liter (L)
• Platelet count ≥100 × 10^9/L (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to study drug administration)
• Hemoglobin at least 8.0 grams per deciliter (g/dL) at Baseline (blood transfusions are allowed during the screening period to correct hemoglobin values less than 8.0 g/dL) Note: As blood transfusions are permitted to meet the hemoglobin criteria, participants requiring transfusion must not be known to be refractory to red blood cell or platelet transfusions.
• Adequate renal function, defined as:
• A serum creatinine based on age/gender, derived from the Schwartz formula for estimating glomerular filtration rate (GFR)
• Or creatinine clearance or GFR ≥50 milliliters per minute (mL/min)/1.73 meters squared (m^2) based on a 12 or 24 hour urine creatinine collection
• Adequate liver function, defined as:
• Bilirubin (sum of conjugated + unconjugated) ≤1.5 × upper limit of normal (ULN) for age
• Alanine aminotransferase (ALT) ≤110 units per Liter (U/L). For the purpose of this study, the ULN for ALT is 45 U/L
• Serum albumin ≥2 g/dL
• Informed consent: All participants and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines. Participants must be willing to comply with all aspects of the protocol.
• Pregnancy, breastfeeding, contraception: Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 International Units per Liter [IU/L] or equivalent units of β-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
• Females of childbearing potential (all post pubertal females will be considered to be of childbearing potential unless they have early menopause [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]) who:
• Do not agree to use a highly effective method of contraception for the entire study period and for 6 months after study drug discontinuation, ie:
• Total abstinence (if it is their preferred and usual lifestyle);
• An intrauterine device (IUD) or intrauterine system (IUS);
• A contraceptive implant;
• 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
• Do not have a vasectomized partner with confirmed azoospermia. For sites outside of the European Union (EU), it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, or the participant has commenced/adjusted/changed oral hormonal contraceptive product/dose within 4 weeks prior to study drug administration, then the participant must agree to use a medically acceptable method of contraception, ie, double barrier methods of contraception such as condoms plus diaphragm or cervical/vault cap with spermicide.
• 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 3 months after study drug discontinuation). No sperm donation is allowed during the study period or for 3 months after study drug discontinuation.
•Concomitant medications:
• Corticosteroids: Participants receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to study drug administration (except when indicated for Central Nervous System [CNS] metastases, then participants must not have received corticosteroids for at least 28 days)
• Anticancer Agents: participants who are currently receiving other anticancer agents
• Anti-GVHD agents Post-transplant: Participants who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant
• Strong CYP3A4 inducers/inhibitors
• Received prior therapy with eribulin mesylate
• Any other malignancy that required treatment (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in situ), within 2 years prior to study drug administration
• Has hypersensitivity to eribulin or any of the excipients
• Has a prior history of viral hepatitis (B or C) as demonstrated by positive serology (presence of antigens) or have an uncontrolled infection requiring treatment. Participants with a known prior history of hepatitis B or C may be eligible pending agreement with the sponsor.
• Has > Grade 1 peripheral sensory neuropathy or > Grade 1 peripheral motor neuropathy graded according to the Modified ("Balis") Pediatric Scale of Peripheral Neuropathies
• Has cardiac pathology: Participants with known congestive heart failure, symptomatic or left ventricular (LV) ejection fraction <50% or shortening fraction <27%
• Participants with congenital long QT syndrome, bradyarrhythmias, or QTc >480 msec on at least 2 separate electrocardiograms (ECGs).
• Has CNS Disease: Participants with brain or subdural metastases are not eligible unless the metastases are asymptomatic and do not require treatment or have been adequately treated by local therapy (eg, surgery or radiotherapy) and have discontinued the use of corticosteroids for this indication for at least 4 weeks prior to study drug administration. Confirmation of radiographic stability must be done by comparing the brain scan (CT or MRI) performed during the Screening Period, using the same imaging modality, to a brain scan performed earlier (and following local therapy where applicable). Participants must be clinically stable. It is not the intention of this protocol to treat participants with active brain metastases. Note: CNS imaging is required to confirm eligibility for participants with a known history of CNS disease.
• Have had or are planning to have the following invasive procedures:
• Major surgical procedure or significant traumatic injury within 28 days 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
• Core biopsy, including bone marrow biopsy, within 2 days prior to study drug administration
• Fine needle aspirate within 3 days prior to study drug administration
• Has any serious concomitant illness that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments
• Participants with known human immunodeficiency virus (HIV); due to lack of available safety data for eribulin therapy in HIV-infected participants

• Adults, age 60 years or older at the time of diagnosis
• Subjects or their legal representative must be able to understand and provide written informed consent
• Cohort Inclusion Criteria
•Group A: Subjects must have previously untreated acute myeloid leukemia (AML) according to the WHO classification with no prior treatment other than hydroxyurea. Prior therapy for myelodysplastic syndrome (MDS), myeloproliferative syndromes (MPD), or aplastic anemia is permitted but not with hypomethylating agents.
• Cohort Inclusion Criteria
•Group B: Subjects must have relapsed or refractory AML according to the WHO classification. For study purposes, refractory AML is defined as failure to ever achieve CR or recurrence of AML within 6 months of achieving CR; relapsed AML is defined as all others with disease after prior remission. (Group B is not currently recruiting. Expected to begin recruiting in 3rd quarter 2017.)
• Isolated myeloid sarcoma (meaning, patients must have blood or marrow involvement with AML to enter the study)
• Acute promyelocytic leukemia
• Symptomatic central nervous system (CNS) involvement by AML
• Signs of leukostasis requiring urgent therapy
• Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis
• Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up
• Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the trial or would confound the interpretation of the results of the trial

• Histopathologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction (GEJ) adenocarcinoma that is metastatic or locally advanced and unresectable.
• Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan (or MRI at the discretion of the principal investigator (PI)), as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
• Experienced documented objective radiographic or clinical disease progression during first-line therapy or within 4 months after the last dose of first-line therapy with any platinum/fluoropyrimidine doublet with or without anthracycline (epirubicin or doxorubicin) or taxane (docetaxel) for unresectable or metastatic disease.
• At least 18 years of age.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Normal bone marrow and organ function as defined below:
• Absolute neutrophil count (ANC) ≥ 1,500/µL
• Hemoglobin ≥ 9.0 g/dL (5.58 mmol/L)
• Platelets ≥ 100,000/µL
• Total bilirubin ≤ 1.5 mg/dL (25.65 µmol/L)
• AST(SGOT)/ALT(SGPT) ≤ 3.0 x institutional upper limit of normal (IULN) (or ≤ 5.0 x IULN in the setting of liver metastases)
• Creatinine ≤ 1.5 x IULN OR creatinine clearance ≥ 40 mL/min/1.73 m2 for patients with creatinine levels > 1.5 x IULN (that is, if serum creatinine is > 1.5 x IULN, a 24-hour urine collection to calculate creatinine clearance must be performed)
• Urinary protein ≤ 1+ on dipstick or routine urinalysis (UA); if dipstick or routine UA is ≥ 2+, a 24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 hours
• Adequate coagulation function as defined by INR ≤ 1.5 and PTT ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy.
• All clinically significant toxic effects (except peripheral neuropathy) of prior locoregional therapy, surgery, or other anticancer therapy have resolved to ≤ Common Terminology Criteria for Adverse Events (CTCAE) grade 1.
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Women of childbearing potential must have a negative serum pregnancy test within 7 days of study entry.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
• Squamous cell or undifferentiated gastric cancer.
• Received any chemotherapy (including irinotecan) other than platinum and fluoropyrimidine with or without anthracycline or taxane for advanced gastric or GEJ adenocarcinoma.
• Received previous systemic chemotherapy with a cumulative dose of > 900 mg/m^2 of epirubicin or > 400 mg/m^2 of doxorubicin.
• Received any previously systemic therapy (including investigational agents) targeting VEGF or the VEGFR signaling pathways. Other previous targeted therapies are permitted if stopped at least 28 days prior to start of treatment.
• A history of other malignancy ≤ 3 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix or other solid tumors treated curatively and without evidence of recurrence.
• Currently receiving any other investigational agents.
• History or evidence of known brain metastases or carcinomatous meningitis. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to monoclonal antibody treatment, any components used in the ramucirumab DP preparation, irinotecan, or other agents used in the study.
• Any grade 3-4 GI bleeding within 3 months prior to enrollment.
• History of gastrointestinal perforation and/or fistulae within 6 months prior to enrollment.
• History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port of catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to enrollment.
• History of any arterial thromboembolic event, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina within 6 months prior to enrollment.
• Diagnosis of symptomatic congestive heart failure (NYHA II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
• Uncontrolled or poorly controlled hypertension (> 160 mmHg systolic or > 100 mmHg diastolic for > 4 weeks) despite standard medical management.
• Presence of serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to enrollment.
• Major surgery within 28 days prior to first dose of protocol therapy.
• Minor surgery/subcutaneous venous access device placement within 7 days prior to first dose of protocol therapy.
• Receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.
• The patient has elective or planned major surgery to be performed during the course of the clinical trial.
• Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.
• Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis (i.e. ascites from cirrhosis requiring diuretics or paracentesis).
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, metabolic disorders or other nonmalignant organ or systemic disease or secondary effects of cancer that induce a high medical risk and make assessment of survival uncertain, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant and/or breastfeeding.
• Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with ramucirumab and irinotecan. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

1. Has a histologically confirmed diagnosis of endometrial carcinoma (EC) 2. Documented evidence of advanced, recurrent or metastatic EC. 3. Has radiographic evidence of disease progression after 1 prior systemic, platinum-based chemotherapy regimen for EC. Participants may have received up to 1 additional line of platinum-based chemotherapy if given in the neoadjuvant or adjuvant treatment setting. Note: There is no restriction regarding prior hormonal therapy. 4. Has historical or fresh tumor biopsy specimen for determination of mismatch repair (MMR) status. 5. Has at least 1 measurable target lesion according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and confirmed by Blinded Independent Central Review BICR. 6. Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days of starting study treatment. 7. Is not pregnant, breastfeeding, and agrees to use a highly effective method of contraception during the treatment period and for at least 120 days (for participants treated with lenvatinib plus pembrolizumab) or at least 180 days (for participants treated with treatment of physician's choice [TPC]) after the last dose of study treatment. 1. Has carcinosarcoma (malignant mixed mullerian tumor), endometrial leiomyosarcoma and endometrial stromal sarcomas. 2. Has unstable central nervous system (CNS) metastases. 3. Has active malignancy (except for endometrial cancer, definitively treated in-situ carcinomas [e.g. breast, cervix, bladder], or basal or squamous cell carcinoma of the skin) within 24 months of study start. 4. Has gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib. 5. Has a pre-existing greater than or equal (>=) Grade 3 gastrointestinal or non-gastrointestinal fistula. 6. Has radiographic evidence of major blood vessel invasion/infiltration. 7. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study treatment. 8. Has a history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability within 12 months of the first dose of study treatment. 9. Has an active infection requiring systemic treatment. 10. Has not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy. 11. Is positive for Human Immunodeficiency Virus (HIV). 12. Has active Hepatitis B or C. 13. Has a history of (non-infectious) pneumonitis that required treatment with steroids, or has current pneumonitis. 14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study. 15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to study start -Has an active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years. 16. Is pregnant or breastfeeding. 17. Has had an allogenic tissue/solid organ transplant. 18. Has received >1 prior systemic chemotherapy regimen (other than adjuvant or neoadjuvant) for Endometrial Cancer. Participants may receive up to 2 regimens of platinum-based chemotherapy in total, as long as one is given in the neoadjuvant or adjuvant treatment setting. 19. Has received prior anticancer treatment within 28 days of study start. All acute toxicities related to prior treatments must be resolved to Grade ≤1, except for alopecia and Grade ≤2 peripheral neuropathy. 20. Has received prior treatment with any treatment targeting VEGF-directed angiogenesis, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 21. Has received prior treatment with an agent directed to a stimulatory or co-inhibitory T-cell receptor other than an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, and who has discontinued from that treatment due to a Grade 3 or higher immune-related adverse event. 22. Has received prior radiation therapy within 21 days of study start with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks of study start. Participants must have recovered from all radiation-related toxicities and/or complications prior to randomization. 23. Has received a live vaccine within 30 days of study start. 24. Has a known intolerance to study treatment (or any of the excipients). 25. Prior enrollment on a clinical study evaluating pembrolizumab and lenvatinib for endometrial carcinoma, regardless of treatment received. 26. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks of study start. 27. Participants with urine protein ≥1 gram (g)/24 hour. 28. Prolongation of corrected QT (QTc) interval to >480 milliseconds (ms). 29. Left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram (ECHO).

• Patient must have a histologically confirmed diagnosis hepatocellular carcinoma; known fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC will be excluded
• Locally advanced or metastatic disease
• Patients with locally advanced or metastatic disease must have disease deemed not amenable to surgical and/or locoregional therapies or patients who have progressed following surgical and/or locoregional therapies.
• Measurable disease, as defined as lesions that can accurately be measured in at least one dimension according to RECIST version 1.1 at least 1 cm with contrast enhanced dynamic imaging (magnetic resonance imaging or computed tomography).
• Child-Pugh Score A
• Age ≥ 18 years
• ECOG Performance score of 0-1
• Life expectancy greater than 6 months
• Following baseline laboratory values: 1. Total bilirubin ≤ 2.0 mg/ml 2. INR ≤ 1.7 3. Hgb ≥ 8.5 g/dl 4. AST, ALT ≤5 times ULN 5. Platelet count ≥ 50,000/mm3 6. Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 50 mL/min 7. Albumin ≥ 2.5 g/dl 8. Absolute neutrophil ≥ 1,500 cells/mm3
• Male and female subjects of child bearing potential must agree to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication
• Women of childbearing potential must have a negative pregnancy test within 72 hours prior to receiving the first dose of study medication
• Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, or HCV-HCC defined as follows: HBV-HCC: Controlled (treated) hepatitis B subjects will be allowed if they meet the following criteria: Antiviral therapy for HBV must be given for at least 12 weeks and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. Subjects on active HBV therapy with viral loads under 100 IU/ml should stay on the same therapy throughout study treatment. Subjects who are anti-HBc (+), negative for HBsAg, negative for anti-HBs, and have an HBV viral load under 100 IU/mL do not require HBV anti-viral prophylaxis. HCV-HCC: active or resolved HCV infection as evidenced by detectable HCV RNA or antibody. Patients who have failed HCV therapy as evidenced by detectable HCV RNA will be eligible. Subjects with chronic infection by HCV who are treated (successfully or treatment failure) or untreated are allowed on study. In addition, subjects with successful HCV treatment are allowed as long as there are ≥4 weeks between completion of HCV therapy and start of study drug. Successful HCV treatment definition: SVR12.
•Prior therapy is allowed provided the following are met: at least 4 weeks since prior locoregional therapy including surgical resection, chemoembolization, radiotherapy, or ablation. Provided target lesion has increased in size by 25% or more or the target lesion was not treated with locoregional therapy. Patients treated with palliative radiotherapy for symptoms will be eligible 1 week after treatment as long as the target lesion is not the treated lesion.
• Prior liver transplant;
• Patient who has received previous systemic therapy for HCC;
• Clinically significant, uncontrolled heart disease and/or recent events including any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening;
• History of documented congestive heart failure (New York Heart Association functional classification III-IV);
• Documented cardiomyopathy;
• Patient has a left ventricular ejection fraction <40% as determined by MUGA scan or ECHO (MUGA and ECHO are not required prior to enrollment);
• Known human immunodeficiency virus (HIV) positive (testing not required);
• History of thromboembolic events (including both pulmonary embolism and deep venous thrombus but not including tumor thrombus) within the last 6 months;
• Hypersensitivity to IV contrast; not suitable for pre-medication;
• Active or fungal infections requiring systemic treatment within 7 days prior to screening;
• Known history of, or any evidence of, interstitial lung disease or active non-infectious pneumonitis;
• Evidence of poorly controlled hypertension which is defined as systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg despite optimal medical management;
• Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication;
• Active, known, or suspected autoimmune disease with the following exceptions i) Subjects with vitiligo, type I diabetes mellitus, resolved childhood asthma or atopy are permitted to enroll; ii) Subjects with suspected autoimmune thyroid disorders may be enrolled if they are currently euthyroid or with residual hypothyroidism requiring only hormone replacement. iii) Subjects with psoriasis requiring systemic therapy must be excluded from enrollment
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the study or compromise compliance with the protocol (e.g. chronic pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral infections, etc.);
• Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient participation in the study or compromise compliance with the protocol (e.g. chronic pancreatitis, active untreated or uncontrolled fungal, bacterial, or viral infections, etc.);
• Known history of active bacillus tuberculosis;
• Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days of study administration. Inhaled or topical steroids and adrenal replacement doses >10 mg/day prednisone equivalents are permitted in the absence of autoimmune disease;
• Patient who has received radiotherapy ≤ 4 weeks prior to study entry. Palliative radiotherapy for symptomatic control is acceptable (if completed at least 2 weeks prior to study drug administration and no additional radiotherapy for the same lesion is planned);
• Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects (tumor biopsy is not considered as major surgery);
• Clinically apparent ascites on physical examination, ascites present on imaging studies is allowed;
• Patient has a known hypersensitivity to any of the excipients of bavituximab or pembrolizumab or monoclonal antibody;
• Active gastrointestinal bleeding within previous 2 months;
• History of any condition requiring anti-platelet therapy (aspirin >300 mg/day, clopidogrel >75 mg/day);
• Prisoners or subjects who are involuntarily incarcerated;
• Symptomatic or clinically active brain metastases;
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after contraception and until the termination of gestation, confirmed by a positive hCG laboratory test;
• Prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agents;
• Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.

• Women or men aged =>18 years with histologically documented triple-negative breast cancer (TNBC) or HR+/HER2- adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Adequate hematologic and organ function within 14 days prior to treatment initiation
• Histologically documented TNBC or HR+/HER2- adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to resection with curative intent
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Eligible for taxane monotherapy, as per local investigator assessment (e.g., absence of rapid clinical progression, life-threatening visceral metastases, or the need for rapid symptom and/or disease control which may require combination chemotherapy)
• HR+/HER2- breast cancer that is not considered appropriate for endocrine-based therapy and meets one of the following: patient has recurrent disease <=5 years of being on adjuvant endocrine therapy or if patient with de novo metastatic disease have progressed within 6 months of being on first line endocrine therapy.
• Consent to submit a formalin-fixed, paraffin-embedded tumor (FFPE) tissue block or freshly cut unstained, serial tumor slides from the most recently collected tumor tissue for central molecular analysis
• Confirmation of biomarker eligibility using an appropriately validated molecular assay at a diagnostic laboratory, Clinically Laboratory Improvement Amendments (CLIA) or equivalently accredited i.e., valid results from either central testing or local testing of tumor tissue or blood demonstrating PIK3CA/AKT1/PTEN-altered status
• Treatment with approved or investigational cancer therapy within 14 days prior to treatment initiation
• Any previous chemotherapy for inoperable locally advanced or metastatic TNBC or HR+/HER2- adenocarcinoma of the breast (patients receiving neo/adjuvant chemotherapy eligible provided they have at least a 12 month disease-free interval)
• History of or known presence of brain or spinal cord metastases
• Malignancies other than breast cancer within 5 years prior to treatment initiation (except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer)
• Prior treatment with an Akt inhibitor (prior PI3K or mTOR inhibitors are allowed)
• History of malabsorption syndrome or other condition that would interfere with enteral absorption or results in the inability or unwillingness to swallow pills
• Active infection requiring systemic anti-microbial treatment (including antibiotics, anti-fungals, and anti-viral agents)
• Known human immunodeficiency virus (HIV) infection
• Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis, current drug or alcohol abuse, or cirrhosis
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of treatment (or anticipated need during study)
• Pregnant or breastfeeding, or intending to become pregnant during the study
• Clinically significant cardiac dysfunction (including NYHA Class II/III/IV heart failure, left ventricular ejection fraction [LVEF] <50%, active ventricular arrhythmia requiring medication, history of myocardial infarction within 6 months of treatment initiation, clinically significant electrocardiogram [ECG] abnormalities).
• Need for chronic corticosteroid therapy of >=10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a chronic disease
• Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 peripheral neuropathy
• Uncontrolled clinical symptoms including pleural effusion, pericardial effusion, or ascites, tumor-related pain, hypercalcemia (or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy)
• History of Type I or Type II diabetes mellitus requiring insulin
• Grade >=2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia
• History of or active inflammatory bowel disease or active bowel inflammation
• Clinically significant lung disease (including pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, active infection/ history of opportunistic infections)
• Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of treatment
• Grade >=2 peripheral neuropathy

• Patients must have histologically confirmed, relapsed/refractory ALK+ ALCL (with ALK positivity defined by immunohistochemistry and/or fluorescence in situ hybridization [FISH]/cytogenetics from any prior biopsy), MCL, or BCL6+ DLBCL (with BCL6 positivity defined by immunohistochemistry from any prior biopsy) and meet the following criteria:
• Patients must have measurable disease that has not been previously irradiated, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional imaging or >= 10 mm with spiral computed tomography (CT) scan; if the patient has been previously irradiated, there must be evidence of progression since the radiation
• Please note, this trial includes mandatory tumor biopsies pre-treatment, during cycle 1 and at the time of disease progression of accessible tumor; having accessible tumor for biopsy is not required for eligibility; we expect that at least 80% of patients will have accessible tumor for these biopsies, however
• Prior therapy
• Please note, the washout period for prior therapies cannot be shortened
• Please note, prior therapies can be from any time in the past
• ALK+ ALCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included a multiagent chemotherapy regimen including an anthracycline, if not contraindicated, and prior brentuximab; prior crizotinib or other ALK inhibitor therapy, while recommended, is not mandatory; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
• MCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included a multiagent chemotherapy regimen and prior ibrutinib or other BTK inhibitor therapy; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
• BCL6+ DLBCL: patients must have disease that has relapsed and or is refractory to prior therapy, which must have included an anthracycline, if not contraindicated; patients must have relapsed following or be ineligible for, or refuse, autologous stem cell transplant
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 3 months
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 75,000/mcL, unless due to marrow involvement by lymphoma in which case a platelet count of >= 30,000/mcL will be used
• Total bilirubin =< 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome or hemolysis, in which case =< 3.0 x ULN is allowed
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
• Creatinine =< 1.5 x ULN or a creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Potassium above the institutional lower limit of normal (supplementation to meet this is allowed)
• Magnesium above the institutional lower limit of normal (supplementation to meet this is allowed)
• Human immunodeficiency virus (HIV)+ patients are eligible for the trial provided they meet the other study criteria in addition to the following:
• CD4+ T-cells >= 250/mm^3
• HIV sensitive to antiretroviral therapy
• Zidovudine not allowed
• Long term survival anticipated on the basis of HIV alone were it not for the lymphoma
• No concurrent acquired immunodeficiency syndrome (AIDS)-defining illness other than the lymphoma
• The effects of AT13387 (onalespib) on the developing human fetus are unknown; for this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after the completion of AT13387 (onalespib) administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; 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 4 months after completion of AT13387 (onalespib) administration
• Although the pharmacokinetic (PK) data in humans is still unknown, the potential for drug-interaction cannot be ruled out; pre-clinical studies suggest that AT13387 (onalespib) is a substrate of P-glycoprotein (P-gp), a moderate inhibitor of BCRP and P-gp, and a strong inhibitor of MATE 1/2-K; patients must be willing to not take St. John wort or grapefruit juice while participating in this trial and should avoid drugs that are strong inducers of P-gp, and to switch to alternative drugs when available
• Hepatitis B positive patients are eligible; prophylactic hepatitis B virus (HBV) therapy is recommended but only if there is no circulating virus detectible
• Transformed lymphoma patients are eligible
• Ability to understand and the willingness to sign a written informed consent document
• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; steroids for symptom palliation are allowed, but must be either discontinued or on stable doses at the time of initiation of protocol therapy
• Patients who are receiving any other investigational agents; all investigational agents other than ibrutinib must have been discontinued at least 4 weeks prior to beginning treatment; prior ibrutinib therapy must have been discontinued at least 2 weeks prior to beginning therapy
• Patients with known leptomeningeal or brain metastases should be excluded from this clinical trial; imaging or spinal fluid analysis to exclude central nervous system (CNS) involvement is not required, unless there is clinical suspicion by the treating investigator
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AT13387 (onalespib)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• There will be no exclusion of patients with known visual impairment or symptoms, including by not limited to peripheral flashes (photopsia), blurred or double vision, floaters, color distortion and dimness, difficulties with light/dark accommodation, tunnel vision or other field defects, halos, apparent movement of stationary objects, and complex disturbances; patients will have a baseline ophthalmologic exam to serve as a point of comparison and further exams as needed should visual symptoms develop; no pretreatment eye exam findings or ocular symptoms have been associated with an increased risk of ocular toxicity seen with AT13387
• Pregnant women are excluded from this study because AT13387 (onalespib) has the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AT13387 (onalespib), breastfeeding should be discontinued if the mother is treated with AT13387 (onalespib)
• Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
• Prior history of another malignancy (except for non-melanoma skin cancer or in situ cervical or breast cancer) unless disease free for at least three years; patients with prostate cancer are allowed if prostate specific antigen (PSA) is less than 1
• Patients should not receive immunization with attenuated live vaccine within one week of study entry or during study period
• History of noncompliance to medical regimens
• Consistent corrected QT (QTc) > 450 msec for men and > 470 msec for women by Fridericia formula, on 3 separate electrocardiograms (ECGs)
• Left ventricular ejection fraction (LVEF) < 50%, regardless of whether there are symptoms of heart failure

• Patients must have clinically and radiographically suspected and previously untreated International Federation of Gynecologic and Obstetrics (FIGO) stage III or IV epithelial ovarian, primary peritoneal or fallopian tube cancer, high grade, for whom the plan of management will include neoadjuvant chemotherapy (NACT) with interval tumor reductive surgery (TRS) who have undergone biopsies for histologic confirmation
• Institutional confirmation of Mullerian epithelial adenocarcinoma on core biopsy (not cytology or fine needle aspiration) or laparoscopic biopsy; (for phase II of the study formalin-fixed paraffin-embedded [FFPE] tissue should be available for laboratory analysis); patients with the following histologic epithelial cell types are eligible: high grade serous carcinoma, high grade endometrioid carcinoma, clear cell carcinoma, or a combination of these
• All patients must have measurable disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1; measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI
• Appropriate stage for study entry based on the following diagnostic workup:
• History/physical examination within 28 days prior to registration
• Radiographic imaging of the chest, abdomen and pelvis within 28 days prior to registration documenting disease consistent with FIGO stage III or IV disease
• Further protocol-specific assessments
• Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status of 0, 1, or 2 within 28 days prior to registration
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl; this ANC cannot have been induced by granulocyte colony stimulating factors (within 14 days prior to registration)
• Platelets greater than or equal to 100,000/mcl (within 14 days prior to registration)
• Hemoglobin greater than 9.0 mg/dl (transfusions are permitted to achieve baseline hemoglobin level) (within 14 days prior to registration)
• Estimated creatinine clearance (CrCl) >= 50 mL/min/1.73 m^2 according to the Cockcroft-Gault formula (within 14 days prior to registration)
• Bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN (within 14 days prior to registration)
• Alkaline phosphatase =< 2.5 x ULN (within 14 days prior to registration)
• Neurologic function: neuropathy (sensory and motor) less than or equal to Common Terminology Criteria for Adverse Events (CTCAE) grade 1
• Ability to swallow and retain oral medication
• The patient must provide study-specific informed consent prior to study entry
• Patients with suspected non-gynecologic malignancy, such as gastrointestinal
• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer and other specific malignancies are excluded if there is any evidence of other malignancy being present within the last three years (2 years for breast cancer); patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
• Patients who have received prior chemotherapy for any abdominal or pelvic tumor within the last three years are excluded; patients may have received prior adjuvant chemotherapy and radiotherapy for localized breast cancer, provided that it was completed more than 2 years prior to registration, the patient remains free of recurrent or metastatic disease and hormonal therapy has been discontinued
• Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis or thoracic cavity within the last three years are excluded; prior radiation for localized cancer of the head and neck or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease
• Patients who have received any targeted therapy (including but not limited to vaccines, antibodies, tyrosine kinase inhibitors) or hormonal therapy for management of their epithelial ovarian, fallopian tube or peritoneal primary cancer
• Patients with mucinous carcinoma, low grade endometrioid carcinoma, low grade serous carcinoma or carcinosarcoma
• Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, unless all of the following conditions are met: stage not greater than I-A, grade 1 or 2, no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including serous, clear cell or other FIGO grade 3 lesions
• Severe, active co-morbidity defined as follows:
• Chronic or current active infectious disease requiring systemic antibiotics, antifungal or antiviral treatment
• Known brain or central nervous system metastases or history of uncontrolled seizures
• Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from enrollment, New York Heart Association class III or IV congestive heart failure, and serious arrhythmia requiring medication (this does not include asymptomatic atrial fibrillation with controlled ventricular rate)
• Partial or complete gastrointestinal obstruction
• Patients who are not candidates for major abdominal surgery due to known medical comorbidities
• Patients with any condition that in the judgment of the investigator would jeopardize safety or patient compliance with the protocol
• Patients who are unwilling to be transfused with blood components
• Concurrent anticancer therapy (e.g. chemotherapy, radiation therapy, biologic therapy, immunotherapy, hormonal therapy, investigational therapy)
• Receipt of an investigational study drug for any indication within 30 days or 5 half-lives (whichever is longer) prior to day 1 of protocol therapy
• Patients who, in the opinion of the investigator, are unable or unlikely to comply with the dosing schedule and study evaluations
• Patients who are pregnant or nursing; women of child-bearing potential (WOCBP) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; WOCBP must have a screening negative serum or urine pregnancy test within 14 days of registration; a second pregnancy test must be done within 24 hours prior to the start of the first cycle of study treatment; women must not be breastfeeding
• Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile) do not require contraception
• Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy and/or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 month amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level greater than 40mIU/mL
• Known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection or known history of tuberculosis

• Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) metastatic cancer of the following histologies: melanoma (MEL), Merkel cell carcinoma (MCC), triple-negative breast cancer (TNBC), ovarian carcinoma, renal cell carcinoma (RCC), colorectal cancer, urothelial carcinoma, or sarcoma.
• Life expectancy > 12 weeks as determined by the Investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Measurable disease per RECIST 1.1.
• Patients enrolled in Cohorts 1-5, Cohort A, Cohort B and Phase 2 Doublet must be refractory to all therapies known to confer clinical benefit to their disease.
• Fresh tumor tissue available for cellular characterization and programmed cell death protein 1 (PD-L1) status.
• Injected lesions (up to two) must be between 20 mm and 90 mm in diameter for IT injection; lesions must be accessible for baseline and on-treatment biopsies.
• Demonstrated adequate organ function within 14 days of Cycle 1 Day 1 (C1D1).
• Use of an investigational agent or an investigational device within 21 days before administration of first dose of study drug(s).
• Patients treated with prior interleukin-2 (IL-2).
• Patients who have been previously treated with a toll-like receptor (TLR) agonist (excluding topical agents) and patients who have received experimental cancer vaccines.
• Patients who have received systemic interferon (IFN)α within the previous 6 months prior to enrollment to the study.
• Other active malignancy, except non-melanomic skin cancer
• Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.
• Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients must have recovered from all radiation-related toxicities, not required corticosteroids and have not had radiation pneumonitis.
• Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women at Screening.
• History of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following:
• Unstable angina or myocardial infarction.
• Congestive heart failure (NYHA Class III or IV).
• Uncontrolled clinically significant arrhythmias.
• Need for > 2 antihypertensive medications for management of hypertension (including diuretics).
• Patients with a history of any retinal disorders (e.g., retinal detachment, diabetic retinopathy, retinal hemorrhage, macular degeneration).

• Patients must have histologically confirmed MIBC (T2-T4a, N0-N1, M0 per American Joint Commission on Cancer [AJCC]) pure or mixed histology urothelial carcinoma. Clinical node-positive (N1) patients are eligible provided the lymph nodes (LNs) are confined to the true pelvis and are within the planned surgical LN dissection template.
• The initial TURBT that showed muscularis propria invasion should be within 8 weeks prior to beginning study therapy. Patients must have sufficient baseline tumor tissue from either initial or repeat TURBTs. The local site pathologist will be asked to estimate and record the rough approximate percentage of viable tumor in the TURBT sample (initial or repeat TURBT with highest tumor content) to document at least 20% viable tumor content prior to registration.
• Patients must be ineligible for cisplatin-based chemotherapy due to any of the following:
• Creatinine clearance(CrCl) <60 mL/min with Easter Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1
• Hearing impaired ≥ Grade 2 by CTCAE criteria
• Neuropathy ≥ Grade 2 by CTCAE criteria
• Heart failure New York Heart Association (NYHA) ≥ III
• Patients must be medically fit for TURBT and RC.
• Age ≥ 18 years.
• Ability to understand and willingness to sign Institutional Review Board (IRB)-approved informed consent.
• Willing to provide tumor tissue, blood, and urine samples for research.
• Adequate organ function as measured by the following criteria, obtained ≤ 4 weeks prior to registration:
• Absolute Neutrophil Count (ANC) ≥ 1000/mm³ (stable off growth factor within 4 weeks of first study drug administration)
• Platelets ≥ 100,000/mm³
• Hemoglobin ≥ 8 g/dL
• Serum Creatinine Clearance ≥ 30 mL/min using the Cockcroft-Gault formula
• Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 3x Upper Limit of Normal (ULN)
• Total Bilirubin ≤ 1.5x ULN (in the absence of previously diagnosed Gilbert's disease)
• Women must not be pregnant or breastfeeding since we do not know the effects of nivolumab and lirilumab on the fetus or breastfeeding child.
• Sexually active women of child-bearing potential with a non-sterilized male partner and sexually active men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 5 months for women and 7 months for men following last dose of study drugs.
• Active or prior documented autoimmune disease within the past 2 years prior to Screening or other immunosuppressive agent within 14 days of study treatment.
• Patients may not have locally advanced unresectable or metastatic urothelial carcinoma as assessed on baseline radiographic imaging obtained within 28 days prior to study registration.
• Patients may not have concurrent upper urinary tract (i.e. ureter, renal pelvis) invasive urothelial carcinoma. Patients with history of non-invasive (Ta, Tis) upper tract urothelial carcinoma that has been definitively treated with at least one post-treatment disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence of residual disease are eligible.
• Patients may not have another malignancy that could interfere with the evaluation of safety or efficacy of the study drugs. Patients with a prior malignancy will be allowed without study chair approval in the following circumstances:
• Not currently active and diagnosed at least 3 years prior to the date of registration.
• Non-invasive diseases such as low risk cervical cancer or any cancer in situ.
• Localized (early stage) cancer treated with curative intent (without evidence of recurrence and intent for further therapy), and in which no chemotherapy was indicated.(e.g. low/intermediate risk prostate cancer, etc.).
• Patients may not have received any prior immune checkpoint inhibitor (i.e. anti-KIR, anti-PD-1, anti-PD-L1, or other).
• Patients may not have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury or specific anti-cancer treatment ≤ 4 weeks prior to starting study drug, or patients who have had percutaneous biopsies or placement of vascular access device ≤ 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury.
• Patients must not have clinically significant cardiac disease.
• Patients may not have chronic active liver disease or evidence of acute or chronic Hepatitis B Virus (HBV) or Hepatitis C (HCV).
• Patients may not have known diagnosis of human immunodeficiency virus (HIV) infection. Testing is not required in absence of clinical suspicion.
• Patients may not have known diagnosis of any condition (e.g. post-hematopoietic or solid organ transplant, pneumonitis, inflammatory bowel disease, etc.) that requires chronic immunosuppressive therapy. Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment of gout are permitted.
• Patients with any serious and/or uncontrolled concurrent medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) or psychiatric illness that could, in the investigator's opinion, cause unacceptable safety risks or potentially interfere with the completion of the treatment according to the protocol are not eligible.
• Patients may not have any live viral vaccine used for prevention of infectious diseases within 4 weeks prior to study drug(s).
• Patients unwilling or unable to comply with the protocol.

1. Eligibility waivers are not permitted. Subjects must meet all of the inclusion and exclusion criteria to be registered to the study. Study treatment may not begin until a subject is registered. 2. Patients must provide informed written consent 3. ECOG performance status 0-1. 4. Clinical stage operable I, II or III invasive mammary carcinoma, which is ER-positive by IHC and HER2-negative by Herceptest (0 or 1+) or not amplified by FISH as per routine clinical testing Patients who have measurable residual tumor at the primary site Patients who will undergo surgical treatment with either segmental resection or total mastectomy 5. Measurable tumor i. Measurable disease: a mass that can be reproducibly measured by physical exam and calipers or ultrasound and is at least 1 cm in size 6. The pathology report from the initial diagnosis has been reviewed by either UTSW or Parkland Hospital, Department of Pathology and meets eligibility criteria. Available core biopsies from the time of diagnosis have been requested. These may include the paraffin block or sections from the paraffin-embedded tumor blocks. 7. Post-menopausal female subjects ≥18 years of age, as defined by any of the following:
• Subjects at least 55 years of age;
• Subjects under 55 years of age and amenorrhoeic for at least 12 months or follicle-stimulating hormone (FSH) values ≥40 IU/L and estradiol levels ≤20 IU/L;
• Prior bilateral oophorectomy or prior radiation castration with amenorrhea for at least 6 months.
• (There is no upper age limit for enrollment to this study) 8. No prior chemotherapy for this primary breast cancer. 9. Patients with a prior history of contralateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer. 10. 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. 11. Subjects must have ended hormone replacement therapy (HRT) (e.g., conjugated estrogens tablets, USP, [Premarin]), at least 7 days prior to receiving the first dose of randomized therapy. 12. Patients must have adequate hepatic and renal function. All tests must be obtained less than 4 weeks from study entry. This includes: 1. Creatinine <1.5X upper limits of normal 2. Bilirubin, SGOT, SGPT <1.5X upper limits of normal 13. Able to swallow and retain oral medication 1. Patients with locally advanced disease who are candidates for other preoperative chemotherapy at the time of initial evaluation. This may include patients with locally advanced disease such as:
• Inflammatory breast cancer (T4d)
• Fixed axillary lymph node metastases (N2)
• Metastasis to ipsilateral internal mammary node (N3) 2. Locally recurrent breast cancer 3. Evidence of distant metastatic disease (i.e. lung, liver, bone, brain, etc.) 4. Serious medical illness that in the judgment of the treating physician places the patient at high risk of operative mortality. 5. Severe uncontrolled malabsorption condition or disease (i.e. grade II/III diarrhea, severe malnutrition, short gut syndrome) 6. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. 7. Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of letrozole.

• Histologically confirmed cancers for which no curative therapy exists.
• Documented HER2 mutation.
• Pediatric patients (at least 12 but less than 18 years of age at signing of informed consent) may be recruited in the Fibrolamellar Carcinoma cohort.
• Prior treatment with any pan-HER tyrosine kinase inhibitor (eg, lapatinib, afatinib, dacomitinib, neratinib).
• Patients who are receiving any other anticancer agents.
• Symptomatic or unstable brain metastases.
• Women who are pregnant or breast-feeding. Note: There are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.

For more information regarding Bristol Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com
• Participants with a first diagnosis of HCC who have undergone a curative resection or ablation
• Participants are eligible to enroll if they have non-viral related-HCC, or if they have HBV-HCC, or HCV-HCC
• Child-Pugh Score 5 or 6
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• Any evidence of tumor metastasis or co-existing malignant disease
• Participants previously receiving any prior therapy for HCC, including loco-regional therapies
• Participants who have undergone a liver transplant or those who are in the waiting list for liver transplantation Other protocol defined inclusion/exclusion criteria could apply

Key For Phase 1
• Patients with a locally advanced or metastatic solid tumor who:
• have progressed on or are intolerant to standard therapy, or
• no standard therapy exists, or in the opinion of the Investigator, are not candidates for or would be unlikely to tolerate or derive significant clinical benefit from standard therapy, or
• decline standard therapy
• Prior MKIs with anti-RET activity are allowed. However, prior treatment with a selective RET inhibitor(s) is prohibited.
• A RET gene alteration is not required initially. Once adequate PK exposure is achieved, evidence of RET gene alteration in tumor and/or blood is required as identified through molecular assays, as performed for clinical evaluation.
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type.
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance Score (LPS) ≥ 40% (age < 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment.
• Adequate hematologic, hepatic and renal function.
• Life expectancy of at least 3 months. For Phase 2 As for phase 1 with the following modifications:
• For Cohorts 1 and 3 Subjects must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy.
• Cohorts 1-4: enrollment will be restricted to patients with evidence of a RET gene alteration in tumor. However, a positive germline DNA test for a RET gene mutation is acceptable in the absence of tumor tissue testing for patients with MTC.
• Cohorts 1-4: at least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type and not previously irradiated.
• Cohort 4: radiographic PD within the previous 14 months. Note: Patients otherwise eligible for cohort 4 who do not demonstrate radiographic PD within the previous 14 months may be enrolled to cohort 5 if a compelling rationale is provided by the investigator and approved by the Sponsor. Cohort 5: (up to 150 patients):
• Cohorts 1-4 without measurable disease;
• MTC not meeting the requirements for Cohorts 3 or 4; (a known RET mutation is not required)
• MTC syndrome spectrum cancers (e.g. MTC, pheochromocytoma) or poorly differentiated thyroid cancers with other RET alteration/activation may be allowed with prior Sponsor approval;
• cfDNA positive for a RET gene alteration not known to be present in a tumor sample. Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1-4: an additional known oncogenic driver.
• Prior treatment with a selective RET inhibitor
• Investigational agent or anticancer therapy within 5 half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292. In addition, no concurrent investigational anti-cancer therapy is permitted. LOXO-292 may be started within less than 5 half-lives or 2 weeks of prior therapy if considered by the Investigator to be safe and within the best interest of the patient, with prior Sponsor approval.
• Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LOXO-292.
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation, which must be completed at least 4 weeks prior to the first dose of study treatment.
• Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Patients are eligible if neurological symptoms and CNS imaging are stable and steroid dose is stable for 14 days prior to the first dose of LOXO-292 and no CNS surgery or radiation has been performed for 28 days, 14 days if stereotactic radiosurgery [SRS].
• Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to planned start of LOXO-292 or prolongation of the QT interval corrected (QTcF) > 470 msec on all 3 ECGs during Screening.
• Required treatment with certain strong CYP3A4 inhibitors or inducers.

1. Age ≥ 18 2. Written and signed informed consent must be obtained 3. ECOG Performance Status 0 or 1 4. Weight ≥ 35 kg 5. Subjects must have histologically or cytologically, confirmed pancreatic adenocarcinoma: Cohort A: Subjects with previously untreated metastatic pancreatic adenocarcinoma (1st line metastatic disease) not previously treated with systemic therapies. Cohort B: Subjects with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-based chemotherapy (without exposure to 5-FU, capecitabine, oxaliplatin) 2nd line metastatic disease 6. Subjects must have at least 1 measurable lesion according to RECIST v1.1 7. All subjects must consent to providing archival tumor specimens 1. Receipt of any conventional or investigational anticancer therapy within 21 days or palliative radiotherapy within 14 days prior to the scheduled first dose of study treatment. 2. Prior receipt of any immune-related therapy 3. Concurrent enrollment in another therapeutic clinical study. Enrollment in observational studies will be allowed 4. Subjects with a history of venous thrombosis within the past 3 months 5. Subjects with prior history of myocardial infarction, transient ischemic attack, or stroke in the last 3 months prior to start of treatment 6. Active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment 7. Other invasive malignancy within 2 years. 8. Any history of leptomeningeal disease or cord compression. 9. Current or prior use of immunosuppressive medication within 14 days prior to the first dose