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

• 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 since fetal toxicities or teratogenic effects have been noted for several of the study drugs; 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.
• Archival tissue of a metastatic lesion obtained within 1 year prior to study registration (within 4 weeks preferred) and tumor tissue from nephrectomy is required if available. In addition to archival tissue of a metastatic lesion and nephrectomy, patients must have at least one site of disease (not including bone metastases) accessible for biopsy. If biopsy/resection of a new lesion or primary tumor and slow freezing of fresh tissue for single cell RNAseq study (as specified in the CLM) is not feasible, the subject is not eligible for the study. All biopsies must be core needle or excisional. Fine needle aspirate is not acceptable. NOTE: The tissue collected from a surgical resection or multiple core biopsies of either a metastatic lesion or primary tumor for the slow freezing of fresh tissue after the patient has signed consent for the study could also be used for collecting the FFPE specimens.
• ECOG performance status 0-2.
• Age ≥ 18 years.
• 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
• 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 5 months after the last dose of study drug. NOTE: Contraception is not required for male participants.
• 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. NOTE: "Women of childbearing potential" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of 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 less than 40 mIU/ml.
• Women must not be breastfeeding.
• 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
• Tumor biopsy prior to combination treatment is mandatory. If a biopsy/resection of a new lesion or primary tumor and slow freezing of fresh tissue for single cell RNAseq study (as specified in the CLM) is not feasible, the subject is not eligible for the study. All biopsies must be core needle or excisional. Fine needle aspirate is not acceptable.
• 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

• 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

• 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.

1. Subjects with a diagnosis of iobenguane avid, high-risk neuroblastoma based on Revised INRC criteria at the time of study enrollment with recurrent or progressive disease at any time prior to enrollment, regardless of overall response to frontline therapy, where frontline therapy includes a minimum of 4 cycles of induction therapy at any time prior to enrollment. 2. May have had prior 131I-MIBG therapy, provided: 1. It has been at least 6 months from the date of last 131I-MIBG ; 2. Response was other than progressive disease on first restaging after 131I-MIBG ; 3. Prior 131I-MIBG was given as monotherapy and not in combination with systemic anticancer agents; 4. Cumulative lifetime dose of 131I-MIBG at enrollment does not exceed 18 mCi/kg. 3. All soft tissue lesions identified on CT/MRI scans must be iobenguane avid lesions on an (123I)-iobenguane scan, or 1. any progressive non-iobenguane avid lesion is proven by biopsy to be a non-neuroblastoma lesion. 2. any other non-avid lesion is comprised of a fibrotic or scarred mass as shown by routine imaging and confirmed by the investigator. 4. Adequate cryopreserved autologous peripheral blood stem cells or bone marrow (at least 2 aliquots of 2.0 × 10exp6 CD34/kg at the time of study enrollment). 5. If a male, must agree to use an adequate contraception method as deemed appropriate by the Investigator (e.g., vasectomy, condoms) or partner using effective contraception and to not donate sperm during the study and for 90 days after receiving the last dose of study drug. 6. If a female of childbearing potential, have a negative serum pregnancy test result prior to each dosing and, if sexually active, be practicing an effective method of birth control [e.g., intrauterine device, double-barrier method (i.e., diaphragm, or a cervical cap) with intravaginal spermicidal foam, cream or gel], or male partner sterilization throughout the study. 7. Age at study entry ≥1 year. 8. Previous platelet transfusions are permitted, as long as the subject has a platelet count ≥50,000/μL without transfusion support for at least 1 week. 9. Subjects must have a minimum pulse oximetry measurement of at least 94% at baseline. 10. An absolute neutrophil count ≥750/μL without growth factor for 5 days. 11. Liver function parameter results: total bilirubin ≤2 × upper limit of normal for age, and Serum alanine aminotransferase (glutamic-pyruvic transaminase) and serum aspartate aminotransferase (glutamic-oxaloacetic transaminase) ≤ 10 times the upper limit of normal (for all sites, the upper limit of normal for alanine aminotransferase is defined as 45 U/L). 12. Normal thyroid function as measured by T4 or TSH or have abnormal results that are not considered clinically important by the Investigator or may be receiving levothyroxine. 13. Cardiac Function: shortening fraction of ≥ 27% by echocardiogram or ejection fraction ≥ 50% documented by echocardiogram or radionuclide angiogram within 1 month prior to Visit 1 (Baseline). 14. Karnofsky Performance Status (for subjects >16 years of age) or the Lansky Performance Status Performance Status (for subjects 1 to 16 years of age) ≥50%. 15. Full recovery from the toxic effects of any prior therapy. 16. Coagulation Function: 1. International Normalized Ratio (INR) < 1.5 2. Partial thromboplastin time (PTT) < 1.5 times upper limit of normal. 1. Subjects within 5 half-lives after any antibody-based immunotherapy, or have not recovered from effects of any biologic therapy. 2. Subjects <12 weeks after myeloablative therapy with autologous stem cell transplant. 3. Subjects who have had an allogeneic stem cell treatment less than 4 months from Visit 1 are excluded. Those who have received allogeneic stem cell treatment more than 4 months from Visit 1 must have recovered and have no active graft versus host disease (GVHD) to be eligible. 4. Subjects must not have received radiation for a minimum of 2 weeks prior to study enrollment. Subjects whose only site(s) of disease have been radiated are eligible as long as the subject has MIBG avidity 2 weeks after completion of radiation. A minimum of 12 weeks prior to study enrollment is required following prior large field radiation therapy (ie, craniospinal, whole abdominal, total lung, > 50% marrow space) 5. History of total body irradiation. 6. Subjects do not have adequate renal function defined as GFR ≥ 70 mL/min/1.73 m2 either by creatinine clearance or radioisotope direct measurement or by calculation with the Schwartz formula 7. Subjects who are on hemodialysis. 8. Pregnancy or breastfeeding. 9. Significant active infections including active hepatitis B, or hepatitis C infection, or known infection with human immunodeficiency virus (HIV) (testing for HIV is not required prior to study entry). 10. Clinically important cardiac, pulmonary, and hepatic impairment. 11. Vorinostat treatment exclusion criteria (subjects, who meet any one of these criteria and otherwise meet eligibility criteria, are still eligible for 131I-MIBG monotherapy) 1. Since valproic acid has HDAC inhibitory activity, patients must not have received valproic acid within 30 days of study entry. 2. Since vorinostat may prolong the QT interval, patients must not be receiving other medications known to prolong the QT interval at the time of study entry . Pentamidine must not have been received within 1 week of study enrollment. 3. Patients with a history of deep venous thrombosis that was not associated with the presence of a central venous catheter. 4. Patients who are receiving Coumadin.

Key
• 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), renal cell carcinoma (RCC), colorectal cancer, head and neck squamous cell carcinoma (HNSCC), 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 1-10, 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. Any liver lesion targeted for injection must not exceed 50 mm at the time of injection.
• Demonstrated adequate organ function within 14 days of Cycle 1 Day 1 (C1D1). Key
• 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.
• Patients with a history of any retinal disorders (e.g., retinal detachment, diabetic retinopathy, retinal hemorrhage, macular degeneration).
• Uveal melanoma will be excluded
• Patients with tumor that invade the superior vena cava or other major blood vessels. Additional general and tumor specific inclusion and exclusion criteria will apply.

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 0-2. 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. 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 ≤40 pg/mL (140 pmol/L) or in postmenopausal ranges per local or institutional reference ranges;
• 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) 7. No prior chemotherapy for this primary breast cancer. 8. Patients with a prior history of contralateral breast cancer are eligible if they have no evidence of recurrence of their initial primary breast cancer. 9. 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. 10. 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. 11. Patients must have adequate hepatic and renal function. All tests must be obtained less than 4 weeks from study entry. This includes: 1. Creatinine <2X upper limits of normal 2. Bilirubin, SGOT, SGPT <1.5X upper limits of normal 12. 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 adenocarcinoma of the prostate.
• Metastatic prostate cancer documented by positive bone scan and/or measurable soft tissue metastatic lesions by CT or magnetic resonance imaging (MRI).
• Progressive disease at study entry demonstrated during continuous androgen-deprivation therapy (ADT)/post orchiectomy defined as one or more of the following:
• PSA progression
• Radiographic progression per Response Evaluation Criteria in Solid Tumors (RECIST)1.1 for soft tissue and/or per Prostate Cancer Working Group 3 (PCWG3) for bone, with or without PSA progression
• Be able and willing to undergo mandatory tumor biopsy of at least one metastatic site.
• Have adequate organ function.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• Prior therapy with cytochrome P450 (CYP)17 inhibitors.
• Prior treatment with abemaciclib or any cyclin-dependent kinase (CDK) 4 & 6 inhibitors.
• Prior cytotoxic chemotherapy for metastatic castration resistant prostate cancer (participants treated with docetaxel in the metastatic hormone-sensitive prostate cancer [mHSPC] are eligible), prior radiopharmaceuticals for prostate cancer, or prior enzalutamide, apalutamide, darolutamide or sipuleucel-T. Participants who had prior radiation or surgery to all target lesions.
• Currently enrolled in a clinical study involving an investigational product.
• Gastrointestinal disorder affecting the absorption or ability to swallow large pills.
• Clinically significant heart disease, active or chronic liver disease, moderate/severe hepatic impairment (Child-Pugh Class B and C).

• Provide written informed consent
• Histologically confirmed cancers for which no curative therapy exists
• Documented HER2 or EGFR exon 18 mutation
• Participants must agree and commit to use appropriate methods of contraception as outlined in the protocol
• At least one measurable lesion, defined by RECIST v1.1
• Participants harboring ineligible somatic HER2 mutations
• Prior treatment with any HER2-directed tyrosine kinase inhibitor (e.g., lapatinib, afatinib, dacomitinib, neratinib) is excluded with the following exception: patients with EGFR exon 18 mutated NSCLC who may have received afatinib, osimertinib, or other pan HER or EGFR TKIs remain eligible
• Participants who are receiving any other anticancer agents
• Symptomatic or unstable brain metastases
• Women who are pregnant or breast-feeding There are additional inclusion and exclusion criteria. The study center will determine if criteria for participation are met.

Key For Phase 1:
• Participants with a locally advanced or metastatic solid tumor that:
• Has progressed on or is intolerant to standard therapy, or
• For which 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 multikinase inhibitors (MKIs) with anti-RET activity are allowed
• 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) greater than or equal to (≥) 40 percent (%) (age less than [<] 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 Cohort 1: Participants 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 and 2:
• Enrollment will be restricted to participants with evidence of a RET gene alteration in tumor
• At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate to tumor type and not previously irradiated
• Cohorts 3 and 4: Enrollment closed
• Cohort 5:
• Without measurable disease but otherwise meet criteria for Cohorts 1 and 2;
• MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with neuroendocrine features/differentiation, 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
• Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who discontinued another RET inhibitor due to intolerance may be eligible with prior Sponsor approval
• Cohort 7: Participants must have a histologically confirmed stage IB-IIIA NSCLC by AJCC (The American Joint Committee on Cancer) version 8. The tumor must have been deemed resectable by a thoracic surgeon, the participant must be determined to be medically operable based on the determination of a thoracic surgeon, and the participant must not have received prior systemic therapy, including prior radiation therapy, for NSCLC. Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
• Cohorts 3 and 4: Enrollment closed
• Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
• Investigational agent or anticancer therapy (including chemotherapy, biologic therapy, immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5 half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292 (selpercatinib). In addition, no concurrent investigational anti-cancer therapy is permitted Note: Potential exception for this exclusion criterion will require a valid scientific justification and approval from the Sponsor
• Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LOXO-292 (selpercatinib)
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292 (selpercatinib), with the exception of participants 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 Common Terminology Criteria for Adverse Events (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. Participants 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 (selpercatinib) 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 (selpercatinib) or prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds (msec)
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications

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

• Patients must have a histopathologically confirmed diagnosis of an aggressive B-cell non-Hodgkin lymphoma that is recurrent or refractory to standard therapy
• For the purpose of this study, aggressive B-cell NHL will be deemed any lymphoma belonging to one of the following groups according to the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms
• For the purposes of stratification, diagnoses are grouped into 2 categories:
• Category A
• Burkitt lymphoma
• Burkitt-like lymphoma with 11q aberration
• High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
• High-grade B-cell lymphoma, not otherwise specified (NOS)
• Category B
• Diffuse large B-cell lymphoma (DLBCL), NOS
• Diffuse large B-cell lymphoma (DLBCL), NOS; germinal center B-cell type
• Diffuse large B-cell lymphoma (DLBCL), NOS; activated B-cell type
• Large B-cell lymphoma with IRF4 rearrangement
• T-cell/histiocyte-rich large B-cell lymphoma
• Primary DLBCL of the central nervous system (CNS)
• Primary cutaneous DLBCL, leg type
• Epstein-Barr virus (EBV)+ DLBCL, NOS
• EBV+ mucocutaneous ulcer
• DLBCL associated with chronic inflammation
• Lymphomatoid granulomatosis
• Primary mediastinal (thymic) large B-cell lymphoma
• Intravascular large B-cell lymphoma
• ALK+ large B-cell lymphoma
• Plasmablastic lymphoma
• Primary effusion lymphoma
• Human herpesvirus (HHV)-8+ DLBCL, NOS
• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma
• Patients must have measurable disease, defined as at least one lesion that is > 15 mm (1.5 cm) in the longest axis on cross-sectional imaging and measurable in two perpendicular dimensions per computed tomography (spiral computed tomography [CT]), positron emission tomography (PET)-CT or magnetic resonance imaging (MRI)
• Patients must have disease that has relapsed after or is refractory to at least 2 lines of standard therapy; the remaining standard treatment options are unlikely to be effective in the opinion of the treating physician, or patient is felt to be ineligible for such therapies or the patient refuses such therapies; patients who have undergone autologous stem cell transplant are eligible as long as they meet all other criteria
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy of greater than 12 weeks
• White blood cell (WBC) >= 2000/mm^3 (within 14 days of registration)
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of registration)
• Platelet count >= 100,000/mm^3 (within 14 days of registration)
• Hemoglobin > 9.0 g/dL (within 14 days of registration)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (within 14 days of registration)
• Aspartate transaminase (aspartate aminotransferase [AST]) =< 2.5 x ULN (within 14 days of registration)
• Calculated creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula) (within 14 days of registration)
• Females of child bearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG])
• Ability to understand and the willingness to sign a written informed consent document
• Patient has received chemotherapy, targeted agent, or radiotherapy within 4 weeks or at least 5 half-lives, whichever is longer, prior to registration
• Palliative (limited-field) radiation therapy is permitted, if all of the following criteria are met:
• Repeat imaging demonstrates no new sites of bone metastases
• The lesion being considered for palliative radiation is not a target lesion
• Patient has received immunotherapy (including monoclonal antibodies) within 4 weeks prior to registration
• Patients who have not recovered to grade 1 or less from any adverse events due to agents administered more than 4 weeks earlier (excluding alopecia)
• Patients who are receiving any other investigational agents
• Patients should be excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• Patients who have received autologous stem cell transplant (ASCT) =< 12 weeks prior to the first dose of study drug
• Patients with a prior history of allogeneic stem cell or solid organ transplantation
• Patients with evidence of active disease in the central nervous system (CNS) defined as either the presence of active lesions on MRI obtained within 4 weeks of registration or progressive neurological decline
• Patients with primary CNS lymphoma who develop systemic recurrence following standard therapy may be included as long as no active CNS disease is present at the time or enrollment; similarly, patients with secondary involvement of the CNS from a systemic lymphoma may be included as long as the CNS disease has been optimally treated and they demonstrate no evidence of active CNS disease
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CDX-1127 (varlilumab) and/or nivolumab
• History of severe hypersensitivity reaction to any monoclonal antibody
• 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
• Pregnant women are excluded from this study because CDX-1127 (varlilumab) and nivolumab are agents with 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 CDX-1127 (varlilumab) or nivolumab, breastfeeding should be discontinued if the mother is treated with CDX-1127 (varlilumab) or nivolumab
• Patients with human immunodeficiency virus (HIV) are eligible for the study provided they meet the other protocol criteria in addition to the following:
• Undetectable HIV load by standard polymerase chain reaction (PCR) clinical assay within 60 days prior to registration
• Absolute CD4 count of >= 200 mm^3 within 60 days prior to registration
• Willing to maintain adherence to combination antiretroviral therapy
• No history of acquired immunodeficiency syndrome (AIDS) defining condition (other than lymphoma or CD4 cell count < 200 mm^3)
• Likely to have near normal lifespan if not for the presence of relapsed/refractory lymphoma
• Patients with evidence of hepatitis B virus (HBV) are eligible provided there is minimal hepatic injury and the patient has undetectable HBV on suppressive HBV therapy; patient must be willing to maintain adherence to HBV therapy
• Patients with previously treated and eradicated hepatitis C virus (HCV) who have minimal hepatic injury are eligible
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• Patients 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 (precipitating event)
• 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; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if =< 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
• Patients with other active malignancy =< 3 years prior to registration for which active treatment is required must be excluded; patients with composite lymphomas that have a non-B-cell component must be excluded EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

• A female subject is eligible to participate if she is not pregnant (negative serum pregnancy test at screening; female subjects with elevated serum beta human chorionic gonadotropin (βhCG) and a demonstrated non-pregnant status through additional testing are eligible) and at least 1 of the following conditions applies:
• Not a woman of childbearing potential (WOCBP)
• WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for 6 months after the final study treatment administration
• Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study treatment administration.
• Female subject must not donate ova starting at screening and throughout the study period, and for 6 months after the final study treatment administration.
• A male subject with female partner(s) of childbearing potential:
• must agree to use contraception during the treatment period and for 6 months after the final study treatment administration.
• A male subject must not donate sperm during the treatment period and for 6 months after the final study treatment administration.
• Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study treatment administration.
• Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.
• Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 28 days prior to randomization.
• Subject has radiologically evaluable disease (measurable and/or non-measurable disease according to RECIST 1.1), per local assessment, ≤ 28 days prior to randomization. For subjects with only 1 evaluable lesion and prior radiotherapy ≤ 3 months before randomization, the lesion must either be outside the field of prior radiotherapy or have documented progression following radiation therapy.
• Subject's tumor expresses CLDN18.2 in ≥ 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.
• Subject has a HER2-negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen.
• Subject has ECOG performance status 0 or 1.
• Subject has predicted life expectancy ≥ 12 weeks.
• Subject must meet all of the following criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to randomization. In case of multiple central laboratory data within this period, the most recent data should be used to determine eligibility.
• Hemoglobin (Hb) ≥ 9 g/dl. Subjects requiring transfusions are eligible if they have a post-transfusion Hgb ≥ 9 g/dL.
• Absolute Neutrophil Count (ANC) ≥ 1.5x10^9/L
• Platelets ≥ 100x10^9/L
• Albumin ≥ 2.5 g/dL
• Total Bilirubin ≤ 1.5 x upper limit of normal (ULN) without liver metastases (or < 3.0 x ULN if liver metastases are present)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN without liver metastases (or ≤ 5 x ULN if liver metastases are present)
• Estimated creatinine clearance ≥ 30 mL/min
• Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
• Subject has received prior systemic chemotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. However, subject may have received either neo-adjuvant or adjuvant chemotherapy as long as it was completed at least 6 months prior to randomization.
• Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma ≤ 14 days prior to randomization and has not recovered from any related toxicity.
• Subject has received treatment with herbal medications or other treatments that have known antitumor activity within 28 days prior to randomization.
• Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subjects using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of systemic corticosteroids or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.
• Subject has received other investigational agents or devices within 28 days prior to randomization.
• Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies.
• Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.
• Subject has prior severe allergic reaction or intolerance to any component of CAPOX.
• Subject has known dihydropyrimidine dehydrogenase (DPD) deficiency.
• Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting.
• Subject has significant gastric bleeding and/or untreated gastric ulcers that exclude the subject from participation.
• Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive hepatitis B surface antigen (HBs Ag)) or C infection. NOTE: Screening for these infections should be conducted per local requirements.
• For subjects who are negative for HBs Ag, but hepatitis B core antibody (HBc Ab) positive, an HB deoxyribonucleic acid (DNA) test will be performed and if positive, the subject will be excluded.
• Subjects with positive hepatitis C virus (HCV) serology, but negative HCV ribonucleic acid (RNA) test are eligible.
• Subjects treated for HCV with undetectable viral load results are eligible.
• Subject has an active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization.
• Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization.
• Subject has significant cardiovascular disease, including any of the following:
• Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident (CVA) or hypertensive crisis within 6 months prior to randomization.
• History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes
• QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female subjects
• History or family history of congenital long QT syndrome
• Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate controlled atrial fibrillation for > 1 month prior to randomization are eligible).
• Subject has a history of central nervous system (CNS) metastases and/or carcinomatous meningitis from gastric/GEJ cancer..
• Subject has known peripheral sensory neuropathy > grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality.
• Subject has had a major surgical procedure ≤ 28 days prior to randomization.
• Subject is without complete recovery from a major surgical procedure ≤ 14 days prior to randomization.
• Subject has psychiatric illness or social situations that would preclude study compliance.
• Subject has another malignancy for which treatment is required.
• Subject has any concurrent disease, infection, or co-morbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data.

• Stratum I
• Patients must be less than 18 years of age at the time of diagnosis.
• Patients must have histological verification of the diagnosis of Langerhans cell histiocytosis according to the criteria described in Section 6.1
• Signed informed consent form
• Stratum II
• Patients of Stratum I who have:
• Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
• AD intermediate or worse in non-risk organs or AD better in risk organs after 12 weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuation treatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum I treatment
• Stratum III
• Patients from Stratum I who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as
• Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
• PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have to be fulfilled) AND/OR
• Liver dysfunction (or digestive involvement with protein loss)
• Total protein <55 g/L or substitution dependency
• Albumin <25 g/L or substitution dependency (at least one of the two criteria to be fulfilled)
• Stratum IV
• Patients from Stratum I or Stratum III who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I OR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological dysfunction, liver dysfunction, or both of them) as defined in Table XI (see Section 10.3.1).
• Informed consent: All patients or their legal guardians (if the patient is <18 years of age) must sign an Ethics or institutional Review Board approved consent form indicating their awareness of the investigational nature and the risks of this study. When appropriate, younger patients will be included in all discussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiac and pulmonary function to undergo reduced intensity HCT based upon local institutional guidelines, or at a minimum meet requirements noted in eligibility checklist Appendix A-VIII_1. However, significant hepatic and pulmonary dysfunction, if secondary to underlying LCH disease activity, will not exclude patients from protocol enrollment and should be discussed with the National PI Coordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent with ND-CNSLCH irrespective of previous treatments (also those not registered to other Strata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion in the hypothalamus-pituitary axis). In patients with already established diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion is needed for inclusion into the study
• Stratum VI -- Patients with newly diagnosed SS-LCH and localization other than "multifocal bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as consent for longterm follow-up has not been withheld.
• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested before chemotherapy)
• LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis, lung fibrosis, etc.) in the absence of active disease
• Prior systemic therapy
• Stratum II
• Patients with progressive disease in risk organs
• Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without evidence of active LCH in the same organ or in any other locations
• No written consent of the patient or his/her parents or legal guardian
• Stratum III
• The presence of any of the following criteria will exclude the patient from the study:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as the only evidence of risk organ involvement.
• Inadequate renal function as defined by serum creatinine > 3x normal for age
• Stratum IV
• Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
• Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
• Uncontrolled active life-threatening infection.
• Decreased renal function with a GFR of less than 50ml/1.73m2/min.
• Pregnancy or active breast feeding
• Failure to provide signed informed consent
• Stratum VI
• Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible for Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible for Stratum I, Group 2)

1.1 Pathologically (histologically or cytologically) proven diagnosis of NSCLC with, medically inoperable (or patients who refuse resection) stage IIIA or stage IIIB disease (AJCC 8th edition); 1.1.1 Inoperable Stage IIIA disease is defined by multiple and/or bulky N2 mediastinal lymph nodes on computed tomography (CT) scan such that, in the opinion of the treating investigator, the patient was not a candidate for surgical resection. 1.1.2 N2 disease must have been documented by biopsy, or at a minimum by fluorodeoxyglucose positron emission tomography (PET) or CT if nodes were more than 2 cm in short axis diameter. 1.1.3 T4 disease is often considered resectable at the discretion of a thoracic surgeon. Patients with T4N0 or T4N1 disease can be enrolled if their case is reviewed by a thoracic surgeon and felt to be unresectable or if they are either medically inoperable or refuse surgery. 1.1.4 Stage IIIB patients have N3 or T4N2 status. N3 status must have been documented by the presence of a contralateral (to the primary tumor) mediastinal lymph node or supraclavicular or scalene lymph node proven by biopsy, or at a minimum by fluorodeoxyglucose uptake on PET or more than 2 cm in short axis diameter on CT scan. Patients with disease extending into the cervical region (defined as disease extending above cricoid cartilage) are not eligible. 1.2 Appropriate stage for study entry based on the following diagnostic workup: 1.2.1 History/physical examination, including documentation of height, weight and vital signs, within 30 days prior to registration; 1.2.2 CT scan with IV contrast (CT scan without contrast acceptable if IV contrast is medically contraindicated) of the lung and upper abdomen through the adrenal glands within 60 days prior to registration (recommended within 30 days prior to registration); 1.2.3 MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated) within 60 days prior to registration; note: the use of intravenous contrast is required for the MRI or CT (unless medically contra-indicated). 1.2.4 Whole-body FDG-PET/CT within 60 days prior to registration; 1.3 Age ≥ 18 years; 1.4 Life expectancy ≥ 12 weeks 1.5 Zubrod Performance Status of 0-1 within 30 days prior to registration; 1.6 Adequate respiratory function within 180 days prior to registration defined as follows: FEV1 > 1.2 liters; DLCO ≥ 50% predicted; 1.7 Patients with post-obstructive pneumonia are eligible provided they no longer require intravenous antibiotics at registration; 1.8 Patients with a pleural effusion that is transudative, cytologically negative and non-bloody, are eligible if the radiation oncologist feels the tumor can be encompassed within a reasonable field of radiotherapy; if pleural fluid is too small a volume to effectively sample by thoracentesis and does not show increased metabolic activity on CT/PET imaging, the patient will be remain eligible. 1.9 Allowable type and amount of prior therapy 1.10 Adequate organ and marrow function as defined below 1.10.1 Absolute neutrophil count >1.5 × 109/L 1.10.2 Platelet count >100 × 109/L 1.10.3 Baseline or post-transfusion Hemoglobin ≥9.0 g/dL 1.10.4 Serum bilirubin≤ 1.5x upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed in consultation with their physician. 1.10.5 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5x ULN. 1.10.6 Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min as determined by Cockcroft-Gault (using actual body weight); Males: Creatinine CL = Weight (kg) × (140
•Age) (mL/min) 72 × serum creatinine (mg/dL) Females: Creatinine CL = Weight (kg) × (140
•Age) × 0.85 (mL/min) 72 × serum creatinine (mg/dL) 1.11 Negative serum pregnancy test within three days prior to registration for women of childbearing potential. 1.12 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. 1.12.1 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). 1.12.2 Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 1.13 Ability to understand and the willingness to sign a written informed consent. 2.1 Definitive clinical or radiologic evidence of metastatic disease; 2.2 Subjects may not be receiving any other investigational agents for the treatment of the cancer under study. 2.3 Current invasive malignancy (except non-melanomatous skin cancer, localized bladder and prostate cancer). Carcinoma in situ of the breast, oral cavity, or cervix are permissible regardless of timing; 2.4 Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields. For example, patients with prior breast radiotherapy treatments would likely be excluded; 2.5 Prior systemic treatment with chemotherapy, targeted therapy or an anti-PD-1, anti-PD-L1 including durvalumab, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways for NSCLC; 2.6 A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 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; 2.7 Severe, active co-morbidity defined as follows: 2.7.1 Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable. 2.7.2 Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone 2.7.3 Active infection including tuberculosis, hepatitis B, hepatitis C. 2.7.4 History of allogenic organ transplantation. 2.7.5 History of symptomatic or previously established interstitial lung disease; 2.7.6 History of severe hypersensitivity reaction to any monoclonal antibody or allergy to study drug components; 2.7.7 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP. 2.8 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, in the opinion of the investigator, would limit compliance with study requirements. 2.9 Pregnancy, nursing females, or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic. 2.10 Patients whose radiation treatment plans are likely to encompass a volume of whole lung receiving ≥ 35% of lung volume. V20s up to 37% will be permitted and viewed as a minor deviation, provided that the treating radiation oncologist believes this level of exposure is within patient tolerance. 2.11 Planned radiation cardiac dose V50 >25%.

• Tissue diagnosis of benign or malignant tumor of the breast (left-sided only) or thorax 1. Stage I to III 2. ECOG performance status 0-1 3. The patient must be deemed an appropriate candidate for adjuvant ordefinitive radiation therapy with or without regional nodal irradiation 4. Radiation therapy planning should be CT scan-based using 3D conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT) or volumetric arc therapy (VMAT). 5. 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. 5.1 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). 5.2. A female of postmenopausal status is defined as patients over 60 or greater OR patients age 50-59 who meet the following criteria:
• s/p bilateral oophorectomy, OR
• with intact uterus without menses in the past 12 months OR,
• with biochemical confirmation of post-menopausal status (estradiol in the menopausal range based on local laboratory criteria) 6. Ability to understand and the willingness to sign a written informed consent. 1. Prior thoracic radiation therapy 2. Neoadjuvant, adjuvant or prior HER-2 directed therapy 3. Subjects may not be receiving any investigational agents for the treatment of the cancer under study. 4. Tissue expander placement after mastectomy 5. Diagnosis of connective tissue disorders, including systemic lupus erythematosis, scleroderma, or dermatomyositis 6. Known metastases 7. 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, in the opinion of the investigator, would limit compliance with study requirements 8. eGFR <30 9. Any contraindication to MRI (including, but not limited to metal implants and devices contraindicated at 3T, breast tissue expanders, non-MR compatible IV port, claustrophobia) 10. History of psychiatric or addictive disorders that would preclude obtaining informed consent 11. Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

• All B-ALL patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to treatment and enrollment on AALL1731. APEC 14B1 is not a requirement for B-LLy patients. B-LLy patients may directly enroll on AALL1731.
• Age at diagnosis:
• Patients must be >= 365 days and < 10 years of age (B-ALL patients without DS).
• Patients must be >= 365 days and =< 31 years of age (B-ALL patients with DS).
• Patients must be >= 365 days and =< 31 years of age (B-LLy patients with or without DS).
• B-ALL patients without DS must have an initial white blood cell count < 50,000/uL (performed within 7 days prior to enrollment).
• B-ALL patients with DS are eligible regardless of the presenting white blood cell count (WBC) (performed within 7 days prior to enrollment).
• Patient has newly diagnosed B-cell ALL, with or without Down syndrome: > 25% blasts on a bone marrow (BM) aspirate;
• OR if a BM aspirate is not obtained or is not diagnostic of B-ALL, the diagnosis can be established by a pathologic diagnosis of B-ALL on a BM biopsy;
• OR a complete blood count (CBC) documenting the presence of at least 1,000/uL circulating leukemic cells;
• OR patient has newly diagnosed B-cell LLy Murphy stages I or II, with or without Down syndrome.
• Note: For B-LLy patients with tissue available for flow cytometry, the criterion for diagnosis should be analogous to B-ALL. For tissue processed by other means (i.e., paraffin blocks), the methodology and criteria for immunophenotypic analysis to establish the diagnosis of B-LLy defined by the submitting institution will be accepted (diagnostic biopsy for B-LLy must be performed within 14 days prior to enrollment).
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.
• All patients and/or their parents or legal guardians must sign a written informed consent.
• Patient must not have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy. Note: patients with Down syndrome with a prior history of transient myeloproliferative disease (TMD) are not considered to have had a prior malignancy. They would therefore be eligible whether or not the TMD was treated with cytarabine.
• With the exception of steroid pretreatment or the administration of intrathecal cytarabine, patients must not have received any prior cytotoxic chemotherapy for either the current diagnosis of B ALL or B LLy or for any cancer diagnosed prior to initiation of protocol therapy on AALL1731.
• For patients receiving steroid pretreatment, the following additional exclusion criteria apply:
• Non-DS B-ALL patients must not have received steroids for more than 24 hours in the 2 weeks prior to diagnosis without a CBC obtained within 3 days prior to initiation of the steroids.
• DS and non-DS B-LLy patients must not have received > 48 hours of oral or IV steroids within 4 weeks of diagnosis.
• Patients who have received > 72 hours of hydroxyurea.
• B-ALL patients who do not have sufficient diagnostic bone marrow submitted for APEC14B1 diagnostic testing and who do not have a peripheral blood sample submitted containing > 1,000/uL circulating leukemia cells.
• Patient must not have acute undifferentiated leukemia (AUL).
• Non-DS B-ALL patients with central nervous system [CNS]3 leukemia (CNS status must be known prior to enrollment).
• Note: DS patients with CNS3 disease are eligible but will be assigned to the DS-High B-ALL arm. CNS status must be determined based on a sample obtained prior to administration of any systemic or intrathecal chemotherapy, except for steroid pretreatment.
• Non-DS B-ALL patients with testicular leukemia. (Note: DS patients with testicular disease are eligible but will be assigned to the DS-High B-ALL arm).
• For LLy patients, the following additional exclusion criteria apply:
• T-Lymphoblastic Lymphoma.
• Morphologically unclassifiable lymphoma.
• Absence of both B-cell and T-cell phenotype markers in a case submitted as lymphoblastic lymphoma.
• CNS positive disease or testicular involvement.
• M2 (5%
•25% blasts) or M3 (> 25% blasts) marrow.
• Patients with known Charcot-Marie-Tooth disease.
• Patients with known MYC translocation associated with mature (Burkitt) B-cell ALL, regardless of blast immunophenotype.
• Patients requiring radiation at diagnosis.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

1. Voluntarily signed consent; 2. Age of ≥ 18 and ≤ 80 years; 3. Received sufficient prior lines of myeloma therapy; 4. Received treatment with at least one proteasome inhibitor, one IMiD and daratumumab. 5. The patients should have measurable disease per IMWG definition. 6. Estimated life expectancy > 12 weeks; 7. ECOG performance score 0-1; 8. Patients should have reasonable CBC counts, renal and hepatic functions; 9. Sufficient venous access for leukapheresis collection, and no other contraindications to leukapheresis; 10. Women of childbearing age must undergo a serum pregnancy test with negative results before screening, and are willing to use effective and reliable method of contraception for at least 6 months after T cell infusion; 11. Men must be willing to use effective and reliable method of contraception for at least 6 months after T cell infusion. 1. Pregnant or lactating women; 2. HIV, active hepatitis C virus (HCV), or active hepatitis B virus (HBV) infection; 3. Any uncontrolled active infection; 4. AEs from previous treatment that have not recovered; 5. Patients who have had anti-BCMA therapy; 6. Patients who have graft versus host disease (GvHD); 7. Patients have received stem cell transplantation less than 12 weeks before leukapheresis; 8. Patients have received any anti-cancer treatment before leukapheresis; 9. Patients have received steroids before leukapheresis or lymphodepletion; 10. Patients have plasma cell leukemia, Waldenström macroglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome or clinically significant symptomatic immunoglobulin light chain (AL) amyloidosis with evidence of end-organ damage; 11. Patients have been administered live attenuated vaccine before leukapheresis or lymphodepletion; 12. Patients allergic to Flu, Cy, tocilizumab, dimethyl sulfoxide (DMSO) or CT053 CAR BCMA T cell; 13. Patients have clinical significant cardiac conditions that researchers believe that participating in this clinical trial may endanger the health of the patients; 14. Patients have clinical significant pulmonary conditions; 15. Patients are known to have active autoimmune diseases including but not limited to psoriasis, rheumatoid arthritis and other needs of long-term immunosuppressive therapy; 16. Patients with second malignancies in addition to MM are not eligible; 17. Patients have central nervous system (CNS) metastases or CNS involvement; 18. Patients have significant neurologic disorders; 19. Patients are unable or unwilling to comply with the requirements of clinical trial; 20. Patients have received major surgery prior to leukapheresis or prior to lymphodepletion.

1. Signed informed consent and mental capability to understand the informed consent 2. Male or female patients > 18 years of age 3. Histologically or cytologically documented locally advanced or metastatic solid tumor malignancies refractory to or otherwise ineligible for treatment with standard-of-care agents/regimens, including but not limited to:
• Malignant melanoma
• Hormone receptor negative breast cancer
• Gastro-esophageal cancer
• Non-small cell lung cancer
• Head and neck cancer
• Hepatoma
• Renal cell carcinoma 4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 5. Evaluable or measurable disease as follows:
• A minimum of 3 RECIST-evaluable lesions: one that is suitable for injection and biopsied; one non-injected that will be biopsied for abscopal effect; and one measurable lesion that will be followed for response only.
• Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous injection only, including those lesions that are visible, palpable, or detectable by standard radiographic or ultrasound methods. Neither surgical procedures nor endoscopically-guided injections including those to endobronchial, endoluminal, or endosinusial spaces shall be allowed. While no anatomic locations are required or disallowed, lesions selected for intratumoral injection must, in the opinion of the investigator:
• Not be immediately adjacent to blood vasculature or other physiologic landmarks in such a way that will accrue undue safety risk to the patient
• Have longest diameter ≥ 10 mm and ≤ 50 mm
• Be fully efficacy evaluable per RECIST v1.1 criteria 6. Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA) 7. ECG without evidence of clinically meaningful conduction abnormalities or active ischemia as determined by the investigator 8. Acceptable organ and marrow function as defined below:
• Absolute neutrophil count > 1,500 cells/μL
• Platelets > 50,000 cells/μL
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 times ULN. If liver metastases are present, AST/ALT < 5 times ULN
• Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min using the Cockcroft-Gault formula
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN 9. Women of child-bearing potential (defined as a female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months with an appropriate clinical profile at the appropriate age, e.g., greater than 45 years) must have a negative serum pregnancy test prior to first dose of study drug 10. Male and female patients with reproductive potential must agree to use two forms of highly effective contraception throughout the study 11. Phase I combination only: Demonstrated RECIST stable disease through ≥ 4 consecutive cycles of an approved PD-1 or PD-L1 targeted ICI with no Grade ≥ 3 CTCAE events considered by the investigator to be drug-related. 1. Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug. 2. Failure to recover to Grade 1 or less from clinically significant AEs due to prior anti-cancer therapy. 3. Known untreated brain metastases or treated brain metastases that have not been stable (scan showing no worsening of central nervous system (CNS) lesion[s] and no requirement of corticosteroids) ≥ 4 weeks prior to study enrollment 4. Baseline prolongation of QT/QTc interval (QTc interval > 470) 5. 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 in opinion of the investigator would limit compliance with study requirements 6. Women who are pregnant or breastfeeding 7. Phase I combination only: Prior tumor progression through PD-1 or PD-L1 targeted ICI therapy.

Key 1. Age ≥18 years 2. Histologically or cytologically documented Stage I to II NSCLC, with clinical Stage I/II lymph node-negative (T1 to T3N0M0) disease and planned to receive definitive treatment with SBRT. Patients may be medically inoperable or are medically operable and refusing surgery or choosing to have SBRT (Stereotactic Body Radiation Therapy) as definitive therapy 3. Completion of SoC SBRT as definitive treatment prior to randomization 4. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) PS of 0, 1, or 2 5. Life expectancy of at least 12 weeks 6. Body weight >30 kg 7. Tumor sample required 8. Adequate organ and marrow function required 9. Patients with central or peripheral lesions are eligible 10. Staging studies must be done within 8 weeks before randomization Key 1. Mixed small cell and non-small cell cancer histology 2. History of allogeneic organ transplantation 3. History of another primary malignancy with exceptions 4. History of active primary immunodeficiency 5. Any unresolved toxicity National Cancer Institute (NCI) CTCAE Grade ≥2 from SBRT (Stereotactic Body Radiation Therapy)

Inclusion Criteria for Part 1: Dose Escalation Phase: All patients must meet the following criteria prior to the first dose of study drug: 1. Signed informed consent. Consent must be obtained prior to any study-related procedure. 2. Age ≥ 18 years 3. Histologically confirmed AML or MDS: 1. AML
•relapsed or refractory AML and refuses or is not a candidate for intensive chemotherapy (due to prior failure or not eligible due to expected intolerance) or allogeneic transplant 2. MDS
•relapsed or refractory MDS with > 5% blasts in the marrow or any blasts in the peripheral blood. Patients must have failed prior treatment with an HMA (azacitidine, decitabine, or other HMA agent); failure is defined as intolerance to HMA, lack of response (no CR by at least 6 cycles), or have IWG-defined progressive disease during or after treatment with an HMA. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 5. Life expectancy of > 2 months in the Investigator's opinion 6. White blood cells (WBC) ≤ 25,000 cells/mm3 (may receive hydroxyurea to bring WBC count down prior to and during the first cycle of treatment with study drug if necessary) 7. Creatinine ≤ 2 × upper limit of normal (ULN) 8. Adequate liver test parameters: total bilirubin < 2.5 × ULN (if disease related or secondary to Gilbert's disease, then total bilirubin < 3.5 mg/dL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) < 3 × ULN 9. Prothrombin time (PT) / international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 × ULN 10. Patients and partners of childbearing potential must be willing to use adequate contraception during the study and for 2 months after last study drug administration. Adequate contraception means less than 1% chance of pregnancy may occur with proper use of the method(s). Exclusion Criteria for Part 1: Dose Escalation Phase: A patient is not eligible to enroll into the study if they have any of the following: 1. Any CNS (cerebral/meningeal) disease related to underlying malignancy 2. History of seizures 3. Acute promyelocytic leukemia 4. Prior anti-CD123 therapy outside of this study 5. Any clinically significant graft-versus-host disease (GVHD) secondary to prior allogenic transplant. Patients must be > 90 days from transplant and have been on no immunosuppressive therapy for > 30 days. Topical corticosteroids for minor skin rash (<5% body surface area) is acceptable. Prior solid organ transplant is acceptable provided the patient is on no immunosuppressive therapy. 6. Any therapy or experimental treatment for MDS or AML within 7 days of the first dose of study drug. Must have recovered to Grade ≤ 1 from any Grade 2 to 4 toxicity from previous treatment. The use of hydroxyurea is acceptable and does not exclude the patient. 7. Active, uncontrolled infection requiring systemic therapy. If the infection is controlled or has resolved, maintenance and/or prophylactic systemic antimicrobials are permitted. 8. Major surgery within 3 weeks prior to first dose of study drug 9. Known to be positive for HIV, hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) 10. Pregnant or breast feeding 11. Any other active systemic malignancies. Exceptions: noninvasive non-melanoma skin cancer, in situ carcinoma, cervical intraepithelial neoplasia, and breast or prostate cancer that is well controlled with anti-hormonal therapy 12. Any current autoimmune disorder requiring immunosuppressive therapy 13. Requires more than a replacement dose of corticosteroids (i.e., > 10 mg/day of prednisone or equivalent) 14. Any uncontrolled medical condition, including but not limited to: 1. Symptomatic congestive heart failure ≥ Class III (New York Heart Association Functional Classification) 2. Uncontrolled hypertension 3. Unstable angina 4. Myocardial infarction within previous 6 months 5. Clinically significant arrhythmias not controlled by medication 6. Uncontrolled metabolic disorders such as hypercalcemia 15. Substance use disorder, psychiatric, cognitive, or any other condition that, in the opinion of the Investigator, would pose a risk to the patient's safety, may compromise the patient's ability to understand and comply with the protocol or provide informed consent, or interfere with the study evaluation 16. Any difficulty complying with protocol requirements that may increase the risk associated with study participation or study drug administration, or may cause a safety concern for the patient Inclusion Criteria for Part 2: Dose Expansion Phase Individuals eligible to participate in this study must meet all of the following: All patients must meet the following criteria prior to the first dose of study drug: 1. Signed informed consent. Consent must be obtained prior to any study-related procedure. 2. Age: >18 years 3. Histologically confirmed AML: Subjects must have de novo (primary) AML (any WHO 2016 classification excluding acute promyelocytic leukemia, AML with myelodysplasia-related features, and Therapy-related secondary AML (except in Cohort 1 or Cohort 2) 4. Cohort 1: Fit primary or secondary AML patients (Age: >18 years) in 1st or 2nd relapse with last CR <1 year or primary refractory disease; Relapsed patients must have relapsed a maximum of two times after standard induction therapy for AML; 5. Cohort 2: Poor prognostic but fit primary or secondary AML patients who are treatment-naïve or in 1st relapse; patients in relapse must have relapsed only once after induction/consolidation therapy for AML, i.e., they must be in 1st relapse 6. Cohort 3: Fit primary AML patients with FLT3-negative intermediate or adverse risk AML (including but not limited to: TP53, RUNX1 and ASXL1 mutations and/or complex cytogenetics) who are treatment-naïve or in 1st relapse with a duration of CR1<1 year 7. Cohort 3: Patients are required to be either not in CR or be in CR is MRD positive (≥01% level) by MFC (Central Laboratory) post induction/consolidation to be eligible for APVO436 treatments. 8. Cohort 4: MRD+ (at ≥0.1% level by multicolor-multiparameter flow cytometry [MFC] in Central Lab) high-risk 1st remission AML patients 9. Cohort 4: Patients must be newly diagnosed AML patients in 1st remission who achieved their first remission after standard chemotherapy with a standard induction regimen with or without post-induction consolidation. 10. Cohort 5: Patients must be AML patients who were in 1st relapse and achieved a 2nd remission after standard chemotherapy with a standard induction regimen with or without post-induction consolidation. 11. Cohorts 1-5: If patient was treated with Cytarabine-containing induction or consolidation regimen, a minimum of 21 days must have passed since the last Cytarabine dose to allow for resolution of the side effects 12. Cohorts 1-3: Patients must have CD123-positive AML as confirmed by flow cytometry in Central Laboratory 13. Cohorts 4 and 5: Patients archived bone marrow or peripheral blood leukemic blast cells must be CD123-positive
•local laboratory results are acceptable. If cells are available, the positivity should be confirmed by Central Laboratory. 14. Patients with precedent MDS are not eligible 15. MRD+ AML patients in Cohort 4 or Cohort 5 must be in CR (CR/CRi) for no more than 6 months and be MRD+, as determined by central hematopathology laboratory 16. MRD+ AML patients in Cohort 4 or Cohort 5 must first have an evaluable screening bone marrow sample confirmed as MRD+ by central hematopathology laboratory 17. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 18. Life expectancy of > 2 months in the Investigator's opinion 19. Creatinine ≤ 2 × upper limit of normal (ULN) 20. Adequate liver test parameters: total bilirubin < 2.5 × ULN (if disease related or secondary to Gilbert's disease, then total bilirubin < 3.5 mg/dL), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) < 3 × ULN 21. Prothrombin time (PT) / international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 × ULN 22. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) may participate, provided they meet the following conditions: 1. Must agree to use physician-approved contraceptive methods (e.g., abstinence, intrauterine device, oral contraceptive, double barrier device) throughout the study and for 3 months following the last dose of APVO436; and 2. Must have a negative serum or urine pregnancy test within 7 days prior to beginning treatment on this study. 23. Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 3 months following the last dose of APVO436 Exclusion Criteria for Part 2: Dose Expansion Phase Subjects with any of the following will not be eligible for study participation: 1. Acute promyelocytic leukemia (APL) with t(15;17) translocation 2. Absolute peripheral blood myeloblast count greater than 20,000/mm3
•may receive hydroxyurea to reduce and control the myeloblast count down prior to and during the first week of the first cycle of treatment with study drug if necessary if deemed medically necessary and appropriate by the treating physician 3. Patients with active central nervous system (CNS) involvement by AML will be excluded. A lumbar puncture does not need to be performed unless there is clinical suspicion of CNS involvement per investigator judgement. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS AML is allowed with the approval of the sponsor. 4. History of seizures 5. Prior anti-CD123 therapy with APVO436; prior anti-CD123 therapy with bispecific antibodies, recombinant fusion proteins or antibody-drug conjugates is allowed. 6. Prior allogeneic, unrelated or autologous hematopoietic stem cell transplantation is allowed only in Cohort 5. The transplant must have been performed more than 100 days before the date of dosing on this study without any Grade ≥2 graft-versus-host disease (GVHD) secondary to prior allogenic transplant. Patients must be > 100 days from transplant and have been on no immunosuppressive therapy for > 30 days. Topical corticosteroids for minor skin rash (<5% body surface area) is acceptable. 7. Prior allogeneic, unrelated or autologous hematopoietic stem cell transplantation is not allowed for Cohorts 1 to 4 8. Prior solid organ transplant is acceptable provided the patient is on no immunosuppressive therapy. 9. Any therapy or experimental treatment for AML within 7 days of the first dose of study drug. Must have recovered to Grade ≤ 1 from any Grade 2 to 4 toxicity from previous treatment. The use of hydroxyurea is acceptable and does not exclude the patient. 10. Active, uncontrolled infection requiring systemic therapy. If the infection is controlled or has resolved, maintenance and/or prophylactic systemic antimicrobials are permitted. 11. Major surgery within 3 weeks prior to first dose of study drug 12. Known to be positive for HIV, hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) 13. Uncontrolled hypertension, defined as blood pressure ≥ 140/90 mm Hg despite maximum medical intervention 14. History of congenital long QT syndrome or torsades de pointes 15. Pathologic bradycardia or heart block (excluding first degree heart block) 16. Prolonged baseline QTc, defined as QTcF (Fredericia correction) interval >480 msec (including subjects with a bundle branch block) 17. History of ventricular arrhythmia (excluding PVCs) 18. Major surgery within 28 days prior to informed consent 19. Unstable angina pectoris within 28 days 20. Myocardial infarction and/or new ST elevation or depression or new Q wave on ECG within 6 months 21. Any history of stroke 22. Symptomatic congestive heart failure Class III or greater (New York Heart Association Functional Classification) 23. On full dose anti-coagulation defined as warfarin intended to raise the INR to 2-3 24. Major hemorrhagic event within 28 days requiring transfusion of packed red blood cells 25. Prior history of hypertensive crisis or hypertensive encephalopathy 26. Clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless a lumbar puncture was performed to confirm the absence of leukemic blasts in the cerebrospinal fluid (CSF) 27. Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) 28. Any open wound 29. Pregnant and nursing subjects are excluded because the effects of APVO436 on a fetus or nursing child are unknown 30. Treatment with any anticancer therapy (standard or investigational) within the previous 14 days prior to the first dose of study drug. In addition, subjects must have fully recovered (NCI CTCAE Grade 1) from the clinically significant toxic effects of that treatment. The use of hydroxyurea in subjects with rapidly proliferating disease is allowed only during Cycle 1. Hydroxyurea is allowed prior to starting the study, and may be used for two weeks after dosing in Cycle 1 (e.g., Days 1-14 dosed with hydroxyurea) 31. Substance use disorder, psychiatric, cognitive, or any other condition that, in the opinion of the Investigator, would pose a risk to the patient's safety, may compromise the patient's ability to understand and comply with the protocol or provide informed consent, or interfere with the study evaluation, study participation, or follow-up 32. Any difficulty complying with protocol requirements that may increase the risk associated with study participation or study drug administration, or may cause a safety concern for the patient 33. Any uncontrolled medical condition, including but not limited to: 1. Uncontrolled hypertension 2. Unstable angina 3. Clinically significant arrhythmias not controlled by medication 4. Uncontrolled metabolic disorders such as hypercalcemia 34. Any other active systemic malignancies. Exceptions: noninvasive non-melanoma skin cancer, in situ carcinoma, cervical intraepithelial neoplasia, and breast or prostate cancer that is well controlled with anti-hormonal therapy 35. Any current autoimmune disorder requiring immunosuppressive therapy with more than a replacement dose of corticosteroids (i.e., > 10 mg/day of prednisone or equivalent)

• Participants with a first diagnosis of HCC who have undergone either a curative resection or ablation (radiofrequency ablation [RFA] or microwave ablation [MVA] only) within 4-12 weeks of randomization
• Documented diagnosis of HCC that has been completely resected or ablated (RFA or MVA only)
• Absence of major macrovascular invasion (except Vp1/Vp2) and extrahepatic spread
• Absence of extrahepatic spread as confirmed by CT or MRI scan of the chest, abdomen, pelvis, and head prior to and following curative procedure
• Full recovery from surgical resection or ablation within 4 weeks prior to randomization
• High risk for HCC recurrence after resection or ablation
• For patients who received post-operative transarterial chemoembolization: full recovery from the procedure within 4 weeks prior to randomization
• For patients with resected HCC, availability of a representative baseline tumor tissue sample
• ECOG Performance Status of 0 or 1
• Child-Pugh Class A status
• Adequate hematologic and end-organ function
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm
• Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• Evidence of residual, recurrent, or metastatic disease at randomization
• Clinically significant ascites
• History of hepatic encephalopathy
• Prior bleeding event due to untreated or incompletely treated esophageal and/or gastric varices within 6 months prior to randomization
• Have received more than 1 cycle of adjuvant TACE following surgical resection
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Significant cardiovascular disease within 3 months prior to Day 1 of Cycle 1, unstable arrhythmia, or unstable angina
• History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Active tuberculosis
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• Pregnant or breastfeeding, or intending to become pregnant during the study or within 5 months after the final dose of atezolizumab or within 6 months after the final dose of bevacizumab. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to Day 1 of Cycle 1.
• Co-infection with HBV and HCV
• Co-infection with HBV and hepatitis D viral infection
• Clinical significant uncontrolled or symptomatic hypercalcemia
• Any treatment for HCC prior to resection or ablation, including systemic therapy and locoregional therapy such as TACE
• Treatment with systemic immunostimulatory or immunosuppressive agents
• Inadequately controlled arterial hypertension
• History of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease
• Evidence of bleeding diathesis or significant coagulopathy
• Current or recent use of aspirin or full-dose oral or parenteral anticoagulants
• Core biopsy within 3 days of Day 1 of Cycle 1
• History of GI fistula, GI perforation, or intra-abdominal abscess
• Serious non-healing or dehiscing wound
• Major surgical procedure within four weeks
• Chronic daily treatment with a non-steroidal anti-inflammatory drug

• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient is suspected of having localized newly-diagnosed HGG, excluding metastatic disease
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Patient and/or their parents or legal guardians have signed informed consent for eligibility screening on APEC14B1 Part A.
• PRE-ENROLLMENT ELIGIBILITY SCREENING (STEP 0): Specimens obtained at the time of diagnostic biopsy must be submitted through APEC14B1 as soon as possible (ASAP), preferably within 13 calendar days of the procedure.
• Patients must be >= 3 years and =< 21 years of age at the time of enrollment
• Patients must have eligibility confirmed by Rapid Central Pathology and Molecular Screening Reviews performed on APEC14B1
• Newly diagnosed high-grade glioma with BRAFV600-mutation
• Positive or negative results for H3 K27M by immunohistochemistry (IHC)
• Histologically confirmed high-grade glioma (World Health Organization [WHO] grade III or IV) including but not limited to: anaplastic astrocytoma (AA), anaplastic pleomorphic xanthoastrocytoma (aPXA), anaplastic gangliogliomas (aGG), glioblastoma (GB), and high-grade astrocytoma, not otherwise specified (NOS)
• Patients must have had histologic verification of a high-grade glioma diagnosis. Cerebrospinal fluid (CSF) cytology by lumbar puncture must be done if clinically indicated and determined to be safe prior to study enrollment. If cytology proves positive, the patient would be considered to have metastatic disease and would, therefore, be ineligible.
• A pre- and post-operative brain magnetic resonance imaging (MRI) with and without contrast and a baseline spine MRI with contrast must be obtained prior to enrollment. The requirement for a post-operative MRI is waived for patients who undergo biopsy only. If the spine MRI is positive, the patient would be considered to have metastatic disease and would be ineligible.
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age.
• Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment).
• Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment).
• Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 (within 7 days prior to enrollment) or
• A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
• Age 3 to < 6 years (Male 0.8 mg/dL, Female 0.8 mg/dL)
• Age 6 to < 10 years (Male 1 mg/dL, Female 1 mg/dL)
• Age 10 to < 13 years (Male 1.2 mg/dL, Female 1.2 mg/dL)
• Age 13 to 16 < years (Male 1.5 mg/dL, Female 1.4 mg/dL)
• Age >= 16 years (Male 1.7 mg/dL, Female 1.4 mg/dL)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment), and
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L (within 7 days prior to enrollment). For the purpose of this study, the ULN for SGPT is 45 U/L.
• Patients with a seizure disorder may be enrolled if their seizures are well controlled while on non-enzyme inducing anticonvulsants permitted on this study.
• Patients must be enrolled and protocol therapy must be projected to begin no later than 31 days after definitive surgery (day 0). If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.
• 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 with intrinsic brainstem or primary spinal cord tumors will be excluded.
• Patients with metastatic disease (defined as neuraxis dissemination either by imaging or by cytology) will be excluded.
• Patients must not have received any prior tumor-directed therapy including chemotherapy, radiation therapy, immunotherapy, or bone marrow transplant for the treatment of HGG other than surgical intervention and/or corticosteroids.
• Previous treatment with dabrafenib or another RAF inhibitor, trametinib or another MEK inhibitor, or an ERK inhibitor.
• Patients with a history of a malignancy with confirmed activating RAS mutation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib, trametinib, and their excipients.
• Uncontrolled medical conditions (e.g., diabetes mellitus, hypertension, liver disease, or uncontrolled infection), psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol; or unwillingness or inability to follow the procedures required in the protocol.
• Presence of active gastrointestinal (GI) disease or other condition (e.g., small bowel or large bowel resection) that will interfere significantly with the absorption of drugs.
• History of hepatitis B virus, or hepatitis C virus infection (patients with laboratory evidence of cleared hepatitis B virus and/or hepatitis C virus may be enrolled).
• History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
• Recent myocardial infarction (within the last 6 months);
• Uncontrolled congestive heart failure;
• Unstable angina (within last 6 months);
• Clinically significant (symptomatic) or known, uncontrolled cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular [AV] block without a pacemaker) except sinus arrhythmia within the past 24 weeks prior to the first dose of study treatment;
• Coronary angioplasty or stenting (within last 6 months);
• Intra-cardiac defibrillators;
• Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram.
• Patients with a history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR), or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension).
• Patients with presence of interstitial lung disease or pneumonitis.
• Female patients who are pregnant are ineligible since there is yet no available information regarding human fetal or teratogenic toxicities.
• Lactating females are not eligible unless they have agreed not to breastfeed their infants for the duration of the study and for 4 months following discontinuation of study therapy.
• Female patients of childbearing potential are not eligible unless a negative pregnancy test result has been obtained.
• Sexually active patients of reproductive potential (male or female) are not eligible unless they have agreed to use an effective contraceptive method for the duration of their study participation and for 4 months following discontinuation of study therapy. Male patients (including those who have had a vasectomy) taking dabrafenib and trametinib combination therapy must use a condom during intercourse while on study and for 16 weeks after stopping treatment, and should not father a child during these periods. Women of childbearing potential should use effective non-hormonal contraception during therapy and for 4 weeks following discontinuation of dabrafenib and at least 4 months following the last dose of trametinib in patients taking combination therapy. Women should be advised that dabrafenib may decrease the efficacy of hormonal contraceptives and an alternate method of contraception, such as barrier methods, should be used.

1. At least 18 years of age. Both men and women and members of all races and ethnic groups will be included. 2. Willing and able to provide written informed consent 3. Pathologic diagnosis of rectal adenocarcinoma 4. Stage III or Stage II with at least 1 of the following high-risk features:
• Distal (<1cm from anal ring)
• cT4 or within 3mm of MR fascia
• Not candidate for sphincter preservation
• Extramural venous invasion 5. No prior treatment for rectal adenocarcinoma 6. Eastern Cooperative Group (ECOG) performance status of 0-1. 7. Laboratory values supporting acceptable organ and marrow function within 21 days of eligibility confirmation. Defined as follows:
• WBC ≥ 3,000/mL;
• ANC WBC ≥ 1,500/mL;
• PLT ≥ 100,000/mL;
• T Bili ≤ 1.5 x upper limit of normal (ULN);
• AST/ALT ≤ 2.5 x ULN;
• Creatinine not above ULN, or creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal. 8. Female participants of childbearing potential (FOCBP) must have a negative serum or urine pregnancy test (per institutional standards) within 72 hours prior to the start of study drug. FOCBP must agree to use highly-effective method(s) of contraception (Appendix A) during the study and for 90 days after the last dose of study drugs. FOCBP are those who have not been surgically sterilized or have not been free from menses for >1 year without an alternative medical cause. 9. Male participants must agree to use an adequate method of contraception (Appendix A) starting with the first dose of study therapy through 90 days after the last dose of study drugs. 1. Distant nodal disease (retroperitoneal nodes) including inguinal nodes, or any metastatic disease by CT or PET 2. Prior RT to the pelvis. 3. Uncontrolled comorbid illness or condition including an active infection, congestive heart failure, unstable angina, cardiac arrhythmia, or psychiatric illness that would limit compliance with the study requirements. 4. Prior treatment with any anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways. 5. Any positive history for HIV/AIDS, HTLV, hepatitis B or hepatitis C virus indicating acute or chronic infection. 6. Any active known or suspected autoimmune disease. Participants with 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 are permitted to enroll. 7. Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to the first dose of study drug. Inhaled steroids and adrenal replacement steroid doses up to 10 mg daily prednisone equivalent are permitted (although not encouraged) in the absence of active autoimmune disease. 8. Malignancy in the past 3 years that required active treatment except locally curable cancers or cancers deemed by the treating physicians to not impact the subject's survival duration. 9. Participants receiving any other investigational agent, standard antineoplastic agents, or immunosuppressive agents. 10. Known history of interstitial lung disease. 11. Received live vaccine within 6 weeks prior to randomization. 12. Psychiatric illness/social situations that would limit consenting and compliance with study requirements. 13. Participants who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants. 14. Patient is not a candidate for the full treatment regimen.

• Ability to understand and the willingness to sign a written informed consent document
• Morphologically documented relapsed/refractory acute myeloid leukemia (AML) as defined by World Health Organization (WHO) criteria after at least 1 prior therapy for AML with the exception of hydroxyurea. Patients with myelodysplastic syndrome (MDS) transformed to AML that have been treated with hypomethylating agents may be considered if they fulfill one or more of the following criteria: 1) patient has a left ventricular ejection fraction of 45% or less; 2) patient has a serum creatinine of >= 1.4 gm/dl; 3) patient is age 75 or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Women must not be pregnant or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days prior to start of study drug administration
• Participants must agree to use an adequate method of contraception
• Must be able to take oral medications
• Creatinine clearance >= 30 mL/min; calculated by the Cockcroft Gault formula or measured by 24 hours urine collection
• Total serum bilirubin =< 1.5 x upper limit of normal (ULN) unless thought to be due to leukemic involvement
• Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 3.0 x ULN unless thought to be due to leukemic involvement
• Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype)
• Active central nervous system involvement with AML
• Concurrent active malignancy with expected survival of less than 1 year. For example, candidates with treated skin cancers, prostate cancer, breast cancer, etc. without metastatic disease are candidates for therapy since their expected survival exceeds that of relapsed or refractory AML. All subjects with concurrent malignancies will be reviewed by the principal investigator (PI) prior to enrollment
• Clinically significant graft versus host disease (GVHD) or active GVHD requiring initiation or escalation of treatment within 28 day screening period
• Participants with rapidly progressive disease (defined by blast count doubles within 48 hours) or organ dysfunction
• Clinically significant coagulation abnormality, such as disseminated intravascular coagulation
• Participants who are currently receiving any other investigational agents
• Known clinically significant liver disease defined as ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, portal hypertension, or history of autoimmune hepatitis
• Untreated human immunodeficiency virus (HIV) or active hepatitis C detectable by polymerase chain reaction (PCR), or chronic hepatitis B (patients positive for hepatitis B core antibody who are receiving intravenous immunoglobulin [IVIG] are eligible if hepatitis [Hep]B PCR is negative)
• Known history of cerebrovascular accident, myocardial infarction, or intracranial hemorrhage within 2 months of enrollment
• Clinically significant surgery within 2 weeks of enrollment
• Per PI discretion, active infection that is not well controlled by antibacterial or antiviral therapy
• Participants with known history of tuberculosis (TB; Mycobacterium tuberculosis) are not eligible for participation. At investigator discretion, latent TB test should be performed for individuals considered to be at high-risk (e.g., immune compromised, persons that have traveled to, or emigrated from, regions with high rates of TB)
• Cancer-directed therapy within 1 week prior to starting treatment, with the exception of hydroxyurea, which is allowed to control white blood cell count
• Unwillingness to receive infusion of blood products
• Participant on any of the following therapies need to be discussed with the sponsor investigator:
• Strong and moderate CYP3A inhibitors
• Strong and moderate CYP3A inducers
• Patients with uncontrolled white blood cell count (defined as > 50 K/mm^3 not controlled with hydroxyurea)
• Patients with known sensitivity to ruxolitinib or venetoclax

• Men or women greater than or equal to 18 years old.
• Pathologically documented, locally-advanced or metastatic malignancy with, KRAS p.G12C mutation identified through molecular testing. Exclusion Criteria
• Active brain metastases from non-brain tumors.
• Myocardial infarction within 6 months of study day 1.
• Gastrointestinal (GI) tract disease causing the inability to take oral medication.

• Patients must have histologically confirmed World Health Organization (WHO) grade II-III meningioma which has relapsed after prior radiation therapy with radiologically progressive or recurrent disease
• Patients must have measurable disease, defined as at least 1 lesion that can be accurately measured in at least one dimension as >= 1 cm on brain magnetic resonance imaging (MRI) but with the maximum dimension =< 5 cm OR gross tumor volume < 20 cm^3. All the relapsed disease would need to be eligible to be treated with reirradiation
• Patients must have at least one prior surgery with available archival formalin-fixed paraffin-embedded (FFPE) tumor blocks of the initial or recurrent meningioma. If there are multiple tumor blocks from multiple surgeries, the most recent tumor block (and ideally of the relapsed tumor after initial radiation therapy) should be submitted. If a tumor block is not available, an alternative of 20-30 unstained slides may be submitted instead. Annotation regarding whether the tumor block is before or after initial radiation therapy should be provided
• Prior initial radiation therapy may include external beam radiation or radiosurgery, or combination of both. However, the total dose of prior radiation exposure to the site of recurrent tumor (for consideration of re-irradiation) cannot be more than 70 Gy. The duration since the previous radiation exposure to the site of reirradiation need to be at least 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
• Serum creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional normal
• The effects of nivolumab and/or ipilimumab on the developing human fetus are unknown. For this reason and because radiation therapy is known to be teratogenic, women of childbearing potential (WOCBP) 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. WOCBP should use an adequate method to avoid pregnancy for 5 months after the last dose of investigational drug. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) 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 7 months after the last dose of investigational product. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) 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 or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of 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 less than 40 mIU/mL
• WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of investigational product. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of investigational product. These durations have been calculated using the upper limit of the half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active with WOCBP use contraception for 5 half-lives plus 100 days
• 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
• Ability to understand and the willingness to sign a written informed consent document or, if decision-making capacity is impaired, consent of a legally authorized representative (e.g., spouse, adult child, live-in caretaker).
• Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
• Patients who have had radiation therapy (to the site of reirradiation) within 6 months prior to entering the study
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1); however, alopecia, sensory neuropathy =< grade 2, or other =< grade 2 not constituting a safety risk based on the investigator's judgment are acceptable
• Patients who are receiving any other investigational agents
• Patients who have previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and/or ipilimumab
• History of severe hypersensitivity reaction to any monoclonal antibody
• Current use of immunosuppressive medication (EXCEPT for the following: Intranasal, inhaled, topical steroids, or local steroid injection [e.g. intra-articular injection]; systemic corticosteroids at doses =< 4 mg/day of dexamethasone or equivalent; steroids as premedication for hypersensitivity reactions [e.g. computed tomography (CT) scan premedication])
• 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. However, patients with human immunodeficiency virus (HIV) on stable therapy with minimal viral loads and patients with hepatitis B and hepatitis C who have received treatment with minimal viral loads will be eligible
• Pregnant women are excluded from this study because radiation therapy is teratogenic and that the effects of nivolumab and/or ipilimumab on the developing human fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab and/or ipilimumab, breastfeeding should be discontinued if the mother is treated with nivolumab and/or ipilimumab
• Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded. These include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease. Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• Patients 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 (precipitating event)
• Prior organ transplantation including allogeneic stem cell transplantation
• Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
• Live vaccination within 4 weeks of the first dose of nivolumab and while on trial is prohibited except for administration of inactivated vaccines