Stage 1
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 within 7 days prior to randomization
• Locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC) with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of
• Liver Diseases criteria in cirrhotic patients
• Child-Pugh class A within 7 days prior to randomization
• Disease that is not amenable to curative surgical and/or locoregional therapies
• No prior systemic treatment for HCC
• Life expectancy >= 3 months
• Availability of a representative tumor specimen that is suitable for determination of PD-L1 and/or additional biomarker status via central testing Stage 1 and Stage 2
• Measurable disease according to Response Evaluation Criteria in Solid Tumors v1.1
• Adequate hematologic and end-organ function within 7 days prior to initiation of study treatment
• Documented virology status of hepatitis, as confirmed by screening tests for hepatitis B virus
•(HBV) and hepatitis C virus (HCV)
• Negative HIV test at screening
• For women of childbearing potential: agreement to remain abstinent or use contraception and for men: agreement to remain abstinent or use contraception, and agreement to refrain from donating sperm Stage 2
• ECOG Performance Status of 0, 1, or 2
• Ability to initiate Stage 2 treatment within 3 months after experiencing unacceptable toxicity not related to atezolizumab or RO7247669 or loss of clinical benefit as determined by the investigator while receiving Stage 1 treatment
• Availability of a tumor specimen from a biopsy performed upon discontinuation of Stage 1 (if deemed clinically feasible) Stage 1
• Prior treatment with CD137 agonists or immune checkpoint inhibitors
• Treatment with investigational therapy within 28 days prior to initiation of study
• Treatment with locoregional therapy to liver within 28 days prior to initiation of study, or non-recovery from side effects of any such procedure
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding
• Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study
• AEs from prior anti-cancer therapy that have not resolved to Grade <= 1 or better, with the exception of alopecia of any grade
• Inadequately controlled hypertension
• History of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease
• History of hemoptysis within 1 month prior to initiation of study
• Evidence of bleeding diathesis or significant coagulopathy
• Current or recent use of asprin (>325 mg/day) or treatment with clopidogrel, dipyramidole, ticlopidine, or cilostazol
• Current or recent use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose
• Core biopsy or other minor surgical procedure within 3 days prior to initiation of study
• History of abdominal or tracheoesophageal fistula, GI perforation, or intra-abdominal abscess, intestinal obstruction and/or clinical signs/symptoms of GI obstruction
• Evidence of abdominal free air not explained by paracentesis or recent surgery
• Serious, non-healing/dehiscing wound, active ulcer, or untreated bone fracture
• Grade >=2 proteinuria
• Metastatic disease involving major airways/blood vessels, or centrally located mediastinal tumor masses of large volume
• History of intra-abdominal inflammatory process
• Radiotherapy within 28 days or abdominal/pelvic radiotherapy within 60 days prior to initiation of study with the exception of palliative radiotherapy to bone lesions within 7 days prior to initiation of study
• Major surgery, open biopsy, or significant traumatic injury within 28 days prior to initiation of study; or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to initiation of study; or anticipation of need for major surgery during study or non-recovery from side effects of any such procedure
• Chronic daily treatment with NSAID
• Eligible only for control arm Stage 1 and 2
• Fibrolamellar or sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
• History of hepatic encephalopathy
• Moderate or severe ascites
• HBV and HCV coinfection
• Symptomatic, untreated, or actively progressing CNS metastases
• History of leptomeningeal disease
• Uncontrolled tumor-related pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
• Uncontrolled or symptomatic hypercalcemia
• Active or history of autoimmune disease or immune deficiency
• History of IPF, organizing pneumonia, drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Active TB
• Significant CV disease within 3 months prior to initiation of study, unstable arrhythmia, or unstable angina
• Major surgery, other than for diagnosis, within 4 weeks prior to initiation of study, or anticipated major surgery during study
• History of malignancy other than HCC within 5 years prior to screening
• Severe infection within 4 weeks prior to initiation of study
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study
• Prior allogeneic stem cell or solid organ transplantation
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known allergy or hypersensitivity to any of the study drugs or any of their excipients Treatment with systemic immunostimulatory, immunosuppressive agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study
• Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study
• Patients entering Stage 2: immunotherapy-related adverse events that have not resolved to Grade 1 or better or to baseline at time of consent

• Patient must be >= 18 years of age
• Patient must have a histologically confirmed diagnosis of combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CC) at the local laboratory based on the 2019 World Health Organization (WHO) classification, including the classical type and intermediate cell carcinoma
• The classical type defines primary liver carcinoma with unequivocal features of both HCC and CC differentiation within the same tumors on routine histopathology with hematoxylin and eosin stains regardless of the proportion of each histology observed
• The intermediate cell carcinoma defines cancers with biphenotypic differentiation in which cells have a morphology intermediate between hepatocytes and cholangiocytes. Intermediate cell carcinoma may be associated with expression of both hepatocyte and cholangiocytic markers. Distinct HCC and CC arising in the same liver, fibrolamellar HCC, morphologically typical HCCs with only immunohistochemical expression of keratin or other cholangiocytic markers, or morphologically typical CCs with only immunohistochemical expression of hepatocytic markers will be excluded
• NOTE: Local pathology review constitutes adequate documentation of histology for initial study enrollment and treatment
• Patient must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Patient must have disease which is unresectable or metastatic
• Patient must be Child Pugh class A
• Patients with prior locoregional therapy are eligible provided the following are met:
• Prior loco-regional therapy including surgical resection, chemoembolization, radiotherapy, or ablation was completed > 4 weeks prior to randomization
• Treated target lesion has increased in size by > 25% or the target lesion was not treated with loco-regional therapy
• Patients treated with palliative radiotherapy for symptoms must have completed radiotherapy > 7 days prior to randomization and the target lesion must not have been the treated lesion
• Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible
• Leukocytes >= 3,000/mcL (must be obtained =< 14 days prior to protocol randomization)
• Absolute neutrophil count (ANC) >= 1,500/mcL (must be obtained =< 14 days prior to protocol randomization)
• Hemoglobin >= 9 g/dL (Patient may be transfused to meet this criterion) (must be obtained =< 14 days prior to protocol randomization)
• Platelets >= 80,000/mcL (must be obtained =< 14 days prior to protocol randomization)
• Total bilirubin =< 3 x institutional upper limit of normal (ULN) (must be obtained =< 14 days prior to protocol randomization)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5.0 x institutional ULN (must be obtained =< 14 days prior to protocol randomization)
• Creatinine =< 1.5 x institutional ULN (must be obtained =< 14 days prior to protocol randomization)
• International normalized ratio (INR) =< 1.5 x Institutional ULN (for patients not receiving anticoagulant therapy) (must be obtained =< 14 days prior to protocol randomization). For patients receiving therapeutic anticoagulation, the patient must be on a stable anticoagulant regimen
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial
• For patients with evidence of prior or active hepatitis B virus (HBV) infection (positive hepatitis B surface antigen [HBsAg] test and/or positive total hepatitis B virus core antibody [HBcAb] test at screening), the patient must be on suppressive therapy, for at least 2 weeks prior to randomization and willing to continue antiviral treatment for the length of the study
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Patient must have measurable disease. Baseline measurements and evaluations of all sites of disease must be obtained within 4 weeks prior to randomization
• Patients with untreated or incompletely treated varices with bleeding or high-risk for bleeding must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to randomization. Patients who have undergone an EGD within 6 months of prior to randomization do not need to repeat the procedure
• Patient must not have any prior history of systemic therapy for cHCC-CC
• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.
• All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy
• A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Patient must not expect to conceive or father children by abstaining from sexual intercourse or by using accepted and effective method(s) of contraception while on protocol treatment and for 6 months after the last dose of protocol treatment. Accepted and effective method(s) of contraception include those with a failure rate of < 1% per year including bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovluation, hormonal releasing intrauterine devices, and copper intrauterine devices. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception
• Patient must not have new or progressive brain metastases (active brain metastases) or leptomeningeal disease
• Patients must not have laboratory evidence of active co-infection of HBV (positive HBsAg test) and hepatitis C virus (HCV) (detectable HCV ribonucleic acid [RNA]). Patients with a history of HCV infection but who are negative for HCV RNA by polymerase chain reaction (PCR) will be considered non-infected with HCV
• Patient must not have had a prior allogenic bone marrow or solid organ transplant
• Patient must not have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on baseline chest computed tomography scan
• Patient must not have active or a history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible
• Patients with controlled type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible provided all of following conditions are met:
• Rash must cover < 10% of body surface area
• Disease is well controlled at baseline and requires only low-potency topical corticosteroids
• There is no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
• Patient must not have received prior treatment with immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
• Patient must not be on treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to randomization, or anticipate the need for systemic immunosuppressive medication during study treatment, with the following exceptions:
• Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible
• Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
• Patient must not have inadequately controlled arterial hypertension (defined as systolic blood pressure (BP) >= 150 mmHg and/or diastolic blood pressure > 100 mmHg) prior to randomization. Patients may be on antihypersensitive medications to meet and maintain this criteria
• Patient must not have significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to randomization
• Patient may not have a history of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to randomization
• Patient must not have any evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
• Patient must not have uncontrolled tumor-related pain. Patients requiring pain medication must be on a stable regimen at the time of randomization
• For patients with symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization. Patients must be recovered from the effects of radiation prior to randomization. There is no required minimum recovery period
• For patients with asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) they must be considered for loco-regional therapy if appropriate prior to randomization
• Patient must not have uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX) are allowed
• Patient must not have active tuberculosis
• Patient must not have undergone any major surgical procedure, other than for diagnosis, within 4 weeks prior to randomization, or have the anticipation of need for a major surgical procedure during the study
• Patient must not have any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of the agents used on this study, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• Patient must not have received any live, attenuated vaccines (e.g., FluMist [registered trademark]) within 4 weeks prior to randomization, during treatment with atezolizumab, and for 5 months after the last dose of atezolizumab
• Patient must not have received any treatment with investigational therapy within 28 days prior to randomization
• Patient must have not received treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to randomization
• Patients must not have a history of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Patient must not have a known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• Patient must not have a known allergy or hypersensitivity to any component of the atezolizumab and bevacizumab formulation

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Patient must have histologically-confirmed T2 or T3 gallbladder cancer discovered incidentally at the time of or following routine cholecystectomy for presumed benign disease
• NOTE: Patients with histologically-confirmed Tis, T1a, T1b, or T4 tumors are not eligible
• Patient must have undergone initial cholecystectomy within 12 weeks prior to randomization
• Patient must have the ability to understand and the willingness to sign a written informed consent document
• Leukocytes >= 3,000/mcL (obtained =< 28 days prior to randomization)
• Absolute neutrophil count >= 1,500/mcL (obtained =< 28 days prior to randomization)
• Platelets >= 100,000/mcL (obtained =< 28 days prior to randomization)
• Total bilirubin =< institutional upper limit of normal (ULN) except in patients with Gilbert's syndrome. Patients with Gilbert's syndrome are eligible if direct bilirubin < 1.5 x ULN of the direct bilirubin (obtained =< 28 days prior to randomization)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained =< 28 days prior to randomization)
• Serum creatinine =< institutional ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 (Based on Cockcroft Gault estimation) (obtained =< 28 days prior to randomization)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association functional classification. To be eligible for this trial, patients should be class 2B or better
• Patient must not have any evidence of metastatic disease or inoperable loco-regional disease based on high-quality, preoperative, cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging [MRI]) of the chest, abdomen, and pelvis (C/A/P) obtained within 6 weeks prior to randomization, defined as
• No radiographic evidence of distant disease (M1 disease)
• No radiographic evidence of tumor invasion into multiple extrahepatic organs (T4 disease)
• No radiographic evidence of distant lymph node involvement (celiac, para-aortic, para-caval lymph nodes)
• No evidence of new-onset ascites
• Soft tissue thickening within or in direct communication with the gallbladder fossa, peri-portal lymph node involvement, involvement of one extrahepatic organ, and other disease within the confines of what constitutes 'localized resectable' disease are allowable
• Women must not be pregnant or breast feeding due to the potential harm to unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All females of child bearing potential must have a serum or urine pregnancy test to rule out pregnancy within 14 days prior to randomization. A female of childbearing potential is defined as any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and sexually active males must not expect to conceive or father children by being strongly advised to use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study

• Patients must have a radiologically consistent (early enhancement and delayed enhancement washout) or pathologically confirmed diagnosis of hepatocellular carcinoma that is not eligible for curative resection, transplantation, or ablative therapies.
• Prior radiation, liver directed therapy (including bland, chemo- or radioembolization, or ablation), or hepatic resection are permitted if ≥4 weeks from start of therapy. Extra-hepatic palliative radiation is permitted if completed ≥2 weeks prior to first dose of study therapy and the patient has recovered to ≤ grade 1 toxicity.
• Patients must have radiographically measurable disease (RECIST1.1) in at least one site not previously treated or with progression after radiation or liver directed therapy (including bland, chemo- or radio-embolization, or ablation) either within the liver or in a metastatic site.
• Patients must have either progressed or deemed intolerant of first-line systemic therapy. More than one line of systemic therapy is not permitted. The last dose should be at least 2 weeks from first dose of study therapy. Prior treatment may not contain cabozantinib.
• Recovery to ≤ grade 1 from toxicities related to any prior treatments, unless the AEs were clinically non-significant and/or stable on supportive therapy
• Must have a Child-Pugh score of B7 or B8
• Must have an ECOG performance status of 0-1.
• Ability to understand and willingness to sign IRB-approved informed consent.
• Willing to provide archived tissue, if available, from a previous diagnostic biopsy.
• Must be able to tolerate CT and/or MRI with contrast.
• Adequate organ function obtained ≤ 2 weeks prior to enrollment.
• Must not have uncontrolled ascites (requiring paracentesis within 3 months of screening) or hepatic encephalopathy requiring hospitalization (within 6 months of screening)
• Must not have prior history of organ transplantation.
• No known brain metastasis unless adequately treated with radiotherapy and/or surgery and stable for at least 4 weeks before registration. Eligible subjects must have been without corticosteroid treatment at the time of registration.
• Must not have undergone a major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (e.g., simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
• Must not have an active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ. Patients with history of malignancy are eligible provided primary treatment of that cancer was completed > 1 year prior to enrollment and the patient is free of clinical or radiologic evidence of recurrent or progressive malignancy.
• Must not have uncontrolled, significant intercurrent or recent illness including, but not limited to the following conditions:
• Cardiovascular disorders (Congestive heart failure or uncontrolled hypertension; or stroke, myocardial infarction, or other ischemic or thromboembolic event within 6 months before first dose)
• Gastrointestinal disorders, including those associated with a high risk of perforation or fistula formation
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon of red blood or other history of significant bleeding within 12 weeks before first dose
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
• Lesions invading or encasing any major blood vessels except thromboses of portal/hepatic vasculature attributed to underlying liver disease and/or liver tumor
• Other clinically significant disorders that would preclude safe study participation (serious non-healing wound/ulcer/bone fracture; uncompensated/symptomatic hypothyroidism; known HIV)
• Must not have untreated or incompletely treated varices with bleeding or high risk for bleeding. Subjects treated with adequate endoscopic therapy (in accordance with institutional standards) without any episodes of recurrent overt GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible
• Must not have a psychiatric illness, other significant medical illness, or social situation (such as involuntary incarceration) which, in the investigator's opinion, would limit compliance or ability to comply with study requirements
• Women must not be pregnant or breastfeeding since cabozantinib may harm the fetus or child.
• Women of child-bearing potential (not surgically sterilized and between menarche and 1-year post menopause) and men must agree to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms) OR abstinence prior to study entry, for the duration of study participation, and for 4 months following completion of study therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Prisoners or subjects who are involuntarily incarcerated, or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness would be excluded.
• Concomitant treatment with strong inducers or inhibitors of CYP3A4 is not allowed. Patients must discontinue the drug(s) at least 14 days prior to first study dose on the study.
• Concomitant anticoagulation with oral anticoagulants (e.g. warfarin, direct thrombin and factor Xa inhibitors), or platelet inhibitors (e.g. clopidogrel) is not allowed.
• Must not have corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days before first dose of study treatment.

• Has a histologically- or cytologically-confirmed advanced (metastatic and/or unresectable) solid tumor (except breast or ovarian cancers whose tumor has a germline or somatic BRCA mutation) that is not eligible for curative treatment and for which standard of care therapy has failed. Participants must have progressed on or be intolerant to standard of care therapies that are known to provide clinical benefit. There is no limit on the number of prior treatment regimens.
• Has either centrally-confirmed known or suspected deleterious mutations in at least 1 of the genes involved in HRR or centrally-confirmed HRD.
• For participants receiving prior platinum (cisplatin, carboplatin, or oxaliplatin either as monotherapy or in combination) for advanced (metastatic and/or unresectable) solid tumor, have no evidence of disease progression during the platinum chemotherapy.
• Has measurable disease per RECIST 1.1 or PCWG-modified RECIST 1.1 as assessed by the local site Investigator/radiology and confirmed by BICR.
• Is able to provide a newly obtained core or excisional biopsy of a tumor lesion or either an archival formalin-fixed paraffin embedded (FFPE) tumor tissue block or slides.
• Has a life expectancy of at least 3 months.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1, as assessed within 3 days of treatment initiation.
• Male participants must agree to use contraception during the treatment period and for at least 90 days (3 months) after the last dose of study treatment and refrain from donating sperm during this period.
• Female participants must not be pregnant or breastfeeding. Additionally, female participants must either not be a woman of childbearing potential (WOCBP) or, if a WOCBP, agree to use contraception during the treatment period and for at least 30 days (1 month) after the last dose of study treatment.
• Has adequate organ function.
• Has a known additional malignancy that is progressing or has required active treatment in the last 5 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, ductal carcinoma in situ, or cervical carcinoma in situ that has undergone potentially curative therapy are not excluded.
• Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML.
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis. Note: Participants with previously treated brain metastases may participate if radiologically stable, clinically stable, and without requirement for steroid treatment for at least 14 days prior to the first dose of study treatment.
• Has received colony-stimulating factors (e.g., granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF] or recombinant erythropoietin) within 28 days prior to the first dose of study treatment.
• Has a known history of human immunodeficiency virus (HIV) infection.
• Has known active hepatitis infection (i.e., Hepatitis B or C).
• Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (e.g., gastrectomy, partial bowel obstruction, malabsorption).
• Has received prior therapy with olaparib or with any other polyadenosine 5' diphosphoribose (poly[ADP ribose]) polymerization (PARP) inhibitor.
• Has a known hypersensitivity to the components or excipients in olaparib.
• Has received previous allogenic bone-marrow transplant or double umbilical cord transplantation (dUCBT).
• Has received a whole blood transfusion in the last 120 days prior to entry to the study. Packed red blood cells and platelet transfusions are acceptable if not performed within 28 days of the first dose of study treatment.

• Patients in Group F must have a body surface area (BSA) >= 0.6 m^2
• 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; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• Patients must be newly diagnosed with histologically-proven primary pediatric hepatic malignancies including hepatoblastoma or hepatocellular carcinoma, except as noted below; patients with a diagnosis of hepatocellular neoplasm, not otherwise specified, should be classified and treated per hepatoblastoma treatment arms; note that rapid central pathology review is required in some cases; please note: all patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by immunohistochemistry (IHC) according to the practices at the institution
• Patients with histology consistent with pure SCU must have positive INI1/SMARCB1 staining
• For all Group A patients, WDF status as determined by rapid review will be used to further stratify patients to Group A1 or A2
• For Groups B, C and D, rapid review is required if patients are either >= 8 years of age or have an alphafetoprotein (AFP) =< 100 at diagnosis
• For all Groups E and F patients, rapid central pathology review is required
• In emergency situations when a patient meets all other eligibility criteria and has had baseline required observations, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy
• Clinical situations in which emergent treatment may be indicated include, but are not limited to, the following circumstances:
• Anatomic or mechanical compromise of critical organ function by tumor (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.)
• Uncorrectable coagulopathy
• For a patient to maintain eligibility for AHEP1531 when emergent treatment is given, the following must occur:
• The patient must have a clinical diagnosis of hepatoblastoma, including an elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility criteria at the time of emergent treatment
• Patient must be enrolled on AHEP1531 prior to initiating protocol therapy; a patient will be ineligible if any chemotherapy is administered prior to AHEP1531 enrollment
• Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to undergoing a diagnostic biopsy, pathologic review of material obtained in the future during either biopsy or surgical resection must either confirm the diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be included in the analysis of the study aims
• Patients may have had surgical resection of the hepatic malignancy prior to enrollment; all other anti-cancer therapy for the current liver lesion is prohibited
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 or
• A serum creatinine based on age/gender as follows:
• Age: maximum serum creatinine (mg/dL)
• 1 month to < 6 months: 0.4 (male and female)
• 6 months to < 1 year: 0.5 (male and female)
• 1 to < 2 years: 06 (male and female)
• 2 to < 6 years: 0.8 (male and female)
• 6 to < 10 years: 1 (male and female)
• 10 to < 13 years: 1.2 (male and female)
• 13 to < 16 years: 1.5 (male), 1.4 (female)
• >= 16 years: 1.7 (male), 1.4 (female)
• Total bilirubin =< 5 x upper limit of normal (ULN) for age
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 10 x upper limit of normal (ULN) for age
• Shortening fraction of >= 28% by echocardiogram (for patients on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior to study enrollment) or
• Ejection fraction of >= 47% by echocardiogram or radionuclide angiogram (for patients on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior to study enrollment)
• Group F patients only: QT/corrected QT (QTc) interval =< 450 milliseconds for males and =< 470 milliseconds for females (assessed within 8 weeks prior to study enrollment)
• Normal pulmonary function tests (including diffusion capacity of the lung for carbon monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at rest, known requirement for supplemental oxygen) (for patients receiving chemotherapy [Groups A, B, C, D, E2, F]); for patients who do not have respiratory symptoms or requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
• 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
• Prior chemotherapy or tumor directed therapy (i.e. radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser); therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible
• Patients who are currently receiving another investigational drug
• Patients who are currently receiving other anticancer agents
• Patients with uncontrolled infection
• Patients who previously received a solid organ transplant, other than those who previously received an orthotopic liver transplantation (OLT) as primary treatment of their hepatocellular carcinoma
• Patients with hypersensitivity to any drugs on their expected treatment arm
• Group C: Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD)
• Group D:
• Patients with chronic inflammatory bowel disease and/or bowel obstruction
• Patients with concomitant use of St. John's wort, which cannot be stopped prior to the start of trial treatment
• Group F:
• Patients with peripheral sensitive neuropathy with functional impairment
• Patients with a personal or family history of congenital long QT syndrome
• These criteria apply ONLY to patients who may receive chemotherapy (all groups other than Group E1):
• 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
• Note for Group F: patients of childbearing potential should use effective birth control during treatment with sorafenib and for at least 2 weeks after stopping treatment

PHASE 1 Key 1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by protocol specified tests. 2. ECOG PS 0-1. 3. Age ≥18 (or age ≥ 20 of age as required by local regulation). 4. Capability to swallow capsules intact (without chewing, crushing, or opening). 5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only measurable disease as defined by RECIST version 1.1 is allowed. 6. Prior cytotoxic chemotherapy is allowed. 7. Prior immunotherapy is allowed. 8. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer therapy to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 Grade less than or equal to 1. 9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria. 10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without supplementation 11. Life expectancy ≥ 3 months. PHASE 2 Key Inclusion Criteria 1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene fusion. 2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based local testing using either: 1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction (qPCR) test will be accepted to determine molecular eligibility. • Adequate tumor tissue needs to be sent to the Sponsor designated central diagnostic laboratory for retrospective confirmation by a central diagnostic laboratory test selected by the Sponsor. OR 2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of fusion status by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment will be accepted to determine molecular eligibility.
• Adequate tumor tissue must be sent to the Sponsor designated central diagnostic laboratory for prospective confirmation by a central diagnostic laboratory test selected by the Sponsor PRIOR to enrollment. 3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1. 4. Age ≥12 (or age ≥ 20 as required by local regulation). 5. Willing and able to provide written institutional review board (IRB)/institutional ethics committee-approved Informed Consent or an Assent signed by a parent or legal guardian for subjects age 12 to 17. 6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST (v1.1) are eligible. 7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3 rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all inclusion and exclusion criteria are met. i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv. EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+ solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors 8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol specified criteria. 9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without supplementation 10. Life expectancy ≥ 3 months. Key Exclusion Criteria PHASE 1 and PHASE 2 1. Concurrent participation in another therapeutic clinical trial. 2. Symptomatic brain metastases or leptomeningeal involvement. 3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the skin, or any in situ carcinoma that has been completely resected, requiring therapy within the previous 2 years. 4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Palliative radiation (≤10 fractions) must have been completed at least 48 hours prior to study entry 5. Clinically significant cardiovascular disease (either active or within 6 months prior to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (New York Heart Association Classification Class ≥ II), cerebrovascular accident or transient ischemic attack, symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2 6. Any of the following cardiac criteria: Mean resting corrected QT interval (ECG interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval. 7. Known active infections (bacterial, fungal, viral including HIV positivity). 8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption. 9. Peripheral neuropathy of CTCAE ≥grade 2. 10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior radiation pneumonitis are not excluded.

• 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. 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.

1. Prior SOT of kidney, liver, heart, lung, pancreas, small bowel, or any combination of these (SOT cohort); or prior allogeneic HCT (HCT cohort) 2. A diagnosis of locally-assessed, biopsy-proven EBV+ PTLD 3. Availability of appropriate partially HLA-matched and restricted tabelecleucel has been confirmed by the sponsor 4. Measurable, 18F-deoxyglucose (FDG)-avid (Deauville score ≥ 3) systemic disease using Lugano Classification response criteria by positron emission tomography (PET)-diagnostic computed tomography (CT), except when contraindicated or mandated by local practice, then magnetic resonance imaging (MRI) may be used.For subjects with treated central nervous system (CNS) disease, a head CT and/or brain/spinal MRI as clinically appropriate will be required to follow CNS disease response per Lugano Classification response criteria. 5. Treatment failure of rituximab or interchangeable commercially available biosimilar monotherapy (SOT subgroup A or HCT cohort) or rituximab plus any concurrent or sequentially administered chemotherapy regimen (SOT subgroup B) for treatment of PTLD. 6. Eastern Cooperative Oncology Group performance status ≤ 3 for subjects aged ≥ 16 years; Lansky score ≥ 20 for subjects < 16 years 7. For HCT cohort only: If allogeneic HCT was performed as treatment for an acute lymphoid or myeloid malignancy, the underlying primary disease for which the subject underwent transplant must be in morphologic remission 8. Adequate organ function 1. Absolute neutrophil count ≥ 1000/μL, (SOT cohort) or ≥ 500/μL (HCT cohort), with or without cytokine support 2. Platelet count ≥ 50,000/μL, with or without transfusion or cytokine support. For HCT cohort, platelet count < 50,000/μL but ≥ 20,000/μL, with or without transfusion support, is permissible if the subject has not had grade ≥ 2 bleeding in the prior 4 weeks (where grading of the bleeding is determined per the National Cancer Institute's Common Terminology Criteria for Adverse Events [CTCAE], version 5.0) 3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin each < 5 × the upper limit of normal; however, ALT, AST, and total bilirubin each ≤ 10 × upper limit of normal is acceptable if the elevation is considered by the investigator to be due to EBV and/or PTLD involvement of the liver as long as there is no known evidence of significant liver dysfunction 9. Subject or subject's representative is willing and able to provide written informed consent 1. Burkitt lymphoma, classical Hodgkin lymphoma, or any T cell lymphoma 2. Daily steroids of > 0.5 mg/kg prednisone or glucocorticoid equivalent, ongoing methotrexate, or extracorporeal photopheresis 3. Untreated CNS PTLD or CNS PTLD for which the subject is actively receiving CNS-directed chemotherapy (systemic or intrathecal) or radiotherapy at enrollment. NOTE:Subjects with previously treated CNS PTLD may enroll if CNS-directed therapy is complete. 4. Suspected or confirmed grade ≥ 2 graft-versus-host disease (GvHD) per the Center for International Blood and Marrow Transplant Research consensus grading system at enrollment 5. Ongoing or recent use of a checkpoint inhibitor agent (eg, ipilimumab, pembrolizumab, nivolumab) within 3 drug half-lives from the most recent dose to enrollment 6. For HCT cohort: active adenovirus viremia 7. Need for vasopressor or ventilatory support 8. Antithymocyte globulin or similar anti-T cell antibody therapy ≤ 4 weeks prior to enrollment 9. Treatment with Epstein-Barr virus cytotoxic T lymphocytes or chimeric antigen receptor T cells directed against B cells within 8 weeks of enrollment (SOT or HCT cohorts), or unselected donor lymphocyte infusion within 8 weeks of enrollment (HCT cohort only) 10. Female who is breastfeeding or pregnant or female of childbearing potential or male with a female partner of childbearing potential unwilling to use a highly effective method of contraception 11. Inability to comply with study-related procedures

• Patients with histologically confirmed solid tumor malignancies with residual tumors present that require standard of care chemotherapy for a minimum number of cycles. All anatomical sites and all tumor histologies are eligible including central nervous system tumors. Both newly diagnosed and/or newly relapsed patients are eligible.
• Patients ages 8
•25 years
• In the opinion of the investigator, patients must be thought to be able to lie still for imaging without sedation for 20
•30 minutes.
• Patients must have a performance status of > 50% (Lansky or Karnofsky).
• Patients of childbearing potential must have a negative urine or serum pregnancy test as per institution's standard of care within 7 days prior to [18F]FLT PET/CT imaging.
• Ability to understand and the willingness to sign a written informed consent/assent.
• Patients with known allergic or hypersensitivity reactions to previously administered radiopharmaceuticals of similar chemical or biologic composition to [18F]FLT
• Newly diagnosed subjects who had prior chemotherapy or radiotherapy before enrollment in the study. Relapsed patients are eligible prior to starting their relapsed chemotherapy regimen if they meet the other eligibility criteria.
• Subjects for whom chemotherapy is not a standard of care primary therapy option.
• Patients who are pregnant or breast-feeding.
• Patients with no residual tumor (i.e. complete resection at diagnosis or relapse).

• Histologically or cytologically documented locally advanced or metastatic solid tumor malignancy.
• Progressed or was intolerant to all available therapies known to confer clinical benefit appropriate for their tumor type, and for which the patient was eligible and willing to receive, or refused SOC treatments that are perceived to have marginal clinical benefit.
• Adequate bone marrow, kidney and liver function.
• Performance status of 0 or 1.
• Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1 except for AEs not constituting a safety risk by Investigator judgement.
• Prior treatment targeting ILT2 and/or ILT4 or targeting HLA-G.

1. ≥ 18 years of age 2. Histopathological or cytologically documented locally advanced or metastatic solid tumors who have no available standard therapeutic treatment options 3. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 5. Adequate organ function confirmed at screening and within 10 days of initiating treatment, as evidenced by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Hemoglobin (Hgb) ≥ 8 g/dl
• Platelets (plt) ≥ 75 x 10^9/L
• AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver metastases are present
• Total bilirubin ≤ 1.5 x ULN
• Calculated creatinine clearance ≥ 50 mL/min (Cockcroft Gault formula) 6. Negative pregnancy test within 72 hours before starting study treatment in all premenopausal women and women < 12 months after the onset of menopause 7. Must agree to take sufficient contraceptive methods to avoid pregnancy during the study and until at least 6 months after ceasing study treatment 8. Able to sign informed consent and comply with the protocol 1. Women who are pregnant or lactating 2. Women of child-bearing potential (WOCBP) who do not use adequate birth control 3. Patients with any hematologic malignancy, including leukemia (any form), lymphoma, and multiple myeloma 4. Patients with a history of primary central nervous system tumors or carcinomatous meningitis. 5. Patients with the following mood disorders as judged by the Investigator or a psychiatrist:
• Medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia; a history of suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm to others)
• ≥ CTCAE grade 3 anxiety 6. Impaired cardiac function or significant diseases, including but not limited to any of the following:
• left ventricular ejection fraction (LVEF) < 45% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO)
• Congenital long QT syndrome
• QTcF ≥ 480 msec on screening ECG
• Unstable angina pectoris ≤ 3 months prior to starting study drug
• Acute myocardial infarction ≤ 3 months prior to starting study drug 7. Patients with:
• unresolved diarrhea ≥ CTCAE grade 2, or
• impairment of gastrointestinal (GI) function, or
• GI disease that may significantly alter the absorption of TT-00420 8. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., uncontrolled hypertension, uncontrolled hypertriglyceridemia, or active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol 9. Patients who have received chemotherapy, targeted therapy, or immunotherapy ≤ 4 weeks (6 weeks for nitrosourea or mitomycin-C) prior to starting study drug or who have not recovered from side effects of such therapy 10. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy 11. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy 12. Patients who have been treated with any hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF) ≤ 4 weeks prior to starting study drug. 13. Patients who are currently receiving treatment with therapeutic doses of warfarin sodium or any other coumarin-derivative anticoagulants 14. Patients who have received systemic corticosteroids ≤ 2 weeks prior to starting study drug or who have not recovered from the side effects of such treatment. 15. Patients who are currently receiving treatment with strong CYP3A inhibitors or inducers ≤ 2 weeks prior to starting study drug. 16. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory; patients with well controlled HIV might be enrolled) 17. Known history of active infection with Hepatitis B or Hepatitis C 18. Has received a live-virus vaccination within 30 days of planned first dose 19. Inability to swallow or tolerate oral medication 20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that, in the opinion of the investigator, might confound the results of the trial, interfere with the patient's safe participation and compliance in the trial.

• Each patient must meet the following criteria to be enrolled in this study. 1. Be able to and provide written informed consent and be willing and able to comply with all study procedures 2. Adult, 18 years and older 3. AL amyloidosis Mayo stage IIIa based on the 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement at the time of Screening 4. Measurable hematologic disease at Screening as defined by at least one of the following: 1. Involved/Uninvolved Free Light Chain Difference (dFLC) > 4 mg/dL or 2. Involved Free Light Chain (iFLC) > 4 mg/dL with abnormal ratio or 3. Serum Protein Electrophoresis (SPEP) m-spike > 0.5 g/dL 5. Histopathological diagnosis of amyloidosis AND confirmation of AL derived amyloid deposits by at least one of the following: 1. Immunohistochemistry or 2. Mass spectrometry or 3. Characteristic electron microscopy appearance 6. Cardiac involvement as defined by: a. Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure AND b. At least one of the following: i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening or iii. Cardiac MRI with gadolinium contrast agent diagnostic or cardiac amyloidosis 7. Planned first-line treatment for plasma cell dyscrasia is a CyBorD-based regimen administered as Standard of Care (SoC) 8. Adequate bone marrow reserve and hepatic function as demonstrated by: 1. Absolute neutrophil count ≥ 1.0 x 109/L 2. Platelet count ≥ 75 x 109/L 3. Hemoglobin ≥ 9 g/dL 4. Total direct bilirubin ≤ 2 times the upper limit of normal (x ULN) unless due to Gilbert's syndrome. 5. Aspartate aminotransferase (AST) ≤ 3 x ULN 6. Alanine aminotransferase (ALT) ≤ 3 x ULN 7. Alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly and isozymes specific to liver, rather than bone) 9. Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective physician approved contraception from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer 10. Men must be surgically sterile or must agree to use effective physician approved contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of his PCD therapy, whichever is longer
• Patients who meet any of the following criteria will not be permitted entry to the study. 1. Have any other form of amyloidosis other than AL amyloidosis 2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after screening laboratory samples are obtained and prior to randomization is allowed. 3. Has POEMS syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% or biopsy-proven bony or extramedullary plasmacytoma AND any one or more of the following CRAB features: a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the ULN or > 2.75 mmol/L (> 11mg/dL) ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177mol/L (> 2mg/dL) iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a hemoglobin value < 100g/L iv. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR b. Any one of the following biomarkers of malignancy: i. 60% or greater clonal plasma cells on bone marrow examination ii. More than one focal lesion on MRI that is at least 5mm or greater in size 4. Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion 5. Taking prednisone or its equivalent > 10 mg/day 6. Taking doxycycline 7. Receiving dialysis 8. Planned stem cell transplant during the first 6 months of protocol therapy. Stem cell collection during the protocol therapy is permitted. 9. Have had myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias within 6 months prior to screening or percutaneous cardiac intervention with recent stent or coronary artery bypass grafting within 4 months prior to screening. Exacerbation of chronic condition or new acute condition will require discussion and approval by the Medical Monitor. 10. Left Ventricular Ejection Fraction (LVEF) is < 40% by echocardiogram at Screening 11. Have severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area < 1.0 cm2) or severe congenital heart disease 12. Have history of sustained ventricular tachycardia or aborted ventricular fibrillation or a history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker/implantable cardioverter-defibrillator (ICD) is indicated but not placed. (Participants who do have a pacemaker or ICD are allowed in the study.) 13. QT corrected by Fridericia (QTcF) is > 550 msec. Participants who have a pacemaker may be included regardless of calculated QTc interval. 14. There is evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following: 1. First degree Atrioventricular (AV)-block 2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) 3. Right or left bundle branch block 4. Atrial fibrillation with a controlled ventricular rate. (An uncontrolled ventricular rate [i.e., > 110 beats per minute] determined by an average of three beats in lead II or representative beats in lead II is not allowed) 15. Have had major surgery within 4 weeks of randomization or is planning major surgery during the study. Patients with surgical procedures conducted under local anesthesia may participate 16. There is active malignancy (including lymphoma) with the exception of any of the following: 1. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer 2. Adequately treated stage I cancer from which the patient is currently in remission and has been in remission for > 2 years 3. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 mg/mL 4. Other localized and/or low risk malignancies may be permitted with Medical Monitor approval. 17. Have received an investigational drug/device in another clinical investigational study within 60 days before Screening 18. Hypersensitivity to the study drug 19. Have received a live vaccine within 4 weeks prior to first dose of CyBorD 20. Women who are breast feeding 21. Have any other medical, social or psychological factors that could affect the patient's safety or ability to consent personally or comply with study procedures.

1. Must have provided informed consent in a manner approved by the Investigator's Institutional Review Board (IRB) prior to any study-related procedure being performed. If a participant is unable to provide informed consent due to his/her medical condition, the participant's legally authorized representative may consent on behalf of the study participant, as permitted by local law and institutional Standard Operating Procedures; 2. Aged greater than or equal to 18 years at the time of informed consent; 3. Recent use of an FDA-approved immune checkpoint inhibitor (ICI, defined as administered an immune checkpoint inhibitor ≤ 6 months of myocarditis diagnosis), alone or in combination with other cancer therapies (i.e. chemotherapy, radiation therapy or targeted therapy). The FDA-approved ICI could be given as part of a clinical trial but not in combination with a new investigational agent which may cause myocarditis; 4. A diagnosis of myocarditis. 5. Hospitalized at the time of randomization; 6. On 1000 mg of solumedrol per day for myocarditis or with an intent to initiate 1000 mg of solumedrol per day for myocarditis within 24 hours of first administration of study drug; 7. Serum evidence of ongoing myocardial injury: Serum evidence of ongoing myocardial injury will be defined as an institutional troponin (either conventional or high-sensitivity troponin I or T, using the standard institutional assay) with a value that is ≥5 times the upper limit of the reference standard normal for that institution. The troponin assay may be adjusted based on sex depending on institutional standards. This value of troponin of ≥5 times above the institutional upper limits of normal value must be noted within 10 days prior to potential randomization. The 10-day period can be in the outpatient or inpatient setting. For example, a participant with a troponin value that on one occasion was ≥5 times the upper limits of institutional normal in the 10-day window prior to potential randomization (whether in the inpatient or outpatient setting), but later decreases below that threshold, typically due to starting corticosteroids, would still be considered eligible; 8. The following laboratory parameters, not older than 48 hours at the time of randomization, and measured as part of usual care:
• Total white blood cell (WBC) count >2,500/μl
• Absolute neutrophil count (ANC) >1,500/μL
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <20 times the upper limit of the institutional normal ranges; 9. Women of childbearing potential (i.e., not postmenopausal, or surgically sterilized) must have a negative highly sensitive urine or serum pregnancy test prior to randomization. Participating women of childbearing potential must be willing to consistently use effective methods of contraception from screening until at least 90 days after administration of the last dose of study drug. Participating men must also be willing to consistently use effective methods of contraception from screening until at least 90 days after administration of the last dose of study drug; and 10. Must be willing and able to abide by all study requirements and restrictions. 1. Must not have experienced any of the following (as defined in the section on the primary endpoint) in the 30-day period prior to randomization:
• A sudden cardiac arrest
• Cardiogenic shock as defined. A significant bradyarrhythmia (Mobitz type II second degree atrioventricular block or third degree (complete) atrio-ventricular (AV) block, for which an intervention with a temporary or permanent pacemaker is completed or recommended).
• A significant tachyarrhythmia (ventricular fibrillation of any duration or sustained ventricular tachycardia (>30 seconds, >120 beats per minute); or a ventricular tachyarrhythmia requiring intervention. 2. Recent (≤2 month) exposure to abatacept or belatacept. 3. Concurrent or recent (≤2 month) use of the following non-corticosteroid immunosuppressive therapies prior to randomization: mycophenolate, JAK STAT inhibitors (including but not limited to upadacitinib, tofacitinib, baricitinib, and filgotinib), tacrolimus, anti-thymocyte globulin, alemtuzumab, infliximab, and plasma exchange. The use of intravenous immunoglobulin is permitted prior to randomization and during study treatment. 4. Currently enrolled in another interventional study utilizing systemic agents for the management of ICI-related toxicities. 5. Female who is pregnant, breastfeeding, or is considering becoming pregnant during the study or for approximately 90 days after the last dose of study drug. 6. Male who is considering fathering a child or donating sperm during the study or for approximately 30 days after the last dose of study drug. 7. Any active, chronic, or recurrent viral infection that, based on the investigator's clinical assessment, makes the participant an unsuitable candidate for the study. These may include hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a single episode) herpes zoster, and disseminated (even a single episode) herpes simplex. Active HBV and HCV are defined as: HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for Hepatitis B core antibody (HBc Ab) positive (+) participants; HCV: HCV ribonucleic acid (RNA) detectable in any participant with anti-HCV antibody (HCV Ab). Patients with active Covid-19 infection will be excluded. This is defined as the period of ongoing symptoms in the setting of a positive Covid-19 test, or until 10 days after symptom onset and after resolution of fever for at least 24 hours, without the use of fever-reducing medications. 8. Known active tuberculosis (TB), history of incompletely treated TB, suspected or known extrapulmonary TB, suspected or known systemic bacterial or fungal infections; 9. Receipt of any live vaccine within four weeks prior to the first dose of study drug, or expected need of live vaccination during study participation including at least 90 days after the last dose of IV study drug. 10. Any medical condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or interpretation of the study results, or that would, in the opinion of the Investigator, increase the risk of the participant by participating in the study. 11. Any factors that, in the Investigator's opinion, are likely to interfere with study procedures, such as history of noncompliance with scheduled appointments.

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:
• Cohorts 1-4 without measurable disease
• MCT not meeting the requirements for Cohorts 3 or 4
• 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 may be eligible with prior Sponsor approval
• Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET fusion; determined to be medically operable and tumor deemed resectable by a thoracic surgical oncologist, without prior systemic treatment 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 2 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)
• Participants with implanted pacemakers may enter the study without meeting QTc criteria due to nonevaluable measurement if it is possible to monitor for QT changes.
• Participants with bundle branch block may be considered for study entry if QTc is appropriate by a formula other than Fridericia's and if it is possible to monitor for QT changes.
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers and certain prohibited concomitant medications
• Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior systemic therapy for NSCLC.

• Have advanced breast cancer or another solid tumor with the presence of a PIK3CA H1047R mutation (or other Sponsor and SRC-approved, activating PIK3CA mutations other than H1047R mutation)
• Have adequate archival tumor tissue sample available or be approved by the Sponsor for enrollment if no tumor sample is available.
• Have stopped all cancer treatment and have recovered from the major side effects
• Have adequate organ function, as measured by blood tests
• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale
• Patients must have
• Measurable disease --- Patients with non-breast tumor types must have at least 1 measurable lesion
• Non-measurable bone disease (at least one bone lesion in breast cancer patients only)
• For patients with an ER+ breast cancer diagnosis:
• If female, must be postmenopausal
• If male, must agree to use hormone suppression
• Phase 1a: -- Dose escalation and backfill patients:
• Advanced solid tumor
• Patients may have had up to 5 prior regimens for advanced disease
• Phase 1b:
• Part A:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 2 prior regimens for advanced disease
• Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required
• Part B:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 2 prior regimens for advanced disease.
• Part C:
• ER+/HER2- advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease. ---- Prior CDK4/6 inhibitor therapy required.
• Have a diagnosis of diabetes mellitus Type 2
• Part D:
• Advanced breast cancer
• Patients may have had up to 5 prior regimens for advanced disease.
• Part E:
• Advanced solid tumor
• Patients may have had up to 3 prior regimens for advanced disease
• Medical Conditions
• Colorectal cancer
• Endometrial cancers with specific concurrent oncogenic alterations
• A history of known active or suspected
• Diabetes mellitus Type 1 or
• Diabetes mellitus Type 2 requiring antidiabetic medication (Phase 1a and all parts of Phase 1b except Part C).
• Serious concomitant systemic disorder
• Known or suspected history of untreated or uncontrolled central nervous system (CNS) involvement.
• Active uncontrolled systemic bacterial, viral, fungal, or parasitic infection, or other clinically significant active disease process
• Prior exposure to PI3K/AKT/mTOR inhibitor(s), except in certain circumstances

• Each patient must meet the following criteria to be enrolled in this study. 1. Be able to and provide written informed consent and be willing and able to comply with all study procedures 2. Adult, 18 years and older 3. AL amyloidosis Mayo stage IIIb based on the 2013 European Modification of the 2004 Standard Mayo Clinic Staging in patients with advanced cardiac involvement at the time of Screening 4. Measurable hematologic disease at Screening as defined by at least one of the following: 1. Involved/Uninvolved Free Light Chain Difference (dFLC) > 4 mg/dL or 2. Involved Free Light Chain (iFLC) > 4 mg/dL with abnormal ratio or 3. Serum Protein Electrophoresis (SPEP) m-spike > 0.5 g/dL 5. Histopathological diagnosis of amyloidosis AND confirmation of AL derived amyloid deposits by at least one of the following: 1. Immunohistochemistry or 2. Mass spectrometry or 3. Characteristic electron microscopy appearance 6. Cardiac involvement as defined by: a. Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure AND b. At least one of the following: i. Endomyocardial biopsy demonstrating AL cardiac amyloidosis or ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening or iii. Cardiac MRI with gadolinium contrast agent diagnostic or cardiac amyloidosis 7. Planned first-line treatment for plasma cell disorder is a CyBorD-based regimen administered as Standard of Care (SoC) 8. Adequate bone marrow reserve and hepatic function as demonstrated by: 1. Absolute neutrophil count ≥ 1.0 x 109/L 2. Platelet count ≥ 75 x 109/L 3. Hemoglobin ≥ 9 g/dL 4. Total direct bilirubin ≤ 2 times the upper limit of normal (x ULN) unless due to Gilbert's syndrome. 5. Aspartate aminotransferase (AST) ≤ 3 x ULN 6. Alanine aminotransferase (ALT) ≤ 3 x ULN 7. Alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly and isozymes specific to liver, rather than bone) 9. Women of childbearing potential (WOCBP) must have a negative pregnancy test during Screening and must agree to use highly effective physician approved contraception from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer 10. Men must be surgically sterile or must agree to use effective physician approved contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of his PCD therapy, whichever is longer.
• Patients who meet any of the following criteria will not be permitted entry to the study. 1. Have any other form of amyloidosis other than AL amyloidosis 2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after screening laboratory samples are obtained and prior to randomization is allowed. 3. Has POEMS syndrome or multiple myeloma defined as clonal bone marrow plasma cells > 10% or biopsy-proven bony or extramedullary plasmacytoma AND any one or more of the following CRAB features: a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1mg/dL) higher than the ULN or > 2.75 mmol/L (> 11mg/dL) ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177mol/L (> 2mg/dL) iii. Anemia: hemoglobin value of > 20g/L below the lowest limit of normal, or a hemoglobin value < 100g/L iv. Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, or PET/CT. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR b. Any one of the following biomarkers of malignancy: i. 60% or greater clonal plasma cells on bone marrow examination ii. More than one focal lesion on MRI that is at least 5mm or greater in size 4. Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion 5. Taking prednisone or its equivalent > 10 mg/day 6. Taking doxycycline 7. Receiving dialysis 8. Planned stem cell transplant during the first 6 months of protocol therapy. Stem cell collection during the protocol therapy is permitted. 9. Have had myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias within 6 months prior to screening or percutaneous cardiac intervention with recent stent or coronary artery bypass grafting within 4 months prior to screening. Exacerbation of chronic condition or new acute condition will require discussion and approval by the Medical Monitor. 10. Left Ventricular Ejection Fraction (LVEF) is < 40% by echocardiogram at Screening 11. Have severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area < 1.0 cm2) or severe congenital heart disease 12. Have history of sustained ventricular tachycardia or aborted ventricular fibrillation or a history of atrioventricular nodal or sinoatrial nodal dysfunction for which a pacemaker/implantable cardioverter-defibrillator (ICD) is indicated but not placed. (Participants who do have a pacemaker or ICD are allowed in the study.) 13. QT corrected by Fridericia (QTcF) is > 550 msec. Participants who have a pacemaker may be included regardless of calculated QTc interval. 14. There is evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following: 1. First degree Atrioventricular (AV)-block 2. Second degree AV-block Type 1 (Mobitz Type 1/Wenckebach type) 3. Right or left bundle branch block 4. Atrial fibrillation with a controlled ventricular rate. (An uncontrolled ventricular rate [i.e., > 110 beats per minute] determined by an average of three beats in lead II or representative beats in lead II is not allowed) 15. Have had major surgery within 4 weeks of randomization or is planning major surgery during the study. Patients with surgical procedures conducted under local anesthesia may participate 16. There is active malignancy (including lymphoma) with the exception of any of the following: 1. Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer 2. Adequately treated stage I cancer from which the patient is currently in remission and has been in remission for > 2 years 3. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 mg/mL 4. Other localized and/or low risk malignancies may be permitted with Medical Monitor approval. 17. Have received an investigational drug/device in another clinical investigational study within 60 days before Screening 18. Hypersensitivity to the study drug 19. Have received a live vaccine within 4 weeks prior to first dose of CyBorD 20. Women who are breast feeding 21. Have any other medical, social or psychological factors that could affect the patient's safety or ability to consent personally or comply with study procedures.

• Age -- Age ≤ 30 years at time of initial qualifying solid tumor diagnosis
• Diagnosis -- Histologic diagnosis of solid malignancy (excluding brain tumors and lymphoma) that meets at least one of the following criteria:
• Refractory, defined as tumor progression after initiation of standard first line therapy without having achieved a prior partial or complete remission OR Biopsy proven residual disease at the completion of planned standard initial front-line therapy.
• Recurrent, defined as tumor progression after achieving a prior partial or complete remission
• Newly diagnosed high risk disease, defined as having an expected event free survival of < 50% at 2 years.
• Lacks definitive diagnosis or classical genomic findings after histologic review and standard molecular testing (rare tumor group).
• Examples include (eligibility not limited to these examples):
• Histology typically associated with a fusion in which fusion is not detected.
• Ewing-like sarcoma
• Undifferentiated sarcoma
• Inflammatory myofibroblastic tumor without ALK fusion
• Infantile fibrosarcoma without NTRK fusion
• Specimen Samples
• Sufficient tumor specimen available to meet the minimum requirements for profiling from diagnosis or progression / recurrence --- OR
• Surgery / biopsy planned as part of clinical care that is anticipated to yield sufficient material to meet the minimum requirements for profiling; OR
• Patient has already had molecular profiling and patient has not yet started matched targeted therapy based on the report .
• No Therapy Planned -- Patients who have declined further anticancer therapy will be excluded.
• Performance Status -- Patients with Lansky (age < 16 years) or Karnofsky (age ≥16 years) score < 50 will be excluded.
• Life Expectancy -- Patients with anticipated life expectancy < 3 months will be excluded.

• 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

• Be male at any age.
• Be scheduled to undergo surgery, chemotherapy, drug treatment and/or radiation for the treatment or prevention of a medical condition or malignancy with risk of causing permanent and complete loss of subsequent testicular function.
• Or, have a medical condition or malignancy that requires removal of all or part of one or both testicles.
• Have newly diagnosed or recurrent disease. Those who were not enrolled at the time of initial diagnosis (i.e., patients with recurrent disease) are eligible if they have not previously received therapy that is viewed as likely to result in complete and permanent loss of testicular function.
• Have two testicles if undergoing elective removal of all or part of a testicle for fertility preservation only. Note: removal of both testicles will limit fertility preservation options.
• Sign an approved informed consent and authorization permitting the release of personal health information. The patient and/or the patient's legally authorized guardian must acknowledge in writing that consent for specimen collection has been obtained, in accordance with institutional policies approved by the U.S. Department of Health and
• Consent for serum screening tests for infectious diseases [HIV-1, HIV-2, Hepatitis B, Hepatitis C], to be performed at the time of testicular tissue harvesting.
• Undergo a full history and physical examination and obtain standard pre-operative clearance (based on the most recent ACC/AHA Guideline for Perioperative Cardiovascular Evaluation for Noncardiac Surgery) as determined by their primary surgeon.
• Participating in long term follow-up is a requirement of the protocol.
• Diagnosed with psychological, psychiatric, or other conditions which prevent giving fully informed consent.
• Diagnosed with an underlying medical condition that significantly increases their risk of complications from anesthesia and surgery.

Inclusion: 1. Histologically confirmed relapsed or refractory solid tumor as follows:
• For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
• For dose expansion and tumor specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll. EWS is not eligible for TOPO and CTX tumor-specific cohorts.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement. Histopathology confirmation of both EWSR1-ETS or FUS-ETS rearrangement partners is required OR availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or have refractory disease and at least evaluable disease in at least one site other than bone marrow that can be followed by imaging. 2. Age ≥2 and <21 years at the time of study entry. 3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age. 4. Adequate bone marrow function.
• Absolute neutrophil count ≥1000/mm3;
• Platelet count ≥100,000/mm3 (transfusion independent, no platelet transfusion in past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed). 5. Adequate renal function: Serum creatinine level based on age/gender must within protocol specified limits. 6. Adequate liver function, including:
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;
• Total bilirubin ≤1.5 × ULN for age, unless the patient has documented Gilbert's syndrome. 7. Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma. Patients with EWS enrolled to Phase 2 portion of the study are eligible with evaluable disease (eg, bone only disease with no soft tissue component). 8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia. 9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit. Exclusion: 1. Phase 1 and tumor specific cohorts: For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on these medications are eligible. Phase 2 portion: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ and did not progress while on these medications are eligible. 2. Prior intolerability to IRN and/or TMZ plus/minus palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for TOPO and CTX combination. 3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of Cycle 1 Day 1 (C1D1) are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination (See Section 5.7.1 for list of products.) 4. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas. 5. Prior irradiation to >50% of the bone marrow (see Appendix 9). 6. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry. 7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries. 8. For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, IRN and/or TMZ. For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX. 9. Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days. 10. Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days post radiation and 4 weeks post-surgery and are neurologically stable. 11. Hereditary bone marrow failure disorder. 12. QTc >470 msec. 13. History of clinically significant or uncontrolled cardiac disease, including:
• History of or active congestive heart failure; if patient had congestive heart failure resolve and >1 year from resolution, patient will be considered eligible;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• Need for medications known to prolong the QT interval;
• Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
• Left ventricular ejection fraction <50% or shortening fraction <28%. 14. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy). 15. Severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product 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. 16. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.

Inclusion Criteria 1. Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ cell cancer, or unknown primary tumor. 2. Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI contrast, an MRI without contrast is acceptable if lesions are visible) 3. All brain metastases must be outside the brain stem (midbrain, pons and medulla). 4. Patient must have 10 or less brain metastases. 5. The maximum diameter of any lesion must be less than or equal to 3.0 cm. 6. Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one additional brain metastasis that can be targeted with SRS 7. Age ≥ 18 years. 8. ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or better. 9. All men, as well as women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. A female of child-bearing potential is any woman (regardless of sexual orientation, marital status, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Medically acceptable birth control (contraceptives) includes:
• Approved hormonal contraceptives (such as birth control pills, patch, or ring: Depo-Provera, Implanon), or
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a substance that kills sperm) 10. Ability to understand and the willingness to sign a written informed consent. Exclusion Criteria 1. Patients had craniotomy and surgery to the brain within 7 days from the date of SRS. 2. Patients with leptomeningeal metastasis. NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology, unless a parenchymal lesion can adequately explain the neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion. 3. Patients with a contraindication to both MRI (with or without contrast) and CT scan (with contrast) 4. Patients with life expectancy < 3 months. 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 the opinion of the investigator, would limit compliance with study requirements. 6. Subjects must not be pregnant or nursing at the time of SRS treatment due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

• Patients can have either histologically confirmed malignancy that is radiologically evaluable and metastatic or unresectable, or have a malignancy for which a PD-1/PD-L1 inhibitor has been approved in the adjuvant setting. Eligible tumor types include solid tumors and malignancies in which there is known evidence of clinical activity for single agent PD-1 or PD-L1 antibodies. Nivolumab is Food and Drug Administration (FDA)-approved for the treatment of melanoma, non-small cell lung cancer (NSCLC), Merkel cell cancer, bladder cancer, renal cell carcinoma (RCC), gastric cancer, hepatocellular carcinoma (HCC), cervical cancer, head and neck cancer, Hodgkin lymphoma (HL), metastatic small cell lung cancer (SCLC), and any solid tumor with microsatellite instability (MSI)-high status confirmed. Patients with HL are eligible but must follow standard response criteria. Additional tumor types may be eligible on a case by case basis upon discussion with principal investigator (PI). Patients enrolling on the trial for adjuvant use will be restricted to those with histology for which a PD-1/PD-L1 inhibitor has been approved in the adjuvant setting including but not limited to NSCLC, melanoma, RCC, cervical cancer, and bladder cancer
• Patients who have previously received other forms of immunotherapy (high-dose [HD] IL-2, IFN, CTLA-4) are allowed. Patients must not have received cytokine immunotherapy for at least 4 weeks before nivolumab administration. Patients who have received prior anti-CTLA4 will be allowed and the washout period is 6 weeks
• Age >= 18 years; children are excluded from this study but may be eligible for future pediatric phase 1 combination trials
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Karnofsky >= 60)
• Life expectancy of greater than 12 weeks
• Leukocytes >= 1,000/mcL
• Absolute neutrophil count >= 500/mcL
• Platelets >= 50,000/mcL
• Total bilirubin =< 2 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN or < 8 x institutional ULN for patients with liver metastases or an autoimmune disease that is contributing to the elevation of these values
• Creatinine ULN OR glomerular filtration rate (GFR) >= 30 mL/min (if using the Cockcroft-Gault formula)
• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviral therapy with undetectable viral load within 6 months are eligible for this trial
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
• If history of hepatitis C virus (HCV) infection, must be treated with undetectable HCV viral load
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS) specific treatment is not required and is unlikely to be required for at least 4 weeks (or scheduled assessment after the first cycle of treatment), and a risk-benefit analysis (discussion) by the patient and the investigator favors participation in the clinical trial
• The effects of nivolumab on the developing human fetus are unknown. For this reason, women of child-bearing 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 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. 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. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception. 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. 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 90 days. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document
• Patients with more than one autoimmune disease are eligible. The treating physician would determine which autoimmune disease is dominant and the patient would be treated under that specific cohort
• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (AEs) due to agents administered more than 4 weeks earlier have not resolved or stabilized. Palliative (limited-field) radiation therapy (RT) is permitted (2 week washout from start of treatment), 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
• Patients with prior therapy with an anti-PD-1 or anti-PD-L1
• Patients with prior allogeneic hematologic transplant
• Patients who are receiving any other anticancer investigational agents
• 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
• Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) bleeding, 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. For the IBD (UC and CD) cohort, an endoscopic assessment, disease activity index, and disease specific inclusion/exclusion criteria will substitute for these factors in determining eligibility with the exception of abdominal carcinomatosis, which should prompt further evaluation

• Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
• Diagnosis of advanced cancer
• Patient-reported 2-month weight loss of at least 5 pounds (2.3 kilograms) and/or physician-estimated caloric intake of less than 20 calories/kilogram of body weight per day
• The patient must perceive loss of appetite and/or weight as a problem; and have an appetite score of 4 or worse on the "Please rate your appetite…." question that requires a patient response on a 0-10 numeric rating scale
• Not receiving ongoing tube feedings or parenteral nutrition at the time of registration
• Not currently using systemic adrenal steroids (with the exception of short-term dexamethasone within 3 days of chemotherapy for control of chemotherapy side effects)
• No use of androgens, progesterone analogs, or other appetite stimulants within the past month
• Patient should not have poorly controlled hypertension or congestive heart failure at registration
• Patient should not have an obstruction of the alimentary canal, malabsorption, or intractable vomiting (defined as vomiting more than 3 times per day over the preceding week)
• Not currently using olanzapine for another medical condition or had previously used olanzapine for chronic nausea or for any pre-existing psychotic disorder
• Patient should not have had a previous blood clot at any time in the past
• No history of poorly controlled diabetes
• No symptomatic leptomeningeal disease or known brain metastases as these patients may have difficulty taking oral medications
• No history of hypersensitivity to olanzapine or megestrol acetate
• No COVID-19 infection in the past that, in the opinion of the treating physician, had left patients with compromised taste, which has not resolved at the time of registration
• Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. Therefore, for women of childbearing potential only, a negative urine or serum pregnancy test done =< 14 days prior to registration is required
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2
• Estimated life expectancy of 3 months or longer
• Serum creatinine =< 2.0 mg/dL
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
• Fasting glucose > 1410 mg/dl
• Granulocytes > 1000/hpf
• No treatment with another antipsychotic agent, such as risperidone, quetiapine, clozapine, butyrophenone within 30 days of enrollment
• In order to complete the mandatory patient-completed measures, participants must be able to speak and/or read English or Spanish. Sites seeking to enroll Spanish-speaking patients should have access to Spanish speaking staff on site or through the use of a translation service to be able to conduct the informed consent discussion in Spanish, and to conduct the weekly phone calls
• Psychiatric illness which would prevent the patient from giving informed consent
• Medical condition such as uncontrolled infection (including human immunodeficiency virus [HIV]), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
• Patients who cannot swallow oral formulations of the agents
• Patients with impaired decision-making capacity (such as with a diagnosis of dementia or memory loss) are not eligible for this study
• No presence of a hormone-sensitive tumor, such as breast, endometrial, or prostate cancer (this exclusion criterion is intended to circumvent any confounding antineoplastic effects of megestrol acetate)

• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must be >= 12 months and =< 21 years of age at the time of study enrollment
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients with recurrent or refractory solid tumors, including non-Hodgkin lymphomas, histiocytoses (e.g. langerhans cell histiocytosis [LCH], juvenile xanthogranuloma [JXG], histiocytic sarcoma), and central nervous system (CNS) tumors are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG); in cases where patient enrolls prior to histologic confirmation of recurrent disease, patient is ineligible and should be withdrawn from study if histology fails to confirm recurrence; please note: Patients with Hodgkin lymphoma and plexiform neurofibroma are not eligible
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor Testing Requirement: Tumor sample availability requirement for stage 1 of Pediatric MATCH (patients enrolled from start of study in July 2017 through 12/31/21); Patients must have an formalin-fixed paraffin-embedded (FFPE) tumor sample available for MATCH study testing from a biopsy or surgery that was performed at any point after initial tumor recurrence/progression, or be planned to have a procedure to obtain such a sample that is considered to be of potential benefit by the treating clinicians; a tumor sample from a clinically performed diagnostic (pre-treatment) biopsy will be acceptable for enrollment onto Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse intrinsic pontine gliomas) or thalamus
• Please note: Samples that have been decalcified using standardly utilized acid-based decalcification methods are not generally suitable for MATCH study testing; the nucleic acids will have been degraded in the decalcification process
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Tumor molecular profiling report availability requirement for Stage 2 of Pediatric MATCH (patients enrolled starting 2022): In stage 2 of the study, no tumor samples will be submitted for centralized clinical tumor profiling; instead, a tumor molecular profiling report from a College of American Pathologists (CAP)/ Clinical Laboratory Improvements Amendments (CLIA)-approved testing laboratory must be submitted for review by the Molecular Review Committee (MRC)
• This molecular profiling must have been performed on a tumor sample that was obtained at any point after initial tumor recurrence/progression and must be accompanied by a pathology report for the same tumor specimen; a molecular profiling report for a diagnostic (pre-treatment) tumor sample will be acceptable for enrollment onto Pediatric MATCH only for children with high-grade gliomas of the brainstem (diffuse intrinsic pontine gliomas) or thalamus. In the event that molecular profiling reports are available from multiple timepoints, the most recent report should be prioritized for study submission
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age); note: neurologic deficits in patients with central nervous system (CNS) tumors must have been stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have radiographically measurable disease; measurable disease based on imaging obtained less than or equal to 56 days prior to enrollment; patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all subprotocol criteria at time of enrollment onto the APEC1621SC screening protocol, but will need to meet all criteria prior to enrollment on any assigned treatment subprotocol. Patients must be enrolled onto a subprotocol within 2 weeks (14 days) of treatment assignment
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age); Note: neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of treatment with subprotocol specified therapy, the patients must have radiographically measurable disease; patients with neuroblastoma who do not have measurable disease but have MIBG+ evaluable are eligible; measurable disease in patients with CNS involvement is defined as any lesion that is at minimum 10 mm in one dimension on standard MRI or CT
• Note: The following do not qualify as measurable disease:
• Malignant fluid collections (e.g., ascites, pleural effusions)
• Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
• Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
• Elevated tumor markers in plasma or CSF
• Previously radiated lesions that have not demonstrated clear progression post radiation
• Leptomeningeal lesions that do not meet the measurement requirements for RECIST 1.1
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of enrollment onto a subprotocol, the following general criteria for initiation of therapy will be required:
• Patients must have fully recovered from the acute toxic effects of all prior anticancer therapy and must meet the following minimum duration from prior anticancer directed therapy prior to enrollment to the subprotocol; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately
• Cytotoxic chemotherapy or other anticancer agents known to be myelosuppressive: for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anticancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the last dose of agent; for agents not listed, the duration of this interval must be discussed with the study chair and the study-assigned research coordinator prior to enrollment
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
• Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total-body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
• Autologous stem cell infusion including boost infusion: >= 42 days
• Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer (NK) cells, dendritic cells, etc.)
• X-ray therapy (XRT)/External Beam Irradiation including Protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation; note: radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: For patients with solid tumors without known bone marrow involvement:
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: 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:
• Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
• Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
• Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
• Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
• Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
• Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Serum glutamate pyruvate transaminase (SGPT) (alanine transferase [ALT]) =< 135 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L)
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients must be able to swallow intact capsules/tablets, unless otherwise specified in the subprotocol to which they are assigned
• GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Agent specific limitations on prior therapy will be included with specific treatment subprotocols
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, or because there is currently no available information regarding human fetal or teratogenic toxicities; pregnancy tests must be obtained in females who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Concomitant medications
• Corticosteroids: at the time of consent and enrollment to regimen specific subprotocols, patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment to the subprotocol will not be eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Investigational drugs: patients must meet criteria for prior therapy at the time of consent and enrollment to a subprotocol; other investigational agents may not be administered to patients while they are receiving study drug as part of a subprotocol
• Anticancer agents: patients must meet criteria for prior therapy at the time of consent and enrollment to a subprotocol; other investigational agents may not be administered to patients while they are receiving study drug as part of a subprotocol
• Anti-GVHD agents post-transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have an uncontrolled infection are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have had a prior solid organ transplant are not eligible
• GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Additional agent specific criteria will be included with specific treatment subprotocols