• Has a histologically confirmed diagnosis of locally advanced/metastatic RCC with clear cell component
• Has measurable disease per RECIST 1.1 as assessed by BICR
• Can submit an archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
• Has had disease progression on or after having received first-line systemic treatment for locally advanced or metastatic RCC with prior anti-programmed cell death 1 ligand 1 (PD-1/L1) plus anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) combination OR anti-PD-1/L1 plus a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) combination
• Has received no more than 3 prior systemic regimens for locally advanced or metastatic RCC
• Has a Karnofsky performance status (KPS) score of at least 70% assessed within 10 days prior to the first dose of study intervention
• A male participant is eligible to participate if he is abstinent from heterosexual intercourse or agrees to use contraception during the intervention period and for at least 5 days after the last dose of study intervention
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: Not a (woman of childbearing potential) WOCBP or a WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 30 days after the last dose of study intervention
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 24 hours before the first dose of study intervention
• Is a WOCBP who has a positive urine pregnancy test within 24 hours prior to randomization
• Has hypoxia (a pulse oximeter reading <92% at rest), requires intermittent supplemental oxygen, or requires chronic supplemental oxygen
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years except for basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ [e.g., breast carcinoma, cervical cancer in situ] that have undergone potentially curative therapy
• Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction ≤6 months from Day 1 of study drug administration or New York Heart Association Class III or IV congestive heart failure
• Has moderate to severe hepatic impairment (Child-Pugh B or C)
• Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], or recombinant erythropoietin [EPO]) ≤28 days prior to the first dose of study intervention
• Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
• Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption)
• Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan) formulations
• Has received prior treatment with belzutifan or another hypoxia-inducible factor (HIF)-2α inhibitor
• Has received any type of small molecule kinase inhibitor (including investigational kinase inhibitor) ≤2 weeks before randomization
• Has received any type of systemic anticancer antibody (including investigational antibody) ≤4 weeks before randomization
• Has received prior radiotherapy ≤2 weeks prior to first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids
• Has had major surgery ≤3 weeks prior to first dose of study intervention
• Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (eg, bosentan, efavirenz, modafinil) inducers of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study
• Is currently participating in a study of an investigational agent or is currently using an investigational device
• Has an active infection requiring systemic therapy
• Has active tuberculosis (TB)
• Has a diagnosis of immunodeficiency
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of hepatitis B (HBV) or known active hepatitis C (HCV) infection
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not the best interest of the participant to participate, in the opinion of the treating investigator

1. Cytologically or histologically and radiologically confirmed solid tumor that is inoperable, locally advanced, metastatic, or recurrent:
• Dose-Escalation Stage:
• Subjects with UC (including renal pelvis, ureter, bladder, urethra) after prior platinum-based therapy, or
• Subjects with RCC (clear cell, non-clear cell histology) with or without prior systemic anticancer therapy
• Expansion Stage:
• Inoperable locally advanced or metastatic solid tumor (UC, RCC, CRPC, NSCLC, TNBC, OC, EC, HCC, GC/GEJC, CRC, H&N cancer, and DTC as outlined above) 2. Measurable disease per RECIST 1.1 as determined by the investigator. 3. Tumor tissue material available (archival or recent tumor biopsy) 4. Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. 5. Age eighteen years or older on the day of consent. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 7. Adequate organ and marrow function. 8. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception. 9. Female subjects of childbearing potential must not be pregnant at screening. 1. Prior treatment with cabozantinib or immune checkpoint inhibitors including anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy except in Expansion Cohorts 5, 7,19 and 20. Other restrictions regarding prior therapy may apply. 2. Known brain metastases or cranial epidural disease unless adequately treated and stable for at least 4 weeks before first dose of study treatment. 3. Concomitant anticoagulation with oral anticoagulants. 4. Subject is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment. 5. Administration of a live, attenuated vaccine within 30 days before first dose of study treatment. 6. The subject has uncontrolled, significant intercurrent or recent illness, including, but not limited to, an active or history of autoimmune disease or immune deficiency; idiopathic pulmonary fibrosis, organizing pneumonia, pneumonitis; active infection requiring systemic treatment, infection with human immunodeficiency virus (HIV), AIDS-related illness, acute or chronic hepatitis B or C infection, positive test for tuberculosis, moderate to severe hepatic impairment (Child-Pugh B or C). 7. Pregnant or lactating females. 8. Previously identified allergy or hypersensitivity to components of the study treatment formulations. 9. Diagnosis of another malignancy within 2 years before first dose of study treatment.

• ELIGIBILITY CRITERIA FOR RANDOMIZATION:
• Patients with a renal mass consistent with a clinical stage >= T2Nx renal cell carcinoma (RCC) or TanyN+ RCC for which radical or partial nephrectomy is planned
• Patients must have no clinical or radiological evidence of distant metastases (M0) unless the presumed M1 disease is planned to be resected/definitively treated (e.g., thermal ablation, stereotactic radiation) at the same time or within a 12 week window from the date of the initial procedure such that the patient is considered "no evidence of disease" (M1 NED)
• Liver, bone, or brain metastases are not permitted
• No more than 3 metastases are permitted and all must be able to be removed or definitively treated within 12 weeks of the primary tumor resection
• If histological confirmation of RCC has not been done within 12 months prior to randomization, patient must be willing to undergo a core biopsy for this purpose if randomized to Arm A
• NOTE: This histologic confirmation can be a (1) standard of care diagnostic biopsy or (2) a research biopsy or a planned metastasectomy. Tissue must be obtained with results available prior to the neoadjuvant dose
• Patients randomized to Arm A: core tumor biopsy must have demonstrated RCC of any histology, including sarcomatoid, unclassified, or "unknown histology" (if preoperative biopsy was uninformative) with exception below for non-diagnostic biopsies
• If the biopsy performed following randomization clearly demonstrates a benign condition, oncocytoma or a different type of cancer that is not RCC, the patient is not eligible and must come off study
• A non-diagnostic biopsy is considered a good faith effort and does not need to be repeated unless deemed clinically necessary by the treating investigator
• Patient must not have any prior systemic or local anti-cancer therapy for the current RCC
• Patient must not have undergone a partial nephrectomy for the current RCC
• Patient must not have had a metastasectomy for the current RCC diagnosis unless performed to render patient NED (in addition to the planned nephrectomy) within 6 months of the current diagnosis
• Patient must not have received current or past antineoplastic systemic therapies for RCC: i.e., chemotherapy, hormonal therapy, immunotherapy, or standard or investigational agents for treatment of RCC
• Patient must not have received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Patient must not have a prior history of RCC that was treated with curative intent within the past 5 years
• Patients with a prior RCC that was treated > 5 years before, are eligible if the current tumor is consistent with a new primary in the opinion of the treating investigator
• Patients with bilateral synchronous RCCs are eligible if they can be resected or definitively treated at the same time or within a 12 week window from time of initial nephrectomy (partial or radical) or procedure and maintain adequate residual renal function; the patient is not eligible if both kidneys are to be completely removed and subsequent hemodialysis will be required
• Permitted forms of local therapy for second tumor:
• Partial or radical nephrectomy
• If tumor is =< 3 cm: thermal ablation (e.g., radiofrequency ablation, cryoablation or stereotactic radiosurgery)
• Patients cannot have concurrent malignancies, with the following exceptions:
• Adequately treated basal cell or squamous cell skin cancer
• In situ cervical cancer
• A history of superficial Ta urothelial cancer is permitted (as long as not currently undergoing treatment) whereas T1 or greater disease is excluded if < 3 years from diagnosis; concurrent persistent disease is not permitted
• Adequately treated stage I or II cancer from which the patient is currently in complete remission
• Any other cancer and stage from which the patient has been disease-free for at least 3 years prior to the time of randomization and as long as they are not receiving any current treatment (e.g. adjuvant or maintenance systemic or local therapy)
• Concurrent low risk prostate cancer on active surveillance
• Patient must not have active known or suspected autoimmune disease. The following autoimmune disorders are permitted: patients with vitiligo, type I diabetes mellitus, controlled/stable hypo or hyperthyroidism due to autoimmune or non-autoimmune conditions (hormone replacement is allowed), psoriasis not requiring systemic treatment, or other conditions not expected to recur
• Patient must not have any ongoing condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications with the exceptions outlined below; patient must not have received any treatment with other immunosuppressive agents within 14 days prior to the first dose of study drug with the following exceptions:
• Topical, ocular, intra-articular, intranasal, inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone or the equivalent are permitted in the absence of active autoimmune disease
• A brief (less than 3 weeks) course of corticosteroids (any amount) for prophylaxis (for example: contrast dye allergy) or for treatment of non-autoimmune conditions (for example: nausea, delayed-type hypersensitivity reaction caused by a contact allergen) is permitted
• Patient must not have uncontrolled adrenal insufficiency
• Patient must not have known evidence of chronic active liver disease or evidence of acute or chronic hepatitis B Virus (HBV) or hepatitis C (HCV); HBV and HCV testing must be completed within 8 weeks prior to randomization
• NOTE: If the patient has been treated and cured, and the HCV ribonucleic acid (RNA) is undetectable, the patient is eligible for this study
• Patient must not have any serious intercurrent illness, including ongoing or active infection requiring parenteral antibiotics
• Patient must not have known evidence of human immunodeficiency virus (HIV) infection, since the effects of nivolumab on anti-retroviral therapy have not been studied; HIV testing is only required if past or current history is suspected
• Patient must not have any known medical condition (e.g. a condition associated with uncontrolled diarrhea such as ulcerative colitis or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or interfere with the interpretation of safety results
• Patient must not have had any major surgery within 28 days prior to randomization
• Patient must not be currently enrolled in other clinical trials testing a therapeutic intervention
• Patient must not have any history of severe hypersensitivity to a monoclonal antibody
• Patient must have the ability to understand and the willingness to sign a written informed consent document
• Women must not be pregnant or breast-feeding, as the effects of nivolumab on the developing human fetus or in the nursing infant are unknown; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy; a female of childbearing potential is 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 for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use accepted and effective method(s) of contraception, as described in the Informed Consent Form (ICF), or abstain from sexual intercourse for the duration of their participation in the study; women of childbearing potential must use adequate methods to avoid pregnancy for 5 months after the last dose of nivolumab; sexually active males must use adequate methods to avoid pregnancy for 7 months after the last dose of nivolumab
• White blood cells >= 2000/uL (within 8 weeks prior to randomization)
• Absolute neutrophil count (ANC) >= 1,500/mm^3 (within 8 weeks prior to randomization)
• Platelet count >= 100,000/mm^3 (within 8 weeks prior to randomization)
• Hemoglobin >= 9.0 g/dL (within 8 weeks prior to randomization)
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or calculated creatinine clearance (CrCl) >= 40mL/min (within 8 weeks prior to randomization)
• Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 x ULN) (within 8 weeks prior to randomization)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 8 weeks prior to randomization)

• Documented histologic or cytologic diagnosis of renal cell cancer (RCC). All subtypes of RCC are eligible including but not limited to clear cell, papillary, chromophobe, translocation, collecting duct carcinoma, medullary carcinoma, and unclassified categories. Enrollment of non-clear cell patients will be limited to 20% of the total sample size (~ 42 patients). Once this goal is met, accrual of non-clear cell patients will be discontinued (a notice will be sent out 2 weeks in advance). Sarcomatoid and rhabdoid differentiation are allowed
• Presence of at least 2 metastatic bone lesions not treated with prior radiation is required
• The presence of bone metastases can be detected by computed tomography (CT), magnetic resonance imaging (MRI), Tc-99m bone scan or positron emission tomography (PET) (fludeoxyglucose F-18 [FDG] or sodium fluoride [NaF]) imaging. Patients with non-measurable bone-only disease are allowed. Patients may have received prior radiation therapy for bone metastases or other external radiation >= 14 days prior to registration, as long as they still have at least 2 metastatic bone lesions that were not treated with radiation. Patients with visceral metastases are allowed, as long as they have at least two untreated bone metastases
• No more than 2 prior lines of systemic therapy including but not limited to anti-angiogenic therapy, checkpoint inhibitors, mammalian target of rapamycin (mTOR) inhibitors, clinical trial compounds or cytokine-based therapy. Prior radiation therapy does not count as a prior systemic therapy
• No prior treatment with cabozantinb
• No treatment with any type of small molecular kinase inhibitor (including investigational kinase inhibitors) within 2 weeks or 5 half-lives (whichever is shorter) of registration or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 3 weeks of registration
• No prior hemibody external radiotherapy
• No prior therapy with radium-223 dichloride or systemic radiotherapy (such as samarium, strontium)
• No major surgery within 6 weeks of randomization. Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Moh's or other topical skin surgery, Lasik eye surgery are not considered major surgery. Patients who have had a nephrectomy may be registered >= 3 weeks after surgery, providing there are no wound-healing complications. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
• Recovery to baseline or =< grade 1 CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically nonsignificant and/or stable on supportive therapy
• The use of osteoclast targeted therapy including either bisphosphonates or denosumab is mandated on this study except in patients with contraindications as determined by the treating investigator, including:
• Hypocalcemia
• Hypophosphatemia
• Renal impairment including those with a glomerular filtration rate (GFR) < 35 mL/min using the Cockcroft-Gault equation or acute renal impairment
• Hypersensitivity to drug formulation
• Dental condition or need for dental intervention that per the investigator would increase the risk of osteonecrosis of jaw (ONJ).
• Use of osteoclast targeted therapy or reason against use needs to be recorded in the electronic case report form (eCRF). Additionally, reason for discontinuation of osteoclast targeted therapy need to be appropriately documented in the eCRF
• 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 pregnancy test done =< 28 days prior to registration is required. A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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)
• Karnofsky performance status >= 60%
• Symptomatic bone pain defined as either regular use of analgesic medication for cancer related bone pain (>= level 1; World Health Organization [WHO] ladder for cancer pain) or prior SSE defined as bone pain requiring radiation, bone pain secondary to a pathologic fracture related to a bone metastasis, symptomatic spinal cord compression related to a bone metastasis, surgery to bone secondary to symptomatic bone metastasis or radiographic progression of bone metastases as defined by the presence of bone metastases on radiographic imaging
• No brain metastases or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator
• No imminent or established spinal cord compression based on clinical symptoms and/or imaging. In patients with untreated imminent or established spinal cord compression, treatment with standard of care as clinically indicated should be completed at least 2 weeks before registration
• No imminent or impending pathologic fracture based on clinical symptoms and/or imaging. In patients with untreated imminent or impending pathologic fracture, treatment with standard of care as clinically indicated should be completed at least 2 weeks before registration
• No significant, uncontrolled intercurrent or recent illness, including but not limited to the following conditions:
• Cardiovascular disorders: Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia; uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment; stroke (including transient ischemic attack), myocardial infarction, or other ischemic event, within 6 months before randomization; thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1 month before randomization; screening Fridericia's correction formula (QTcF) =< 500 msec
• Gastrointestinal disorders: Disorders associated with a high risk of perforation or fistula formation: active inflammatory bowel disease, active diverticulitis, active cholecystitis, active symptomatic cholangitis or active appendicitis, active acute pancreatitis or active acute obstruction of the pancreatic or biliary duct, or active gastric outlet obstruction; abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 3 months before randomization. Note: Complete healing of an intra-abdominal abscess must be confirmed before randomization
• No clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before randomization
• No lesions invading major pulmonary blood vessels
• No other clinically significant disorders:
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (with no medications prohibited by this protocol [e.g. drug-drug interactions]) with undetectable viral load within 6 months 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 (with no medications prohibited by this protocol [e.g. drug-drug interactions]), 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 (with no medications prohibited by this protocol [e.g. drug-drug interactions])
• No serious non-healing wound or ulcer
• No malabsorption syndrome
• No uncompensated/symptomatic hypothyroidism
• No moderate to severe hepatic impairment (Child-Pugh B or C)
• No requirements for hemodialysis or peritoneal dialysis
• No history of solid organ transplantation
• No chronic concomitant treatment with strong CYP3A4 inducers or inhibitors. Because the list of these agents is constantly changing, it is important to regularly consult a frequently updated medical reference. Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7 days prior to registration
• No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants include:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count >= 100,000/mm^3
• Hemoglobin >= 10 g/dl (transfusions allowed)
• Calculated (calc.) creatinine clearance >= 30 mL/min using the Cockcroft-Gault equation
• Total bilirubin =< 1.5 x upper limit of normal (ULN), for patients with Gilberts disease =< 3.0 x ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN
• Urine protein to creatinine (UPC) ratio =< 1 mg/mg OR 24-hr urine protein < 1g

• PRE-REGISTRATION ELIGIBILITY CRITERIA
• Histologically confirmed muscle-invasive urothelial carcinoma of the bladder, urethra, upper tract, or lymph node positive (LN+) disease; variant histology allowed as long as urothelial carcinoma is predominant (any amount of squamous differentiation is allowed); any component of neuroendocrine carcinoma is excluded
• Paraffin tissue samples obtained by transurethral resection of muscle-invasive bladder tumor, upper tract resection, or radical cystectomy/nephrectomy/ureterectomy/nephroureterectomy/cystoprostatectomy or urethrectomy must be available; this specimen submission is mandatory prior to registration as results will be used for stratification; specimens from radical/definitive surgery (radical cystectomy/nephrectomy/ureterectomy /nephroureterectomy/cystoprostatectomy and LN dissection) are preferred over transuretheral resection, if available
• Patient must fit into one of the following three categories:
• Patients who received neoadjuvant chemotherapy and pathologic stage at surgical resection is >= pT2 and/or N+ OR
• Patients who are not cisplatin-eligible (according to >= 1 of the following criteria: Eastern Cooperative Oncology Group [ECOG] performance status of 2, creatinine clearance < 60 mL/min, grade >= 2 hearing loss, grade >= 2 neuropathy, or New York Heart Association class III heart failure and pathologic stage at surgical resection is >= pT3 or pN+) OR
• Patients that decline adjuvant cisplatin-based or other systemic chemotherapy based on an informed discussion with the physician and pathologic stage at surgical resection is >= pT3 or pN+
• The 7th edition of American Joint Committee on Cancer (AJCC) staging will be utilized; patient must have had radical cystectomy (cystoprostatectomy for men) and lymph node dissection (for bladder primary), or nephrectomy, nephroureterectomy or ureterectomy (for uppertract tumors) or urethrectomy (in addition to a radical cystectomy-either simultaneously or in the past) >= 4 weeks but =< 16 weeks prior to pre-registration; patients who have had a partial cystectomy as definitive therapy are not eligible
• No gross cancer at the surgical margins; microscopic invasive urothelial carcinoma positive margins are allowed; carcinoma in situ (CIS) at margins is considered negative margins
• No evidence of residual cancer or metastasis after surgery; patients with upper tract urothelial carcinoma must have a negative cystoscopy within 3 months prior to pre-registration; if the bladder has been removed a cystoscopy is not required
• No metastatic disease (or radiologic findings "concerning" for metastatic disease) on cross-sectional imaging (according to Response Evaluation Criteria in Solid Tumors [RECIST] version [v]1.1 criteria)
• No active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease; human immunodeficiency virus (HIV) (+) patients are eligible as long as they have: cd4 > 200, undetectable viral load and on highly active antiretroviral therapy (HAART) therapy
• No current pneumonitis or prior history of non-infectious pneumonitis that required steroids within the previous 5 years
• Patients with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible
• Patients with rheumatoid arthritis and other arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible
• No known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• No postoperative/adjuvant systemic therapy
• No prior treatment with any therapy on the PD-1/PD-L1 axis
• No treatment with any other type of investigational agent =< 4 weeks before pre-registration
• No major surgery =< 4 weeks before pre-registration
• No radiation therapy =< 4 weeks before pre-registration
• No neoadjuvant chemotherapy =< 4 weeks before pre-registration
• Not currently requiring hemodialysis
• 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
• ECOG performance status =< 2
• Absolute neutrophil count (ANC) >= 1,200/mm^3
• Leukocytes >= 3,000/ mm^3
• Platelet count >= 75,000/mm^3
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Bilirubin for patients with Gilbert's =< 3.0 x ULN
• Calculated (calc.) creatinine clearance >= 30 mL/min (using either Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] or Cockcroft-Gault formula)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN)
• Serum albumin >= 2.8 g/dL
• For women of childbearing potential only: a negative urine or serum pregnancy test done =< 7 days prior to pre-registration is required
• REGISTRATION ELIGIBILITY CRITERIA: Results of central PD-L1 testing available; Q2 Solutions will forward the PD-L1 results to the statistical center and the statistical center will notify the site that the result is available; since the results with be blinded to the site the notification from the Alliance registration/randomization office will serve as a confirmation of this eligibility criteria; after sites receive the confirmation e-mail from Alliance they can register the patient

Key
• Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) metastatic cancer of the following histologies: melanoma (MEL), Merkel cell carcinoma (MCC), triple-negative breast cancer (TNBC), renal cell carcinoma (RCC), colorectal cancer, head and neck squamous cell carcinoma (HNSCC), or sarcoma.
• Life expectancy > 12 weeks as determined by the Investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Measurable disease per RECIST 1.1.
• Patients enrolled in Cohorts 1-10, Cohort A, Cohort B and Phase 2 Doublet must be refractory to all therapies known to confer clinical benefit to their disease.
• Fresh tumor tissue available for cellular characterization and programmed cell death protein 1 (PD-L1) status.
• Injected lesions (up to two) must be between 20 mm and 90 mm in diameter for IT injection; lesions must be accessible for baseline and on-treatment biopsies. Any liver lesion targeted for injection must not exceed 50 mm at the time of injection.
• Demonstrated adequate organ function within 14 days of Cycle 1 Day 1 (C1D1). Key
• Use of an investigational agent or an investigational device within 21 days before administration of first dose of study drug(s).
• Patients treated with prior interleukin-2 (IL-2).
• Patients who have been previously treated with a toll-like receptor (TLR) agonist (excluding topical agents) and patients who have received experimental cancer vaccines.
• Patients who have received systemic interferon (IFN)α within the previous 6 months prior to enrollment to the study.
• Other active malignancy, except non-melanomic skin cancer
• Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis.
• Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients must have recovered from all radiation-related toxicities, not required corticosteroids and have not had radiation pneumonitis.
• Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for women at Screening. History of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following:
• Unstable angina or myocardial infarction.
• Congestive heart failure (NYHA Class III or IV).
• Uncontrolled clinically significant arrhythmias.
• Patients with a history of any retinal disorders (e.g., retinal detachment, diabetic retinopathy, retinal hemorrhage, macular degeneration).
• Uveal melanoma will be excluded
• Patients with tumor that invade the superior vena cava or other major blood vessels. Additional general and tumor specific inclusion and exclusion criteria will apply.

Key 1. Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion, amplification) as identified by local testing in a Clinical Laboratory Improvement Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab outside the United States (US) is required. 2. Age <12 years. 3. Prior cytotoxic chemotherapy is allowed. 4. Prior immunotherapy is allowed. 5. 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. 6. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology Criteria (RANO) criteria at time of enrollment. 7. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 14 days prior to enrollment. 8. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least 50. 9. Life expectancy greater than or equal to 12 weeks. 10. Adequate hematologic, renal and hepatic function. Phase 2 1. Age 12 to <25 years 2. Cohort Specific
• Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors (including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI naïve;
• Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS tumors), that are TRK TKI pre-treated;
• Cohort 3: subjects with tumors or ALCL characterized by other ALK/ROS1/NTRK alterations or NTRK fusions without centrally confirmed measurable disease or not otherwise eligible for Cohort 1 or 2. 3. Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by BICR prior to enrollment. Key Exclusion Criteria (Phase 1 and Phase 2): 1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only. 2. Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery. 3. Known active infections (bacterial, fungal, viral including HIV positivity). 4. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut syndrome) or other malabsorption syndromes that would impact drug absorption. 5. 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 (QTc) > 470 msec obtained from three 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, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval 6. Peripheral neuropathy of CTCAE ≥grade 2. 7. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers.

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 monotherapy (SOT cohort, subgroup A or HCT cohort) or rituximab plus chemotherapy (SOT cohort, subgroup B) for treatment of PTLD. 6. Eastern Cooperative Oncology Group performance status ≤ 3 for subjects aged > 16 years; Lansky score ≥ 20 for subjects from birth to 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 (TBILI) each < 5 × the upper limit of normal (ULN); however, ALT, AST, and total bilirubin each ≤ 10 × ULN 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 (CIBMTR) 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 (CAR) 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

• STEP I REGISTRATION CRITERIA
• Histologically documented renal cell carcinoma with clear cell component, including patients who have sarcomatoid features.
• Any metastatic disease, including visceral, lymph node, other soft tissue and bone, measurable per RECIST 1.1.
• Measurable disease as defined in the protocol.
• Must be intermediate or poor risk patient per International Metastatic Renal Cell Carcinoma Database (IMDC) criteria (1 or more of the following: Karnofsky performance status [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemic treatment for metastatic disease, hemoglobin less than lower limit of normal [LLN], corrected calcium concentration greater than upper limit of normal [ULN], absolute neutrophil count greater than ULN, platelet count > ULN).
• Central nervous system (CNS) disease permitted, if stable and not otherwise causing symptoms or needing active treatment.
• Karnofsky performance status >= 70%.
• No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but not limited to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab, tremelimumab, and ipilimumab), or any other drug or antibody specifically targeting T-cell co-stimulation or checkpoint pathways. The only exception is for prior treatment with nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- or post-operative trials, as long as > 1 year since completion of systemic therapy.
• No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days] and prior adjuvant sunitinib > 180 days since completion and prior immunotherapy as above are allowed).
• No cancer therapy less than 28 days prior to registration; this includes radiation therapy, except for bone lesions less than 14 days prior to registration. There must be a complete recovery and no ongoing complications from radiotherapy.
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative serum or urine pregnancy test done =< 14 days prior to registration is required.
• Age >= 18 years
• Absolute neutrophil count (ANC) >= 1,500/mm^3.
• Platelet count >= 100,000/mm^3.
• Hemoglobin >= 8 g/dL.
• Calculated (Calc.) creatinine clearance >= 30 mL/min.
• Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
• Total bilirubin =< 1.5 x upper limit of normal (ULN).
• Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present.
• STEP 2 REGISTRATION ELIGIBILITY CRITERIA
• Successful completion of at least 1 cycle of ipilimumab/nivolumab.
• Resolution of any treatment-related adverse events to grade 1 or less per dose modification section (this criteria does not include any adverse events [AEs] not attributable to treatment which are present due to disease). Exceptions for this criteria include patients receiving replacement hormone treatments (such as levothyroxine for treatment-related hypothyroidism or glucocorticoid replacement for adrenal insufficiency). Please contact study chair if further discussion is needed.
• No more than 70 days from last dose of ipilimumab/nivolumab.
• Active autoimmune disease requiring ongoing therapy.
• Ongoing acute toxicity > grade 2 from previous treatment.
• History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies.
• History of human immunodeficiency virus (HIV) or active hepatitis B/C, or active tuberculosis (purified protein derivative [PPD] response without active TB is allowed).
• Concurrent use of immunosuppressive medication including prednisone above 10 mg daily.
• Uncontrolled adrenal insufficiency.
• Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic BP > 90 mmHg).
• Major surgery less than 28 days prior to registration.
• Any serious non-healing wound, ulcer, or bone fracture within 28 days prior to registration.
• Any arterial thrombotic events within 180 days prior to registration.
• Clinically significant hematuria, hematemesis, or hemoptysis within 12 weeks prior to registration.
• Cavitating pulmonary lesions or known endotracheal or endobronchial disease manifestations.
• Lesions encasing or invading any major blood vessels (this does not include tumor thrombus extending into/through renal vein/inferior vena cava [IVC]). Patients with tumor thrombus extending into/through renal vein are considered eligible.
• Moderate of severe hepatic impairment (Child-Pugh B or C).
• Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) in the 180 days prior to registration. (Any asymptomatic, treated pulmonary embolism or asymptomatic, treated deep venous thrombosis > 30 days prior to registration allowed).
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms.
• Unstable cardiac arrhythmia within 6 months prior to registration.
• Any gastrointestinal (GI) bleeding =< 180 days, hemoptysis, or other signs of pulmonary hemorrhage =< 90 days prior to registration.
• History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to registration.
• Active peptic ulcer disease, inflammatory bowel disease, or malabsorption syndrome within 28 days prior to registration.
• Untreated hypothyroidism, evidence of pancreatitis, history of organ transplant, or history of congenital QT syndrome.
• Active treatment with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct Xa inhibitor betrixaban or platelet inhibitors (e.g., clopidogrel) within 5 days of registration. Allowed anticoagulants include: prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH), therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, apixaban. Allowed also in patients with known brain metastases who are on a stable dose of the anticoagulant for at least 1 week prior to registration without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
• Significant cardiac ischemia events (ST elevation myocardial infarction [STEMI] or non-ST elevation myocardial infarction [NSTEMI]) within 6 months or active NY Heart Association class 3-4 heart failure symptoms

• Metastatic disease defined as new or progressive lesions on cross-sectional imaging or bone scan. Patients must have at least:
• One measurable site of disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• One bone lesion on bone scan (tec99 or sodium fluoride [NaF] positron emission tomography [PET]/computed tomography [CT], CT, or magnetic resonance imaging [MRI]) for the bone-only cohort
• Histologically confirmed diagnosis of one of the following metastatic cohorts:
• Small cell/ neuroendocrine carcinoma of the bladder
•All urothelial carcinomas with any amount of neuroendocrine differentiation (including small cell differentiation) will be included. If the tumor is purely neuroendocrine, metastasis from another site of origin should be clinically excluded.
• Adenocarcinoma of the bladder, or urachal adenocarcinoma, or bladder/urethra clear cell adenocarcinoma
•must be pure (per World Health Organization [WHO] definition), (i.e. urothelial carcinoma with glandular differentiation is not considered a pure adenocarcinoma.
• Squamous cell carcinoma of the bladder
•must be pure (i.e. urothelial carcinoma with squamous differentiation is not considered a pure squamous cell carcinoma).
• Plasmacytoid urothelial carcinoma
•Tumor should show predominantly > or equal ~50% plasmacytoid histology (including all types of discohesive growth, such as tumors with signet-ring and/or rhabdoid features as well).
• Any penile cancer
• Sarcomatoid renal cell carcinoma
•Tumor should be predominantly sarcomatoid ~50% (including rhabdoid differentiation) is also unclassified renal cell carcinomas (RCCs): all (assuming they are high grade with metastasis) malignant angiomyolipomas are allowed.
• Sarcomatoid urothelial carcinoma
•Tumor should show predominantly ~ 50% sarcomatoid differentiation.
• Renal medullary carcinoma
•Per WHO definition, ideally confirmed with immunostains.
• Renal collecting duct carcinoma
•Per WHO definition (medullary involvement, predominant tubular morphology, desmoplastic stromal reaction, high grade cytology, infiltrative growth pattern, and absence of other renal cell carcinoma subtype or urothelial carcinoma).
• Bone only urothelial carcinoma or other non-prostate GU tumor
• Urethra carcinoma
•May be of any histology but if urothelial carcinoma then must be isolated to the urethra and not have metachronous or synchronous urothelial carcinoma of the bladder.
• Other miscellaneous histologic variants of the urothelial carcinoma, such as, but not limited to: micropapillary (Tumor should show predominantly > or equal 50% micropapillary architecture), giant cell, lipid-rich, clear cell and nested variants (Tumor should predominantly > or equal 50% show these features), large cell neuroendocrine carcinoma, lymphoepithelioma-like carcinoma and mixed patterns will be considered, as well as small cell neuroendocrine prostate cancer (Only treatment-naïve primary small cell of prostate with any amount of small cell component allowed. Post-treatment small cell prostatic carcinomas are not allowed), Malignant testicular Sertoli or Leydig cell tumors, and papillary and chromophobe RCC.
• Note: Translocation positive renal cell carcinoma patients are eligible. However, AREN1721 should be considered before this trial.
• Hematoxylin and eosin (H&E) slides from diagnostic tumor tissue for retrospective central pathology review
• Patients may have received up to 2 systemic anti-cancer treatments or be treatment naive. Patients with small cell carcinoma should have received a platinum-based combination regimen either as neoadjuvant, adjuvant or first-line treatment). Patients in the bone-only cohort may be urothelial carcinoma histology but must receive standard cisplatin-based chemotherapy (if cisplatin-eligible).
• Patients must be able to swallow oral formulation of the tablets
• Karnofsky performance status >= 80%
• Absolute neutrophil count (ANC) >= 1,000/mcL
• Platelet count >= 75,000/mcL
• Total bilirubin =< 1.5 x upper limit of normal (ULN). For subjects with known Gilbert's disease or similar syndrome with slow conjugation of bilirubin, total bilirubin =< 3.0 mg/dL
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3.0 x institutional upper limit of normal (ULN) (or =< 5 x ULN for patients with liver metastases or Gilbert's disease)
• Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40 mL/min/1.73 m^2 (calculated using the Chronic Kidney Disease Epidemiology [CKD-EPI] equation or Cockcroft-Gault formula) for patients with creatinine levels above institutional normal
• Hemoglobin >= 9 g/dL (transfusion of packed red blood cells [PRBCs] allowed)
• Serum albumin >= 3.2 g/dL
• Lipase and amylase =< 2.0 x ULN and no radiologic (on baseline anatomical imaging) or clinical evidence of pancreatitis
• Prior treatment with MET or VEGFR inhibitors is allowed. However, prior cabozantinib will not be allowed. Also, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are also not allowed
• Prior treatment with any therapy on the PD-1/PD-L1 axis or anti- CTLA-4/CTLA-4 inhibitors is allowed, either in the perioperative or in the metastatic setting. However, patients that have received both prior MET or VEGF and prior PD-1/PD-L1/CTLA-4 (sequentially or in combination) are not allowed
• Human immunodeficiency virus (HIV)-positive patients are eligible if on stable dose of highly active antiretroviral therapy (HAART), no clinically significant drug-drug interactions are anticipated with the current HAART regimen, CD4 counts are greater than 350 and viral load is undetectable
• Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication only and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies etc. are eligible but should be considered for rheumatologic evaluation for the presence of target organ involvement and potential need for systemic treatment
• Patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones or medications (e.g. thyroiditis managed with propylthiouracil [PTU] or methimazole) including physiologic oral corticosteroids are eligible
• Patients who have evidence of active or acute diverticulitis, intra-abdominal abscess, and gastrointestinal (GI) obstruction, within 12 months are not eligible
• Women of childbearing potential must have a negative pregnancy test =< 7 days prior to registration
• Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea >= 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason
• Pregnant women may not participate in this study because with cabozantinib, nivolumab, and ipilimumab have potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib, nivolumab, and ipilimumab, breastfeeding should be discontinued if the mother is treated with these agents
• The patient has received no cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2 weeks before the first dose of study treatment
• The patient has received no radiation therapy:
• To the lungs and mediastinum or abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy
• To brain metastasis within 3 weeks for whole-brain radiotherapy (WBXRT), and 2 weeks for stereotactic body radiation therapy (SBRT) before the first dose of study treatment
• To the abdomen within 4 weeks before the first dose of study treatment, or has ongoing complications, or is healing from prior radiation therapy
• To any other site(s) within 2 weeks before the first dose of study treatment
• The patient has received no radionuclide treatment within 6 weeks of the first dose of study treatment
• The patient has received no prior treatment with a small molecule kinase inhibitor within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment
• The patient has received no prior treatment with hormonal therapy within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment. Subjects receiving gonadotropin-releasing hormone (GnRH) agonists and antagonists are allowed to participate
• The patient has not received any other type of investigational agent within 14 days before the first dose of study treatment
• The patient must have recovered to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia, neuropathy and other non-clinically significant adverse events (AEs) defined as lab elevation with no associated symptoms or sequelae
• The patient may not have active brain metastases or epidural disease. Patients with brain metastases previously treated with whole brain radiation or radiosurgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain imaging with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scans for subjects with known brain metastases is required to confirm eligibility
• No concomitant treatment with warfarin. Aspirin (up to 325 mg/day), thrombin or factor Xa inhibitors, low-dose warfarin (=< 1 mg/day), prophylactic and therapeutic low molecular weight heparin (LMWH) are permitted
• No chronic concomitant treatment with strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort) or strong CYP3A4 inhibitors
• Because the lists of these agents are constantly changing, it is important to regularly consult medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• The patient has not experienced any of the following:
• Clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment
• Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood per day within 1 months before the first dose of study treatment
• Any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
• The patient has no tumor invading any major blood vessels
• The patient has no evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib. Patients with rectal tumor masses are not eligible.
• The patient has no uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders including:
• Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening.
• Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment
• The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization. Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard
• Any history of congenital long QT syndrome
• Any of the following within 6 months before registration of study treatment:
• Unstable angina pectoris
• Clinically-significant cardiac arrhythmias (patients with atrial fibrillation are eligible)
• Stroke (including transient ischemic attack [TIA], or other ischemic event)
• Myocardial infarction
• Cardiomyopathy
• No significant gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:
• Any of the following that have not resolved within 28 days before the first dose of study treatment:
• Active peptic ulcer disease
• Acute diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, or malabsorption syndrome
• None of the following within 2 years before the first dose of study treatment:
• Abdominal fistula or genitourinary fistula
• Gastrointestinal perforation
• Bowel obstruction or gastric outlet obstruction
• Intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 2 years before the first dose of study treatment
• Disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement are not eligible
• No other clinically significant disorders such as:
• Severe active infection requiring IV systemic treatment within 14 days before the first dose of study treatment
• Serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment
• History of organ or allogeneic stem cell transplant
• Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment (for asymptomatic patients with an elevated thyroid-stimulating hormone [TSH], thyroid replacement may be initiated if clinically indicated without delaying the start of study treatment)
• No history of major surgery as follows:
• Major surgery within 3 months of the first dose of ca

• The patient must have histologic or cytologic evidence of a malignant solid tumor and must have disease that is resistant to or relapsed following available standard systemic therapy, or for which there is no standard systemic therapy or reasonable therapy likely to result in clinical benefit.
• The patient must have advanced disease, defined as cancer that is either metastatic, OR locally advanced and unresectable (and for which additional radiation therapy or other locoregional therapies are not considered feasible).
• The patient must have disease that is measurable by standard imaging techniques, per the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), or evaluable per RECIST 1.1. (For patients with prior radiation therapy, measurable lesions must be outside of any prior radiation field[s], unless disease progression has been documented at that disease site subsequent to radiation.)
• The patient is ≥18 years old.
• The patient has an ECOG PS of 0-2.
• The patient has adequate baseline organ function, as demonstrated by the following:
• Serum creatinine ≤1.5 × institutional upper limit of normal (ULN) or calculated creatinine clearance >30 mL/min.
• Serum albumin ≥2.5 g/dL.
• Bilirubin ≤1.5 × institutional ULN.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × institutional ULN (patients with hepatic metastases must have AST/ALT ≤5 times ULN).
• International normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 × ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤1.5 × ULN.
• The patient has adequate baseline hematologic function, as demonstrated by the following:
• Absolute neutrophil count (ANC) ≥1.5×10⁹/L
• Hemoglobin ≥8 g/dL, with no red blood cell (RBC) transfusions within the prior 14 days.
• Platelet count ≥100×10⁹/L, with no platelet transfusions within the prior 14 days.
• If the patient is a woman of child bearing potential (WOCBP), she has had a negative serum or urine pregnancy test within 1 week prior to treatment.
• The patient (male and female) agrees to use acceptable contraceptive methods for the duration of time on the study, and continue to use acceptable contraceptive methods for 1 month after the last dose of SL-801.
• The patient has signed informed consent prior to initiation of any study-specific procedures or treatment.
• The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.
• The patient has persistent clinically significant ≥Grade 2 toxicities from previous anticancer therapy (excluding Grade 2 chemotherapy-related neuropathy which is permitted, and excluding Grade 2-3 laboratory abnormalities if they are not associated with symptoms, are not considered clinically significant by the Investigator, and can be managed with available medical therapies).
• The patient has received treatment with chemotherapy, external-beam radiation, or other systemic anticancer therapy within 28 days prior to study entry (Patients with advanced prostate cancer who are receiving luteinizing hormone releasing hormone [LHRH] agonists are permitted onto the study and should continue use of these agents during study treatment).
• The patient has received treatment with an investigational systemic anticancer agent within 28 days prior to C1D1.
• The patient has previously received treatment with SL-801 or another investigational agent that inhibits the XPO1/CRM1 pathway.
• The patient has an additional active malignancy that may confound the assessment of the study endpoints. Patients with a past cancer history (active malignancy within 2 years prior to study entry) with substantial potential for recurrence must be discussed with the Sponsor before study entry. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia), organ-confined prostate cancer with no evidence of progressive disease.
• The patient has clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association Class 3 or 4 congestive heart failure [Appendix 1], uncontrolled angina, history of myocardial infarction, unstable angina or stroke within 6 months prior to study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication).
• The patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic obstructive pulmonary disease, pulmonary hypertension) that, in the Investigator's opinion, would put the patient at significant risk for pulmonary complications during the study.
• The patient has known active or suspected brain or leptomeningeal metastases. (Central nervous system [CNS] imaging is not required prior to study entry unless there is a clinical suspicion of CNS involvement). Patients with stable, treated brain metastases are eligible provided there is no evidence of CNS disease growth on imaging for at least 3 months following radiation therapy or other locoregional ablative therapy to the CNS.
• The patient is receiving immunosuppressive therapy for prophylaxis following a prior organ transplant (solid organ or allogeneic stem cell) or management of immune-mediated toxicities due to immunotherapy. Low-dose corticosteroid (defined as < 10mg/day of prednisone or equivalent) therapy is permitted.
• The patient has uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, disseminated intravascular coagulation, or psychiatric illness/social situations that would limit compliance with study requirements.
• The patient is pregnant or breast feeding.
• The patient has known positive status for human immunodeficiency virus active or chronic Hepatitis B or Hepatitis C.
• The patient is oxygen-dependent.
• The patient has any medical condition which in the opinion of the Investigator places the patient at an unacceptably high risk for toxicities.

• Advanced solid tumor for which, in the opinion of the investigator, no other standard therapy offers greater benefit.
• A solid tumor diagnosis in the setting of:
• a) a documented NTRK fusion and a clinical history of relapse following a response to a prior TRK inhibitor
• b) a documented NTRK fusion unresponsive to a prior TRK inhibitor
• c) a documented NTRK fusion and a clinical history of intolerance to a prior TRK inhibitor
• NTRK gene fusions will be identified in a CLIA-certified (or equivalently-accredited diagnostic) laboratory. If such a report cannot be provided, other available certifications/accreditations are required and need to be documented. Patients with infantile fibrosarcoma (IFS) or congenital mesoblastic nephroma (CMN) may be enrolled based on an ETV6+ FISH test without identifying NTRK3.
• Performance Status: Eastern Cooperative Oncology Group (ECOG) score ≤ 2 in adults or Karnofsky Performance Score (KPS) Score≥50% (age ≥ 16 years) or Lansky Performance Score (LPS) ≥ 40% (age < 16 years).
• Life expectancy of at least 3 months.
• Adequate hematologic, hepatic and renal function.
• Patients with stable central nervous system (CNS) primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms have been stable for 7 days prior to the first dose of selitrectinib.
• Ability to receive study drug orally or by enteral administration
• Prior exposure to second generation TRK inhibitor (e.g. selitrectinib, repotrectinib (TPX-0005)), taletrectinib (DS-6501b/AB-106)). Exception is in case patient presented intolerance to the second generation TRK inhibitor agent and the duration of exposure was less than 28 days. No previous treatment with selitrectinib is allowed.
• Concurrent treatment with a strong CYP3A4 inhibitor or inducer, consumption of grapefruit juice or Seville oranges, or drugs associated with QT prolongation.
• Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of selitrectinib, or prolongation of QT interval corrected for heart rate (QTc interval) >480 milliseconds within past 6 months
• Major surgery within 7 days of enrollment
• Uncontrolled systemic bacterial, fungal or viral infection.
• Pregnancy or lactation.
• Known hypersensitivity to selitrectinib or Ora-Sweet® SF and OraPlus® for patients receiving liquid formulation.

Key For Phase 1
• Patients with a locally advanced or metastatic solid tumor who:
• have progressed on or are intolerant to standard therapy, or
• no standard therapy exists, or in the opinion of the Investigator, are not candidates for or would be unlikely to tolerate or derive significant clinical benefit from standard therapy, or
• decline standard therapy
• Prior MKIs with anti-RET activity are allowed.
• A RET gene alteration is not required initially. Once adequate PK exposure is achieved, evidence of RET gene alteration in tumor and/or blood is required as identified through molecular assays, as performed for clinical evaluation.
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as appropriate to tumor type.
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance Score (LPS) ≥ 40% (age < 16 years) with no sudden deterioration 2 weeks prior to the first dose of study treatment.
• Adequate hematologic, hepatic and renal function.
• Life expectancy of at least 3 months. For Phase 2 As for phase 1 with the following modifications:
•For Cohort 1 (up to 250 patients): Subjects must have received prior standard therapy appropriate for their tumor type and stage of disease, or in the opinion of the Investigator, would be unlikely to tolerate or derive clinical benefit from appropriate standard of care therapy.
• Cohorts 1 and 2: enrollment will be restricted to patients with evidence of a RET gene alteration in tumor.
• Cohorts 1 and 2: 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: (up to 200 patients):
• Cohorts 1 and 2 without measurable disease;
• 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 (up to 50 patients):
• Patients who otherwise are eligible for Cohorts 1, 2 or 5 who discontinued another RET inhibitor due to intolerance may be eligible with prior Sponsor approval. 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: Patients otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval.
•Investigational agent or anticancer therapy (including chemotherapy, biologic therapy, immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5 half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292 (selpercatinib). In addition, no concurrent investigational anti-cancer therapy is permitted. Note: Potential exception for this exclusion criterion will require a valid scientific justification and approval from the Sponsor.
• Major surgery (excluding placement of vascular access) within 4 weeks prior to planned start of LOXO-292 (selpercatinib).
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned start of LOXO-292 (selpercatinib), with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation, which must be completed at least 4 weeks prior to the first dose of study treatment.
• Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy.
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Patients are eligible if neurological symptoms and CNS imaging are stable and steroid dose is stable for 14 days prior to the first dose of LOXO-292 (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) > 470 msec.
• Required treatment with certain strong CYP3A4 inhibitors or inducers and certain prohibited concomitant medications.

Inclusion Criteria
• ≥2 years and <18 years of age for enrolment in Phase 1 or ≥2 years and ≤21 years of age for enrolment in Phase 2.
• Recurrent or refractory solid tumors
• Phase 1: All solid tumors (measurable or evaluable disease), including primary central nervous system (CNS) tumors; exclusion of hepatoblastoma and lymphomas. Participants with diffuse intrinsic pontine glioma, optic pathway glioma, or pineal tumors with elevated tumor markers (alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [ß-hCG][or human chorionic gonadotropin [hCG])do not require histological or cytological confirmation of diagnosis
• Phase 2: Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET), Rhabdomyosarcoma, High Grade Glioma (HGG) (all must have measurable disease); exclusion of Diffuse Intrinsic Pontine Glioma
• Histologically or cytologically confirmed diagnosis
• Measurable disease that meets the following criteria (Phase 2): 1. RECIST 1.1 (for all tumor types except HGG): At least 1 lesion of ≥1.0 cm in the longest diameter for a non lymph node or ≥1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computed tomography /magnetic resonance imaging (CT/MRI) 2. Response Assessment in Neuro-Oncology (RANO) for high grade glioma (HGG): At least one lesion must be measurable as defined as a bi dimensionally contrast enhancing lesion with clearly defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices which are preferably at most 5 mm apart with 0 mm skip Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion
• Karnofsky performance score ≥50 for participants>16 year of age and Lansky play score ≥50 for participants ≤16 years of age. Neurologic deficits in participants with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment. Participants 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
• Prior Therapy
• Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy
• Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
• Anti-cancer agents not known to be myelosuppressive (eg, not associated with reduced platelet or absolute neutrophil counts): ≥7 days after the last dose of agent
• Monoclonal antibodies: ≥21 days or 3 half-lives (whichever is shorter) of the antibody must have elapsed after the last dose of a monoclonal antibody (including checkpoint inhibitors). 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. Participants receiving corticosteroids, who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment, are not eligible
• Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth factor 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
• Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥21 days after the completion of interleukins, interferons or cytokines (other than hematopoietic growth factors)
• Stem cell infusions (with or without total body irradiation): Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocytes infusion or boost infusion: ≥84 days after infusion and no evidence of graft versus host disease; Autologous stem cell infusion including boost infusion: ≥42 days
• Cellular Therapy: ≥42 days after the completion of any type of cellular therapy (eg, modified T cells, natural killer cells, dendritic cells, etc)
• Radiotherapy (XRT)/External Beam Irradiation including Protons: ≥14 days after local XRT; ≥150 days after total body irradiation, craniospinal XRT or if radiation to ≥50% of the pelvis; ≥42 days if other substantial bone marrow radiation.
• Radiopharmaceutical therapy: ≥42 days after systemically administered therapy.
• Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted or mammalian target of rapamycin (mTOR)-targeted therapies: Must not have received prior exposure to lenvatinib; May have previously progressed on an mTOR inhibitor; No more than 2 prior VEGF/VEGFR-targeted therapies (For Phase 2 only); Must not have received prior VEGF/VEGFR-targeted therapy in combination with an mTOR inhibitor (For Phase 2 only)
• Adequate bone marrow function for participants with solid tumors without known bone marrow involvement
• Adequate bone marrow function for participants with known bone marrow metastatic disease
• Adequate renal function
• Adequate liver function
• Adequate cardiac function
• Adequate neurologic function
• Adequate blood pressure (BP) control with or without antihypertensive medications
• Adequate coagulation
• Adequate pancreatic function
• Adequate metabolic function
• Adequate glycemic control
• Participants must have a minimum body surface area (BSA) of 0.6 m^2 at study entry. Exclusion Criteria
• Participants who have had or are planning to have the following invasive procedures
• Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to enrolment
• Central line placement or subcutaneous port placement is not considered major surgery. External central lines must be placed at least 3 days prior to enrollment and subcutaneous ports must be placed at least 7 days prior to enrollment
• Fine needle aspirate within 7 days prior to enrolment
• Surgical or other wounds must be adequately healed prior to enrolment
• For purposes of this study, bone marrow aspirate and biopsy are not considered surgical procedures and therefore are permitted within 14 days prior to start of protocol therapy
• Participants who have non-healing wound, unhealed or incompletely healed fracture, or a compound (open) bone fracture at the time of enrolment
• Participants having an active infection requiring systemic therapy.
• Participants with a known history of active hepatitis B (defined as hepatitis B surface antigen reactive or hepatitis B virus- deoxyribonucleic [DNA] detected) or known active hepatitis C virus (HCV, defined as HCV- Ribonucleic acid [RNA] detected). Note: No testing for hepatitis B and hepatitis C is required unless mandated by the local health authority.
• Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required at screening only when mandated by the local health authority
• Clinical evidence of nephrotic syndrome prior to enrolment
• Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 21 days prior to enrolment
• Thrombotic/ thromboembolic event requiring systemic anticoagulation within 90 days prior to enrollment
• Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment obtained within 28 days prior to study enrollment for Participants with HGG
• Diagnosis of lymphoma
• Radiographic evidence of major blood vessel invasion/infiltration.
• Evidence of untreated CNS metastases (exception: participants with primary CNS tumors and leptomeningeal disease)
• Participants who are currently receiving enzyme-inducing anticonvulsants
• Participants chronically receiving strong cytochrome P450 3A4 (CYP3A4)/P-glycoprotein (P-gp) inhibitors or inducers within 7 days prior to study enrollment
• Females who are breastfeeding or pregnant. For females of childbearing potential, a negative screening pregnancy test must be obtained within 72 hours before the first dose of study drug

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. 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);
• 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. 7. Measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or INRC for neuroblastoma. 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. 10. Evidence of a personally signed and dated informed consent document indicating that the patient or a legally acceptable representative/parent(s)/legal guardian of minors, has been informed of all pertinent aspects of the study. Minor study patients also must provide age appropriate assent according to the local guidelines, where applicable. 11. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures. Exclusion: 1. 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. 2. Prior intolerability to IRN and/or TMZ, for palbociclib with IRN and TMZ combination and prior intolerability to TOPO and/or CTX for palbociclib with 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. Prior growth factors (including filgrastim) within 7 days before study entry or PEG-filgrastim within 14 days before study entry. 5. Radiation therapy within 14 days before study entry. 6. Systemic anti cancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas. 7. Previous high dose chemotherapy requiring stem cell rescue within 90 days or persistent AE >Grade 1. 8. Prior irradiation to >50% of the bone marrow (see Appendix 9). 9. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half lives, whichever is longer, prior to study entry. 10. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries. 11. Known or suspected hypersensitivity to palbociclib, IRN and/or TMZ. 12. 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. 13. 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. 14. Hereditary bone marrow failure disorder. 15. QTc >470 msec. 16. 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%. 17. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy). 18. Evidence of serious active or uncontrolled bacterial, fungal or viral infection or known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness. 19. Other 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. 20. 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. 21. Fertile male patients and female patients of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 90 after the last dose of investigational product.

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. 10. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 11. 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.

• 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

• 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.