A Phase II Study of Nivolumab With Ipilimumab and Cabozantinib in Patients With Untreated Renal Cell Carcinoma Brain Metastases

Inclusion Criteria 1. Signed Informed Consent Form (ICF) 2. Ability and willingness to comply with the requirements of the study protocol 3. Age ≥18 years 4. Life expectancy \>12 weeks 5. Asymptomatic and off steroids for at least 10 days except patients: who have mild symptoms from intracranial disease that do not affect their performance status 6. Prior therapies for extracranial metastatic renal cell carcinoma as long as it did not include anti- CTLA-4 or cabozantinib or MET inhibitors 7. Patients with histologically confirmed metastatic renal cell carcinoma and at least one measurable intracranial target lesion for which all of the following criteria are met: \- Previously untreated or progressive after previous local therapy(limited to SRS and surgery) * Immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy. * 5mm to 30mm, as determined by MRI with contrast. 8. Adequate hematologic and essential organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (C1D1) * Absolute neutrophil count (ANC) ≥1500 cells/µL * White blood cell (WBC) counts \>2500/µ -- Lymphocyte count ≥500/µL * Platelet count ≥ 100,000/µL; * Hemoglobin ≥9.0 g/dL * Serum albumin≥2.8g/dl * Total bilirubin ≤1.5×upper limit of normal (ULN) with the following exception: Patients with known Gilbert disease who have serum bilirubin level ≤3×ULN may be enrolled. \- Alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN). * Aspartate aminotransferase (AST) ≤ 3x upper limit of normal (ULN). * Alkaline phosphatase ≤5×ULN in patients with documented bone metastases. * Serum creatinine ≤ 1.5x ULN or calculated creatinine clearance ≥ 40mL/min (≥ 0.675mL/sec) using the Cockcroft-Gault equation: Males: (140 - age) x weight (kg)/(serum creatinine \[mg/dL\] × 72)Females: \[(140 - age) x weight (kg)/(serum creatinine \[mg/dL\] × 72)\] × 0.85 * Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤ 1 g. 9. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate \[\<1% per year\] when used consistently and correctly) and to continue its use for at least 12 months after the last dose of Cabozantinib and Nivolumab 10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2 (see Appendix 5) 11. INR and aPTT ≤1.5×ULN within 7 days prior to study enrollment 12. Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. Exclusion Criteria 1. Symptomatic brain metastases requiring immediate local interventions such as craniotomy or SRS or whole brain radiation. 2. Patients who require immediate surgical or radiotherapy interventions for extra-cranial lesions. 3. Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible. 4. Requiring corticosteroid dose in 10 days prior to administration of first dose of study drug with following exceptions \- Symptomatic patients who have stable or decreasing corticosteroid use in the past 10 days may be included 5. Patients with Leptomeningeal disease. 6. Any approved anticancer therapy, including chemotherapy and hormonal therapy within 4 weeks prior to initiation of study treatment; however, the following are allowed: * Hormone-replacement therapy or oral contraceptives * Herbal therapy \>1 week prior to Cycle 1, Day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to Cycle 1,Day 1) 7. Current, recent (within 3 weeks of the first infusion of this study), or planned participation in an experimental drug study. 8. AEs from prior anticancer therapy that have not resolved to Grade ≤1 except for alopecia. 9. Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; \>Childes A cirrhosis; fatty liver; and inherited liver disease. 10. Patients with acute leukemias, accelerated/blast-phase chronic myelogenous leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma. 11. Patients who are pregnant, lactating, or breastfeeding. 12. Known hypersensitivity to recombinant human antibodies. 13. Inability to undergo MRI secondary to Metal implant and Gadolinium contrast allergy. 14. Inability to comply with study and follow-up procedures. 15. History of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis with the following exception: * Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. * Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible * Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations * Rash must cover less than 10% of body surface area (BSA), Disease is well controlled at base