Rapid Sequencing of Approved Therapies in Patients With Metastatic or Unresectable Clear Cell Renal Cell Carcinoma

Inclusion Criteria: * Age ≥ 18 years at the time of study entry * Capable of understanding and complying with the protocol requirements and must have signed the informed consent document * ECOG performance status of 0 or 1 or KPS of at least 80% * Life expectancy ≥ 12 weeks * Histologically confirmed advanced (not amenable to curative surgery or radiation therapy) or metastatic (stage IV) RCC with predominantly clear cell component (sarcomatoid differentiation \<50%) a. Patients with localized RCC who develop metastatic disease post definitive nephrectomy, with or without systemic therapy in the adjuvant setting, are eligible * Patients with favorable, intermediate, or poor risk categories as defined by the MSKCC Prognostic Model or the IMDC consortium (Appendix A) will be eligible for the study * Evidence of measurable disease per RECIST 1.1 (i.e., ≥1 malignant tumor mass ≥10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm) * Adequate normal organ, marrow and coagulation function based on below labs within 14 days before first dose of study treatment: 1. Hgb ≥ 9.0g/dL 2. White blood count ≥ 2500/ µL 3. ANC ≥1 x 109/L (≥1500/L) without growth factor support 4. Plt count ≥ 100 x 109 /L (≥100,000/L) without transfusion 5. Total serum bilirubin ≤1.5 x institutional ULN; Gilbert's disease, Total serum bilirubin ≤3 x institutional ULN 6. Serum transaminases (AST/ALT) ≤3 x the institutional ULN; ALP ≤5 x the institutional ULN with documented bone metastasis 7. Serum albumin ≥ 2.8 g/dl 8. PT/INR or PTT test ≥ 1.3 x the laboratory ULN 9. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 30 mL/min 10. UPCR ≤ 1mg/mg (≤113.2 mg/mmol) or 24-h urine protein ≤ 1 g * Representative FFPE tumor block (archival or recent acquisition) with an associated anonymized pathology report must be available for central testing. * Recovery to baseline or ≤ Grade 1 (CTCAE v. 5.0) from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy. * Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment (See Appendix E). * Female subjects of childbearing potential must not be pregnant at screening (negative serum or urine pregnancy test within 2 weeks prior to the first dose of therapy). Female subjects are considered to be of childbearing potential unless one of the following criteria are met: 1. Documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) 2. Documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes. In addition, females \< 55 years-of-age must have a serum FSH level \> 40 mIU/mL to confirm menopause). 3. Note: documentation may include review of medical records, medical examinations, or medical history interview by the study site Exclusion Criteria: * Prior treatment with cabozantinib, nivolumab, ipilimumab, or any other systemic kidney cancer directed therapy for advanced disease (i.e. must be treatment naïve for advanced disease; adjuvant treatment post definitive local therapy is acceptable). * Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) within 4 weeks or five half-lives of the anti-cancer therapy prior to the first dose of study drug, whichever is shorter. * Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment. * Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks, or systemic treatment with radionuclides within 6 weeks before first dose of study treatment; ongoing clinically relevant complications from prior radiation therapy are not eligible. * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment. * 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 are the following: 1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins. 2. 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. * The subject has uncontrolled, significant inter-current or recent illness including, but not limited to, the following conditions: 1. Cardiovascular disorders: I. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias. II. Uncontrolled hypertension defined as sustained blood pressure \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment. III. Stroke (including TIA), MI, or other ischemic event, or thromboembolic event (e.g., DVT, PE) within 6 months before first dose of study treatment. IV. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation (see exclusion criterion #6) for at least 1 week before first dose of study treatment 2. GI disorders including those associated with a high risk of perforation or fistula formation: I. The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction. II. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment. III. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment. * Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose of study treatment. * Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. * Lesions invading or encasing any major blood vessels. * Other clinically significant disorders that would preclude safe study participation. 1. Serious non-healing wound/ulcer/bone fracture. 2. Uncompensated/symptomatic hypothyroidism. 3. Moderate to severe hepatic impairment (Child-Pugh B or C). * Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 2 weeks before first dose of study treatment. Minor surgeries within 10 days before first dose of study treatment. Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible. * Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per ECG within 14 days before first dose of study treatment. Note: If a single ECG shows a QTcF with an absolute value \> 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility. * Current or prior use of immunosuppressive medication within 21 days before the first dose of protocol therapy, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. * Pregnant or lactating females. * Inability to swallow tablets. * History of hypersensitivity to cabozantinib, nivolumab, ipilimumab, lenvatinib, everolimus, or any excipient or history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. * Any other active malignancy at time of first dose of study treatment or diagnosis of another malignancy within 3 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. * History of leptomeningeal carcinomatosis. * Treatment with systemic immune-stimulatory agents (including but not limited to IL-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment. * Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving protocol therapy or anticipation that such a live, attenuated vaccine will be required during the study. * Any prior Grade ≥3 irAE while receiving any previous immunotherapy agent, or any unresolved irAE \> Grade 1. * Active or prior documented autoimmune disease within the past 2 years including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone may be eligible for this study. * Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis) or history of GI disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug. * History of primary immunodeficiency. * History of prior allogeneic stem cell or solid organ transplant. * Participation in another clinical study with an investigational product within 28 days prior to enrolment in the study. * Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.