Cabozantinib In Combo With NIVO + IPI In Advanced NCCRCC

Inclusion Criteria:

* histologically or cytologically confirmed unresectable advanced or metastatic nccRCC, including but not limited to:

  * Papillary RCC, any type
  * Unclassified RCC
  * Translocation RCC
  * Chromophobe RCC
  * Collecting duct RCC
  * Renal cell carcinoma with 80% or more sarcomatoid features on primary nephrectomy specimen or a biopsy
  * Other nccRCC histologies in discussion with principal investigator
* Measurable disease as per RECIST 1.1. See Section 11 for the evaluation of measurable disease.
* Age ≥ 18 years
* ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A)
* Participants must undergo fresh tumor biopsy after registration but prior to the start of treatment unless medically unsafe or not feasible. If a fresh tumor biopsy is not medically safe or not feasible, confirmation of the availability of archival tumor tissue is required. For archival tissue, a recommended minimum of 20 unstained slides should be obtained.
* Normal organ and marrow function as defined below:

  * absolute neutrophil count ≥1,500/mcL
  * platelets ≥100,000/mcL
  * hemoglobin ≥9g/dL (transfusions allowed)
  * total bilirubin ≤2.0 x institutional upper limit of normal with the following exception: patients with known Gilbert disease should have a serum bilirubin ≤ 3 x ULN
* AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal with the following exception: patients with known liver metastases should have AST and ALT ≤ 5 x ULN
* creatinine clearance ≥30 mL/min/1.73 m2 according to the Cockcroft-Gault equation.
* Normal coagulation INR ≤ 1.5
* Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for 5 months after the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 7 months after completion of cabozantinib, nivolumab or ipilimumab administration.
* Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

\- Patients could be untreated or have received prior lines of therapies. Patients who receive prior therapy may receive only one VEGF based therapy. A combination therapy (e.g.

lenvatinib+everolimus) is considered 1 line of therapy.

* Previous therapy with CD137 agonists and immune checkpoint inhibitors, including but not limited to inhibitors of the PD-1/PD-L1 and/or CTLA-4 axes. Previous treatment with IFNα or IL-2 is allowed if received \> 4 weeks from enrollment.
* Treatment with small molecule tyrosine kinase inhibitors within 2 weeks of enrollment, or any other anticancer agent within 4 weeks of enrollment.
* Prior therapy with cabozantinib
* Patients receiving any other therapeutic investigational agents.
* Treatment with hydroxychloroquine within two weeks of treatment start.
* Radiotherapy for nccRCC within 14 days of first study treatment with the exception of a single fraction of radiation administered for palliation of symptoms.
* Untreated brain metastases. Patients might be included if they underwent radiation therapy or surgery at least 4 weeks prior enrollment. Stability of the central nervous system disease should be confirmed by brain MRI or CT-scan or as determined by treating investigator. Patients should not be receiving prednisone dose \>10 mg/d at C1D1.
* Other malignancy diagnosed within 2 years of first study treatment unless negligible risk of metastases or death (included but not limited to carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ of the breast, non-muscle invasive urothelial carcinoma, or other malignancy not deemed to impact patients 5-year life expectancy).
* Significant cardiovascular disorders including:

  * Significant cardiovascular disease including dyspnea of New York Heart Association (NYHA) class II or greater, myocardial infarction within the previous 3 months of first study treatment, unstable arrhythmias, unstable angina. Patients with known coronary artery disease or congestive heart failure not meeting the above criteria, or left ventricular ejection fraction \< 50%, must be on a stable and optimized in the opinion of the treating physician, in consultation with a cardiologist when appropriate.
  * Uncontrolled hypertension (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg). Anti-hypertensive therapy is allowed.
  * Personal history of hypertensive crisis or hypertensive encephalopathy within the previous 3 months of registration.
  * Personal history of stroke or transient ischemic attack within 3 months of registration.
  * Significant vascular disease, such as but not limited to aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis, within 6 months of registration.
* Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per electrocardiogram (ECG). Furthermore, subjects with a history of additional risk factors for torsades de pointes (eg, long QT syndrome) are also excluded.
* Known history of severe allergic reactions attributed to compounds of similar chemical or biologic composition human antibodies, or known hypersensitivity to any component of cabozantinib, nivolumab or ipilimumab products.
* Systemic immunosuppressive medications including but not limited to: Corticosteroids at a dose \> 10mg equivalent prednisone daily, cyclosporin, azathioprine, methotrexate, thalidomide, anti-tumor necrosis factor (TNF) agents, hydroxychloroquine, within 2 weeks of first study dose.

  * Patients who have received acute, low-dose systemic immunosuppressant medications may be enrolled.
  * Patients with adrenal insufficiency on physiologic replacement doses of steroids may be enrolled.
  * The use of inhaled, topical, intraocular, or intraarticular corticosteroids or mineralocorticoids are allowed
* Prior allogenic stem cell or solid organ transplant.
* Personal history of autoimmune disease including: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or glomerulonephritis. Patients with a history of autoimmune-related hypothyroidism on thyroid replacement hormone, or those with autoimmune dermatologic conditions not requiring the use of prednisone \> 10 mg or equivalent are eligible.
* History of idiopathic pulmonary fibrosis, organized pneumonia, or evidence of active pneumonitis on screening imaging CT of the chest. History of radiation pneumonitis in the radiation field is permitted.
* History of following infectious diseases:

  * Active or chronic hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening).
  * Active hepatitis C infection. Patients with positive hepatitis C antibody test are eligible if PCR is negative for hepatitis C viral DNA.
  * Infection requiring therapeutic oral or IV anti-microbials within 2 weeks of first study treatment. Patients receiving routine antimicrobial prophylaxis for dental procedures are eligible.
  * Known positive test for HIV.
* Administration of a live, attenuated vaccine within 3 weeks for first study treatment.
* Bleeding diathesis, or significant coagulopathy in the absence of therapeutic anticoagulation.
* Use of strong inhibitors and inducers of CYP3A4
* Significant bleeding, including but not limited to hematemesis, hematuria, hemoptysis of \> 0.5 teaspoon (2.5 mL), within 3 months before registration.
* Invasion of major pulmonary blood vessels. A discussion with PI may be needed if invading lesions are suspected.
* Concomitant use of dipyramidole, ticlopidine, clopidogrel, cilostazol is excluded. Aspirin (≤ 325 mg per day) is allowed. Prophylactic anticoagulation with oral or parenteral anticoagulants for the patency of venous access devices or other indications is allowed.

Therapeutic use of low-molecular weight heparin (such as enoxaparin) and subcutaneous or oral Factor Xa inhibitors are allowed. Use of warfarin is prohibited.

* Significant GI conditions at risk of perforation or bleeding, including but not limited to:

  * Active GI obstruction or requirement of routine parenteral nutrition or tube feedings.
  * Personal history of abdominal or tracheoesophageal fistula or GI perforation within 6 months of registration.
  * Evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
  * Serious, non-healing or dehiscing wound or active ulcer.
* Major surgical procedure to include major dental, oral or maxillofacial procedures within 14 days of first study treatment.
* Proteinuria as demonstrated by \> 1.5 gram of protein in a 24-hour urine collection. All patients with ≥ 2+ protein on urinalysis must undergo 24-hour urine collection for protein.
* Unable to swallow pills.
* Malabsorption syndrome.
* Inability to receive IV medications
* Pregnant or lactating women.