Cabozantinib, Nivolumab, and Ipilimumab for the Treatment of Metastatic Non-clear Cell Renal Cell Cancer

Inclusion Criteria

• Histologically or cytologically confirmed unresectable advanced or metastatic nccRCC, including but not limited to: * Papillary renal cell carcinoma (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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
• Participants must undergo fresh tumor biopsy after registration but prior to the start of treatment unless medically unsafe or not feasible. For the lesion that is biopsied, if it is a target lesion per RECIST 1.1, then the lesion should be moved to non-target. If the patient has only one target lesion per RECIST 1.1 at baseline, and this is the only lesion amenable to biopsy, then it can be biopsied and followed as a target lesion without excluding the patient from the trial. 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
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 9 g/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 upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x 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 m^2 according to the Cockcroft-Gault equation
• International normalized ratio (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 who have received more than one prior line of vascular endothelial growth factor (VEGF) based therapy are excluded. 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 IFNalpha or IL-2 is allowed if received > 4 weeks from enrollment
• Treatment with small molecule tyrosine kinase inhibitors within 2 weeks from last dose or 4 half-lives, whichever is shorter, 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 magnetic resonance imaging (MRI) or CT-scan or as determined by treating investigator. Patients should not be receiving prednisone dose > 10 mg/d at cycle 1 day 1 (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)
• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), the direct factor Xa inhibitor betrixaban, platelet inhibitors (e.g., clopidogrel), and chronic use of aspirin above low dose levels for cardio-protection per local applicable guidelines, Allowed anticoagulants are the following: * 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
• 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 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 > 140 mmHg and/or diastolic blood pressure > 90 mmHg). Anti-hypertensive therapy is allowed * Personal history of hypertensive crisis or hypertensive encephalopathy within the previous 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 * Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose if symptomatic ** Subjects with a diagnosis of incidental, subsegmental pulmonary embolism (PE) or deep vein thrombosis (DVT) within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation for at least 1 week before first dose of study treatment * Iatrogenic arterial embolization procedures such as tumor arterial embolization or splenic artery embolization are allowed
• 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 (e.g., 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 > 10 mg equivalent prednisone daily, cyclosporine, 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 intra articular 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 * Autoimmune disease that has been symptomatic or required treatment within the past two years from the date of registration
• 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 polymerase chain reaction (PCR) is negative for hepatitis C viral deoxyribonucleic acid (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 human immunodeficiency virus (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 principal investigator (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 gastrointestinal (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
• Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 2 weeks 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
• Urine protein-to-creatinine (UPC) ratio =< 2 mg/mg
• Unable to swallow pills
• Malabsorption syndrome
• Inability to receive IV medications
• Pregnant or lactating women