Alternate Cabozantinib Dosing Schedule Alone and in Combination with Nivolumab for the Treatment of Metastatic Kidney Cancer and Neuroendocrine Tumors

Inclusion Criteria

• COHORTS A AND B: Histologically or cytologically confirmed advanced renal cell carcinoma (RCC) with any clear cell or non-clear cell component. 100% sarcomatoid is permissible
• COHORTS A AND B: Patient may have had any number of prior therapies for Cohort A, but for Cohort B patients must not have received any systemic therapy in the metastatic setting * Patients who have received prior (neo)adjuvant immunotherapy with pembrolizumab or similar are eligible for Cohort B IF they completed the adjuvant therapy > 12 months from start of trial therapy * Treatment naïve patients may be treated in Cohort A if deemed not candidates for nivolumab or if felt single agent cabozantinib most appropriate by the treating clinician
• COHORT C: Well differentiated NET, grades 1-3 (any primary site) who have progressed on or are not eligible for somatostatin analogs per treating physician discretion
• COHORT C: Disease progression within prior 12 months
• COHORT C: Prior or concurrent treatment with somatostatin analogue allowed but no limit on lines of therapy (stable dose of somatostatin for 2 months)
• At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
• No evidence of pre-existing uncontrolled hypertension as assessed by investigator. Patients may undergo adjustments or additions to their antihypertensive regimen before or during screening to achieve optimal blood pressure (BP) control
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2
• Leukocytes >= 2,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin (Hgb) > 9 g/dL (> 90 g/L)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (with the exception of individuals with Gilberts syndrome who may have a bilirubin < 3.0 mg/dL)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT]/serum glutamic pyruvic transaminase [SGPT]) =< 3 x ULN
• Alkaline phosphatase (ALP) =< 3 x ULN * ALP =< 5 x ULN with documented bone metastases
• Albumin > 2.8 g/dL
• Creatinine clearance >= 30 Ml/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) =< 1.3 x the laboratory ULN
• Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document
• 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

Exclusion Criteria

• Patients who have had systemic anti-cancer therapy or radiotherapy within 14 days or five half-lives, whichever is shorter. prior to entering the study * 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 would preclude eligibility
• Patients with prior therapy with cabozantinib
• Prior systemic therapy directed at advanced RCC is not allowed for patients enrolled to Cohort B (treatment-naïve group)
• Cohort B only: Active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Cohort B only: Patients have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• Patients may not be receiving any other investigational agents
• History of allergic reactions or hypersensitivity attributed to compound of similar chemical or biologic composition to the agent(s) used in this study
• Current use or anticipated need for treatment with drugs or foods that are known strong CYP3A4 inhibitors and inducers. The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed
• 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: * 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
• 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 would limit compliance with study requirements * Cardiovascular disorders: ** Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias ** Fridericia's correction formula (QTcF) > 500 msec within 28 days before first dose of study treatment ** Uncontrolled hypertension defined as sustained blood pressure (BP) > 160 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment ** 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 of study treatment *** Subjects with a diagnosis of incidental, sub-segmental 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 * Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: ** 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 ** Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment *** Note: Complete healing of an intra-abdominal abscess must be confirmed 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. Subjects with lesions invading the intrahepatic vasculature, including portal vein, hepatic vein, and hepatic artery, are eligible
• 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 demonstrated complete wound healing from a procedure, any of open or non-healing wound, infection or other reason in the opinion of the treatment team prior to first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
• Patients are excluded if they have active, symptomatic brain metastases or leptomeningeal metastases. Subjects with known brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for four weeks (after treatment is complete and within 28 days prior to study drug administration)
• Second malignancy requiring active systemic treatment. Exceptions include non-melanoma skin cancers, localized breast or prostate cancer on adjuvant hormonal therapy
• Gastrointestinal abnormalities including: * Inability to swallow tablets * Requirement for intravenous alimentation * Prior surgical procedures affecting absorption including total gastric resection * Active gastrointestinal bleeding as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy * Malabsorption syndromes
• Significant baseline hepatic impairment, as cabozantinib is typically dose-adjusted with hepatic dysfunction
• HIV+ individuals are excluded if they do not have well controlled HIV. Hence, those who have a detectable viral load (above the lower limit of detection of the relevant viral load test) or a CD4+ count of < 350 cells/μL will be excluded
• Pregnant or breast feeding
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 tsp (2.5ml) of red blood, or other history of significant bleeding within 12 weeks before the first dose of study treatment
• Other clinically significant disorders: serious non-healing wound/ulcer/bone fracture; uncompensated/symptomatic hypothyroidism; moderate to severe hepatic impairment (Child-Pugh B or C)