Inclusion Criteria: 

Informed Consent

• Ability to provide written informed consent in accordance with federal, local, and institutional guidelines

Target Population

• Documented histological or cytological diagnosis of renal cell carcinoma with a clear-cell component
• Age ≥ 18 years
• Karnofsky Performance Score (KPS) ≥ 70%. 
• Estimated Life Expectancy of at least 3 months.
• Measurable Disease per RECIST 1.1 as determined by the Investigator.
• One and not more than two prior systemic lines of therapy (monotherapy or combination regimen) for advanced or metastatic RCC. 
  • Must include either:
    • one anti-angiogenic therapy (any VEGF pathway-targeted agent, used either as monotherapy or as a component of a combination regimen); OR
    • the combination regimen of nivolumab + ipilimumab.
  • Exposure to a prior treatment regimen for ≥4 weeks is considered a prior line of therapy, regardless of reason for its discontinuation (exception: high-dose IL2 will count as prior therapy if >3 doses administered):
    • 4 weeks will be counted from first to last dose for regimens that are intended to be administered on daily schedules (e.g., sunitinib, pazopanib) and from first dose to end of cycle length after last dose for regimens  that are intended to be administered in intervals of ≥ 1 week (e.g., one treatment of a Q2W regimen counts as 2 weeks of therapy).
  • Rechallenge with the same agent or regimen will not be considered a new line of therapy, if the patient had not previously discontinued that agent or regimen because of disease progression.
  • Systemic adjuvant therapy is considered a prior line of therapy if the patient has disease recurrence on or within 1 year after the last dose of adjuvant therapy.
• The patient must have had radiographic evidence of disease progression on or after the most recent systemic therapy and within 6 months before randomization.

Laboratory Findings

• Serum creatinine ≤ 2.0 × upper limit of normal or calculated creatinine clearance:
  • (CCr) ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:
  • CCr = {((l40 – age) x actual body weight)/ (72 x SCr)} x 0.85 (if female).
• Adequate hematological function, defined as absolute neutrophil count ≥ 1,500/mm3, hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3. Transfusions and growth factors must not be used within 2 weeks prior to randomization to meet these requirements.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3.0 × upper limit of normal.
• Total bilirubin ≤ 1.5 × the upper limit of normal. For patients with Gilbert’s disease, ≤ 3 mg/dL (≤ 51.3 μmol/L).
• Urine protein-to-creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol) or 24-hour urine protein < 1 g.

Reproductive Status

• Female patients of childbearing potential must have a negative serum or urine pregnancy test and if sexually active must agree to contraceptive requirements outlined in Section 10.6.12.2. Male patients who are sexually active with heterosexual partners of childbearing potential must agree to contraceptive requirements and sperm donation restrictions outlined in Section 10.6.12.2.

Other Inclusion Criteria

• Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior cancer therapy, unless after discussion with medical monitor adverse events (AEs) are deemed clinically non-significant and/or stable on supportive therapy.

Exclusion Criteria: 

Medical History

• Prior treatment with cabozantinib (or other MET inhibitor) or CB-839.
• Receipt of any anticancer therapy within the following windows before randomization:
  • Small molecule receptor tyrosine kinase inhibitor (TKI) therapy (including investigational) within 2 weeks or 5 half-lives, whichever is longer;
  • Any type of anticancer antibody or cytotoxic chemotherapy within 4 weeks;
  • Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks, or systemic treatment with radionuclides within 6 weeks before randomization. Patients with clinically relevant ongoing complications (per investigator assessment) from prior radiation therapy are not eligible;
  • Other investigational therapy within 4 weeks or 5 half-lives, whichever is longer.
• Patients with active and/or untreated central nervous system (CNS) cancer are not eligible. Patients with treated brain metastases (1) must have documented radiographic stability of at least 4 weeks duration demonstrated on baseline contrast-enhanced CNS imaging (e.g., contrast-enhanced MRI of the brain) prior to randomization and (2) must be symptomatically stable and off of steroids (for the purpose of treating symptoms of brain metastases) at least 2 weeks before randomization.
• Any other current or previous malignancy within the past three years except:
  • Adequately treated basal cell or squamous cell skin cancer;
  • Carcinoma in situ of the cervix;
  • Other neoplasm that, in the opinion of the Principal Investigator and with the agreement of the Medical Monitor, will not interfere with study specific endpoints.
• Previously identified allergy or hypersensitivity to components of the study treatment formulations (Note: patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take cabozantinib and are also excluded).
• Corrected QT interval (QTc) > 500 msec within 1 mo before randomization.
• Cabozantinib should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with clinically relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances.

Concurrent Conditions

• Unable to receive oral medications or any condition that may prevent adequate absorption of oral study medication including refractory nausea and vomiting, uncontrolled diarrhea, malabsorption, small bowel resection or gastric bypass surgery, use of feeding tubes
• Major surgery (e.g., GI surgery) within 6 weeks before first dose of study treatment or incomplete wound healing from any prior surgery. Patients with clinically relevant ongoing complications (per investigator assessment) from prior surgery are not eligible.
• The patient has uncontrolled, significant current or recent illness including, but not limited to, the following conditions:
  • Cardiovascular disorders:
    • Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias;
    • Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
  • Stroke (including TIA), myocardial infarction, or other ischemic event within 6 mo before randomization.
  • Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:
    • Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction;
    • Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intraabdominal abscess within 6 mo before randomization;
    • Complete healing of an intra-abdominal abscess must be confirmed before randomization.
  • Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 mL) of red blood, or other history of significant bleeding within 3 mo before randomization.
  • Moderate to severe hepatic impairment (Child-Pugh B or C).
  • Lesions invading major pulmonary blood vessels.
• Known active infection with HIV or Hepatitis B or C virus.
• Anticoagulation with warfarin at therapeutic doses is prohibited.
  • Note: Anticoagulation with therapeutic doses of low molecular weight heparin (LMWH), direct thrombin inhibitors, factor Xa inhibitors, and platelet inhibitors (e.g., clopidogrel) is allowed in patients without brain metastases who are on stable doses for at least 4 weeks before randomization and have had no complications from the anticoagulation regimen.
• Low-dose aspirin for cardioprotection, and low-dose (prophylactic) low molecular weight heparin (LMWH) are permitted.
• Inability to discontinue proton pump inhibitor use before randomization.
• Any condition including social, psychiatric or medical (including uncontrolled significant concurrent illness) that in the opinion of the Investigator could interfere with treatment or protocol-related procedures.
• Patients who are pregnant or lactating.