Inclusion Criteria:

• Renal cell carcinoma with some component of clear cell histology; histologic documentation of metastatic disease is not required
• Locally advanced (defined as disease not amenable to curative surgery or radiation therapy) or metastatic renal cell carcinoma (RCC) (equivalent to stage IV RCC, according to American Joint Committee on Cancer [AJCC] staging)
• Eligible patients must be intermediate/poor risk, per the International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (Heng) criteria; patients must therefore have as one or more of the following six factors:
  • Time from diagnosis of RCC to systemic treatment < 1 year
    • Note: systemic treatment refers to the initiation of A031203 protocol treatment
  • Hemoglobin < the lower limit of normal (LLN)
  • Corrected calcium > the upper limit of normal (ULN)
  • Karnofsky performance status < 80%
  • Neutrophil count > ULN
  • Platelet count > ULN
• No radiographic evidence of cavitating pulmonary lesion(s)
• No tumor invading the inferior vena cava (IVC) or superior vena cava (SVC) blood vessels
• No evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days prior to registration
• No prior systemic treatment for RCC; supportive therapies such as bisphosphonates (zoledronic acid) or denosumab are permitted
• Patients must not have had a major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure; however, patients who have had a nephrectomy may be enrolled 4 weeks after surgery, providing there are no wound-healing complications; the following are not considered to be major procedures: thoracentesis, paracentesis, port placement, laparoscopy, thoracoscopy, bronchoscopy, endoscopic ultrasonographic procedures, mediastinoscopy, skin biopsies, incisional biopsies, imaging-guided biopsy for diagnostic purposes, and routine dental procedures
• Radiation:
  • To the brain, thoracic cavity, abdomen, or pelvis must be completed at least 90 days before registration;
  • To bone must be completed at least 14 days before registration; and
  • To any other sites must be completed at least 28 days before registration In all cases, there must be complete recovery and no ongoing complications from prior radiation therapy
• No chronic concomitant treatment of strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducers or inhibitors; patients may not have received a strong CYP3A4 inducer within 12 days prior to registration nor a strong CYP3A4 inhibitor within 7 days prior to registration
• Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria; lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm with spiral computed tomography (CT) scan
• No active brain metastases; patients with treated, stable brain metastases for at least three months are eligible as long as they meet the following criteria:
  • Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 3 months, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or CT); (stable dose of anticonvulsants are allowed); treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, linear accelerator [LINAC], or equivalent) or a combination as deemed appropriate by the treating physician; patients with central nervous system (CNS) metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to registration are not eligible
  • Baseline brain imaging (MRI/CT) is required
• No serious non-healing wound, ulcer, or bone fracture requiring intervention within 28 days prior to registration
• No arterial thrombotic events within 6 months prior to registration, including transient ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus, unstable angina or angina requiring surgical or medical intervention in the 6 months prior to registration, or myocardial infarction (MI); patients with clinically significant peripheral artery disease (i.e., claudication on less than one block), significant vascular disease (i.e., aortic aneurysm, history of aortic dissection), or any other arterial thrombotic event are ineligible
• No history of pulmonary embolism or untreated deep venous thrombosis (DVT) within 6 months prior to registration; note: patients with recent DVT who have been treated with therapeutic anticoagulation with low molecular weight heparin for at least 6 weeks are eligible; patients receiving therapeutic warfarin (> 2 mg/day) are not eligible; patients on warfarin may be switched to low molecular weight heparin at the discretion of the treating physician
• No inadequately controlled hypertension (defined as a blood pressure of ≥150 mmHg systolic and/or ≥ 90 mmHg diastolic), or any prior history of hypertensive crisis or hypertensive encephalopathy
• No New York Heart Association (NYHA) class ≥ 2 congestive heart failure
• Ejection fraction on echocardiogram (Echo) or multi gated acquisition scan (MUGA) > 50%
• No corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before randomization; note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed; if the average of these three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard
• No history of congenital QT syndrome
• No unstable cardiac arrhythmia within 6 months prior to registration
• No evidence of any of the following:
  • Clinically-significant gastrointestinal bleeding within 6 months before registration; or
  • Hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood within 3 months before registration; or
  • Any other signs indicative of pulmonary hemorrhage within 3 months before registration
• No history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 6 months prior to registration and complete healing/resolution prior to registration; no percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months prior to registration
• No active peptic ulcer disease, within 28 days before registration
• No inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis within 28 days before registration
• No malabsorption syndrome within 28 days before registration
• No uncompensated hypothyroidism; patients with hypothyroidism on therapy are required to have thyroid stimulating hormone (TSH) within normal limits
• No radiologic or clinical evidence of pancreatitis
• No history of organ transplant
• Patients with active infection requiring systemic treatment within 28 days prior to registration are not eligible
• Patients who are pregnant or nursing are not eligible; women of child bearing potential must have a negative serum or urine pregnancy test within 16 days prior to registration; women of child-bearing potential include:
  • Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea ≥ 12 consecutive months)
  • Women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35m IU/mL
  • Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy)
• Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2
• Archival tissue must be available for submission, though it is optional for patients to choose to participate in the correlative sub studies
• Absolute neutrophil count (ANC) >= 1,500/uL
• Platelet count ≥ 100,000/uL
• Hemoglobin ≥ 9 g/dL; patients may not have had a transfusion within 7 days prior to screening assessment
• Total bilirubin ≤ 1.5 x upper limits of normal
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 x ULN
• Albumin ≥ 2.8 g/dL
• Serum creatinine ≤ 1.5 x ULN, OR calculated creatinine clearance ≥ 30 mL/minute (modified Cockcroft and Gault formula)
• Urine protein to creatinine (UPC) ratio < 1.0; if UPC ≥ 1, then a 24-hour urine protein must be assessed; eligible patients must have a 24-hour urine protein value < 1 g
• Total serum calcium < 12 mg/dL
• International normalized ratio (INR) ≤ 1.2 x ULN; subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation
• TSH within normal limits (WNL); TSH only required for patients on thyroid supplementation