Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study

Inclusion Criteria:

Histological confirmation of RCC with a clear cell component
Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer [AJCC] stage IV) RCC
Patient can comprehend and sign the study informed consent form
Male or female >= 18 years of age at the time of informed consent
Karnofsky performance status (KPS) of >= 70%
No prior systemic therapy for RCC in the neoadjuvant, adjuvant or metastatic setting
At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

Tumor tissue for ribonucleic acid (RNA)-sequencing (tumor tissue from bony metastasis is not suitable but a soft tissue component around bone is acceptable)

Screening tissue consent- Patient must be assigned to either Cluster 1/2 or 4/5. Patients assigned to cluster 3/6/7 will not be eligible for the treatment study
Adequate renal function defined as calculated creatinine clearance >= 30 mL/min per the Cockcroft and Gault formula

Adequate liver function defined by:

Total bilirubin =< 1.5 times the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN

Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during screening and prior to receiving first dose of protocol-indicated treatment

Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or is not postmenopausal
Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 years of age in the absence of other biological or physiological causes

Exclusion Criteria:

=< 14 days before first dose of protocol-indicated treatment:

Major surgery requiring general anesthesia

Inadequately controlled hypertension (systolic blood pressure [SBP] > 160/90 mmHg)

Anti-hypertensive medications are permitted.
Active infection requiring infusional treatment
Has preexisting gastrointestinal or non-gastrointestinal fistula

Proteinuria > 2 g/ 24 hours (hrs)

If patient has 1+ protein on urine dipstick then a 24 hr urine collection is required
Non-healing wounds on any part of the body (for patients assigned to Cabo/Nivo only)
Known clinically significant active bleeding including hemoptysis
Inability to swallow oral medication; or the presence of a poorly controlled gastrointestinal disorder that could significantly affect the absorption of oral study drug (for patients assigned to Cabo/Nivo only) - e.g., Crohn's disease, ulcerative colitis, chronic diarrhea (defined as > 4 loose stools per day), malabsorption, or bowel obstruction

Significant cardiovascular disease or condition including:

Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) functional criteria
Unstable angina pectoris (i.e., last episode =< 3 months prior to first dose of protocol-indicated treatment)
Myocardial infarction within 3 months prior to starting treatment
Subjects with central nervous system (CNS) metastases are eligible after they have completed local therapy (e.g., whole brain radiation therapy [WBRT], surgery or radiosurgery)
Any condition requiring systemic treatment with either systemic corticosteroids (> 10 mg/day prednisone or equivalent daily) or other immunosuppressive medications within 14 days prior to initiating protocol-indicated treatment
In the absence of active autoimmune disease: Subjects are permitted the use of corticosteroids with minimal systemic absorption (e.g., topical, ocular, intra-articular, intranasal, and inhalational), =< 10 mg/day prednisone or equivalent daily; and physiologic replacement doses of systemic corticosteroids =< 10 mg/day prednisone or equivalent daily (e.g., hormone replacement therapy needed in patients with hypophysitis)