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

PRIMARY OBJECTIVE:

I. To improve objective response rate of front-line therapy in advanced renal cell carcinoma (RCC) by prospectively assigning ipilimumab/nivolumab or nivolumab/cabozantinib according to a patient's ribonucleic acid sequence (RNAseq)-defined biologic cluster.

SECONDARY OBJECTIVE:

I. To assess clinical outcome of cluster-assigned treatment in front-line metastatic renal cell carcinoma (mRCC).

EXPLORATORY OBJECTIVE:

I. To assess tissue and peripheral blood for pharmacodynamic correlations with response to treatment.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I:

INDUCTION: Patients receive ipilimumab and nivolumab intravenously (IV) on day 1. Cycles repeat every 21 days for 4 cycles.

MAINTENANCE: Patients receive nivolumab IV on day 1. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive nivolumab IV on day 1 and cabozantinib orally (PO) once a day (QD). Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days from last dose.

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)