A Randomized Phase 2 Trial of Nivolumab, Relatlimab Plus Ipilimumab vs. Nivolumab Plus Ipilimumab in First-line Advanced Renal Cell Carcinoma (RCC)

Eligibility Criteria

• 1. Willing and able to provide a signed and dated written informed consent.
• 2. ≥ 18 years of age
• 3. Confirmed diagnosis of RCC with a clear cell component
• 4. Stage IV metastatic renal cell carcinoma per American Joint Committee on Cancer
• 5. No prior systemic therapy for RCC. Prior neo/adjuvant systemic therapy is not allowed.
• 6. Karnofsky performance status ≥ 70%.
• 7. At least one measurable lesion as defined by RECIST 1.1 (Appendix 3)
• 8. Adequate organ function within 28 days prior to first dose of protocol-indicated treatment, including:
• * White blood cell (WBC) ≥ 2,000 /µL
• * Absolute neutrophil count (ANC) ≥ 1,500/µL
• * Platelets ≥ 100,000/µL
• * Serum creatinine \< 1.5 x upper limit of normal (ULN) or creatinine clearance \> 30 mL/min (measured or calculated by Cockroft-Gault formula)
• * Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who must have total bilirubin \< 3.0 mg/dL)
• * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN
• 9. Women must not be breastfeeding while taking the study drug and for up to five months after the last dose of study drug
• 10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to receiving first dose of protocol-indicated treatment. An extension up to 72 hours prior to the start of study treatment is permissible in situations where results cannot be obtained within the standard 24-hour window.
• * "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.
• * If menopausal status is considered for the purpose of evaluating childbearing potential, women \< 62 years of age must have a documented serum follicle stimulating hormone (FSH) level within laboratory reference range for postmenopausal women, in order to be considered postmenopausal and not of childbearing potential.
• 11. Women of childbearing potential (WOCBP) must agree to follow instructions for acceptable contraception Appendix 5 from the time of signing consent, and for 23 weeks after their last dose of protocol-indicated treatment.
• 1. Prior systemic treatment for RCC of any type including neoadjuvant or adjuvant therapy is not allowed.
• 2. ≤ 28 days before first dose of protocol-indicated treatment:
• 3. ≤ 14 days before first dose of protocol-indicated treatment:
• * Radiosurgery or radiotherapy
• * Minor surgery. (Note: Placement of a vascular access device is not considered minor or major surgery)
• * Active infection requiring infusion treatment.
• 4. Any history of or current CNS metastases
• 5. Any condition requiring systemic treatment with either corticosteroids (\> 10 mg/day prednisone or equivalent daily) or other immunosuppressive medications within 14 days prior to initiating protocol-indicated treatment.
• 6. Active, known or suspected autoimmune disease (see Appendix 1 for a comprehensive list of autoimmune diseases and immune deficiencies).
• 7. Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the investigator to unacceptably increase the risk of study participation; or to prohibit the understanding or rendering of informed consent or anticipated compliance with and interpretation of scheduled visits, treatment schedule, laboratory tests and other study requirements.
• 8. History of myocarditis, regardless of etiology
• 9. Troponin T (TnT) or I (TnI) \> 2× institutional upper limit of normal (ULN)
• 10. Treatment with any live/attenuated vaccine within 30 days of first study treatment