Nivolumab, Relatlimab and Ipilimumab versus Nivolumab and Ipilimumab for the Treatment of Untreated Stage IV Renal Cell Cancer

Inclusion Criteria

• Willing and able to provide a signed and dated written informed consent
• ≥ 18 years of age
• Confirmed diagnosis of RCC with a clear cell component
• Stage IV metastatic renal cell carcinoma per American Joint Committee on Cancer
• No prior systemic therapy for RCC. Prior neo/adjuvant systemic therapy is not allowed
• Karnofsky performance status ≥ 70%
• At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 • A tumor lesion situated in a previously irradiated area is considered a measurable/target lesion only if subsequent disease progression has been documented in the lesion
• White blood cell (WBC) ≥ 2,000 /uL (within 28 days prior to first dose of protocol-indicated treatment)
• Absolute neutrophil count (ANC) ≥ 1,500/uL (within 28 days prior to first dose of protocol-indicated treatment)
• Platelets ≥ 100,000/uL (within 28 days prior to first dose of protocol-indicated treatment)
• Serum creatinine < 1.5 x upper limit of normal (ULN) or creatinine clearance > 30 mL/min (measured or calculated by Cockroft-Gault formula) (within 28 days prior to first dose of protocol-indicated treatment)
• Total bilirubin ≤ 1.5 x ULN (except subjects with Gilbert syndrome, who must have total bilirubin < 3.0 mg/dL) (within 28 days prior to first dose of protocol-indicated treatment)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN (within 28 days prior to first dose of protocol-indicated treatment)
• Women must not be breastfeeding while taking the study drug and for up to five months after the last dose of study drug
• 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
• Women of childbearing potential (WOCBP) must agree to follow instructions for acceptable contraception from the time of signing consent, and for 23 weeks after their last dose of protocol-indicated treatment

Exclusion Criteria

• Prior systemic treatment for RCC of any type including neoadjuvant or adjuvant therapy is not allowed
• ≤ 28 days before first dose of protocol-indicated treatment: * Major surgery requiring general anesthesia
• ≤ 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
• Any history of or current central nervous system (CNS) metastases
• 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 * 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)
• Active, known or suspected autoimmune disease * Subjects with type I diabetes mellitus; endocrine organ dysfunction (e.g., hypothyroidism) that are controlled and only requiring only hormone replacement; skin disorders such as vitiligo, psoriasis or alopecia not requiring systemic treatment; or conditions not expected by the investigator to recur in the absence of an external trigger are permitted to enroll
• 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
• History of myocarditis, regardless of etiology
• Troponin T (TnT) or I (TnI) > 2 x institutional upper limit of normal (ULN) * Participants with TnT or TnI levels between > 1 x to 2 x ULN will be permitted if repeat levels within 24 hours are ≤ 1 x ULN. If TnT or TnI levels are between > 1 x to 2 x ULN within 24 hours, the participant may undergo a cardiac evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the Investigator. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are < 2 x ULN, the participant may undergo a cardiac evaluation and be considered for treatment, based on a favorable benefit/risk assessment by the investigator
• Treatment with any live/attenuated vaccine within 30 days of first study treatment