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

Primary Objectives:

To determine the safety and tolerability of nivolumab, relatlimab and ipilimumab in patients with untreated advanced RCC

• To assess the ORR of nivolumab, relatlimab and ipilimumab in patients with untreated advanced RCC

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 RECIST 1.1 (Appendix 3)

• 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
• 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
• 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 Appendix 5 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 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 (see Appendix 1 for a comprehensive list of autoimmune diseases and immune deficiencies).

• 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× institutional upper limit of normal (ULN)

• Participants with TnT or TnI levels between > 1× to 2× ULN will be permitted if repeat levels within 24 hours are ≤ 1× ULN. If TnT or TnI levels are between > 1× to 2× 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× 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