A Phase 3, Randomized, Open-label, Study of Subcutaneous Nivolumab + Relatlimab Fixed-dose Combination versus Intravenous Nivolumab + Relatlimab Fixed-dose Combination in Participants with Previously Untreated Metastatic or Unresectable Melanoma

The primary objective of this study is to assess whether the **nivolumab** and **relatlimab** levels in the body, when administered subcutaneously, are equivalent to those when administered intravenously. This evaluation is clinically relevant as it may offer an alternative administration route for patients with previously untreated metastatic or unresectable melanoma, potentially improving patient comfort and compliance.

Secondary objectives include evaluating whether subcutaneous administration is not inferior to intravenous administration in preventing the spread of skin cancer. Additionally, the study aims to assess the safety profile and quality of life in patients receiving the drug subcutaneously compared to those receiving it intravenously. These objectives are crucial for understanding the broader implications of administration routes on treatment efficacy and patient well-being.

The clinical trial involves a total of **396 participants** diagnosed with **previously untreated metastatic or unresectable melanoma**. The study population includes both male and female subjects, aged 12 years and older, with a requirement for those aged 12 to under 18 years to weigh at least 40 kg. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less, or a Lansky Performance Score of 80% or higher for those aged 12 to under 18 years, indicating their ability to perform daily activities. The trial population was selected based on confirmed Stage III or Stage IV melanoma, as per the American Joint Committee on Cancer (AJCC) staging system, and participants must be treatment-naive, with the exception of select prior adjuvant or neoadjuvant melanoma therapies, provided all related adverse events have returned to baseline or stabilized. The study includes a vulnerable population, and both genders are represented. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase III**, randomized, open-label study designed to evaluate the pharmacokinetics of a fixed-dose combination of **nivolumab** and **relatlimab** administered subcutaneously versus intravenously in participants with previously untreated metastatic or unresectable melanoma. The trial aims to determine if the subcutaneous administration of the study drugs is not inferior to the intravenous route in terms of drug concentration in the body. The study is expected to run from March 31, 2023, to August 1, 2026, with participant involvement lasting up to 1111 days, depending on individual response and tolerability.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and disease stage. Eligible participants will be randomized to receive either the subcutaneous or intravenous formulation of the study drugs. Follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and ensure compliance with the study protocol. The end-of-study visit will conclude the trial for each participant, during which final assessments will be conducted.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The primary endpoint is to confirm that the subcutaneous administration of the study drugs is not worse than the intravenous administration in terms of drug concentration. Secondary endpoints include evaluating the percentage of participants achieving a partial or complete response. The trial is not classified as low intervention, and it is conducted under the sponsorship of Bristol-Myers Squibb International Corporation.

The clinical trial involves the administration of two experimental medications, both containing the active substances **nivolumab** and **relatlimab**. The first experimental medication is a **solution for infusion** known as Nivolumab/Relatlimab, with the sponsor product code BMS-986213. This formulation is administered via **intravenous infusion**. The maximum daily dose is 160,999,480 mg, and the maximum treatment period is 1111 days. The active substances, nivolumab and relatlimab, are proteins of other origin, provided by Bristol-Myers Squibb International Corporation. The solution is not a pediatric formulation and is not classified as an orphan drug.

The second experimental medication is a **solution for injection** named FDC Nivolumab + Relatlimab + rHuPH20 Injection, also with the sponsor product code BMS-986213. This formulation is administered via **subcutaneous injection**. The maximum daily dose is 32,099,996,099,924,000 mg, with the same maximum treatment period of 1111 days. The active substances, nivolumab and relatlimab, are identical to those in the intravenous formulation, and are also proteins of other origin from Bristol-Myers Squibb International Corporation. This solution is similarly not a pediatric formulation and is not classified as an orphan drug.

In this study, there are no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment mentioned. The primary objective is to assess the pharmacokinetics of the study drugs when administered subcutaneously compared to intravenously. Participant compliance will be monitored throughout the trial to ensure adherence to the dosing schedules.

The efficacy of the clinical trial will be assessed through both primary and secondary endpoints. The primary endpoint focuses on evaluating whether the amount of the study drugs, **nivolumab** and **relatlimab**, administered subcutaneously is not inferior to the amount administered intravenously. This assessment will determine the pharmacokinetic equivalence of the two administration routes.

The secondary endpoint involves measuring the percentage of participants who experience a partial response (PR) or complete response (CR) in their **melanoma** following treatment. This will compare the efficacy of subcutaneous administration to intravenous administration in terms of disease reduction or remission. The responses will be evaluated using standard criteria, such as RECIST v1.1, to ensure consistent and reliable measurement of tumor response.