Phase 3 Randomized Double-Blind Trial of Nivolumab and Relatlimab Versus Nivolumab Monotherapy in Stage III-IV Melanoma Post-Resection

The primary objective of this study is to compare the efficacy, as measured by **recurrence-free survival (RFS)**, of a fixed-dose combination of nivolumab and relatlimab (nivo + rela FDC) versus nivolumab monotherapy in participants with completely resected Stage III/IV melanoma with no evidence of disease (NED). This comparison is clinically relevant as it aims to determine the potential benefits of combination therapy in preventing melanoma recurrence, which is critical for improving long-term patient outcomes.

Secondary objectives include:

• Comparing overall survival (OS) between the nivo + rela FDC and nivolumab monotherapy in the same patient population.
• Assessing the efficacy, as measured by distant metastasis-free survival (DMFS), provided by the combination therapy versus monotherapy.
• Evaluating the safety and toxicity profiles of the combination therapy compared to monotherapy.
• Assessing investigator-assessed outcomes on subsequent systemic therapies.

The clinical trial involves a total of **749 participants** diagnosed with completely resected Stage III or Stage IV melanoma. The study population includes both **male and female** subjects, with an age range starting from 12 years and above, although local regulations may restrict participation to those 18 years and older. Participants are required to have a disease-free status confirmed by a complete physical examination and imaging studies prior to randomization. The trial population was selected based on specific inclusion criteria, including a histologically confirmed melanoma that is completely surgically resected with negative margins. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less, or a Lansky/Karnofsky performance score of 80% or higher for those aged between 12 and 18 years. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase 3**, randomized, double-blind study designed to evaluate the efficacy of adjuvant immunotherapy using a fixed-dose combination of **nivolumab** and **relatlimab** compared to nivolumab monotherapy in participants with completely resected Stage III-IV melanoma. The trial aims to assess the recurrence-free survival (RFS) as the primary endpoint, with secondary endpoints including overall survival (OS), distant metastasis-free survival (DMFS), and the incidence and severity of adverse events (AEs). The study is expected to run from September 2021 to November 2029, with a maximum treatment period of 12 months for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as disease-free status and performance scores. Following randomization, participants will receive either the investigational combination therapy or the comparator monotherapy. Regular follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing the final outcomes and any long-term effects of the treatment.

The expected length of participant involvement is up to 12 months, with conditions for early termination including disease recurrence, unacceptable toxicity, or withdrawal of consent. Participants must meet specific inclusion criteria, such as having a completely resected melanoma and being at least 12 years of age, with performance status requirements varying by age group. The trial excludes individuals with ocular melanoma and those not meeting the performance status criteria. The study's design ensures rigorous assessment of the investigational therapy's efficacy and safety, contributing valuable data to the field of melanoma treatment.

The clinical trial involves the administration of a **fixed-dose combination** of **nivolumab** and **relatlimab**, marketed under the name "Nivo 240 mg and Rela 80 mg per vial." This experimental medication is provided as a **solution for infusion** and is administered intravenously. The dosing schedule involves a maximum daily dose of 9999 mg, with a total treatment period of up to 12 months. The active substances, nivolumab and relatlimab, are proteins of non-chemical origin, developed by Bristol-Myers Squibb International Corporation. The combination is designed to enhance the immune response in patients with completely resected Stage III-IV melanoma.

The comparator treatment in this study is **nivolumab** monotherapy, marketed as "OPDIVO 10 mg/mL concentrate for solution for infusion." This medication is also administered as a **solution for infusion** via the intravenous route. The maximum daily dose for nivolumab monotherapy is 480 mg, with a total maximum dose of 6240 mg over a 12-month period. Nivolumab, a protein-based therapeutic agent, is produced by Bristol-Myers Squibb Pharma EEIG. The monotherapy serves as the standard-of-care treatment against which the efficacy of the fixed-dose combination is compared.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Recurrence-Free Survival (RFS)**. RFS is defined as the time from the date of randomization to the first documented recurrence of melanoma (local, regional, distant, or new primary) or death from any cause, whichever occurs first. This primary endpoint will be evaluated by the investigator to compare the efficacy of the fixed-dose combination of nivolumab and relatlimab versus nivolumab monotherapy in participants with completely resected Stage III-IV melanoma.

Secondary endpoints include **Overall Survival (OS)**, which measures the time from randomization to death from any cause, and **Distant Metastasis-Free Survival (DMFS)**, defined as the time from randomization to the first occurrence of distant metastasis or death. Additionally, the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and other select AEs will be monitored. **Progression-Free Survival 2 (PFS2)** will also be assessed, defined as the time from randomization to the second recurrence or objective disease progression on subsequent systemic therapy, or death from any cause.