A Phase 3, Randomized, Double-Blind Study of Adjuvant Immunotherapy with Nivolumab versus Placebo after Complete Resection of Stage IIB/C Melanoma (CheckMate 76K: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 76K)

The primary objective of this study is to compare the **efficacy**, as measured by recurrence-free survival (RFS), of nivolumab monotherapy versus placebo in participants with completely resected stage IIB/C melanoma with no evidence of disease. This is clinically relevant as it aims to determine the potential of nivolumab to prevent melanoma recurrence, which is critical for improving long-term outcomes in patients at high risk of recurrence.

Secondary objectives include:

• Comparing the overall survival (OS) provided by nivolumab monotherapy versus placebo in the same patient population.
• Assessing the safety and toxicity of nivolumab monotherapy.
• Evaluating distant metastases-free survival (DMFS).
• Evaluating investigator-assessed outcomes on next-line therapies.

The clinical trial involves a total of **318 participants** diagnosed with **completely resected Stage IIb/c melanoma**. The study population includes both male and female subjects, with an age range encompassing young adults, adults, and older adults. Participants were selected based on their diagnosis of stage IIB/C cutaneous melanoma, confirmed through histological examination, and must have undergone complete surgical resection with documented negative margins. The trial population is characterized by a disease-free status, confirmed through comprehensive physical examinations and imaging studies prior to randomization. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial includes individuals who have not received prior treatment for melanoma beyond surgical resection and have adequately recovered from any surgical complications. Both genders are represented, and the study acknowledges the inclusion of a vulnerable population. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **Phase III**, randomized, double-blind, controlled study designed to evaluate the efficacy of **nivolumab** compared to placebo in preventing the recurrence of completely resected Stage IIB/C melanoma. The primary objective is to assess recurrence-free survival (RFS) in participants who have undergone complete surgical resection of melanoma. The trial is expected to conclude by June 29, 2027, with recruitment having commenced on September 30, 2019.

Participants will be randomly assigned to receive either nivolumab or a placebo, with the study maintaining a double-blind design to ensure unbiased results. The trial involves multiple study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of Stage IIB/C melanoma, complete surgical resection with negative margins, and a negative sentinel lymph node biopsy. Participants must also have a documented disease-free status through physical examination and imaging studies conducted within specified timeframes prior to randomization.

Following the inclusion visit, participants will undergo regular follow-up visits to monitor their health status, assess for any signs of melanoma recurrence, and evaluate safety parameters such as adverse events, clinical laboratory values, and vital signs. The end-of-study visit will mark the conclusion of the participant's involvement in the trial, during which final assessments will be conducted to gather comprehensive data on the primary and secondary endpoints, including overall survival (OS) and progression-free survival through next-line therapy (PFS2).

The expected length of participant involvement in the trial is up to 36 months, depending on the treatment arm and individual response to therapy. Conditions that may lead to early termination from the study include the development of unacceptable toxicity, withdrawal of consent, or any other medical condition that, in the opinion of the investigator, warrants discontinuation of the study treatment. The trial is conducted in accordance with ethical guidelines and regulatory requirements to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **OPDIVO** (nivolumab), a concentrate for solution for infusion, with a concentration of 10 mg/mL. This experimental medication is administered via **intravenous use**. The maximum daily dose is 480 mg, with a total maximum dose of 18,720 mg over a treatment period of up to 36 months. Nivolumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF01. The pharmaceutical form is a solution for infusion, and the product is manufactured by Bristol-Myers Squibb Pharma EEIG. Participant compliance with the dosing schedule is monitored throughout the trial.

In addition to the experimental treatment, the study includes a **placebo** group. The placebo is a 0.9% sodium chloride injection, which is also a solution for injection. This non-experimental treatment is used to compare the efficacy of nivolumab in the study. The placebo is administered in the same manner as the experimental drug, ensuring blinding and consistency in the trial protocol.

Another non-experimental treatment used in the study is a 5% **dextrose** solution for injection. This solution serves as a standard-of-care therapy and is administered as needed, following the same route of administration as the other treatments. The use of dextrose solution is intended to maintain participant hydration and electrolyte balance during the trial.

The efficacy of the clinical trial will be assessed by comparing the **recurrence-free survival (RFS)** provided by nivolumab monotherapy versus placebo in participants with completely resected stage IIB/C melanoma with no evidence of disease. The primary endpoint for evaluating efficacy is RFS. Secondary endpoints include overall survival (OS), disease-free survival (DMFS), objective response rates, duration of treatment on next-line therapies, and progression-free survival through next-line therapy (PFS2). Additionally, safety biomarkers such as adverse events (AEs), clinical laboratory values, vital signs, and ECGs will be monitored.

Data collection will involve imaging studies, including CT scans of the chest, abdomen, and pelvis, or MRI scans, to document disease-free status within four weeks prior to randomization. The trial will also require tumor tissue samples from the resected site to be provided to a central laboratory before randomization. The trial is designed as a Phase III, randomized, double-blind study, with an estimated end date of June 29, 2027. The trial aims to provide comprehensive data on the efficacy of nivolumab in preventing melanoma recurrence post-surgery.