Randomized, Double-Blind, Phase III Trial of Adjuvant Nivolumab Versus Placebo in Patients with Resected Esophageal or Gastroesophageal Junction Cancer

The primary objective of this study is to compare **disease-free survival (DFS)** of nivolumab versus placebo in subjects with resected esophageal cancer (EC) or gastroesophageal junction (GEJ) cancer. Disease-free survival is a critical endpoint in oncology trials as it measures the length of time after primary treatment that the patient survives without any signs or symptoms of that cancer. This is particularly relevant for patients with resected EC or GEJ cancer, as it can provide insights into the efficacy of nivolumab in preventing cancer recurrence.

Secondary objectives include:

• Comparing overall survival (OS) of nivolumab versus placebo in subjects with resected EC or GEJ cancer. Overall survival is a vital measure of treatment efficacy, reflecting the length of time patients remain alive following treatment.
• Evaluating 1, 2, and 3-year survival rates of nivolumab versus placebo in subjects with resected EC or GEJ cancer. These survival rates provide additional data on the long-term benefits of nivolumab treatment in this patient population.

The clinical trial involves a total of **807 participants** diagnosed with resected adenocarcinoma or squamous cell carcinoma of the esophagus or gastroesophageal junction. The study population includes both **male and female subjects** who have been diagnosed with Stage II/III carcinoma of the esophagus or gastroesophageal junction. Participants have completed pre-operative chemoradiotherapy followed by surgery and have residual pathologic disease after being surgically rendered free of disease with negative margins following complete resection. The age range of the participants spans from young adults to older adults, specifically including those aged 18 to 64 years and those aged 65 years and older. The trial population was selected based on these specific medical and treatment criteria. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

The clinical trial is a **randomized**, **double-blind**, **controlled** study designed to evaluate the efficacy of **nivolumab** compared to a placebo in subjects with resected esophageal or gastroesophageal junction cancer. The primary objective is to assess **disease-free survival** (DFS), defined as the time from randomization to the first occurrence of cancer recurrence or death. Secondary endpoints include overall survival and survival rates at 1, 2, and 3 years post-randomization. The trial is a Phase III study, with an estimated duration from August 2016 to October 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of Stage II/III carcinoma of the esophagus or gastroesophageal junction, completion of pre-operative chemoradiotherapy, and surgical resection with negative margins. Following randomization, participants will receive either nivolumab or placebo via **intravenous** infusion. The treatment period is up to 12 months, with regular follow-up visits to monitor health status and collect data on DFS and overall survival.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, withdrawal of consent, or disease progression. Participant involvement is expected to last until the end of the study or until early termination criteria are met. The trial aims to provide valuable insights into the potential benefits of nivolumab as an adjuvant therapy in this patient population.

The clinical trial involves the administration of **Nivolumab**, marketed under the name OPDIVO, which is a **concentrate for solution for infusion**. The pharmaceutical form is a solution for infusion, and it is administered via the **intravenous** route. The concentration of the solution is 10 mg/mL. The maximum daily dose is 480 mg, with a total maximum dose of 6240 mg over the treatment period. The treatment period is set for a maximum of 12 months. Nivolumab is a protein-based therapeutic agent, specifically classified under the ATC code L01FF01. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and holds the marketing authorization number EU/1/15/1014/002.

The study also includes a **placebo** treatment, referred to as Placebo for BMS-936558. The placebo is used as a comparator to evaluate the efficacy of Nivolumab in the study. The placebo is administered in the same manner as the experimental drug, ensuring blinding and maintaining the integrity of the study design. The placebo does not contain any active pharmaceutical ingredients and is used to assess the disease-free survival (DFS) in subjects with resected esophageal cancer or gastroesophageal junction cancer. The administration schedule and route for the placebo are identical to those of the active treatment to ensure consistency in the trial protocol.

Efficacy in this clinical trial will be assessed primarily through the measurement of **disease-free survival (DFS)**. DFS is defined as the time from the date of randomization to the first occurrence of cancer recurrence or death from any cause, whichever comes first. This endpoint is crucial for evaluating the effectiveness of nivolumab compared to placebo in subjects with resected esophageal cancer or gastroesophageal junction cancer.

Secondary efficacy endpoints include overall survival (OS) and overall survival rates. OS is determined by the time from randomization to death from any cause. For subjects who are not documented as deceased, OS will be censored at the last date the subject was confirmed to be alive. Additionally, the overall survival rates at 1, 2, and 3 years post-randomization will be calculated, representing the probability of a subject being alive at these time points.