Evaluation of Pembrolizumab Plus Chemotherapy Versus Placebo Plus Chemotherapy in Neoadjuvant/Adjuvant Treatment of Gastric and Gastroesophageal Junction Adenocarcinoma

The primary objective of this Phase III, randomized, double-blind clinical trial is to evaluate **event-free survival (EFS)** in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma undergoing neoadjuvant/adjuvant treatment with pembrolizumab in combination with chemotherapy regimens (cisplatin + capecitabine [XP] or cisplatin + 5-fluorouracil [FP]). This is clinically relevant as EFS is a critical endpoint in assessing the efficacy of cancer treatments, reflecting the time patients remain free from disease-related events.

Secondary objectives include:

• Evaluating the safety and tolerability of **pembrolizumab** in combination with chemotherapy in both the XP/FP and FLOT cohorts.
• Assessing disease-free survival (DFS) for participants who are disease-free post-surgery, as determined by the investigator.
• Evaluating overall survival (OS) in the combined XP/FP and FLOT cohorts.
• Assessing event-free survival (EFS) in the combined XP/FP and FLOT cohorts.

These secondary objectives are crucial for understanding the broader impact of the treatment on patient outcomes, including long-term survival and quality of life.

The clinical trial involves a total of **825 participants** diagnosed with **gastric and gastroesophageal junction (GEJ) adenocarcinoma**. The study population includes both male and female subjects, with an age range that corresponds to category code 3, typically representing adults. Participants were selected based on specific criteria, including having previously untreated localized gastric or GEJ adenocarcinoma, and a requirement to proceed to surgery following pre-operative chemotherapy. All participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. The trial does not include a vulnerable population, and participants must have adequate organ function and a life expectancy of greater than six months. Lifestyle considerations such as diet and physical activity are not specified, but participants of childbearing potential must adhere to contraception guidelines throughout the study duration. The selection process ensures that the trial population is representative of individuals with the specified medical condition, without evidence of metastatic disease.

The clinical trial is a **Phase III**, randomized, double-blind, controlled study designed to evaluate the efficacy and safety of **pembrolizumab** in combination with chemotherapy compared to placebo with chemotherapy in patients with gastric and gastroesophageal junction (GEJ) adenocarcinoma. The trial involves two main treatment arms: pembrolizumab plus chemotherapy (XP or FP) and placebo plus chemotherapy (XP or FP). The primary objectives include assessing event-free survival (EFS), pathological complete response rate, and overall survival (OS). Additionally, the safety and tolerability of pembrolizumab in combination with the FLOT regimen will be evaluated.

The trial is expected to last until May 2024, with participant recruitment having commenced in September 2017. Participants will be involved in the study for a maximum treatment period of 126 days, with pembrolizumab administered for up to 12 cycles. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and adverse events, and an end-of-study visit to assess final outcomes. Participants are required to have previously untreated localized gastric or GEJ adenocarcinoma, with plans for surgery following pre-operative chemotherapy. They must also meet specific inclusion criteria, such as adequate organ function and a life expectancy of more than six months.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial's design ensures that neither the participants nor the investigators know which treatment the participants are receiving, maintaining the double-blind nature of the study. This methodology is crucial for minimizing bias and ensuring the reliability of the trial results.

The clinical trial involves the administration of several **experimental medications** and a placebo. **Oxaliplatin** is administered as an intravenous infusion with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 85 mg/m², with a total maximum dose of 340 mg/m² over a treatment period of 126 days. **Capecitabine** is provided in an oral form, coded as PHF00009MIG, with a maximum daily dose of 2000 mg/m² and a total maximum dose of 168,000 mg/m² over the same treatment period. **Calcium Folinate**, also known as leucovorin calcium, is administered via intravenous infusion, coded as PHF00190MIG, with a maximum daily dose of 200 mg/m² and a total maximum dose of 800 mg/m² over 126 days.

**Fluorouracil** is administered through intravenous infusion, coded as PHF00231MIG, with a maximum daily dose of 2600 mg/m² and a total maximum dose of 24,000 mg/m² over 126 days. **Cisplatin** is also given via intravenous infusion, coded as PHF00015MIG, with a maximum daily dose of 80 mg/m² and a total maximum dose of 480 mg/m² over the same period. **Docetaxel** is administered as an intravenous infusion, coded as PHF00230MIG, with a maximum daily dose of 50 mg/m² and a total maximum dose of 200 mg/m² over 126 days.

**Pembrolizumab**, marketed as Keytruda, is provided as a concentrate for solution for infusion, with a concentration of 25 mg/mL. It is administered intravenously with a maximum daily dose of 200 mg and a total maximum dose of 3400 mg over a 12-week period. The placebo used in the study is designed to match the appearance and administration route of pembrolizumab, ensuring blinding in the trial. The placebo does not contain any active pharmaceutical ingredients.

Participant compliance with the dosing schedule is monitored throughout the trial. The trial aims to evaluate the efficacy and safety of these treatments in subjects with gastric and gastroesophageal junction adenocarcinoma. The study includes both neoadjuvant and adjuvant treatment phases, with the primary objectives being to assess event-free survival, pathological complete response rate, and overall survival. The safety and tolerability of pembrolizumab in combination with the chemotherapy regimen are also evaluated.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include **Event-free Survival (EFS)**, **Pathological Complete Response (pathCR) Rate**, and **Overall Survival (OS)**. These endpoints will be evaluated in both the Pembrolizumab plus chemotherapy and Placebo plus chemotherapy treatment arms. Additionally, the trial will assess the percentage of participants who experience one or more adverse events (AEs) and those who discontinue study treatment due to an AE in the Pembrolizumab plus FLOT and Placebo plus FLOT cohorts.

Secondary endpoints will further evaluate the percentage of participants experiencing AEs and treatment discontinuation due to AEs across different treatment arms and cohorts. Disease-free Survival (DFS) and EFS will also be measured according to the Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) for both the Pembrolizumab plus chemotherapy and Placebo plus chemotherapy treatment arms, as well as the Pembrolizumab plus FLOT and Placebo plus FLOT cohorts. Overall Survival (OS) will be assessed across all treatment arms and cohorts.