Phase III Randomized, Double-Blind, Placebo-Controlled Study of Neoadjuvant-Adjuvant Durvalumab and FLOT Chemotherapy in Resectable Gastric and Gastroesophageal Junction Adenocarcinoma

The primary objective of this study is to compare **Arm A** relative to Arm B on **event-free survival (EFS)** in patients with resectable gastric and gastroesophageal junction cancer. This is clinically relevant as EFS is a critical endpoint in assessing the efficacy of neoadjuvant-adjuvant therapies, providing insights into the potential for disease recurrence or progression following treatment.

Secondary objectives include:

• Comparing Arm A relative to Arm B on overall survival (OS).
• Comparing Arm A relative to Arm B on pathological complete response (pCR) rate.
• Comparing Arm A relative to Arm B on the proportion of patients who undergo gastrectomy or gastrophagectomy.
• Comparing Arm A relative to Arm B on the rate of complete resection (R0).
• Comparing Arm A relative to Arm B on metastasis-free survival (MFS) and disease-specific survival (DSS).
• Comparing Arm A relative to Arm B on disease-free survival in patients who undergo R0 resection surgery.
• Comparing Arm A relative to Arm B on EFS24, EFS36, OS24, OS36, DFS24, and DFS36.
• Comparing Arm A relative to Arm B on efficacy endpoints by PD-L1 expression.
• Comparing Arm A relative to Arm B on disease-related symptoms, impacts, and health-related quality of life (HRQoL).
• Evaluating the pharmacokinetics (PK) of Arm A and Arm B.
• Assessing the immunogenicity of Arm A and Arm B.

The clinical trial involves a total of **564 participants** diagnosed with **gastric or gastroesophageal junction adenocarcinoma** at Stage II or higher, as per the AJCC 8th edition. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on their histologically documented diagnosis and the resectability of their disease. Key lifestyle considerations such as diet and physical activity were not specified. The trial includes individuals with a World Health Organization/ECOG performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have adequate organ and marrow function and a life expectancy of at least 24 weeks. The trial also involves a vulnerable population, although specific details regarding this aspect were not provided. The selection criteria ensure that participants have not received prior anti-cancer therapy for their current malignancy and have undergone radical surgery, with the availability of a tumor sample prior to study entry being a requirement.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled, Phase III study** to evaluate the efficacy of neoadjuvant-adjuvant **durvalumab** in combination with FLOT chemotherapy, followed by adjuvant durvalumab, in patients with resectable gastric and gastroesophageal junction cancer. The primary objective is to compare event-free survival (EFS) between the treatment and control arms. The trial is expected to commence recruitment on December 8, 2023, and conclude by September 27, 2027, with a maximum treatment period of 18 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 histologically documented gastric or gastroesophageal junction adenocarcinoma, stage II or higher, and adequate organ function. Following successful screening, participants will be randomized to receive either the investigational treatment or placebo. The study involves multiple follow-up visits to monitor safety, efficacy, and compliance with the treatment regimen. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.

The expected length of participant involvement is approximately 18 months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study protocols. The trial will utilize intravenous administration for the investigational products, including **docetaxel**, **folinic acid**, **fluorouracil**, and **oxaliplatin**, alongside the placebo. The study aims to provide robust data on the potential benefits of durvalumab in combination with chemotherapy for this patient population.

The clinical trial involves the administration of several **experimental medications** and non-experimental treatments. **Infliximab** is provided as a powder for concentrate for solution for infusion. It is administered intravenously, with a maximum treatment period of 18 months. The dosage is not specified in milliliters, and it is categorized as an auxiliary treatment in the trial.

**Durvalumab**, marketed as IMFINZI, is a concentrate for solution for infusion, administered intravenously. The maximum daily and total dose is 1500 mg, with a treatment period extending up to 18 months. Durvalumab serves as the test treatment in the study.

**Docetaxel** is provided as a concentrate for solution for infusion, administered intravenously. The maximum daily and total dose is 50 mg/m², with a treatment period of 18 months. It is used as a comparator treatment in the trial.

**Folinic Acid** is administered as a solution for injection/infusion, with an intravenous route. The maximum daily and total dose is 200 mg/m², and the treatment period is 18 months. It is also used as a comparator treatment.

**Fluorouracil** is provided as a solution for injection/infusion, administered intravenously. The maximum daily and total dose is 2600 mg/m², with a treatment period of 18 months. It serves as a comparator treatment in the study.

A **placebo** is included in the trial, with no specified pharmaceutical form or route of administration. It is used as a comparator treatment.

**Oxaliplatin** is administered as a concentrate for solution for infusion, with an intravenous route. The maximum daily and total dose is 85 mg/m², and the treatment period is 18 months. It is used as a comparator treatment.

**Mycophenolate Mofetil** is provided in capsule form, administered orally. The dosage is not specified in milligrams, and the treatment period is 18 months. It is categorized as an auxiliary treatment in the trial.

The efficacy of the clinical trial will be assessed by comparing **event-free survival (EFS)** between two study arms. EFS is the primary endpoint and will be used to evaluate the effectiveness of the treatment regimen involving neoadjuvant-adjuvant **durvalumab** and FLOT chemotherapy followed by adjuvant durvalumab in patients with resectable gastric and gastroesophageal junction cancer. Secondary endpoints include **overall survival (OS)** and **pathological complete response (pCR) rate**. These endpoints will provide additional insights into the treatment's impact on patient outcomes.