Phase III Trial of Perioperative FLOT with HIPEC Versus FLOT Alone in Resectable Diffuse Gastric and Gastroesophageal Junction Adenocarcinoma

The primary objective of this study is to compare **progression/disease-free survival (PFS/DFS)** in patients with resectable diffuse type gastric and gastroesophageal junction Type II/III adenocarcinoma. This objective is clinically relevant as it aims to evaluate the efficacy of preventive Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in combination with perioperative FLOT chemotherapy regimen versus FLOT alone. The outcome of this comparison could potentially influence treatment protocols and improve survival outcomes for patients with this type of cancer.

The clinical trial involves participants diagnosed with **resectable diffuse type gastric and gastroesophageal junction Type II/III adenocarcinoma**. The study population includes both male and female subjects aged between 18 and 75 years. Participants are required to have a histologically confirmed, medically operable, resectable diffuse or mixed type adenocarcinoma of the gastroesophageal junction or the stomach, with specific staging criteria. The trial population was selected based on their ability to provide informed consent and comply with the study protocol, including having received 3 to 6 cycles of neoadjuvant FLOT therapy. Participants must not have undergone prior partial or complete tumor resection and should have no preceding cytotoxic or targeted therapy other than the specified neoadjuvant treatment. The health status of participants is assessed to ensure adequate hematological, hepatic, and renal function to allow for surgical procedures. The trial includes a vulnerable population, and both genders are represented. The sponsor has not provided the total number of participants involved in the study.

The clinical trial is designed as a **randomized**, **controlled**, and **double-blind** study to evaluate the efficacy of preventive HIPEC in combination with perioperative FLOT versus FLOT alone in patients with resectable diffuse type gastric and gastroesophageal junction Type II/III adenocarcinoma. The primary objective is to compare progression/disease-free survival (PFS/DFS) in patients. The trial is expected to run from January 18, 2021, to January 30, 2028, with the estimated duration of participant involvement being up to 8 months, depending on the treatment arm and response to therapy.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma, age between 18 and 75 years, and adequate organ function. Following successful screening, participants will be randomized into one of the treatment arms. The treatment phase will include administration of **cisplatin**, **oxaliplatin**, **fluorouracil**, **docetaxel**, and **calcium folinate** through intravenous or intraperitoneal routes, depending on the specific regimen. The maximum treatment period for most drugs is 8 cycles, except for cisplatin, which is limited to 1 cycle.

Follow-up visits will be scheduled to monitor the participants' response to treatment, assess any adverse events, and ensure compliance with the study protocol. These visits will include clinical assessments, laboratory tests, and imaging studies as necessary. The end-of-study visit will occur after the completion of the treatment phase or upon early termination, which may be due to disease progression, unacceptable toxicity, or withdrawal of consent. Participants will be monitored for primary and secondary endpoints, including overall survival (OS), PFS/DFS rates at 2, 3, and 5 years, and quality of life assessments.

Conditions that may lead to early termination from the study include the development of distant metastases, significant protocol deviations, or the investigator's discretion based on the participant's health status. The trial will adhere to ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several **experimental medications**. **Cisplatin** is provided as a solution for injection, with a maximum daily dose of 75 mg/m². It is administered via **intraperitoneal use** for a maximum treatment period of 1 day. The active substance is of chemical origin, and the formulation is not pediatric.

**Oxaliplatin** is administered as a concentrate for solution for infusion. The maximum daily dose is 85 mg/m², with a total maximum dose of 340 mg/m² over a treatment period of 8 weeks. The route of administration is **intravenous use**. The active substance is chemically derived, and the formulation is not intended for pediatric use.

**Fluorouracil** is provided as a solution for injection/infusion, with a maximum daily dose of 2600 mg/m² and a total maximum dose of 10400 mg/m² over 8 weeks. It is administered intravenously. The active substance is of chemical origin, and the formulation is not pediatric.

**Docetaxel** is administered as a concentrate for solution for infusion, with a maximum daily dose of 50 mg/m² and a total maximum dose of 200 mg/m² over 8 weeks. The route of administration is **intravenous use**. The active substance is chemically derived, and the formulation is not intended for pediatric use.

**Calcium folinate** is provided as a solution for injection, with a maximum daily dose of 200 mg/m² and a total maximum dose of 800 mg/m² over 8 weeks. It is administered intravenously. The active substance is of chemical origin, and the formulation is not pediatric.

All medications are classified as chemical medicinal products and are not designated as orphan drugs. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed primarily through the evaluation of **progression-free survival/disease-free survival (PFS/DFS)**. This is defined as the time from randomization to disease progression, relapse after surgery, or death from any cause. If no event is observed, PFS/DFS will be censored at the time of the last tumor assessment. Secondary endpoints include overall survival (OS), which is defined as the time from randomization to death from any cause, with censoring at the last subject contact if no event is observed.

Additional secondary endpoints will measure the rate of patients with peritoneal relapse at 2 and 3 years, PFS/DFS rates at 2, 3, and 5 years, and OS rates at 3 and 5 years. The trial will also assess the rate of surgical serious adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 5.0) for grade ≥ 3 adverse events and laboratory toxicities. Quality of life (QoL) will be evaluated using the EORTC QLQ C30 and EORTC QLQ STO22 questionnaires, focusing on mean values, response, and time to symptom deterioration (TTSD). Post-operative morbidity/mortality at day 30 after surgery will be classified according to the Clavien–Dindo classification, and post-operative pain will be assessed using a visual analog scale (VAS).