Phase III Randomized Trial of Adjuvant mFOLFIRINOX Versus Capecitabine or Gemcitabine in Resected Ampullary Adenocarcinoma Patients

The primary objective of the PRODIGE 98-AMPIRINOX trial is to evaluate the **efficacy** of adjuvant modified FOLFIRINOX compared to single-agent chemotherapy (gemcitabine or capecitabine) in enhancing 2-year **disease-free survival (DFS)** following surgical resection of ampullary adenocarcinoma. This is clinically relevant as improving DFS can potentially lead to better long-term outcomes and reduced recurrence rates in patients with this type of cancer.

Secondary objectives include:

• Overall survival (OS)
• Rate of patients completing 3 and 6 months chemotherapy schedule according to the percentage of administered dose of each product
• Assessment of quality of life using EORTC QLQ-C30 and PAN26
• Assessment of toxicities
• Analyses on OS and DFS by prespecified subgroups

The clinical trial involves participants diagnosed with **ampullary adenocarcinoma**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have undergone a macroscopically complete surgical resection of the adenocarcinoma within 12 weeks prior to enrollment, with no evidence of metastatic disease on a CT scan conducted less than four weeks before inclusion. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. Key lifestyle factors such as diet, physical activity, or habits are not specified in the available data. The trial population was selected based on specific medical criteria, including a post-operative CA19.9 level of less than 180 U/L. The study aims to evaluate the efficacy of adjuvant mFOLFIRINOX compared to single-agent chemotherapy in improving two-year disease-free survival following surgical resection.

The clinical trial is a **randomized**, multicenter, Phase III study designed to evaluate the efficacy of adjuvant chemotherapy with modified FOLFIRINOX compared to single-agent chemotherapy (gemcitabine or capecitabine) in patients with resected **ampullary adenocarcinoma**. The primary objective is to assess the improvement in 2-year disease-free survival (DFS) following surgical resection. The trial is expected to commence recruitment on October 31, 2024, and conclude by October 31, 2028.

Participants will be randomly assigned to receive either the modified FOLFIRINOX regimen or a single-agent chemotherapy. The trial employs a **double-blind** design to ensure unbiased results. The study will involve several key visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically proven adenocarcinoma, complete surgical resection, and specific CA19.9 levels. Follow-up visits will be scheduled to monitor treatment adherence, assess adverse events, and evaluate quality of life using EORTC QLQ-C30 and PAN26 questionnaires. The end-of-study visit will occur after the completion of the treatment period or upon early termination.

The expected duration of participant involvement is up to 24 months, with treatment cycles and follow-up assessments conducted throughout this period. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is the 2-year DFS rate, calculated from the date of randomization to the first relapse or death. Secondary endpoints include overall survival (OS), completion rates of chemotherapy schedules, and the incidence of adverse events graded according to NCI-CTCAE version 5.0.

The clinical trial involves the administration of several **chemotherapy** agents, each with specific pharmaceutical forms, dosages, and routes of administration. **Oxaliplatin** is provided as a solution for infusion, administered intravenously at a maximum daily dose of 85 mg/m². The treatment period for oxaliplatin is up to 24 months. This agent is part of the modified FOLFIRINOX regimen used in the trial.

**Calcium folinate** is also administered as a solution for infusion, with an intravenous route. The maximum daily dose is 400 mg/m², and the treatment duration is up to 24 months. Calcium folinate is used to enhance the efficacy of other chemotherapy agents in the regimen.

**Capecitabine** is available in three different film-coated tablet formulations: 150 mg, 300 mg, and 500 mg. It is administered orally with a maximum daily dose of 1250 mg/m². The treatment period for capecitabine is up to 24 months. This agent serves as a comparator in the trial, evaluating its efficacy against the modified FOLFIRINOX regimen.

**Gemcitabine hydrochloride** is provided as a solution for infusion, administered intravenously at a maximum daily dose of 1000 mg/m². The treatment duration is up to 24 months. Gemcitabine serves as another comparator in the trial, assessing its effectiveness in comparison to the modified FOLFIRINOX regimen.

**Fluorouracil** is administered as a solution for infusion, with an intravenous route. The maximum daily dose is 2400 mg/m², and the treatment period is up to 24 months. Fluorouracil is a component of the modified FOLFIRINOX regimen.

**Irinotecan** is provided as a solution for infusion, administered intravenously at a maximum daily dose of 150 mg/m². The treatment duration is up to 24 months. Irinotecan is another component of the modified FOLFIRINOX regimen.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The trial aims to assess the efficacy of the modified FOLFIRINOX regimen compared to single-agent chemotherapy with capecitabine or gemcitabine in improving 2-year disease-free survival in patients with resected ampullary adenocarcinoma.

The efficacy of the clinical trial will be assessed by evaluating the primary endpoint of 2-year **Disease-Free Survival** (DFS) rate. DFS will be calculated from the date of randomization to the date of first relapse, either locally or metastatic, or the date of death from any cause. Patients who are alive without relapse will be censored at the date of last news, and second cancer occurrences will not be considered as events. The assessment of relapse will be conducted by the investigator according to RECIST v1.1 criteria.

Secondary endpoints include overall survival (OS), which is defined as the time between randomization and death from any cause, with patients alive being censored at the date of last news. The rate of patients completing 3 and 6-month chemotherapy schedules will be evaluated based on the percentage of the administered dose of each product, with a completed cycle defined by at least 80% of each product dispensed. Adverse events will be described using the NCI-CTCAE version 5.0, and quality of life will be assessed using the EORTC QLQ-C30 and PAN26 questionnaires.