Evaluation of Postoperative Chemotherapy Reintroduction with FOLFIRI and Targeted Therapy in Colorectal Cancer Patients with Hepatic Metastases

The primary objective of this study is to demonstrate an improvement in the **disease-free survival** rate at 3 years in patients with colorectal cancer with hepatic metastasis. This is clinically relevant as it aims to assess the efficacy of postoperative reintroduction of chemotherapy in enhancing long-term outcomes for patients who have responded well to preoperative chemotherapy with FOLFIRI, with or without targeted therapy.

Secondary objectives include:

• Comparing the overall survival rates between the two treatment arms.
• Comparing liver-free survival between the two groups.
• Comparing the extra-hepatic recurrence rate between the two groups.
• Assessing the toxicity of postoperative treatment.
• Assessing compliance with postoperative treatment.
• Assessing the rate of further curative treatment of recurrence.

The clinical trial involves participants diagnosed with **colorectal cancer** with hepatic metastasis. The study population includes both male and female subjects aged 18 years and older, with a **WHO performance status** of 0 or 1, indicating they are in relatively good health. The total number of participants is not provided by the sponsor. Participants were selected based on specific criteria, including having histologically proven resected metachronous colorectal liver metastasis (CLM) with curative intent, and having undergone preoperative FOLFIRI-based chemotherapy with or without targeted therapy. The trial does not include a vulnerable population. Participants must be affiliated with a social security scheme and have no more than 10 treated CLM at surgery. Lifestyle considerations such as diet and physical activity are not specified. The trial aims to demonstrate an improvement in the disease-free survival rate at 3 years.

The clinical trial is designed to evaluate the efficacy of postoperative chemotherapy reintroduction in patients with **colorectal cancer** and hepatic metastasis who have shown a favorable response to preoperative chemotherapy. This is a Phase III, randomized, double-blind, controlled trial aimed at demonstrating an improvement in the disease-free survival rate at three years. The trial is expected to commence recruitment on March 1, 2024, and conclude by March 1, 2030. Participants will be randomly assigned to receive either the standard treatment or the investigational regimen, ensuring that neither the participants nor the investigators are aware of the group assignments, thus maintaining the double-blind nature of the study.

The trial will involve a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as histologically proven resected metachronous colorectal liver metastases (CLM), age of 18 years or older, and a WHO performance status of 0 or 1. Following the screening, eligible participants will undergo baseline assessments, including a thoraco-abdominal CT scan, to confirm the absence of extrahepatic or residual liver disease. Subsequent visits will be scheduled for the administration of chemotherapy, monitoring of treatment compliance, and assessment of safety and efficacy endpoints. The primary endpoint is the disease-free survival rate at three years, with secondary endpoints including overall survival, liver-free survival, and safety assessments using the International Common Terminology Criteria for Adverse Events (CTCAE) grading system.

Participants are expected to be involved in the trial for a maximum of 14 treatment cycles, with each cycle lasting approximately two weeks. The total duration of participant involvement will depend on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include the development of contraindications to FOLFIRI-based chemotherapy, the emergence of extrahepatic disease, or significant adverse events that compromise patient safety. The trial will ensure rigorous monitoring and adherence to ethical standards throughout its duration.

The clinical trial involves the administration of several **chemical medicinal products**. **Ondansetron** is utilized in the form of a solution for injection or infusion. It is administered intravenously with a maximum daily dose of 8 mg. The treatment period for ondansetron is limited to one day. This medication is not a pediatric formulation and is used as an auxiliary treatment in the trial.

**Irinotecan** is provided as a solution for infusion and is administered via intravenous infusion. The maximum daily dose is 180 mg/m², with a total treatment period of up to two days. Irinotecan serves as a test product in the trial and is not formulated for pediatric use.

**Methylprednisolone** is administered as a powder for solution for injection. It is delivered intravenously with a maximum daily dose of 120 mg, and the treatment period is restricted to one day. This medication is used as an auxiliary treatment in the study.

**Fluorouracil** is available as a solution for injection and is administered through intravenous bolus use. The maximum daily dose is 400 mg/m², with a total dose of up to 16,800 mg over a two-day treatment period. Fluorouracil is a test product in the trial.

**Calcium Levofolinate** is provided as a solution for injection and is administered intravenously. The maximum daily dose is 200 mg/m², with a treatment period extending up to 14 days. This medication is used as a test product in the study.

**Calcium Folinate** is administered as a powder for solution for infusion, delivered intravenously. The maximum daily dose is 400 mg/m², with a treatment period of up to 14 days. Calcium folinate is also a test product in the trial.

All medications are chemical in origin and are not designated as orphan drugs. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy in this clinical trial will be assessed primarily through the evaluation of the **disease-free survival rate** at 3 years. This primary endpoint will provide a measure of the time patients remain free from any signs of colorectal liver metastases following treatment. Secondary endpoints will include overall survival at 3 years, liver-free survival at 3 years, and the rate of extra-hepatic recurrence. Additionally, safety will be evaluated by assessing chemotherapy-associated toxicity using the International Common Terminology Criteria for Adverse Events (CTCAE) grading system. Compliance will be measured by the ability to administer a total of 12 cycles of FOLFIRI-based chemotherapy, including preoperative treatment. The rate of treatment of recurrence with curative intent will also be monitored.