Evaluation of Neoadjuvant FOLFOX With/Without Hyperthermic Intraperitoneal Chemotherapy Using Mitomycin C in Locally Advanced Colon Adenocarcinoma

The primary objective of this study is to evaluate whether proactive systemic neoadjuvant treatment with FOLFOX, with or without hyperthermic intraperitoneal chemotherapy (HIPEC) using mitomycin C followed by post-surgical adjuvant therapy, increases disease-free survival at 36 months in patients with locally advanced colon cancer compared to standard treatment. Efficacy (5) and safety (4) are the assessed trial scopes.

Secondary objectives include:

• Conducting a stratified analysis based on tumor location, pathologic stage, sex, and age.
• Assessing tumor regression via the Dworak scale.
• Evaluating the R0 resection rate.
• Comparing circulating tumor DNA (ctDNA) levels before and after treatment and their impact on survival.
• Monitoring morbidity and toxicity.
• Determining peritoneal recurrence-free survival at 36 months.
• Analyzing the pattern of disease recurrence.

The sponsor did not provide information regarding the total number of participants. The study population consists of both male and female patients, aged between 18 and 75 years, diagnosed with locally advanced adenocarcinoma of the colon or the rectum-sigmoid junction. Eligible participants must present with microsatellite stability and a tumor stage classified as cT4a/b according to the AJCC TNM eighth edition, or high-risk cT3 with pericolic fat penetration greater than 5mm. Inclusion requires a status of M0, signifying no distant metastasis, and an ECOG performance status of 0-1. Participants are required to utilize highly effective methods of contraception throughout the duration of the study.

This phase III, multi-arm, randomized, and controlled clinical trial evaluates the efficacy of neoadjuvant treatment for patients with locally advanced colon cancer. The study compares proactive systemic neoadjuvant therapy consisting of oxaliplatin, folinic acid, and fluorouracil, with or without hyperthermic intraperitoneal chemotherapy using mitomycin, followed by post-surgical systemic adjuvant treatment with capecitabine, against standard treatment protocols. The primary objective is to determine the effect on disease-free survival at 36 months. The research methodology includes a screening visit to confirm eligibility based on criteria such as adenocarcinoma of the colon or rectum, microsatellite stability, and ECOG performance status. The study involves multiple stages, including neoadjuvant therapy, surgical intervention, and adjuvant therapy, with subsequent follow-up visits to monitor outcomes such as overall survival and peritoneal recurrence-free survival. Participant involvement is expected to continue through the end of the study period, which is estimated to conclude by December 31, 2030. Early termination of participation may occur based on clinical conditions or predefined safety protocols.

The experimental treatment consists of several substances administered as part of a neoadjuvant and adjuvant regimen. Oxaliplatin is administered via intravenous infusion at a dosage of 85 mg/m2. Folinic acid is provided through intravenous infusion at a dose of 400 mg/m2. Fluorouracil is administered via intravenous infusion at a dosage of 1200 mg/m2. Mitomycin is administered for intraperitoneal use at a dose of 30 mg/m2.

The comparator treatment involves Capecitabine, which is administered via the oral route at a dosage of 2000 mg/m2.

The primary efficacy assessment is the disease-free survival (DFS), measured as absolute DFS in months and the probability of DFS at 3 years. Secondary endpoints include overall survival and peritoneal recurrence-free survival, both evaluated as absolute values and probabilities at 3 years. The pattern of recurrence, encompassing peritoneal, hematogenous, or lymphatic routes, will also be analyzed.

Additional efficacy parameters include the tumor regression grade assessed via the Dworak scale. Tumour progression is defined according to RECIST v.1.1 as an absolute increase of at least 5 mm in the sum of diameters of target lesions, accompanied by a relative increase of at least 20% compared to the smallest sum on study, or the appearance of new lesions. The negative rate of ctDNA after treatment will be evaluated to determine its association with survival and recurrence. Survival analysis will be conducted within specific subgroups, including pathologic stage II/III, pT4a/b, pN+, mutated RAS/RAF, and ctDNA status.

Safety and morbidity will be monitored using the Clavien Dindo classification and the Common Terminology Criteria for Adverse Events (CTCAE) v5.0.