Pre-Operative Treatment in REseCTable COlon CanceR

This is an open-label, randomized, controlled, multicenter, phase III study with two parallel arms. Patients with advanced colon cancer, including the upper third of the rectum, clinically staged cT3-4 and or cN+ (defined as lymph nodes with short axis of at least 1cm) are randomized in a 2:1 fashion (favoring preoperative therapy= Arm A) to investigate the efficacy, patient reported quality of life and safety of preoperative mFOLFOXIRI or mFOLFOX-6 or CAPOX followed by surgery versus the standard of care algorithm (surgery followed by stage-guided adjuvant therapy as recommended by the local multidisciplinary tumor board (Arm B)).

The trial will consist of a clinical and translational part. After completion of the treatment algorithm in both arms of the trial, follow-up as scheduled by current guidelines is recommended. Additionally, assessment of quality of life and blood sampling (tumor markers, circulating tumor DNA and potential innovative markers) will be performed for up to 5 years on a three-months basis. During the active part of the study, a radiologic re-assessment prior to surgery will be recommended for all trial subjects of arm A. Tumor biopsies and resected tumor specimens will be collected at screening (baseline sample) and in the course of treatment. Additionally, in case of disease relapse a tumor re-biopsy will be collected as far as considered feasible and safe for the patient by the investigator. The objective of the re-assessments is detection of relapse either radiologically or within the translational material (blood samples with ctDNA dynamics and tumor - if available from relapses). Patients in Arm A will receive a preoperative study drug intervention (mFOLFOXIRI or mFOLFOX-6 or CAPOX) for up to 3 months (6 cycles biweekly or 4 cycles triweekly) after randomization with clinical and safety assessments as specified in (Table 1). Allocation to study treatment FOLFOX/FOLFOXIRI or CAPOX for patients in Arm A is stratified and done by investigator's choice. Beyond clinical or radiological factors, the decision may consider but is not limited to factors such as age, performance status, and patients' perspectives. Since obligatory criteria cannot be made, treatment allocation will not be regulated by the protocol, but stratification will avoid that treatment allocation promotes bias.