This study is a phase II, open-label, multicenter clinical trial designed to evaluate two different treatment options for patients with metastatic colorectal cancer whose disease has progressed after standard therapies. The study compares a rechallenge treatment using irinotecan plus cetuximab with the current standard of care, trifluridine/tipiracil plus bevacizumab, as third-line therapy. Patients enrolled in the study are selected based on specific molecular characteristics of their cancer, identified through circulating tumor DNA analysis from a blood sample. The main purpose of the study is to determine whether the rechallenge with irinotecan and cetuximab leads to a higher tumor response rate compared with trifluridine/tipiracil plus bevacizumab. Secondary objectives include evaluating progression-free survival, overall survival, safety, and quality of life. Patients will be randomly assigned to one of the two treatment groups and will receive treatment until disease progression, unacceptable side effects, or withdrawal of consent. Tumor response will be assessed using standard imaging techniques according to RECIST criteria.
Male or female aged ≥18 years
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤1
Diagnosis of histologically or cytologically confirmed colorectal cancer.
At least one measurable lesion according to RECIST1.1
ECOG PS ≥2
Received more than 2 lines of treatment for metastatic disease.
Previous treatment with trifluridine/tipiracil
RAS/BRAF/EGFR/PIK3CAex20/MAP2K1/MET WT HER2 not amplified status at liquid biopsy analysis during screening.
Parallel
Erbitux (Cetuximab)
DrugThis is an anti-EGFR monoclonal antibody administered in combination with chemotherapy. The dose is 500 mg/m2 over 120 minutes
Bevacizumab
DrugThis is an anti-VEGF monoclonal antibody used as an active comparator in the control arm of the study. The dose is 5 mg/Kg of body weight given once every 2 weeks.
Irinotecan
DrugIrinotecan is a cytotoxic chemotherapy agent administered intravenously in combination with cetuximab the dose is 180 mg/m2 over 90 minutes, once every 2 weeks.
Trifluridine/tipiracil
DrugTrifluridine/tipiracil is an oral antineoplastic combination administered in combination with bevacizumab as part of the control treatment arm. The dose is 5 mg/ m² twice daily on Days 1 to 5 and Days 8 to 12 on a cycle of 28 days.
Objective Response Rate (ORR)
Objective Response Rate (ORR) is defined as the proportion of participants who achieve a complete response (CR) or partial response (PR) according to RECIST version 1.1 criteria. Tumor assessments are based on radiological imaging reviewed centrally by an independent blinded radiology reviewe
Progressio-Free Survival (PFS)
Progression-Free Survival (PFS) is defined as the time from randomization to documented disease progression according to RECIST version 1.1 criteria or death from any cause, whichever occurs first.
Overall Survival (OS)
Overall Survival (OS) is defined as the time from enrollment to death from any cause.
Incidence of Adverse Events and Serious Adverse Events
Safety will be assessed by the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as by changes in clinical laboratory parameters, vital signs, physical examinations, electrocardiogram (ECG) findings, and ECOG performance status. Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Treatment Exposure as a Measure of Tolerability
Tolerability will be assessed by the frequency of treatment discontinuations, dose reductions, and dose delays due to adverse events during study treatment.
Progression-Free Survival (PFS) of the Subsequent Line of Treatment
Progression-Free Survival (PFS) following the subsequent line of treatment is defined as the time from initiation of the first subsequent anticancer therapy to the first documented disease progression according to RECIST v1.1 or death from any cause, whichever occurs first.
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