Study to evaluate the efficacy and safety of cetuximab plus irinotecan compared to investigator's choice therapy in patients with metastatic colorectal cancer.

Prior treatment

• Patients under ongoing treatment with an investigational medication or medical device or participation in another investigational study within the previous 4 weeks.
• Patients with any concurrent condition that, in the investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.
• Pregnant or nursing (lactating) women; women of childbearing potential (premenopausal or less than 12 months of amenorrhea post-menopause) who have not undergone surgical sterilization and who are sexually active that are unwilling to use adequate contraception (such as oral contraceptives, intrauterine contraceptive device or barrier method with spermicide or surgical sterilization) during the study and until 3 months after last dose of study treatment administration.
• Previous or concurrent second malignancy with exception of basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other solid tumors with no evidence of recurrence in the last 5 years.
• Patients with known, untreated central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression; patients with any of these metastases not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required.

Other illness

• Patients with active alcohol or drug addiction or any other condition that, in the investigator's opinion, would interfere with their ability to comply with the study requirements.
• Failure to perform screening examinations.
• Suspected or known allergy or intolerance to any components of the study treatment.
• History of grade 3/4 infusion reactions to cetuximab or panitumumab monoclonal antibodies.

Lab values

• Second-line treatment with anti-EGFR therapy.

Other

• Patients who decline or are unable to understand, provide or are unwilling to sign an informed consent form.
• Unable or unwilling to complete all required screening and/or follow-up assessments.
• Patients with MSI-high (MSI-H) tumors.

• Written informed consent before any study procedure is performed.
• ECOG performance status of 0-1
• Adequate bone marrow (hemoglobin ≥9.0 g/dL, neutrophil count > 1.0 x 109/L and platelet > 50 x 109/L), renal (serum creatinine <2 x upper limit of normal [ULN] and/or bilirubin <2.5 x UNL) and hepatic function (ALT and AST < 2.5 x ULN, ≤ 5 x ULN if liver metastases are present).
• Absence of any psychological, familial, sociological or geographical circumstance potentially hampering compliance with the study protocol.
• Life expectancy >12 weeks, as determined by the investigator.
• Men and women aged 18 years or older.
• Histologically confirmed mCRC.
• RAS wild-type (KRAS and NRAS exon 2,3,4) status in a tissue-based test determined by a local assay before starting first-line treatment.
• Patients must have received two prior regimens of standard chemotherapy for mCRC and must have been refractory to or failed (includes intolerance) to those regimens. ▪ Prior standard chemotherapy may not have included TAS-102 or regorafenib, but must have included all of the following agents: ▪ AntiEGFR monoclonal antibodies (cetuximab or panitumumab) in the firstline setting ▪ Fluoropyrimidines, irinotecan and oxaliplatin (+/- an anti-VEGF pathway inhibitor approved for treatment of mCRC). Reintroduction of a chemotherapeutic regimen will not be considered as a new line of treatment.
• Patients with “acquired” resistance to antiEGFR monoclonal antibodies (cetuximab or panitumumab), defined as: ▪ Response to first-line antiEGFR-based treatment (defined as CR, PR or SD lasting ≥16 weeks). ▪ Documented progression to first-line antiEGFR-based treatment within 4 weeks after the last administration of cetuximab or panitumumab.
• Recovery of any toxicity related to second-line treatment to grade ≤1 according to NCICTCAE version 5.0 at screening, with the exception of grade 2 alopecia or grade 2 neuropathy.
• Triple negative mutation status defined as no detection of clonal mutations in extended RAS (KRAS and NRAS exon 2,3,4), BRAF V600E and EGFR-ECD (V441, S464, G465 and S492) as assessed in liquid biopsy testing for screening before third-line treatment initiation assessed by the central laboratory. Note: A centralized genomic analysis will be performed. For this purpose, peripheral blood will be collected and sent to the central laboratory for detecting RAS, BRAF V600E, and EGFR-ECD mutations on ctDNA by Oncomine CRC NGS analysis.
• At least one measurable lesion, defined as one or more target lesions according to RECIST, version 1.1.