De-escalation Chemotherapies Versus Escalation in Non Pre-treated Unresectable Patients With Metastatic Colorectal Cancer

Inclusion Criteria: * Metastatic colorectal cancer, histologically proven (on primary tumour and/or metastases) * Unresectable and non-pretreated metastases * BRAF wild-type * Patient considered able to receive 3 lines of chemotherapy * At least one measurable target lesion \> 1 cm according to RECIST 1.1 (Appendix 4) * Tumour assessment according to RECIST, performed 4 weeks or less prior to randomization * Age ≥ 18 years * WHO performance status ≤ 2 (Appendix 5) * No major surgery within 4 weeks prior to randomisation. Wound healing must be complete * Life expectancy greater than 3 months * Laboratory tests: Neutrophils ≥ 1500/mm3, platelets ≥ 100,000/mm3, haemoglobin \> 9 g/dL * Creatinine clearance \> 30 mL /min (capecitabine dose modification if the creatinine clearance \< 30-50 mL/min), serum creatinine \< 1.25 x ULN * Liver function tests: bilirubin \< 1.25 x ULN, AST/ALT \< 5 x ULN * Women of childbearing age and men (who have sexual relations with women of childbearing age) must agree to use effective contraception without interruption throughout the duration of treatment and for 6 months after the last administration * Signed informed consent Exclusion Criteria: * Patient with a potentially resectable colorectal cancer; i.e. for whom the goal of chemotherapy would be to make all metastases resectable * Patients with symptomatic metastases * Patient with aggressive disease and a large tumour volume * Active gastroduodenal ulcer, wound or bone fracture * At least one of the following laboratory values: Neutrophils \<1500/mm3, platelets \< 100,000/mm3, haemoglobin \< 9 g/dL, total bilirubin \> 1.5 N, alkaline phosphatase \> 2.5 N (or \> 5 N in case of hepatic involvement), serum creatinine \> 1.5 N, 24 hr proteinuria \> 1 g * Chronic inflammatory bowel disease, extensive resection of the small bowel * Clinically significant coronary artery disease or a history of myocardial infraction within the last 6 months. Uncontrolled hypertension while receiving chronic medication * Abdominal or major extra-abdominal surgical procedure (except diagnostic biopsy) or radiation within 4 weeks before starting treatment * Previous treatment with an anti-angiogenic or irinotecan * Known or suspected central nervous system metastasis CNS metastases, or suspected CNS metastases * Other previous malignancies within 5 years, except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix - Peritoneal macro-nodular carcinomatosis * History of haemoptysis ≥ grade 2 (defined as ≥ 2.5 mL of bright red blood per episode) in the month prior to inclusion * Known hypersensitivity to any component of bevacizumab or to one of the study treatments * Active infection requiring intravenous antibiotics at start of treatment * History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to treatment start * Pregnant or breastfeeding women * Concomitant participation in another clinical study involving a drug during the treatment phase and 30 days before starting the study treatment * Patient unable to undergo medical treatment for geographical, social, psychological or legal reasons.