Multi-Line Therapy Trial in Unresectable Wild-Type RAS Metastatic Colorectal Cancer. A GERCOR Randomized Open-label Phase III Study.

• Signed and dated informed consent, and willing and able to comply with protocol requirements,

• Histologically proven adenocarcinoma of the colon and/or rectum,

• Wild-type RAS tumor no mutation in exon 2 \[codon 12/13\], exon 3 \[codon 59/61\] and exon 4 \[codon 117/146\] of both KRAS and NRAS genes (local assessment, performed either on primary tumor or metastasis), In exceptional circumstances, RAS mutational status (KRAS and NRAS) can be pending at time of randomization, provided it is obtained within the first two cycles of first line therapy

• Metastatic disease confirmed,

• No prior therapy for metastatic disease (in case of previous adjuvant therapy, interval from end of chemotherapy and relapse must be \>6 months for fluoropyrimidine alone or \>12 months for oxaliplatin-based, bevacizumab-based, or cetuximab-based therapy),

• Duly documented unresectable metastatic disease, ie not suitable for complete carcinological surgical resection at inclusion \[NB: patients with unresectable disease at study entry but with any potential of salvage surgery after induction therapy are eligible\],

• At least one measurable or evaluable lesion as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1,

• Age ≥18 years,

• ECOG Performance status (PS) 0-2,

⁃ Hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L; haemoglobin ≥9g/dL,

⁃ Adequate renal function: serum creatinine level \<150µM,

⁃ Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline phosphatase \<5xULN,

⁃ Proteinuria \<2+ (dipstick urinalysis) or ≤1g/24hour,

⁃ Baseline evaluations performed before randomization when the KRAS WT status is known: clinical and blood evaluations no more than 2 weeks (14 days) prior to randomization, tumor assessment (CT-scan or MRI, evaluation of non-measurable lesions) no more than 3 weeks (21 days) prior to randomization,

⁃ Female patients must commit to using reliable and appropriate methods of contraception during the trial and until at least six months after the end of study treatment (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method during the trial and until at least 6 months after the end of the study treatment,

⁃ Registration in a national health care system (CMU included for France).