Multi-Line Therapy Trial in Unresectable Metastatic Colorectal Cancer

Inclusion Criteria:

1. Signed and dated informed consent, and willing and able to comply with protocol requirements,
2. Histologically proven adenocarcinoma of the colon and/or rectum,
3. 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
4. Metastatic disease confirmed,
5. 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),
6. Duly documented unresectable metastatic disease, ie not suitable for complete carcinological surgical resection at inclusion \[NB: patients with unresectable disease at study entry but with any potential of salvage surgery after induction therapy are eligible\],
7. At least one measurable or evaluable lesion as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1,
8. Age ≥18 years,
9. ECOG Performance status (PS) 0-2,
10. Hematological status: neutrophils (ANC) ≥1.5x109/L; platelets ≥100x109/L; haemoglobin ≥9g/dL,
11. Adequate renal function: serum creatinine level \<150µM,
12. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alkaline phosphatase \<5xULN,
13. Proteinuria \<2+ (dipstick urinalysis) or ≤1g/24hour,
14. 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,
15. 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,
16. Registration in a national health care system (CMU included for France).

Exclusion Criteria:

1. History or evidence upon physical examination of CNS metastasis (e.g. non irradiated CNS metastasis, seizure not controlled with standard medical therapy), unless adequately treated,
2. Exclusive bone metastasis,
3. Uncontrolled hypercalcemia,
4. Pre-existing permanent neuropathy (NCI grade ≥2),
5. Uncontrolled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy,
6. Concomitant unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
7. Treatment with any investigational medicinal product within 28 days prior to study entry,
8. Other serious and uncontrolled non-malignant disease,
9. Gilbert's syndrome,
10. Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for \>5 years,
11. Major surgery (open biopsy, surgical resection, wound revision or any other major surgery involving entry into body cavity) or significant traumatic injury within the last 28 days prior to randomization, and/or minor surgical procedure including placement of a vascular device within 2 days of first study treatment,
12. Pregnant or breastfeeding women,
13. Patients with known allergy/hypersensitivity to any component of study drugs,
14. History of arterial thrombo and/or embolic event (e.g. myocardial infarction, stroke,…) within 6 months prior to randomization,
15. Chronic inflammatory bowel disease
16. Total bowel obstruction,
17. History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to randomization,
18. Serious, non-healing wound, active ulcer or untreated bone fracture,
19. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding,
20. Current or recent (within 10 days of randomization) use of aspirin (\>325 mg/d), clopidogrel (\>75 mg/d) or use of oral anticoagulants or thrombolytic agents.
21. Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine
22. Concomitant administration of prophylactic phenytoin.
23. Treatment with sorivudine or its chemically related analogues, such as brivudine.
24. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.
25. Concomitant use with St John's Wort
26. Patients with interstitial pneumonitis or pulmonary fibrosis