Regorafenib With Low-dose Chemotherapies and Aspirin Followed by Standard Chemotherapies in Metastatic Colorectal Cancer

This study evaluates the interest of regorafenib in combination of metronomic chemotherapies and low-dose aspirin as a 2 months induction therapy before chemotherapy initiation in the second-line metastatic colorectal carcinoma

Inclusion Criteria: 1. Patients with histologically proven metastatic colorectal cancer in progression after a first line of chemotherapy +/- targeted therapy 2. Patients must have been treated for their metastatic disease with one of the following regimens as first-line therapy: * FOLFOX (Oxaliplatine, 5-Fluoro-uracil) * FOLFIRI (Irinotecan, 5-Fluoro-uracil) * FOLFIRINOX (Irinotecan, oxaplipatin, 5-Fluoro-uracil) or FOLFOXIRI (irinotecan, oxaliplatin, 5-Fluoro-uracil) * FOLFOX and anti-VEGFA (bevacizumab only) * FOLFIRI and anti-VEGFA (bevacizumab only) * FOLFIRINOX or FOLFOXIRI and anti-VEGFA (bevacizumab only) * FOLFOX and anti-EGFR (Epiderman Growth Factor Recepto) * FOLFIRI and anti-EGFR * FOLFIRINOX or FOLFOXIRI and anti-EGFR Of note, a chemotherapy prescribed for metastases occurring within six months after the end of an adjuvant chemotherapy are considered as a second line of therapy. 3. Patients should have a history of resistance to first line chemotherapy defined by: * Disease progression during the first line of their metastatic disease, less than 3 months after the last exposition to chemotherapy (even a chemotherapy regimen mentioned above or a 5-Fluoro-uracil-based maintenance therapy). * Disease relapse within 6 months after the end of an adjuvant FOLFOX based chemotherapy. * Disease relapse within 6 months after the surgical resection of metastases following a first line of chemotherapy. 4. Life expectancy of at least 3 months 5. Female or male with age ≥18 years old 6. Performance status Eastern Cooperative Oncology Group World Health Organization (ECOG-WHO) ≤1 (Appendix 1), 7. Measurable disease defined according to RECIST v1.1 (scanner or MRI) 8. Molecular status: patients eligible should have microsatellite-stable (MSS) status, absence of BRAF V600E (B(Raf gene, val600-to-glu) mutation and a known RAS (Retrovirus Associated Sequences) status. 9. Adequate bone marrow, liver and renal functions. * Haemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L * Total serum bilirubin ≤ 1.5 times upper normal value (ULN), serum alkaline phosphatase \< 5 times ULN, aminotransferases (AST/ALT) ≤ 3 × ULN in absence of hepatic metastasis or ≤ 5 if presence of hepatic lesions * Cockcroft glomerular filtration rate \> 50 ml/min * Proteinuria \