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

Inclusion Criteria:

1. Patients with histologically proven metastatic colorectal cancer in progressionafter a first line of chemotherapy +/- targeted therapy

2. Patients must have been treated for their metastatic disease with one of thefollowing 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 afterthe 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, lessthan 3 months after the last exposition to chemotherapy (even a chemotherapyregimen mentioned above or a 5-Fluoro-uracil-based maintenance therapy).

• Disease relapse within 6 months after the end of an adjuvant FOLFOX basedchemotherapy.

• Disease relapse within 6 months after the surgical resection of metastasesfollowing 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 alkalinephosphatase < 5 times ULN, aminotransferases (AST/ALT) ≤ 3 × ULN in absence ofhepatic metastasis or ≤ 5 if presence of hepatic lesions

• Cockcroft glomerular filtration rate > 50 ml/min

• Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour

10. No contraindication to Iodine contrast media injection during CT

11. For female patients of childbearing potential, negative pregnancy test within 14days before starting the study drug through at 210 days after the last dose ofregorafenib. Men and women are required to use adequate birth control during thestudy (when applicable),

12. Signed and dated informed consent,

13. Ability to comply with the study protocol, in the Investigator's judgment.

14. Registration in a national health care system (CMU included).

Exclusion Criteria:

1. Diagnosis of additional malignancy within 2 years prior to the inclusion (exceptionof curatively treated basal cell carcinoma of the skin and/or curatively resected insitu cervical and/or bladder cancer),

2. Current participation in a study of an investigational agent. Patients might beincluded at least 21 days following the last investigational agent administration.

3. Any psychological, familial, sociological or geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule; thoseconditions should be discussed with the patient before inclusion in the trial;

4. Patient under judicial protection (curators, autorship) and/or deprived of freedom,

5. Planned surgical procedure within the first month of treatment or any procedure thatmight change the timing of regorafenib administration during the first month oftreatment,

6. Previous exposure to regorafenib,

7. Previous exposure to other anti-angiogenic treatment than bevacizumab,

8. Complete deficit in dihydropyrimidine dehydrogenase (DPD),

9. Major surgical procedure, open biopsy or significant traumatic injury within 28 daysbefore start of study medication,

10. Pregnant or breast-feeding subjects,

11. Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2, unstableangina (anginal symptomatology at rest),

12. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3months),

13. Myocardial infarction less than 6 months before start of study drug,

14. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin arepermitted),

15. Uncontrolled hypertension (Systolic blood pressure >150 mmHg and/or diastolicpressure >100 mmHg despite optimal medical management), or history of hypertensivecrisis, or hypertensive encephalopathy

16. Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2dyspnea),

17. Ongoing infection >grade 2 CTCAE V5 (Appendix 6 ),

18. Known History of human immunodeficiency virus (HIV) infection,

19. Active hepatitis B or C or chronic hepatitis B or C requiring treatment withantiviral therapy,

20. Subjects with seizure disorder requiring medication,

21. History of organ allograft,

22. Subjects with evidence or history of any bleeding diathesis, irrespective ofseverity,

23. Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the startof study medication,

24. Serious, Non-healing wound, active ulcer or untreated bone fracture,

25. History of abdominal fistula, GI perforation, intra-abdominal abscess or active GIbleeding within 6 months prior to inclusion,

26. Dehydration CTCAE v4 grade ≥1,

27. Known hypersensitivity to any of the study drugs, study drug classes or excipient inthe formulation,

28. Interstitial lung disease with ongoing signs or symptoms,

29. Persistent proteinuria of CTCAE Grade 3 (>3.5 g/24 hours),

30. Subject unable to swallow oral medications,

31. Any malabsorption condition, unresolved toxicity higher than CTCAE (V4) Grade 1attributed to any prior therapy/procedure excluding alopecia, hypothyroidism andoxaliplatin induced neuropathy ≤ Grade 2,

32. Systemic anticancer therapy including cytotoxic therapy, signal transductioninhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,

33. Treatment with any other investigational medicinal product within 28 days prior tostudy entry, EXCEPT for ASPIRIN,

34. Co-administration of drugs potentially interacting with regorafenib i.e. CYP3A4 orUGT1A9 (UDP-glucuronosyltransferase 1-9) inducers/inhibitors.