The investigators propose a phase II clinical trial with the objective to investigate the potential clinical interest to associate regorafenib with a metronomic chemotherapy combining capecitabine, cyclophosphamide and low-dose aspirin, for the treatment of patients with metastatic colorectal cancer. The main objective of the study will be to achieve 15% of objective response rate in patients treated with multimodal metronomic chemotherapy and regorafenib.

Inclusion Criteria:

• Patients with histologically proven metastatic colorectal cancer in progression after previous standard treatments (5FU, CPT11, oxaliplatin, anti-VEGF and anti-EGFR therapy if KRAS and NRAS WT), or not considered as candidate for these treatments

• Life expectancy of at least 3 months

• Female or male with age >18 years old

• Performance status = 0 or 1 (Annex 1)

• Measurable disease defined according to RECIST v1.1 (scanner or MRI) (Annex 2)

• Adequate bone marrow, liver and renal functions.

  1. Haemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L
  2. 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
  3. Cockcroft glomerular filtration rate > 50 ml/min
  4. Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour

• Imaging target greater than one cm must be visible on CT,

• No contraindication to Iodine contrast media injection during CT

• For female patients of childbearing potential, negative pregnancy test within 14 days before starting the study drug. Men and women are required to use adequate birth control during the study (when applicable),

• Signed and dated informed consent,

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

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

Exclusion criteria:

• Diagnosis of additional malignancy within 2 years prior to the inclusion (exception of curatively treated basal cell carcinoma of the skin and/or curatively resected in situ cervical cancer),
• Current participation in a study of an investigational agent or in the period of exclusion
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before inclusion in the trial ;
• Patient under judicial protection (curatorship, tutorship) and/or deprived of freedom,
• Planned surgical procedure within the first month of treatment or any procedure that might change the timing of regorafenib administration during the first month of treatment,
• Previous exposure to regorafenib,
• Previous exposure to other anti-angiogenic treatment than bevacizumab and aflibercept,
• Complete deficit in dihydropyrimidine deshydrogenase (DPD),
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication,
• Pregnant or breast-feeding subjects,
• Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2, unstable angina (anginal symptomatology at rest),
• Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months),
• Myocardial infarction less than 6 months before start of study drug,
• Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted),
• Uncontrolled hypertension (Systolic blood pressure >150 mmHg and/or diastolic pressure >100 mmHg despite optimal medical management), or history of hypertensive crisis, or hypertensive encephalopathy
• Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2 dyspnea),
• Ongoing infection >grade 2 CTCAE V5,
• Known History of human immunodeficiency virus (HIV) infection,
• Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,
• Subjects with seizure disorder requiring medication,
• History of organ allograft,
• Subjects with evidence or history of any bleeding diathesis, irrespective of severity,
• Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication,
• Serious, Non-healing wound, active ulcer or untreated bone fracture,
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to inclusion,
• Dehydration CTCAE v5 grade ≥1,
• Known hypersensitivity to any of the study drugs, study drug classes or excipient in the formulation,
• Interstitial lung disease with ongoing signs or symptoms,
• Persistent proteinuria of CTCAE Grade 3 (>3.5 g/24 hours),
• Subject unable to swallow oral medications,
• Any malabsorption condition, unresolved toxicity higher than CTCAE (V5) Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neuropathy ≤ Grade 2,
• Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,
• Treatment with any other investigational medicinal product within 28 days prior to study entry, EXCEPT for ASPIRIN,
• Co-administration of drugs potentially interacting with regorafenib i.e. CYP3A4, CYP2C9 or UGT1A9 inducers/inhibitors.