CARE : Impact of Regorafenib in combination with multimodal metronomic chemotherapy (cyclophosphamide, capecitabine, and low-dose aspirin) on progression-free survival compared with standard Regorafenib for the treatment of chemo-resistant metastatic colorectal cancers

Prior treatment

• 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 and/or bladder cancer),
• Unresolved toxicity higher than CTCAE (v5) Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neuropathy ≤ Grade 2,
• Inadequate organ functions: - known cardiac failure of unstable coronaropathy, respiratory failure, or uncontrolled infection or another life-risk condition - Congestive Heart Failure ≥ New York Heart Association (NYHA) class 2, - Myocardal infarction less than 6 months before start of study drug, unstable angina (anginal symptoms at rest), new-onset angina (begun within the last 3 months), Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted), - Uncontrolled hypertension (defined by 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), - Interstitial lung disease with ongoing signs or symptoms, - Ongoing infection >grade 2 CTCAE V5, - Dehydration CTCAE v5 grade ≥1, - Urinary tract obstruction
• Constitutional or acquired hemorrhagic disease: - Any haemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication, - History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to inclusion, - Serious, Non-healing wound, active peptic ulcer or untreated bone fracture, - Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication,
• 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,
• Known History of human immunodeficiency virus (HIV) infection; Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,
• Receipt of yellow fever vaccine within 28 days prior to study,
• Current participation in a study of an investigational agent or in the period of exclusion
• Previous exposition to regorafenib or anti-angiogenic treatment other than bevacizumab and aflibercept
• Treatment with any other investigational medicinal product within 28 days prior to study entry, EXCEPT for ASPIRIN,
• Systemic anticancer therapy including cytotoxic therapy, signal transduction inhibitors, immunotherapy, and hormonal therapy during this trial or within 3 weeks,
• Chronic treatment with drug potentially interacting with regorafenib i.e. CYP3A4, CYP2C9 or UGT1A9 inductor/inhibitor; Epilectic disorder requiring medication; Recent or concomitant treatment with brivudine,

Other illness

• Known hypersensitivity to any of the study drugs, study drug classes or excipient in the formulation: - History of severe and unexpected reactions to fluoropyrimidine therapy, - History of asthma induced by the administration of salicylates or substances with a similar action, notably non-steroidal anti-inflammatory medicines, - Mastocytosis, for whom the use of acetylsalicylic acid can cause severe hypersensitivity reactions,
• Subject unable to swallow oral medications or any malabsorption condition,
• History of organ allograft,
• 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 ;

Other

• Pregnant or breast-feeding subjects
• Patient under judicial protection (curatorship, tutorship) and/or deprived of freedom,
• Complete deficit in dihydropyrimidine deshydrogenase (DPD),

• Patients with histologically proven metastatic colorectal cancer in progression after previous standard treatments (5FU, CPT11, oxaliplatin, anti-VEGF, trifluridine/tipiracil, and anti-EGFR therapy if KRAS and NRAS WT, anti-BRAF therapy if BRAF V600E mutated, and anti-PD1 if MSI-H/dMMR tumor), or not considered as candidate for these treatments.
  • 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).
  • 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 guidelines (scanner or MRI) (Annex 2)
  • 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 <2+ (dipstick urinalysis) or ≤1g/24hour