REPROGRAM-02 : Induction Regorafenib in combination with metronomic cyclophosphamide, capecitabine, and low-dose aspirin followed by chemotherapy in second line metastatic colorectal cancer carcinoma

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),
• Myocardial infarction less than 6 months before start of study drug,
• Active hepatitis B or C or chronic hepatitis B or C requiring treatment with antiviral therapy,
• Current participation in a study of an investigational agent. Patients might be included at least 21 days following the last investigational agent administration.
• 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,
• Subject unable to swallow oral medications,
• Any malabsorption condition, unresolved toxicity higher than CTCAE (V4) 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 or UGT1A9 inducers/inhibitors,
• Recent or concomitant treatment with brivudine,
• 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,
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days before start of study medication,

Other illness

• 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),
• 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
• Ongoing infection >grade 2 CTCAE V5 (Appendix 4),
• Known History of human immunodeficiency virus (HIV) infection,
• Subjects with seizure disorder requiring medication,
• History of organ allograft,
• Subjects with evidence or history of any bleeding diathesis, irrespective of severity,
• Serious, Non-healing wound, active ulcer or untreated bone fracture,
• Known hypersensitivity to any of the study drugs, study drug classes or excipient in the formulation,
• Interstitial lung disease with ongoing signs or symptoms,
• 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;
• Active peptic ulcer,
• History of asthma induced by the administration of salicylates or substances with a similar action, notably non-steroidal anti-inflammatory medicines,
• Any constitutional or acquired hemorrhagic disease,

Lab values

• Patient on platelet antiaggregants treatment
• QT/QTc interval longer than 450 msec for men and longer than 470 msec for women on the inclusion ECG

Other

• Pregnant or breast-feeding subjects,
• Pleural effusion or ascites that causes respiratory compromise (≥ CTCAE grade 2 dyspnea),
• Dehydration CTCAE v4 grade ≥1,
• Persistent proteinuria of CTCAE Grade 3 (>3.5 g/24 hours),
• Urinary tract obstruction,
• Patient under judicial protection (curatorship, tutorship) and/or deprived of freedom,
• Hypokalemia less than normal, hypomagnesemia, hypocalcemia
• Complete deficit in dihydropyrimidine deshydrogenase (DPD),

• Patients with histologically proven metastatic colorectal cancer in progression after a first line of chemotherapy +/- targeted therapy
• 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 through at 210 days after the last dose of regorafenib. 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).
• Patients must have been treated for their metastatic disease with one of the following regimens as first-line therapy: o FOLFOX o FOLFIRI o FOLFIRINOX or FOLFOXIRI o FOLFOX and anti-VEGFA (bevacizumab only) o FOLFIRI and anti-VEGFA(bevacizumab only) o FOLFIRINOX or FOLFOXIRI and anti-VEGFA (bevacizumab only) o FOLFOX and anti-EGFR o FOLFIRI and anti-EGFR o 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.
• 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 5FU-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.
• Life expectancy of at least 3 months
• Female or male with age ≥18 years old
• Performance status Eastern Cooperative Oncology Group World Health Organization (ECOG-WHO) ≤1 (Appendix 2),
• Measurable disease defined according to RECIST v1.1 (scanner or MRI) (Appendix 3)
• Molecular status: patients eligible should have microsatellite-stable (MSS) status, absence of BRAF V600E mutation and a known RAS status.
• Adequate bone marrow, liver and renal functions. a. Haemoglobin ≥ 9 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L b. 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 c. Cockcroft glomerular filtration rate > 50 ml/min d. Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour