Regorafenib in Combination With Multimodal Metronomic Chemotherapy for Chemo-resistant Metastatic Colorectal Cancers

Exclusion Criteria35

• 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),
• 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 (curators, autorship) and/or deprived of freedom,
• 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 (UDP-glucuronosyltransferase 1-9) inductor/inhibitor; Epileptic disorder requiring medication; Recent or concomitant treatment with brivudine,
• Complete deficit in dihydropyrimidine dehydrogenase (DPD),
• 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,
• Unresolved toxicity higher than CTCAE (v5) Grade 1 attributed to any prior therapy/procedure excluding alopecia, hypothyroidism and oxaliplatin induced neuropathy ≤ Grade 2,
• Subject unable to swallow oral medications or any malabsorption condition,
• 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,
• Myocardial 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,
• History of organ allograft,
• Pregnant or breast-feeding subjects