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

Exclusion Criteria34

• 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. Patients might be included at least 21 days following the last investigational agent administration.
• 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,
• 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,
• Complete deficit in dihydropyrimidine dehydrogenase (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 (Appendix 6 ),
• 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 v4 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 (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 (UDP-glucuronosyltransferase 1-9) inducers/inhibitors.