FOLFIRINOX-R study design: a phase I/II trial of FOLFIRINOX plus regorafenib as first line therapy in patients with unresectable RAS-mutated metastatic colorectal cancer

BackgroundThe chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. In this setting, RAS-mutated metastatic colorectal cancer do not benefit the same from treatment than RAS-wildtype metastatic colorectal cancer do. Together with its antiangiogenic properties, the tyrosine-kinase inhibitor regorafenib has also anti-proliferative activities whatever the RAS status is. The present trial aims at studying the safety and the efficacy of regorafenib in combination with FOLFIRINOX - a chemotherapy triplet using a different dosing schedule than FOLFOXIRI - in patients with RAS-mutated metastatic colorectal cancer.MethodsFOLFIRINOX-R is a prospective, multicentric, non-randomised, dose-finding phase 1-2 trial. The primary endpoints are the determination of the maximum tolerated dose, the recommended phase 2 dose, and the proportion of patients achieving disease control at 48-weeks. Phase 1 follows a 3+3 design (12 to 24 patients to be included). Sixty nine patients will be necessary in phase 2, including 5% non-evaluable ones, with the following assumptions, one-stage Fleming design, alpha =5%, beta =20%, p0=35% and p1=50%. Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of <= 1 and RAS-mutated metastatic colorectal cancer not amenable to surgery with curative intent and not previously treated for metastatic disease. FOLFIRINOX (oxaliplatin 85mg/m(2), folinic acid 400mg/m(2), irinotecan 150-180mg/m(2), 5-fluorouracil: 400mg/m(2) then 2400mg/m(2) over 46h) is administered every 14days. Regorafenib (80 to 160mg, as per dose-level) is administered orally, once daily on days 4 to 10 of each cycle.DiscussionFOLFIRINOX-R is the first phase I/II study to evaluate the safety and efficacy of regorafenib in combination with FOLFIRINOX as frontline therapy for patients with RAS-mutated metastatic colorectal cancer.Trial registrationEudraCT: 2018-003541-42; ClinicalTrials.gov: NCT03828799.