Abstract
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, α = 5%, β = 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 85 mg/m2, folinic acid 400 mg/m2, irinotecan 150–180 mg/m2, 5-fluorouracil: 400 mg/m2 then 2400 mg/m2 over 46 h) is administered every 14 days. Regorafenib (80 to 160 mg, 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.
Highlights
The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer
It is accepted that the addition of targeted therapies such as bevacizumab or as monoclonal antibodies directed to epidermal growth factor receptor to 2-CTx or Chemotherapy triplet (3-CTx) it is beneficial in fit patients when tumor shrinkage is a major objective to allow conversion surgery [2]
FOLFIRINOX is administered as per standard procedures every 14 days (1 cycle = 14 days) as follows, oxaliplatin 85 mg/m2 on day 1, IV infusion over 2 h, immediately followed by folinic acid 400 mg/m2 or calcium levofolinate 200 mg/m2 given as a 2-h IV infusion, with the addition of irinotecan 150–180 mg/m2 as per dose-level given as a 90-min intravenous infusion through a Y-connector immediately followed by 5fluorouracil: 400 mg/m2 IV bolus 2400 mg/m2 over 46 h continuous infusion
Summary
The chemotherapy triplet FOLFOXIRI combined to the anti-VEGF antibody bevacizumab is an option in selected patients with metastatic colorectal cancer. 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 RASmutated metastatic colorectal cancer. Falcone et al [3] reported higher response rates and better survival rates with the use of a chemotherapy triplet (3-CTx) that combined 5fluorouracil, folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) over 2-CTx. our group reported favorable outcomes in patients with unresectable liver metastases from colorectal origin, with the same three drugs but using a different dosing schedule, i.e. the FOLFIRINOX regimen [4]. It is accepted that the addition of targeted therapies such as bevacizumab (a monoclonal antibody which binds circulating vascular endothelial growth factor-A) or as monoclonal antibodies (cetuximab, panitumumab) directed to epidermal growth factor receptor to 2-CTx or 3-CTx it is beneficial in fit patients when tumor shrinkage is a major objective to allow conversion surgery [2]
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