Regorafenib is a multikinase inhibitor with broad anti-angiogenic, anti-stroma and anti-proliferative effects that improved overall survival in patients with mCRC after failure of all approved drugs in the CORRECT phase 3 trial. The different tolerability profile of regorafenib compared with other agents normally used for the treatment of colorectal cancer, caused frequent dose-reductions and interruptions, thereby jeopardizing dose-intensity and limiting incorporation of the drug as standard of care. The CORRECT trial showed that the highest rate and intensity of treatment-related adverse events occurs during the first two cycles. The standard approved dose of regorafenib (160 mg daily three weeks on/one week off) was determined in a phase 1 study and this dose was moved directly into the phase 3 trial. The immediate sub-MTD dose level of 120mg daily 3 weeks on/1 week off did not show any DLT among 7 patients treated in the phase I. In addition, an intermittent dose approach consisting of regorafenib 160 mg daily on a 1 week on/1 week off schedule was tested in combination with chemotherapy in the CORDIAL trial and showed a favorable safety profile.
This randomized phase 2 study will evaluate the tolerability regorafenib using different dose-escalation approaches in patients with treatment refractory mCRC. Patients will be randomized 1:1:1 to receive regorafenib at the standard approved dose (arm A), or at 120 mg daily 3 weeks on/one week off during the first cycle (arm B), or 160 mg daily one week on/one week off during the first cycle (arm C). In arms B and C, the dose will be escalated to the standard dose from cycle two onwards if no limiting toxicity appears. The primary objective is to compare the safety profile of the different treatment arms. Secondary aims include assessment of the percentage of total administered dose over the planned dose, dose intensity during the treatment period and during first two cycles, disease control rate, progression-free survival, time to treatment failure, and overall survival. The trial is in progress; 160 of 295 planned patients have been recruited at the end of March 2017 (first patient 15 July 2016).
Clinical trial identification
Legal entity responsible for the study
Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD) in collaboration with UNICANCER GI
Bayer HealthCare Pharmaceuticals Inc Company
J.M. Viéitez: Consultant or advisory relationship: Amgen, Roche. Honoraria: Servier, Shire. Research funding: Amgen, Roche, Merck Serono. A. Falcone: Consultant or advisory relationship, research funding and honoraria: Amgen, Bayer, Roche, Merck, Servier, Sanofi. F. Ciardiello: Advisory Boards (compensate): Bayer, Roche, Merck, Amgen, Lilly. Research funds: Bayer, Roche. J. Bennouna: Consultant or advisory relationship and honoraria: Roche, BMS, Boehringer-Ingelheim, Astra-Zeneca. J. Tabernero: Consultant or advisory relationship and honoraria: Roche, BMS, Boehringer-Ingelheim, Astra-Zeneca. E. Aranda Aguilar: Advisory role: Amgen, Bayer, Celgene, Merk, Roche, Sanofi. All other authors have declared no conflicts of interest.