Phase II trial of chemotherapy with high-dose FOLFIRI plus bevacizumab in the front-line treatment of patients with metastatic colorectal cancer (mCRC) and genotype UGT1A1∗1/ UGT1A1∗1 or UGT1A1∗1/ UGT1A1∗28 (FFCD 0504 trial): Final results

Background: The combination of high-dose irinotecan (260mg/m2) with LV5FU2 (FOLFIRI HD regimen) is feasible with an acceptable safety profile and promising efficacy data (Ducreux et al. Oncology 2008;74:17-24). The aim of this phase II study was to evaluate the combination of FOLFIRI HD plus bevacizumab (B) in patients (pts) selected on the UGT1A1 polymorphism, which could be predictive of the irinotecan toxicity and efficacy. Methods: Pts with UGT1A1 ∗1/∗1 (group 1) or ∗1/∗28 (group 2) genotypes and previously untreated mCRC were treated with bevacizumab 5 mg/kg D1, irinotecan 260 mg/m2 D1, LV 400 mg/m2 D1, 5FU 400 mg/m2 IV bolus D1 and 5FU 2400 mg/m2 46h infusion D1-2 every 2 weeks. Using Bryant & Day design with objective response rate (ORR) (independent review, H0 ≤ 40%; H1 ≥ 60%) and toxicity (gr 4 neutropenia or febrile neutropenia or gr 3-4 diarrhea; H0 ≥ 20%; H1 ≤5%) as primary endpoints; a total of 108 pts, 54 in each group, was required (alpha 5% and power 80%) with a planned interim analysis after the inclusion of 17 pts by group. The trial will be stopped at interim analysis if ≤ 7 pts had an OR and/or ≥ 3 pts had a severe toxicity. All analyses were performed in ITT. Results: At the time of interim analysis, done when the 17th pt of group 1 had a 6-months follow-up, 86 pts were included (group 1: 40 pts, group 2: 46 pts). Results of primary endpoints at the interim analysis are presented in the table. According to interim analysis rules, the trial was closed to inclusion for unacceptable toxicity. Conclusions: The trial was stopped after interim analysis because of unacceptable toxicity according to trial's criteria, even if toxicity was manageable and most of the patients continued the treatment after dose adaptation. Defined toxicity criteria to stop the trial at interim analysis may have been too strict and not clinically adapted. There is however no clear benefit of the FOLFIRI HD - B combination in terms of efficacy. (Table presented).