PRODIGE 25 (FFCD 11-01) - Phase II randomized trial evaluating aflibercept associated with LV5FU2 regimen as first line treatment of non-resectable metastatic colorectal cancers (FOLFA)

Abstract

Background: Aflibercept has already been used in combination with FOLFIRI in the VELOUR trial (1). The aflibercept‐LV5FU2 combination can be useful and well tolerated in patients ( pts) with never resectable/non symptomatic metastatic colorectal cancer, for whom 5‐FU monotherapy can be suggested to delay the toxicities of combined chemotherapies, then eligible for sequential treatment with first‐line 5‐FU monotherapy. Within this context, it is possible for aflibercept to provide a survival benefit. VELOUR trial did not indicate that toxicity would have a major effect on quality of life and increase the hope of prolonged progression‐free survival in the arm with aflibercept. A previous pharmacogenetic analysis of the FFCD 2000‐05 phase III trial (2) showed a prognostic and predictive effect of the thymidylate synthase (TS)‐5'UTR polymorphism for response and PFS: the 5‐FU monotherapy efficacy was increased in TS 5'3R/3R pts vs 2R2R‐2R3R (2). Stratification in this criterion will confirm or not the prognostic or predictive value of these polymorphisms if linked to the 5‐FU efficacy. Trial design: The major eligibility criteria are: age ≥ 65, performance status WHO ≤ 2, central genotyping of TS in blood DNA. Treatment is administered every14 days with simplified LV5FU2 regimen, preceded or not by perfusion of 4 mg/kg aflibercept. The treatment will be stopped in case of progression (evaluation each 8 weeks) or inacceptable toxicity. The main judgement criterion is proportion of pts alive and without radiologic progression within 6 months. A proportion of more than 40% pts will be interesting and a rate of 60% is expected (α = 5%, Binomial‐exact method and a power of 90%). Secondary criteria are: tolerance of the LV5FU2‐aflibercept combination, time to final deterioration in quality of life, overall survival, prognostic value of TS‐5'UTR polymorphism on PFS. Stratification factors are: centre, age: < 75 vs > 75, TS‐5'UTR polymorphism, metastatic site (1 vs >1). Status: 18 of planned 118 patients have been randomized.