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.
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, TS-5'UTR polymorphism, metastatic site (1 vs >1). Status: 18 of planned 118 patients have been randomized. References: (1) Van Cutsem E et al: J Clin Oncol 30:3499-506, 2012 (2), Boige V et al: J Clin Oncol 28:2556-64, 2010
Clinical trial identification
EudraCT 2014-001837-10; 05 September 2014
Legal entity responsible for the study
All authors have declared no conflicts of interest.