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Πέμπτη 9 Φεβρουαρίου 2017

A Multicenter Phase II Study of Personalized FOLFIRI-Cetuximab for Safe Dose Intensification

Publication date: Available online 9 February 2017
Source:Seminars in Oncology
Author(s): O. Capitain, J.P. Metges, M. Boisdron-Celle, A. Adenis, J.L. Raoul, T. Lecomte, Y.H. Lam, R. Faroux, C. Masliah, A.L. Poirier, V. Berger, A. Morel, E. Gamelin
BackgroundWe conducted a multicenter proof of concept phase II trial in patients with advanced colorectal cancer receiving FOLFIRI-Cetuximab regimens to explore individual drug tailoring using pharmacogenetics and PK-monitoring.MethodsPatients were stratified by their pharmacogenetic/phenotypic status: The irinotecan dose was adjusted according to the number of TA tandem repeats in the UGT1A1 promoter; while the 5-FU dose was initially adjusted according to DPD activity at initial screening (5-FUODPMTox™) followed by PK-guided dose optimization (5-FUODPMProtocol™). An advanced cetuximab PK/PD study was performed but dosage remained unchanged.Results85 patients receiving second line chemotherapy were enrolled. Mean irinotecan doses at 3 months were 247±50, 210±53 and 140±21 mg/m2 for those with 6/6 (33), 6/7 (26) and 7/7 (7) TATA repeats in the UGT1A1 promoter region, respectively. The 5-FU dose was initially reduced in four patients with DPD deficiency but mean 5-FU dose at 3 months was 2412±364 mg/ m2 (1615 to 3170 mg/m2). Grade 4 toxicities were not encountered and grade 4 neutropenia occurred in 6.8%, 5.9% and 0% of patients with 6/6, 6/7 and 7/7 UGT1A1 genotypes. The objective response rate was 25.8%% amongst the 85 patients, 57.3% in patients with tumors WT for KRAS, and 25% in those whose tumor harboured a mutant-KRAS. Secondary resection of hepatic metastases was performed in 31.7% of patients. Median PFS for all 85 patients was 181 days and 200, 132 and 121 days for patients with 6/6, 6/7 and 7/7 UGT1A1 genotypes respectively, differences that were not statistically different. In parallel, a strong relationship was shown between cetuximab AUC and regimen efficacy.ConclusionsPersonalized drug tailoring when administering in FOLFIRI + cetuximab allows for safe and efficient individual dose intensification.



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