Genotype‐directed, dose‐finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms

摘要: Irinotecan-induced severe neutropenia is associated with homozygosity for the UGT1A1*28 or UGT1A1*6 alleles. In this study, we determined maximum-tolerated dose (MTD) of irinotecan in patients UGT1A1 polymorphisms. Patients who had received chemotherapy other than metastatic gastrointestinal cancer were enrolled. divided into three groups according to genotypes: wild-type (*1/*1); heterozygous (*28/*1, *6/*1); homozygous (*28/*28, *6/*6, *28/*6). Irinotecan was given every 2 weeks two cycles. The group a fixed (150 mg/m(2)) serve as reference. MTD guided from 75 150 mg/m(2) by continual reassessment method and groups. Dose-limiting toxicity (DLT) pharmacokinetics evaluated during cycle 1. Of 82 enrolled, DLT assessable 79 (wild-type, 40; heterozygous, 20; homozygous, 19). occurred one patient group, none six (grade 4 neutropenia) group. probability 37.4%. second delayed because 56.3% MTD. AUC(0-24 h) SN-38 significantly greater (P < 0.001) more widely distributed allele can receive starting mg/m(2), but many required reductions treatment subsequent UMIN Clinical Trial Registration number: UMIN000000618.