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

Abstract

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

A Phase I Study of <b><i>UGT1A1</i></b> *<b><i>28/</i></b>*<b><i>6</i></b> Genotype-Directed Dosing of Irinotecan (CPT-11) in Korean Patients with Metastatic Colorectal Cancer Receiving FOLFIRI

“…Allele frequencies of UGT1A1 * 28 are 20-40% in Caucasians and Africans, but less than 20% in Asians. UGT1A1 * 6 , however, is exclusively present in approximately 10-20% of Asians [13,17]. In this study, which only included Korean patients, the allele frequencies of UGT1A1 * 28 and * 6 were 29 and 10%, respectively, which is consistent with a recent Japanese study [21].…”

“…No further dose escalation was performed for the 0 DA group. This early stop decision was based on previous studies that had shown that 0 DA groups had similar toxicity profiles of irinotecan when compared to the 1 DA groups [13,14]. Only 4 patients were identified and placed in the 2 DA group in this study.…”

“…Only 4 patients were identified and placed in the 2 DA group in this study. The 2 DA group patients remained at level −1 (150 mg/m 2 /2 weeks); a further dose escalation was not performed due to poor enrollment related to a low incidence in the patient population and safety concerns based on a reported DLT rate of 37.4% (6/15) in 2 DA groups in a Japanese phase I study that had similar population characteristics [13]. …”

Correlation of UGT1A1 and ERCC1 gene polymorphisms with the outcome of combined irinotecan plus cisplatin treatment in recurrent ovarian cancer

“…Based on the importance of UGT1A1 protease activity in the metabolism of irinotecan, we analyzed the relevance of UGT1A1 genotypes on the adverse reaction to irinotecan (Satoh et al, 2011). The occurrence rate of degree II to IV delayed diarrhea in UGT1A1*28 WW carriers was 52.2% (National Cancer Institute, 2013), and the incidence rate in WM+MM carriers was 72.7%.…”

Clinical usefulness of testing for UDP glucuronosyltransferase 1 family, polypeptide A1 polymorphism prior to the inititation of irinotecan-based chemotherapy

“…In 2005, the US Food and Drug Administration recommended testing for UGT1A1 * 28 polymorphism for dose regulation of irinotecan. As regards colorectal cancer, studies on the optimal dose of irinotecan for the treatment of patients with low enzyme activity have been conducted (19,20). However, the optimal dose of irinotecan for lung cancer patients with low enzyme activity has not been determined and remains a subject of controversy.…”