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

Abstract

Purpose: A UGT1A1 genotype-directed dose escalation of irinotecan (CPT-11) was performed in patients with metastatic colorectal cancer receiving first-line FOLFIRI chemotherapy. Methods: Patients were genotyped for UGT1A1 and stratified according to the number of defective alleles (DA; *28 and *6). The irinotecan dose was escalated with a fixed dose of 5-fluorouracil and leucovorin in a standard 3 + 3 design. Results: In 43 enrolled patients, the maximum tolerated dose (MTD) was 300 mg/m² for the 1 DA group, while the MTD was not reached for the 0 DA group with 1 dose-limiting toxicity (DLT) at 330 mg/m² and for the 2 DA group with 0 DLT at 150 mg/m². Because of the risk of being exposed to unsafe doses, the trial was terminated before the MTD was reached in the 0 DA and 2 DA groups. The recommended doses were 300 (0 DA), 270 (1 DA) and 150 (0 DA) mg/m². The 2 DA group displayed 27% lower SN-38 exposure levels relative to the 0 and 1 DA groups (95% CI, 0.47-1.15). Conclusions: The MTD of irinotecan differed according to the UGT1A1 genotype, and higher doses of irinotecan are feasible with sLV5FU2 compared to the present regulatory approved doses. © 2014 S. Karger AG, Basel

UGT1A1 genotype and irinotecan therapy: general review and implementation in routine practice

“…Importantly, investigations performed on Asian populations led to similar conclusions (some of these studies considered the *6 allele along with the*28) [63,64]. The majority of the irinotecan dose-escalation studies combining irinotecan with 5FU (with or without mAbs) have been performed in Caucasian patients.…”

“…Estimation of optimal doses according to genotype may be approximated from the eight clinical dose-escalation studies based on UGT1A1 genotype published so far [57][58][59][60][61][62][63][64]. Estimation of optimal doses according to genotype may be approximated from the eight clinical dose-escalation studies based on UGT1A1 genotype published so far [57][58][59][60][61][62][63][64].…”

UGT1A1 polymorphisms in cancer: impact on irinotecan treatment

“…52–56 Three studies evaluating irinotecan doses in FOLFIRI showed that the maximal tolerated dose (MTD) in patients with *1/*1, *1/*28, and *1/*6 alleles was higher than the standard doses of the FOLFIRI regimen 52–54. The MTD in the *1/*1 patients was also higher than that of patients with *1/*28 and *1/*6 alleles, and the MTD in patients with *28/*28, *6/*6, and *28/*6 alleles was lower than the current standard doses of the FOLFIRI regimen 53,54. In the Asian population, incorporation of UGT1A1*6 in addition to UGT1A1*28 would be needed for the safety of irinotecan-based chemotherapy.…”

Randomized Phase II Trial of CapOX plus Bevacizumab and CapIRI plus Bevacizumab as First-Line Treatment for Japanese Patients with Metastatic Colorectal Cancer (CCOG-1201 Study)

“…Patients with uridine diphosphate glucuronosyltransferase ( UGT ) 1A1 *6 or *28 homozygous genotypes or with UGT1A1 *6 and *28 compound heterozygous genotypes received a lower irinotecan dose of 150 mg/m 2 . Treatment was continued in both arms until any one of the following occurred: disease progression, unacceptable toxicity, deterioration of ECOG performance status to >2, or withdrawal of patient consent.…”