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01-06-2013 | Original Article

A UGT1A128 and 6 genotype-directed phase I dose-escalation trial of irinotecan with fixed-dose capecitabine in Korean patients with metastatic colorectal cancer

Authors: Kyu-pyo Kim, Ho-Sook Kim, Sun Jin Sym, Kyun Seop Bae, Yong Sang Hong, Heung-Moon Chang, Jae Lyun Lee, Yoon-Koo Kang, Jung Shin Lee, Jae-Gook Shin, Tae Won Kim

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2013

Abstract

Purpose

UGT1A1 genotypes are important when considering treatment with irinotecan-containing regimens. In this study, we determined the dose, efficacy, and tolerability of irinotecan according to UGT1A1 genotypes when combined with capecitabine in patients with metastatic colorectal cancer.

Methods

Patients with histologically confirmed metastatic adenocarcinoma of the colon or rectum were enrolled into a UGT1A1 genotype-directed dose-escalation trial of irinotecan plus fixed-dose capecitabine (2,000 mg/m²/day). The starting dose of irinotecan was different for each genotype group and ranged from 200 to 280 mg/m². Pharmacokinetic concentrations of irinotecan and metabolites were determined by LC/MS/MS.

Results

Fifty patients were genotyped for UGT1A1 *28 and *6, and grouped according to the numbers of defective alleles (DA): 0, 1, and 2. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured. The maximum tolerated dose of irinotecan was 350 mg/m² for the 0 and 1 DA groups, and 200 mg/m² for the 2 DA group. For the 0, 1, and 2 DA groups, mean AUC_last ratios of SN-38G to SN-38 were 7.72, 5.71, and 2.72 (P = 0.0023) and relative dose intensities at recommended dose were 85, 83, and 97 %.

Conclusion

Irinotecan dosing based on UGT1A1*28 and *6 is feasible, and higher doses of irinotecan can be safely administered in patients with 0 or 1 DA, compared to those with 2 DA.

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Title: A UGT1A1*28 and *6 genotype-directed phase I dose-escalation trial of irinotecan with fixed-dose capecitabine in Korean patients with metastatic colorectal cancer
Authors: Kyu-pyo Kim
Ho-Sook Kim
Sun Jin Sym
Kyun Seop Bae
Yong Sang Hong
Heung-Moon Chang
Jae Lyun Lee
Yoon-Koo Kang
Jung Shin Lee
Jae-Gook Shin
Tae Won Kim
Publication date: 01-06-2013
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 6/2013
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2161-6

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