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Published in: Trials 1/2016

Open Access 01-12-2016 | Study protocol

Prospective analysis of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab plus FOLFIRI as the first-line setting: study protocol for a randomized controlled trial

Authors: Yung-Sung Yeh, Hsiang-Lin Tsai, Ching-Wen Huang, Jui-Ho Wang, Yi-Wen Lin, Hsiu-Chih Tang, Yung-Chuan Sung, Chang-Chieh Wu, Chien-Yu Lu, Jaw-Yuan Wang

Published in: Trials | Issue 1/2016

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Abstract

Background

Irinotecan is approved and widely administered to metastatic colorectal cancer (mCRC) patients; however, it can cause severe toxicities including neutropenia and diarrhea. The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of cancer patients to chemotherapy toxicity. Therefore, we plan to explore the effect of the genetic polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) for irinotecan detoxification in mCRC patients. This trial will compare the clinical outcomes and side effects observed in mCRC patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with and without UGT1A1 genotyping and irinotecan dose escalation. A total of 400 mCRC patients were randomized into a study group and a control group.

Methods/Design

This trial is a prospective, multicenter, randomized clinical trial comparing UGT1A1 promoter polymorphism for irinotecan dose escalation in mCRC patients administered with bevacizumab plus FOLFIRI as the first-line setting. The enrolled patients were randomly assigned to one of two groups, a study group and a control group, on the basis of receiving UGT1A1 genotyping or not. The study group receive a biweekly FOLFIRI regimen, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receive the conventional biweekly FOLFIRI regimen without UGT1A1 genotyping. The clinicopathological features, response rates, toxicity, and progression-free survival or overall survival will be compared between the two groups.

Discussion

Patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to comparable toxicities. Such personalized medicine based on genotyping may be feasible for clinical practice.

Trial registration

NCT02256800. Date of registration: 3 October 2014. Date of first patient randomized: 16 January 2015
Literature
1.
Ishida H, Fujita K, Akiyama Y, Sunakawa Y, Yamashita K, Mizuno K, et al. Regimen selection for first-line FOLFIRI and FOLFOX based on UGT1A1 genotype and physical background is feasible in Japanese patients with advanced colorectal cancer. Jpn J Clin Oncol. 2011;41:617–23.CrossRefPubMed
2.
Cecchin E, Innocenti F, D'Andrea M, Corona G, De Mattia E, Biason P, et al. Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. J Clin Oncol. 2009;27:2457–65.CrossRefPubMed
3.
Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343:905–14.CrossRefPubMed
4.
Douillard JY, Cunningham D, Roth AD, Navarro M, James RD, Karasek P, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041–7.CrossRefPubMed
5.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.CrossRefPubMed
6.
Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.CrossRefPubMed
7.
Peeters M, Price T. Biologic therapies in the metastatic colorectal cancer treatment continuum – applying current evidence to clinical practice. Cancer Treat Rev. 2012;38:397–406.CrossRefPubMed
8.
Lu CY, Huang CW, Hu HM, Tsai HL, Huang CM, Yu FJ, et al. Prognostic advantage of irinotecan dose escalation according to uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping in patients with metastatic colorectal cancer treated with bevacizumab combined with 5-fluorouracil/leucovorin with irinotecan in a first-line setting. Transl Res. 2014;164:169–76.CrossRefPubMed
9.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.CrossRefPubMed
10.
Marcuello E, Páez D, Paré L, Salazar J, Sebio A, del Rio E, et al. A genotype-directed phase I-IV dose-finding study of irinotecan in combination with fluorouracil/leucovorin as first-line treatment in advanced colorectal cancer. Br J Cancer. 2011;105:53–7.CrossRefPubMedPubMedCentral
11.
Wang M, Sun DF, Wang S, Qing Y, Chen S, Wu D, et al. Polymorphic expression of UDP-glucuronosyltransferase UGTlA gene in human colorectal cancer. PLoS One. 2013;8:e57045.CrossRefPubMedPubMedCentral
12.
Maitland ML, Grimsley C, Kuttab-Boulos H, Witonsky D, Kasza KE, Yang L, et al. Comparative genomics analysis of human sequence variation in the UGT1A gene cluster. Pharmacogenomics J. 2006;6:52–62.CrossRefPubMed
13.
Thomas SS, Li SS, Lampe JW, Potter JD, Bigler J. Genetic variability, haplotypes, and htSNPs for exons 1 at the human UGT1A locus. Hum Mutat. 2006;27:717.CrossRefPubMed
14.
Tang KS, Chiu HF, Chen HH, Eng HL, Tsai CJ, Teng HC, et al. Link between colorectal cancer and polymorphisms in the uridine-diphosphoglucuronosyltransferase 1A7 and 1A1 genes. World J Gastroenterol. 2005;11:3250–4.CrossRefPubMedPubMedCentral
15.
Kim KP, Hong YS, Lee JL, Bae KS, Kim HS, Shin JG, et al. A phase I study of UGT1A1 *28/*6 genotype-directed dosing of irinotecan (CPT-11) in Korean patients with metastatic colorectal cancer receiving FOLFIRI. Oncology. 2015;88:164–72.CrossRefPubMed
16.
Sunakawa Y, Ichikawa W, Fujita K, Nagashima F, Ishida H, Yamashita K, et al. UGT1A1*1/*28 and *1/*6 genotypes have no effects on the efficacy and toxicity of FOLFIRI in Japanese patients with advanced colorectal cancer. Cancer Chemother Pharmacol. 2011;68:279–84.CrossRefPubMed
17.
Maeda H, Hazama S, Shavkat A, Okamoto K, Oba K, Sakamoto J, et al. Differences in UGT1A1, UGT1A7, and UGT1A9 polymorphisms between Uzbek and Japanese populations. Mol Diagn Ther. 2014;18:333–42.CrossRefPubMedPubMedCentral
18.
Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: updated results from the BICC-C study. J Clin Oncol. 2008;26:689–90.CrossRefPubMed
19.
Ribero D, Wang H, Donadon M, Zorzi D, Thomas MB, Eng C, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. 2007;110:2761–7.CrossRefPubMed
Metadata
Title
Prospective analysis of UGT1A1 promoter polymorphism for irinotecan dose escalation in metastatic colorectal cancer patients treated with bevacizumab plus FOLFIRI as the first-line setting: study protocol for a randomized controlled trial
Authors
Yung-Sung Yeh
Hsiang-Lin Tsai
Ching-Wen Huang
Jui-Ho Wang
Yi-Wen Lin
Hsiu-Chih Tang
Yung-Chuan Sung
Chang-Chieh Wu
Chien-Yu Lu
Jaw-Yuan Wang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Trials / Issue 1/2016
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-016-1153-3

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