Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism.

Abstract

Although individuals carrying the UGT1A1 allele *28 have an increased risk of severe toxicities associated with irinotecan, no phase I study has been conducted based on the polymorphism. This report presents the recommended doses of irinotecan for patients with the respective genotypes. Twenty-seven patients with advanced colorectal cancer were enrolled in this study, and the UGT1A1*28 polymorphism was genotyped before chemotherapy. One course of chemotherapy consisted of irinotecan infused once every 2 weeks at 70, 100, 120, and 150 mg/m(2) at dose levels 1, 2, 3, and 4, respectively, and doxifluridine was administered orally. This treatment continued for at least 12 weeks. The dose-limiting toxicity was determined as grade 3 hematological and non-hematological toxicities for the TA(6)/TA(6) (6/6) and TA(6)/TA(7) (6/7) genotypes. The pharmacokinetics of irinotecan, SN-38, and SN-38 glucuronide, was assessed at dose level 2. Eighteen and nine patients had the 6/6 and 6/7 genotypes, respectively. The maximum tolerated dose (MTD) was not observed up to dose level 4 in patients with the 6/6 genotype. In contrast, MTD was observed at dose level 2 (100 mg/m(2)) in patients with the 6/7 genotype. Patients with the 6/7 genotype had a significantly higher area under the plasma time-concentration curve (0-infinity) SN-38 (P = 0.022) and biliary index (P = 0.030) than those with 6/6. The recommended starting doses of biweekly irinotecan for phase II/III were 150 mg/m(2) for patients with the UGT1A1 6/6 genotype and 70 mg/m(2) for those with the 6/7 genotype, respectively. The gene polymorphism should be considered when determining the precise recommended doses to be administered in phase I studies.

• Authors: Shoichi Hazama, Atsushi Nagashima, Hiroshi Kondo, Shin Yoshida, Ryoichi Shimizu, Atsuhiro Araki, Shigefumi Yoshino, Naoko Okayama, Yuji Hinoda, Masaaki Oka
• Journal: Cancer science (Cancer Sci) Vol. 101 Issue 3 Pg. 722-7 (Mar 2010) ISSN: 1349-7006 [Electronic] England
• PMID: 20028383 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Floxuridine
• Irinotecan
• UGT1A1 enzyme
• Glucuronosyltransferase
• doxifluridine
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives)
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Female
• Floxuridine (administration & dosage)
• Glucuronosyltransferase (genetics)
• Humans
• Irinotecan
• Male
• Middle Aged
• Neoplasm Metastasis
• Polymorphism, Genetic