Phase I study of irinotecan and doxifluridine for metastatic colorectal cancer focusing on the UGT1A1*28 polymorphism.
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.
Hazama
Shoichi
S
Department of Digestive Surgery and Surgical Oncology (Surgery II), Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. hazama@yamaguchi-u.ac.jp
Nagashima
Atsushi
A
Kondo
Hiroshi
H
Yoshida
Shin
S
Shimizu
Ryoichi
R
Araki
Atsuhiro
A
Yoshino
Shigefumi
S
Okayama
Naoko
N
Hinoda
Yuji
Y
Oka
Masaaki
M
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D005467:Floxuridine; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme; C025034:doxifluridine