Phase I/II study of FOLFIRI in Japanese patients with advanced colorectal cancer.
OBJECTIVE
This phase I/II study determined the recommended dose of FOLFIRI (irinotecan, infusional 5-fluorouracil and leucovorin) for Japanese patients with advanced colorectal cancer, and evaluated safety at the recommended dose in patients without the UDP-glucuronosyltransferase 1A1*28 allele which caused reduced enzyme expression.


METHODS
The phase I part assessed the maximum tolerated dose of FOLFIRI to determine the recommended doses of irinotecan and infusional 5-fluorouracil. The doses were escalated from 150 to 180 mg/m(2) (irinotecan) and 2000 to 2400 mg/m(2) (5-fluorouracil). UDP-glucuronosyltransferase 1A1*6 and *28, and pharmacokinetics of irinotecan were observationally examined. In the phase II part, patients without the UDP-glucuronosyltransferase 1A1*28 allele received FOLFIRI at the recommended dose to evaluate safety.


RESULTS
Among 15 patients in the phase I part, dose-limiting toxicity (diarrhea) occurred in one patient who received 150 mg/m(2) irinotecan and 2400 mg/m(2) infusional 5-fluorouracil. The respective recommended doses were 180 and 2400 mg/m(2) for irinotecan and infusional 5-fluorouracil, without reaching the maximum tolerated dose. Twenty-five patients received FOLFIRI at the recommended doses. Grade 3 or 4 neutropenia occurred in 44%, and Grade 3 diarrhea in 4%.


CONCLUSIONS
This phase I/II study demonstrates that the recommended doses of irinotecan and infusional 5-fluorouracil in FOLFIRI for Japanese patients with advanced colorectal cancer who do not possess the UDP-glucuronosyltransferase 1A1*28 allele are 180 and 2400 mg/m(2), respectively. Toxicities occurring at the recommended doses are manageable in these patients.
Yamashita
Keishi
K
Department of Medical Oncology, International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan.
Nagashima
Fumio
F
Fujita
Ken-ichi
K
Yamamoto
Wataru
W
Endo
Hisashi
H
Miya
Toshimichi
T
Narabayashi
Masaru
M
Kawara
Kaori
K
Akiyama
Yuko
Y
Ando
Yuichi
Y
Ando
Masahiko
M
Sasaki
Yasutsuna
Y
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D007564:Japan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000099148:UGT1A1 Enzyme
D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D000099148:UGT1A1 Enzyme