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). UDPglucuronosyltransferase 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