UFT/leucovorin plus irinotecan in advanced or metastatic colorectal cancer

UFT (with leucovorin) and irinotecan both have single-agent activity in col orectal cancer, with non-cross-resistant mechanisms of action, Combining th ese drugs would be anticipated to increase response rates while maintaining the advantages of a regimen based on art orally administered fluoropyrimid ine, This trial aims to determine the maximum tolerated dose, side-effect p rofile, dose-limiting toxicity, and response rate for the combination of UF T plus leucovorin, and irinotecan, The design is for an initial phase I stu dy investigating escalating doses of UFT (250 to 350 mg/m(2)/d) and irinote can (200 to 300 mg/m(2)) with fixed doses of leucovorin at 90 mg/d, in up t o five cohorts of six patients each. UFT and leucovorin are given orally on days 1 to 14 of a 21-day cycle and irinotecan is given intravenously on da y 1. The maximum tolerated dose is defined as the dose at which three of si x patients in a cohort have a dose-limiting toxicity irt the first cycle of treatment, In the second part of the study, the cohort below that experien cing maximum tolerated dose will be expanded up to a total of 20 patients i n order to assess further the toxicity and response rate (phase II). To dat e, 17 assessable patients have been recruited with a medium age of 64 years (range: 35-80 years). At the first dose level (UFT 250 mg/m(2)/d and irino tecan 200 mg/m(2)), no dose-limiting toxicities were seen, and in cohort 2 (UFT 250 mg/m(2)/d and irinotecan 250 mg/m(2)), there was one grade 3 diarr hea. In cohort 3 (UFT 250 mg/m(2)/d and irinotecan 300 mg/m(2)), currently there have been two grade 3/4 toxicities (both neutropenic fever), Thus, th e maximum tolerated dose has not yet been reached. Response has been assess ed in the first six patients, with three having partial response, two havin g stable disease, and one having progressive disease (response rate 50%). W e conclude that this regimen appears feasible with acceptable toxicity at t hese dose levels. There is also evidence of significant antitumor activity similar to that seen with other fluoropyrimidine-based combination regimens but without the requirement for indwelling catheters or inpatient admissio n.