A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin

Background: Irinotecan (CPT-11) and 5–fluorouracil (5–FU)/leucovorin are active agents in colorectal cancer. A sequence-dependent synergism of SN–38 followed by 5–FU/leucovorin in vitro led us to conduct a phase I trial of CPT–11 followed by 5–FU/leucovorin to determine the maximum tolerated dose (MTD) and toxicities of this regimen and to obtain preliminary indications of its activity in patients with advanced solid tumors. Patients and methods: Fifty-six patients were enrolled in sequential cohorts to receive escalating doses of CPT–11 (90 min infusion) on day 1, followed by leucovorin 20 m/m² (intravenous push) and 5–FU (90 min infusion) on days 2–5 of each 21–day cycle. Results: A total of 347 treatment cycles (median 4, range 1–25) were administered. Dose-limiting toxicities were diarrhea, neutropenia and fatigue. Nine patients with colorectal cancer and one with gastric cancer had partial or minor responses. Eight of the 10 had prior chemotherapy. Conclusions: CPT–11 and 5–FU/leucovorin, as constituents of this novel mechanism-based schedule, have promising activity in patients who have received prior chemotherapy. The recommended phase II/III starting doses are CPT–11 275 mg/m² over 90 min on day 1, and 5–FU 400 mg/m² plus leucovorin 20 mg/m² on days 2–5 every 21 days. This combination can be administered safely to this schedule if there is strict adherence to the 90 min infusion time for both CPT–11 and 5–FU.