Phase I dose-finding and pharmacokinetic trial of irinotecan (CPT-11) administered every two weeks

Objectives: This trial was performed to determine the maximum tolerated dos e (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of irino tecan (CPT-11) when administered on a once-every-2-week schedule. Patients and methods: CPT-11 was administered to successive cohorts of pati ents at progressively increasing starting doses ranging from 125 to 350 mg/ m(2). The MTD and DLTs were determined both for CPT-11 alone and for CPT-11 followed by filgrastim (G-CSF). Plasma samples were obtained during the fi rst 24 hours after initial dosing to determine the total concentrations (la ctone + carboxylate forms) of CPT-11; of the active metabolite SN-38; and o f SN-38 glucuronide (SN-38G). Results: Neutropenic fever was the DLT for CPT-11 at the 300 mg/m(2) dose l evel. When G-CSF was added, dose escalation beyond 350 mg/m(2) could not be achieved due to grade 2-3 toxicities that prevented on-time retreatment wi th CPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasma concentrations of SN-38 and SN-38G were approximately 2.5% and 4.2% of the corresponding peak plasma concentration for CPT-11, respectively. The harm onic mean terminal half-lives for CPT-11, SN-38, and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. No predictive correlation was ob served between CPT-11 or SN-38 peak concentration or AUC and first-cycle di arrhea, neutropenia, nausea, or vomiting. Across the range of doses studied , mean CPT-11 clearance was 14.0 +/- 4.0 l/h/m(2) and volume of distributio n was 146 +/- 45.9 l/m(2). Conclusions: When administered every two weeks, the recommended phase II st arting dose of CPT-11 is 250 mg/m(2) when given alone and 300 mg/m(2) when supported by G-CSF. This every-two-week regimen offers a tolerable and acti ve alternative to weekly or every-three-week single-agent CPT-11 therapy.