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

Summary Objectives This trial was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetic profile of irinotecan (CPT-11) when administered on a once-every-2-week schedule Patients and methods CPT-11 was administered to successive cohorts of patients at progressively increasing starting doses ranging from 125 to 350 mg/m2 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 first 24 hours after initial dosing to determine the total concentrations (lactone + carboxylate forms) of CPT11, of the active metabolite SN-38, and of SN-38 glucuronide (SN-38G) Results Neutropenic fever was the DLT for CPT-11 at the 300 mg/m2 dose level When G-CSF was added, dose escalation beyond 350 mg/m2 could not be achieved due to grade 2-3 toxicities that prevented on-time retreatment with 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 harmonic 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 observed between CPT-11 or SN-38 peak concentration or AUC and first-cycle diarrhea, neutropenia. nausea, or vomiting Across the range of doses studied, mean CPT-11 clearance was 140 ± 40 1/h/m2 and volume of distribution was 146 ± 45 9 1/m 2 Conclusions When administered every two weeks, the recommended phase II starting dose of CPT-11 is 250 mg/m2 when given alone and 300 mg/m2 when supported by G-CSF This every-two-week regimen offers a tolerable and active alternative to weekly or every-three-w eek single-agent CPT-11 therapy