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

Objectives:This trial was performed to determine themaximum tolerated dose (MTD), dose-limiting toxicity (DLT), andpharmacokinetic profile of irinotecan (CPT-11) when administered on aonce-every-2-week schedule.Patients and methods:CPT-11was administered to successive cohorts of patients at progressivelyincreasing starting doses ranging from 125 to 350 mg/m². TheMTD and DLTs were determined both for CPT-11 alone and for CPT-11followed by filgrastim (G-CSF). Plasma samples were obtained during thefirst 24 hours after initial dosing to determine the totalconcentrations (lactone + carboxylate forms) of CPT-11; of theactive metabolite SN-38; and of SN-38 glucuronide (SN-38G).Results:Neutropenic fever was the DLT for CPT-11 atthe 300 mg/m² dose level. When G-CSF was added, doseescalation beyond 350 mg/m² could not be achieved due tograde 2–3 toxicities that prevented on-time retreatment withCPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasmaconcentrations of SN-38 and SN-38G were approximately 2.5% and4.2% 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. Nopredictive correlation was observed between CPT-11 or SN-38 peakconcentration or AUC and first-cycle diarrhea, neutropenia, nausea, orvomiting. Across the range of doses studied, mean CPT-11 clearance was14.0 ± 4.0 l/h/m² and volume of distribution was 146± 45.9 l/m².Conclusions:Whenadministered every two weeks, the recommended phase II starting dose ofCPT-11 is 250 mg/m² when given alone and 300 mg/m²when supported by G-CSF. This every-two-week regimen offers a tolerableand active alternative to weekly or every-three-week single-agent CPT-11therapy.