1. Phase I dose-finding and pharmacokinetic trial of irinotecan (CPT-11) administered every two weeks.
- Author
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Rothenberg ML, Kuhn JG, Schaaf LJ, Rodriguez GI, Eckhardt SG, Villalona-Calero MA, Rinaldi DA, Hammond LA, Hodges S, Sharma A, Elfring GL, Petit RG, Locker PK, Miller LL, and von Hoff DD
- Subjects
- Adult, Aged, Antineoplastic Agents, Phytogenic administration & dosage, Camptothecin administration & dosage, Camptothecin analogs & derivatives, Chromatography, High Pressure Liquid, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Granulocyte Colony-Stimulating Factor administration & dosage, Humans, Irinotecan, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms drug therapy, Antineoplastic Agents, Phytogenic pharmacokinetics, Camptothecin pharmacokinetics, Neoplasms metabolism
- Abstract
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 CPT-11; 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-II, 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 14.0 +/- 4.0 l/h/m2 and volume of distribution was 146 +/- 45.9 l/m2., 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-week single-agent CPT-11 therapy.
- Published
- 2001
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