PHASE-I CLINICAL AND PHARMACOKINETIC STUDY OF TOPOTECAN ADMINISTERED BY A 24-HOUR CONTINUOUS-INFUSION

Purpose: To determine the maximum-tolerable dose (MTD) and to investig ate the pharmacokinetics and pharmacodynamics of topotecan in a phase I study. Topotecan is a novel semisynthetic derivative of the anticanc er agent camptothecin and inhibits the intranuclear enzyme topoisomera se I. Broad preclinical activity rationalized further clinical evaluat ion. Patients and Methods: In this phase I trial, topotecan was admini stered by 24-hour continuous infusion every 21 days to patients with s olid malignant tumors. Results: A total of 25 eligible patients, of wh om 22 were pretreated, entered the study, They received the following dosages of topotecan: 2.5, 3.75, 5.60, 8.4, and 10.5 mg/m(2) by 24-hou r infusion. Reversible leukopenia and thrombocytopenia were dose-limit ing, with mild anemia occurring regularly, Other toxicities, such as a lopecia, mucositis, nausea, and vomiting were sporadic and mild. Respo nses were not observed. However, eight patients had stable disease. Th e plasma concentration-time curves were not compatible with standard l inear pharmacokinetic models, and indications were found for the occur rence of nonlinear (saturation) kinetics at the dosages studied, Concl usion: The recommended dose for phase II studies is 8.4 mg/m(2) when a dministered as a 24-hour infusion, which is well tolerated, Further st udies will be necessary to account for the putative nonlinear behavior of the drug.