PHASE-I AND PHARMACOLOGICAL STUDY OF SEQUENTIAL INTRAVENOUS TOPOTECANAND ORAL ETOPOSIDE

We performed a phase I and pharmacological study to determine the maxi mum tolerated dose (MTD) and dose-limiting toxicities (DLT) of a cytot oxic regimen of the novel topoisomerase I inhibitor topotecan in combi nation with the topoisomerase II inhibitor etoposide, and to investiga te the clinical pharmacology of both compounds. Patients with advanced solid tumours were treated at 4-week intervals, receiving topotecan i ntravenously over 30 min on days 1-5 followed by etoposide given orall y twice daily on days 6-12. Topotecan-etoposide dose levels were escal ated from 0.5/20 to 1.0/20, 1.0/40, and 1.25/40 (mg m(-2) day(-1))/(mg bid). After encountering DLT, additional patients were treated at 3-w eek intervals with the topotecan dose decreased by one level to 1.0 mg m(-2) and etoposide administration prolonged from 7 to 10 days to all ow further dose intensification. Of 30 patients entered, 29 were asses sable for toxicity in the first course and 24 for response, The DLT wa s neutropenia. At doses of topotecan-etoposide 1.25/40 (mg m(-2))/(mg bid) two out of six patients developed neutropenia grade IV that laste d more than 7 days, Reduction of the treatment interval to 3 weeks and prolonging etoposide dosing to 10 days did not permit further dose in tensification, as a time delay to retreatment owing to unrecovered bon e marrow rapidly emerged as the DLT. Post-infusion total plasma levels of topotecan declined in a biphasic manner with a terminal half-life of 2.1 +/- 0.3 h, Total body clearance was 13.8 +/- 2.7 l h(-1) m(-2) with a steady-state volume of distribution of 36.7 +/- 6.2 l m(-2). N- desmethyltopotecan, a metabolite of topotecan, was detectable in plasm a and urine. Mean maximal concentrations ranged from 0.23 to 0.53 nmol l(-1), and were reached at 3.4 +/- 1.0 h after infusion. Maximal etop oside plasma concentrations of 0.75 +/- 0.54 and 1.23 +/- 0.57 mu mol l(-1) were reached at 2.4 +/- 1.2 and 2.3 +/- 1.0 h after ingestion of 20 and 40 mg respectively. The topotecan area under the plasma concen tration vs time curve (AUC) correlated with the percentage decrease in white blood cells (WBC) (r(2) = 0.70) and absolute neutrophil count ( AUC) (r(2) = 0.65). A partial response was observed in a patient with metastatic ovarian carcinoma. A total of 64% of the patients had stabl e disease for at least 4 months. The recommended dose for use in phase II clinical trials is topotecan 1.0 mg m(-2) on days 15 and etoposide 40 mg bid on days 6-12 every 4 weeks.