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Phase I Pharmacologic Study of Oral Topotecan and Intravenous Cisplatin: Sequence-Dependent Hematologic Side Effects

From the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, the Netherlands; and SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom.

Address reprint requests to Maja J.A. de Jonge, MD, PhD, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands; email jonge{at}onch.azr.nl

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects.

PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m² either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design.

RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m²/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m²/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence.

CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m²/d PO x 5 preceded by cisplatin 75 mg/m² IV day 1 once every 3 weeks, and topotecan 2.0 mg/m²/d PO followed by cisplatin 75 mg/m² IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

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