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Phase I and Pharmacologic Study of the Combination of Paclitaxel, Cisplatin, and Topotecan Administered Intravenously Every 21 Days as First-Line Therapy in Patients With Advanced Ovarian Cancer

From the Departments of Medical Oncology and Gynecology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands; Department of Medical Oncology, Medical Spectrum Twente, Enschede, the Netherlands; and SmithKline Beecham Pharmaceuticals, Harlow, United Kingdom.

Address reprint requests to Virginie M.M. Herben, PhD, Department of Pharmacy and Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; email apvhe{at}slz.nl

PURPOSE: To evaluate the feasibility of administering topotecan in combination with paclitaxel and cisplatin without and with granulocyte colony-stimulating factor (G-CSF) support as first-line chemotherapy in women with incompletely resected stage III and stage IV ovarian carcinoma.

PATIENTS AND METHODS: Starting doses were paclitaxel 110 mg/m² administered over 24 hours (day 1), followed by cisplatin 50 mg/m² over 3 hours (day 2) and topotecan 0.3 mg/m²/d over 30 minutes for 5 consecutive days (days 2 to 6). Treatment was repeated every 3 weeks. After encountering dose-limiting toxicities (DLTs) without G-CSF support, the maximum-tolerated dose was defined as 5 µg/kg of G-CSF subcutaneously starting on day 6.

RESULTS: Twenty-one patients received a total of 116 courses at four different dose levels. The DLT was neutropenia. At the first dose level, all six patients experienced grade 4 myelosuppression. G-CSF support permitted further dose escalation of cisplatin and topotecan. Nonhematologic toxicities, primarily fatigue, nausea/vomiting, and neurosensory neuropathy, were observed but were generally mild. Of 15 patients assessable for response, nine had a complete response, four achieved a partial response, and two had stable disease.

CONCLUSION: Neutropenia was the DLT of this combination of paclitaxel, cisplatin, and topotecan. The recommended phase II dose is paclitaxel 110 mg/m² (day 1), followed by cisplatin 75 mg/m² (day 2) and topotecan 0.3 mg/m²/d (days 2 to 6) with G-CSF support repeated every 3 weeks.

Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.

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