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Annals of Oncology 12:549-555, 2001
© 2001 European Society for Medical Oncology

research-article

Phase I dose escalation study of topotecan combined with alternating schedules of paclitaxel and carboplatin in advanced solid tumors

F. R. Dunphy, T. L. Dunleavy, B. R. Harrison, C. L. Cantrell, J. L. Visconti, S. M. Pincus, J. M. Richart and P. J. Petruska

Division of Hematology and Oncology, Department of Internal Medicine, Saint Louis Universit Health Sciences Center St Louis, Missouri, USA

Correspondence to: F Dunphy, MD, Saint Louis University Health Sciences Center, Division of Hematology and Oncology, Department of Internal Medicine, 3635 Vista Avenue at Grand Blvd, P O Box 15250, St Louis, MO 63110-0250, USA, E-mail dunphyfr{at}aol.com

Background Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximumtolerated dose of topotecan in combination with pachtaxel and carboplatin

Patients and methods Patients with advanced cancer and performance status ECOG ≤ 2 The starting dose was paclitaxel 175 mg/m2 day 1, carboplatin AUC 6 0 day 1, and topotecan 0 5 mg/m2 daily day 1–5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued

Results Fifty-one patients were entered men women ratio 30. 21 Dose-limiting toxicity (DLT) for the early sequence was neutropenia at doses paclitaxel mg/m2/carboplatin AUC5/ topotecan mg/m2 (PCT) 175/5/0 75 for four to five days DLT for the late sequence was neutropenia at PCT doses of 175/5/ 10 for four days G-CSF 5 µg/kg subcutaneously starting day 6 permitted further topotecan dose escalation After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1 25 for four days Forty-six patients were evaluable for response and of those, there were thirteen partial responses

Conclusions The late sequence resulted in less toxicity and was better tolerated The early sequence maximum-tolerated dose (MTD) was 175/6/0 5 for five days The late sequence MTD was PCT 175/5/0.75 for five days The late sequence MTD with G-CSF was 175/5/1 0 for four days The recommended phase II PCT dose is the late sequence 175/5/10 for four days with G-CSF

carboplatin, hycamtin, paclitaxel, phase I, Taxol, topotecan


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