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Annals of Oncology 15:1284-1294, 2004
© 2004 European Society for Medical Oncology

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors

Background: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks.

Patients and methods: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules.

Results: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses ≥470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses ≥320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear.

Conclusions: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.

K. Mross1, H. Richly2, N. Schleucher2, S. Korfee2, M. Tewes1, M. E. Scheulen2, S. Seeber2, T. Beinert3, M. Schweigert3, U. Sauer1, C. Unger1, D. Behringer4, E. Brendel5, C. G. Haase5, D. Voliotis5 and D. Strumberg2,*

1 Department of Medical Oncology, Tumor Biology Center at the University of Freiburg; 2 Department of Internal Medicine and Medical Oncology, West German Cancer, University Medical School of Essen; 3 Humboldt University Medical School, Berlin; 4 Department of Hematology and Oncology, University Hospital Freiburg; 5 Bayer Healthcare, Pharma Research Center, Wuppertal, Germany

* Correspondence to: Dr Dirk Strumberg, MD, Department of Internal Medicine (Cancer Research), University Medical School of Essen, Hufelandstraße 55, 45122 Essen, Germany. Tel:+49-201-723-3138; Fax:+49-201-723-3138; Email: dirk.strumberg{at}uni-essen.de

Key words: camptothecin glycoconjugate, phase I, topoisomerase I


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