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Clinical Phase I Dose Escalation and Pharmacokinetic Study of High-Dose Chemotherapy with Treosulfan and Autologous Peripheral Blood Stem Cell Transplantation in Patients with Advanced Malignancies¹

Department of Internal Medicine (Cancer Research) and Department of Gynecology and Obstetrics, West German Cancer Center, University of Essen Medical School, D-45122 Essen [M. E. S., R. A. H., C. O., A. H., P. B., A. E. S., S. S.]; Department of Hematology and Oncology, University of Rostock, D-18055 Rostock [J. C., M. F.]; Deutsche Klinik für Diagnostik, D-65191 Wiesbaden [K. M. J.]; Department of Hematology and Oncology, Technical University Dresden, D-01307 Dresden [M. B., G. E.]; Department of Internal Medicine, University of Münster, D-48149 Münster [W. E. B.]; Medac GmbH, D-20354 Hamburg [J. B.]; Department of Hematology and Oncology, University of Halle-Wittenberg, D-06097 Halle [H-H. W.], Germany

ABSTRACT

A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m², and pharmacokinetic parameters were analyzed. At 56 g/m², three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m² treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m². A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.

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