1. ¹Department of Medicine, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Avenue, Illinois, IL 60637, USA
2. ²Cancer Research Center, University of Chicago, 5841 S. Maryland Avenue, Illinois, IL 60637, USA
3. ³Committee on Clinical Pharmacology, University of Chicago, 5841 S. Maryland Avenue, Illinois, IL 60637, USA
4. ⁴Clinical and Experimental Pharmacology, Genentech Inc., 532 Forbes Blvd, San Francisco, California, CA 94080, USA

Correspondence: E E Vokes, E-mail: evokes@medicine.bsd.uchicago.edu

⁵Current address: National University Hospital, Singapore

Received 13 August 2001; Revised 26 November 2001; Accepted 5 December 2001.

Abstract

Losoxantrone is a DNA intercalator that was developed with the potential to replace anthracyclines. The recommended single agent dose of losoxantrone is 50 mg m^-2 every 3 weeks. We conducted a phase I study of losoxantrone and a fixed dose of cyclophosphamide on a q3 weekly schedule. Forty-nine patients were enrolled, of which 46 were evaluable for toxicity. The dose-limiting toxicity was neutropenia at the maximum tolerable losoxantrone dose of 45 mg m^-2. With granulocyte colony-stimulating factor support, significant further dose escalation of losoxantrone was achieved. Cardiotoxicity was seen with cumulative dosing. Pharmacokinetics of losoxantrone revealed linear kinetics and triphasic clearance, with significant interpatient variability. No objective responses were seen in this study. Neutropenia was dose-limiting in this combination with or without granulocyte colony-stimulating factor support. The recommended dose for further testing is cyclophosphamide 500 mg m^-2 followed by losoxantrone 95 mg m^-2 with granulocyte colony-stimulating factor support.