Phase I study of the combination of losoxantrone and cyclophosphamide in patients with refractory solid tumours

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 72 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 72 . With granulocyte colonystimulating 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 72 followed by losoxantrone 95 mg m 72 with granulocyte colony-stimulating factor support.

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

“…The probability density The ratio of mean midazolam AUC in presence and in absence of ketoconazole. AUCs of midazolam in presence and in absence of ketoconazole are calculated from clearance of midazolam, which are digitalized from two studies, Yong et al, 2008and Goh et al, 2002, respectively (as reported in Yong et al, 2008.…”

“…A complete search of the literature using the Metabolism and Transport Drug Interaction Database (University of Washington, Seattle, WA) indentified 11 clinical DDI studies and 16 dosage scenarios from 17 published clinical results using midazolam as CYP3A probe (intravenous and oral) and ketoconazole as inhibitor (400 mg QD and 200 mg QD and BID for various durations) as of 2012 (Olkkola et al, 1994;McCrea et al, 1999;Tsunoda et al, 1999;Goh et al, 2002;Lee et al, 2002;Lam et al, 2003;Eap et al, 2004;Chung et al, 2006;Tham et al, 2006;Yong et al, 2008;Krishna et al, 2009;Stoch et al, 2009). The specific treatment regimens of ketoconazole and midazolam used in the literature reports were reproduced in the simulations.…”