Weekly administration of sagopilone (ZK-EPO), a fully synthetic epothilone, in patients with refractory solid tumours: Results of a phase i trial

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Abstract

Background:Epothilones are a novel class of microtubule-stabilising agents, and sagopilone is a fully synthetic epothilone that has shown marked in vivo and in vitro preclinical activity.Methods:This phase I, open-label study investigated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of weekly sagopilone. Twenty-three patients with malignancy resistant or refractory to standard treatment were enrolled into this study evaluating sagopilone doses from 0.6 to 7.0 mg m 2.Results:The incidence of drug-related haematological adverse events (AEs) was low, with two grade 3 events observed. Nonhaematological AEs were generally mild and reversible; increased γ-GT was the only grade 4 event and grade 3 events comprised peripheral neuropathy (n2), diarrhoea (n1) and fatigue (n1). Two grade 3 events were DLTs (diarrhoea and peripheral neuropathy at 7.0 mg m 2). The MTD of weekly sagopilone was therefore established as 5.3 mg m 2. Stable disease was the best overall response (n3). Microtubule bundle formation in peripheral blood mononuclear cells increased post-treatment, peaking after 1 h. Sagopilone disposition was similar across treatment courses and showed rapidly decreasing serum concentrations after infusion end and a long terminal disposition phase with no obvious accumulation in the serum, probably reflecting a fast uptake into tissues followed by a slow release.Conclusion:Weekly administration of sagopilone could represent an alternative to the 3-weekly administration currently evaluated in phase II trials. © 2009 Cancer Research UK All rights reserved.

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Arnold, D., Voigt, W., Kiewe, P., Behrmann, C., Lindemann, S., Reif, S., … Schmoll, H. J. (2009). Weekly administration of sagopilone (ZK-EPO), a fully synthetic epothilone, in patients with refractory solid tumours: Results of a phase i trial. British Journal of Cancer, 101(8), 1241–1247. https://doi.org/10.1038/sj.bjc.6605327

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