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

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 gamma-GT was the only grade 4 event and grade 3 events comprised peripheral neuropathy (n=2), diarrhoea (n=1) and fatigue (n=1). 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 (n=3). 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.

Figure 1

Visualisation of microtubule bundle formation in peripheral blood mononuclear cells in a patient sample from the 7.0 mg m⁻² dose group (A) before treatment, (B) 1 h after drug application and (C) microtubule bundle formation over time with sagopilone treatment before 1 h and 24 h after the first application of sagopilone during the first treatment course.

Figure 2

The mean concentration–time profile of sagopilone administered weekly at 5.3 mg m⁻² over three treatment cycles.