Phase I and pharmacokinetic study of XR11576, an oral topoisomerase I and II inhibitor, administered on days 1–5 of a 3-weekly cycle in patients with advanced solid tumours

Abstract

XR11576 is an oral topoisomerase I and II inhibitor. The objectives of this phase I study were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to describe the pharmacokinetics (PKs) of XR11576 when administered orally on days 1 -5 every 3 weeks to patients with advanced solid tumours. Patients were treated with escalating doses of XR11576 at doses ranging from 30 to 180 mg day À1 . For PK analysis, plasma sampling was performed during the first and second courses of treatment and XR11576 concentrations were assayed using a validated high-performance liquid chromatographic assay with mass spectrometric detection. In all, 21 patients received a total of 47 courses. The MTD was reached at 180 mg day À1 , with diarrhoea and fatigue as DLT. Nausea and vomiting, although not qualifying for DLT, was ubiquitous. Only in combination with an extensive prophylactic antiemetic regimen consisting of a combination of both dexamethasone and a 5HT3 antagonist was treatment with XR11576 at 120 mg day À1 tolerable. The systemic exposure of XR11576 increased more than proportionally with increasing dose, with a large interpatient variability. No objective responses were seen; four patients experienced stable disease for periods of 12 -30 weeks. In this study, the DLTs of XR11576 were diarrhoea and fatigue. The recommended dose for phase II studies of XR11576 is 120 mg administered orally, on days 1 -5 every 21 days. Alternative regimens are currently being explored.

Recent Advances in the Development of Dual Topoisomerase I and II Inhibitors as Anticancer Drugs

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Benzoquinazoline derivatives as new agents affecting DNA processing

“…1) has entered clinical trials. 10 Finally, similar profile was found for TAS-103 (4, Fig. 1), initially identified as dual inhibitor, 11 although it predominantly acts as a topoIIa inhibitor.…”

Phenazine as an Anticancer Agent

“…Further investigation on the role of topoisomerase inhibition in the mechanism of action of 33, demonstrated that exposure of 33 results in accumulation of topoisomerase I-and II-DNA complexes after long periods, which coincides with the induction of gamma-H2AX foci as a marker for DNA damage (Jobson et al 2009). Although 33 reached Phase I clinical trial in 2004, (de Jonge et al 2004) it was not further pursued because some dimeric phenazine (as XR5944.14 for example) displayed higher activity and therapeutic ratio as detailed below.…”