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(-1). 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(-1), 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(-1) 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.

• Authors: M J A de Jonge, S Kaye, J Verweij, C Brock, S Reade, M Scurr, L van Doorn, C Verheij, W Loos, C Brindley, P Mistry, M Cooper, I Judson
• Journal: British journal of cancer (Br J Cancer) Vol. 91 Issue 8 Pg. 1459-65 (Oct 18 2004) ISSN: 0007-0920 [Print] England
• PMID: 15452551 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• 4-methoxybenzo(a)phenazine-11-carboxylic acid (2-(dimethylamino)-1-methylethyl)amide
• Enzyme Inhibitors
• Phenazines
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors

Topics

• Administration, Oral
• Adolescent
• Adult
• Aged
• Area Under Curve
• Chromatography, High Pressure Liquid
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacokinetics, therapeutic use)
• Female
• Humans
• Male
• Mass Spectrometry
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, metabolism)
• Phenazines (pharmacokinetics, therapeutic use)
• Topoisomerase I Inhibitors
• Topoisomerase II Inhibitors