Clinical

British Journal of Cancer (2004) 91, 1459–1465. doi:10.1038/sj.bjc.6602178 www.bjcancer.com
Published online 28 September 2004

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

M J A de Jonge1, S Kaye2, J Verweij1, C Brock2, S Reade2, M Scurr2, L van Doorn1, C Verheij1, W Loos1, C Brindley3, P Mistry4, M Cooper5 and I Judson2

  1. 1Department of Medical Oncology, Erasmus Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
  2. 2Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
  3. 3Quintiles Limited, Research Avenue South, Heriot Watt University, Research Park, Riccarton, Edinburgh, EH14 4AP, UK
  4. 4Xenova Limited, 957 Buckingham Ave, Slough, SL1 4NL, UK
  5. 5Millennium Pharmaceuticals Inc, 350 Massachusetts Avenue, Cambridge, MA 02139, USA

Correspondence: Dr MJA de Jonge, E-mail: m.dejonge@erasmusmc.nl

Received 13 May 2004; Revised 28 July 2004; Accepted 29 July 2004; Published online 28 September 2004.

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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.

Keywords:

XR11576, topoisomerase I inhibitor, phase I, solid tumours, oral