Clinical Study

British Journal of Cancer (2005) 93, 1222–1229. doi:10.1038/sj.bjc.6602850 www.bjcancer.com
Published online 25 October 2005

Phase I and pharmacological study of the farnesyltransferase inhibitor tipifarnib (Zarnestra®, R115777) in combination with gemcitabine and cisplatin in patients with advanced solid tumours

W S Siegel-Lakhai1, M Crul1, S Zhang2, R W Sparidans3, D Pluim1, A Howes2, B Solanki2, J H Beijnen1,3 and J H M Schellens1,3

  1. 1The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
  2. 2Johnson & Johnson Pharmaceutical Research & Development, PO Box 300, Raritan, NJ, USA
  3. 3Faculty of Pharmaceutical Sciences, Division of Drug Toxicology, Department of Biomedical Analysis, University Utrecht, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands

Correspondence: Dr WS Siegel-Lakhai1, Department of Medical Oncology/Department of Pharmacy and pharmacology, Louwesweg 6, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: apwla@slz.nl

Received 24 August 2005; Revised 29 September 2005; Accepted 30 September 2005; Published online 25 October 2005.

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Abstract

This phase I trial was designed to determine the safety and maximum tolerated dose (MTD) of tipifarnib in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Furthermore, the pharmacokinetics of each of these agents was evaluated. Patients were treated with tipifarnib b.i.d. on days 1–7 of each 21-day cycle. In addition, gemcitabine was given as a 30-min i.v. infusion on days 1 and 8 and cisplatin as a 3-h i.v. infusion on day 1. An interpatient dose-escalation scheme was used. Pharmacokinetics was determined in plasma and white blood cells. In total, 31 patients were included at five dose levels. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia grade 4, neutropenia grade 4, febrile neutropenia grade 4, electrolyte imbalance grade 3, fatigue grade 3 and decreased hearing grade 2. The MTD was tipifarnib 200 mg b.i.d., gemcitabine 1000 mg m-2 and cisplatin 75 mg m-2. Eight patients had a confirmed partial response and 12 patients stable disease. No clinically relevant pharmacokinetic interactions were observed. Tipifarnib can be administered safely at 200 mg b.i.d. in combination with gemcitabine 1000 mg m-2 and cisplatin 75 mg m-2. This combination showed evidence of antitumour activity and warrants further evaluation in a phase II setting.

Keywords:

farnesyltransferase inhibitor, phase I study, pharmacokinetics