Open-label, non-randomised, inter-individual dose escalation of ZK 304709 with the evaluation of safety, tolerability, pharmacokinetics, oral bioavailability and orientating efficacy after daily administration in patients with advanced cancer (7 d treatment and 14 d recovery) Janet S. Graham a, * , Ruth Plummer b , Candice McCoy c , Kristin Kowal d , Herbert Wiesinger d , Katharina Detjen e , Hilary Calvert b , Bertram Wiedenmann e , Jim Cassidy a a Cancer Research UK, Department of Medical Oncology, University of Glasgow, Glasgow G61 1BD, UK b Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle, UK c Bayer HealthCare Pharmaceuticals, Seattle, WA, USA d Bayer Schering Pharma AG, D 13342 Berlin, Germany e Campus Virchow-Klinikum Medical Clinic – Hepatology and Gastroenterology, Humboldt University Berlin, D-13353 Berlin, Germany ARTICLE INFO Article history: Received 5 June 2008 Accepted 9 June 2008 Available online 22 July 2008 Keywords: ZK 304709 Phase I Cell cycle arrest Apoptosis induction Angiogenesis inhibitor ABSTRACT Purpose: The primary objectives of this study were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of ZK 304709, a novel multi-targeted growth inhibitor (MTGI TM ), in man. Secondary end-points included safety evaluation, tolerability, pharmacokinetic profiling and assessment of response using standard and novel surrogate pharmacodynamic end-points. Materials and methods: Patients (n = 40) with advanced solid malignancies were treated with ZK 304709, administered orally once daily for 7 d with 14 d recovery. Doses were escalated in sequential cohorts of three patients with expansion to 6–7 patients should a dose-limit- ing toxicity occur. Results: ZK 304709 was safely administered up to 360 mg. However, above 90 mg blood con- centrations increased only slightly. As this dose was not deemed likely to result in mean- ingful pharmacologic or clinical activity, the trial was stopped before the MTD was ascertained. It was therefore not possible to make a reliable assessment of efficacy or phar- macodynamic end-points. Conclusions: Due to the lack of further increment in blood concentrations above a dose of 90 mg, which was felt from previous animal studies to be unlikely to result in meaningful pharmacologic or clinical activity, this study was stopped early. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction ZK 304709 is a first-in class oral Multi-Target Tumour Growth Inhibitor (MTGI TM ) that blocks tumour cell proliferation and induces apoptosis via inhibition of cell-cycle progression and tumour-induced angiogenesis. It inhibits cyclin-depen- dent kinases (CDKs) 1, 2, 4, 7 and 9; vascular endothelial 0959-8049/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2008.06.006 * Corresponding author: Tel.: +44 7811347958; fax: +44 2083835830. E-mail address: j.graham@imperial.ac.uk (J.S. Graham). EUROPEAN JOURNAL OF CANCER 44 (2008) 2162 – 2168 available at www.sciencedirect.com journal homepage: www.ejconline.com