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)

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-limiting toxicity occur. Results: ZK 304709 was safely administered up to 360 mg. However, above 90 mg blood concentrations increased only slightly. As this dose was not deemed likely to result in meaningful 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 pharmacodynamic 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. (c) 2008 Elsevier Ltd. All rights reserved.