A phase I dose escalation study of the pharmacokinetics and tolerability of ZK 304709, an oral multi-targeted growth inhibitor (MTGI™), in patients with advanced solid tumours

Purpose: The toxicities, pharmacokinetics and recommended dose of oral once daily ZK 304709, a novel multi-targeted growth inhibitor (MTGI™) with activity against cell-cycle progression and angiogenesis, was investigated in patients by administration for 14 consecutive days followed by 14 days recovery. Methods: Patients with solid tumours resistant to standard treatments were enrolled in an accelerated titration design. Results: Thirty-seven patients received ZK 304709 from 15 to 285 mg daily. The most common drug-related adverse events were vomiting, diarrhoea and fatigue. Systemic exposure to ZK 304709 increased with dose up to 90 mg daily but plateaued thereafter, with high inter-individual variability at all doses. Thirteen patients had stable disease as best response as per RECIST criteria. Conclusions: There was no increase in exposure to ZK 304709 with dose escalation above 90 mg, and the MTD was not determined. This study illustrates the importance of phase I pharmacokinetic data to guide dose escalation and drug development.