Abstract
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.
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References
Shapiro GI (2006) Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 24:1770–1782
Benson C, White J, De Bono J et al (2007) A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer 96:29–37
Van Veldhuizen PJ, Faulkner JR, Lara PN et al (2005) A phase II study of flavopiridol in patients with advanced renal cell carcinoma: results of Southwest Oncology Group Trial 0109. Cancer Chemother Pharmacol 56:39–45
Folkman J (1971) Tumour angiogensis: therapeutic implications. N Engl J Med 285:1182–1186
Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342
Siemeister G, Luecking U, Wagner C et al (2006) Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709. Biomed Pharmacother 60:269–272
Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216
Graham JS, Plummer R, McCoy C et al (2008) 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). Eur J Cancer 44:2162–2168
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Scott, E.N., Thomas, A.L., Molife, L.R. et al. 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. Cancer Chemother Pharmacol 64, 425–429 (2009). https://doi.org/10.1007/s00280-009-0968-y
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DOI: https://doi.org/10.1007/s00280-009-0968-y