Annals of Oncology Advance Access originally published online on January 11, 2007
Annals of Oncology 2007 18(4):782-788; doi:10.1093/annonc/mdl469
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© 2007 European Society for Medical Oncology
phase I and pharmacokinetics |
A phase IB, open-label dose-escalating study of the oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK), in combination with FOLFOX4 chemotherapy in patients with advanced colorectal cancer
1 University of Leicester, Leicester, UK
2 University of Duisburg-Essen Medical School, West German Cancer Center, Essen
3 Charite University Hospital CVK, Berlin
4 Schering AG, Berlin, Germany
5 Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
* Correspondence to: Dr A. L. Thomas, Department of Oncology, Leicester Royal Infirmary, Leicester LE1 5WW, UK. Tel: +44-116-2587602; Fax: +44-116-2587599; E-mail: at107{at}le.ac.uk
Background: This open-label, phase IB study was undertaken to determine the safety/toxicity profile and recommended dose of oral once-daily PTK787/ZK 222584 (PTK/ZK) combined with oxaliplatin/5-fluorouracil (5-FU)/leucovorin (FOLFOX4) chemotherapy in patients with advanced colorectal cancer. Secondary objectives were to assess full pharmacokinetics and gather preliminary evidence of antitumor activity.
Patients and methods: Thirty-five patients received escalating doses of PTK/ZK (range 500–2000 mg daily) continuously. Concurrent FOLFOX4 chemotherapy was administered on days 1 and 2 and repeated every 14 days. Dose escalation of PTK/ZK was continued until maximum tolerated dose (MTD) was established and additional patients were then enrolled at MTD dosage.
Results: Mean treatment duration of PTK/ZK was 9.5 months. The MTD was 1250 mg daily with dizziness being the most frequent dose-limiting toxicity (DLT). Hypertension (23%, grade 3) and neutropenia (37%, grades 3 + 4) were the most frequent grade 3 or 4 adverse events. Pharmacokinetic analyses found no evidence for interactions between PTK/ZK and the combination of 5-FU, leucovorin, and oxaliplatin during concomitant use. Median progression-free survival was 11.4 months.
Conclusion: The MTD of PTK/ZK in combination with FOLFOX4 in this patient population is 1250 mg daily. The combination is feasible and safe and is not associated with significant pharmacokinetic interactions.
Key words: colorectal cancer, FOLFOX4 chemotherapy, phase I, PTK/ZK
Received for publication August 24, 2006. Revision received November 15, 2006. Accepted for publication November 16, 2006.
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