Annals of Oncology Advance Access published online on January 11, 2007
Annals of Oncology, doi:10.1093/annonc/mdl469
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© 2007 European Society for Medical Oncology
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.
colorectal cancer, FOLFOX4 chemotherapy, phase I, PTK/ZK
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