Annals of Oncology Advance Access originally published online on February 10, 2005
Annals of Oncology 2005 16(4):558-565; doi:10.1093/annonc/mdi118
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© 2005 European Society for Medical Oncology
Original articles |
Soluble markers for the assessment of biological activity with PTK787/ZK 222584 (PTK/ZK), a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor in patients with advanced colorectal cancer from two phase I trials
1 Tumor Biology Center, Freiburg; 2 ProQuinase GmbH, Freiburg, Germany; 3 Translational and Clinical Development, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 4 Preclinical Research, Novartis Pharma, Basel, Switzerland; 5 Leceister Royal Infirmary Hospital, Leicester, UK; 6 Schering AG, Berlin, Germany
* Correspondence to: Dr J. Drevs, Tumor Biology Center, Department of Medical Oncology, Breisacherstrasse 117, 79106 Freiburg, Germany. Tel: +49-761-206-2178; Fax: +49-761-206-2180; Email: drevs{at}tumorbio.uni-freiburg.de
Background: Plasma and serum biomarkers of angiogenesis and activated endothelial cells were evaluated to assess biological activity of PTK787/ZK 222584 (PTK/ZK), a novel oral angiogenesis inhibitor targeting all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases.
Patients and methods: Patients with colorectal cancer (CRC) (n=63) were enrolled into two phase I/II dose escalation trials of PTK/ZK in 28-day cycles until discontinuation. Patients with stable disease for 
2 months were categorized as ‘non-progressors’. Plasma markers of angiogenesis, VEGF-A and basic fibroblast growth factor (bFGF), and the serum markers of activated endothelial cells, sTIE-2 and sE-Selectin, were assessed at baseline, and pre-dose on days 1, 8, 15, 22 and 28 of every cycle, with additional assessments 10 h post-dose on days 1 and 15. The percentage change from baseline was subsequently correlated with AUC and Cmax of PTK/ZK on day 1, cycle 1 and clinical outcome.
Results: A dose-dependent increase in plasma VEGF-A and bFGF was observed in the first cycle of PTK/ZK treatment. The correlation of change in plasma VEGF-A with AUC and Cmax was characterized by an Emax model, suggesting that a change of 150% from baseline VEGF-A correlated with non-progressive disease. Change from baseline plasma VEGF-A within the first cycle of treatment was significantly correlated with clinical outcome by logistic regression analysis (P=0.027).
Conclusions: In patients with CRC treated with PTK/ZK, changes in plasma VEGF-A and bFGF demonstrate biological activity of PTK/ZK, may help to establish optimal dose and correlate with outcome.
Key words: angiogenesis, biomarker, VEGF, VEGF receptor inhibitor
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