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

TitleSoluble 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
Publication TypeJournal Article
Year of Publication2005
AuthorsJ Drevs, U Zirrgiebel, CIM Schmidt-Gersbach, K Mross, M Medinger, L Lee, J Pinheiro, J Wood, AL Thomas, C Unger, A Henry, WP Steward, D Laurent, D Lebwohl, M Dugan, and D Marmé
JournalAnnals of Oncology
Volume16
Issue4
Start Page558
Pagination558 - 565
Date Published04/2005
Abstract

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 10h 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. © 2005 European Society for Medical Oncology.

DOI10.1093/annonc/mdi118
Short TitleAnnals of Oncology