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.

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 > or =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 C(max) 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 C(max) was characterized by an E(max) model, suggesting that a change of > or =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.

• Authors: J Drevs, U Zirrgiebel, C I M Schmidt-Gersbach, K Mross, M Medinger, L Lee, J Pinheiro, J Wood, A L Thomas, C Unger, A Henry, W P Steward, D Laurent, D Lebwohl, M Dugan, D Marmé
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 16 Issue 4 Pg. 558-65 (Apr 2005) ISSN: 0923-7534 [Print] England
• PMID: 15705616 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Phthalazines
• Protein Kinase Inhibitors
• Pyridines
• vatalanib
• Receptors, Vascular Endothelial Growth Factor

Topics

• Aged
• Biomarkers (blood)
• Clinical Trials, Phase II as Topic (methods)
• Colorectal Neoplasms (blood, drug therapy, enzymology)
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• Phthalazines (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyridines (pharmacology, therapeutic use)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, blood)