Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Morgan, Bruno, Thomas, Anne L., Drevs, Joachim, Hennig, Juergin, Buchert, Martin, Jivan, Asvina, Horsfield, Mark A., Mross, Klauss, Ball, Howard A., Lee, Lucy, Mietlowski, William, Fuxius, Stefan, Unger, Clemens, O'Byrne, Kenneth J., Henry, Andrew, Cherryman, Graham R., Laurent, Dirk, Dugan, Margaret, Marmé, Dieter, & Steward, William P. (2003) Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies. Journal of Clinical Oncology, 21(21), pp. 3955-3964.

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Abstract

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies.

Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status.

Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

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ID Code: 65227
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: biological marker, vasculotropin receptor, vatalanib, angiogenesis inhibitor, contrast medium, dichlorobis(ethylenediamine)rhodium(III), organometallic compound, phthalazine derivative, pyridine derivative, angiogenesis, article, clinical article, clinical trial, colorectal cancer, contrast enhancement, controlled clinical trial, controlled study, drug blood level, drug dose escalation, drug mechanism, drug penetration, drug response, human, liver metastasis, nuclear magnetic resonance imaging, phase 1 clinical trial, priority journal, adult, aged, area under the curve, blood, colorectal tumor, drug administration, drug combination, female, liver tumor, male, metastasis, methodology, middle aged, oral drug administration, pathology, prediction and forecasting, standard, treatment outcome, Administration, Oral, Angiogenesis Inhibitors, Area Under Curve, Biological Markers, Colorectal Neoplasms, Contrast Media, Drug Administration Schedule, Drug Therapy, Combination, Humans, Liver Neoplasms, Magnetic Resonance Imaging, Neoplasm Metastasis, Organometallic Compounds, Phthalazines, Predictive Value of Tests, Pyridines
DOI: 10.1200/JCO.2003.08.092
ISSN: 0732-183X
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: © 2003 by American Society of Clinical Oncology.
Deposited On: 09 Dec 2013 05:07
Last Modified: 09 Dec 2013 05:12

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