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Originally published as JCO Early Release 10.1200/JCO.2008.18.8193 on July 27 2009 © 2009 American Society of Clinical Oncology.
Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor β, and c-Kit, in Patients With Advanced or Metastatic Solid Tumors
From the Department of Medical Oncology, Erasmus University Medical Center, Rotterdam; Departments of Clinical Oncology and Radiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Clinical Pharmacology, Bayer Pharmaceuticals Corporation, Montville, NJ; and the Department of Clinical Pharmacology, Bayer Schering Pharma, Wuppertal, Germany. Corresponding author: Ferry A.L.M. Eskens, Department of Medical Oncology, Room HE-120, Erasmus University Medical Center, PO Box 2040, Rotterdam, 3000 CA, the Netherlands; e-mail: f.eskens{at}erasmusmc.nl. Purpose Telatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-β, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments. Patients and Methods Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily.
Results Fifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade Conclusion Telatinib was safe and well tolerated up to 1,500 mg twice daily. Based on pharmacodynamic and pharmacokinetic end points, telatinib 900 mg twice daily is the recommended dose for subsequent phase II studies. F.A.L.M.E. and N.S. contributed equally to this article. Supported by Bayer, Brussels, Belgium, and Bayer AG Leverkusen, Germany. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006: and at the 2006 Annual Meeting of the American Association for Cancer Research, National Cancer Institute, European Organisation for the Research and Treatment of Cancer, November 7-10, Prague, Czech Republic. Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A formal maximum-tolerated dose was not reached. Telatinib was rapidly absorbed, with median time to peak concentration (tmax) lower than 3 hours after dose. A nearly dose-proportional increase in exposure was observed with substantial variability. Telatinib half-life averaged 5.5 hours. Biomarker analyses showed dose-dependent increase in VEGF levels and decrease in plasma soluble VEGFR-2 levels, with a plateau at 900 mg twice daily. A decrease in tumor blood flow (Ktrans and IAUC60) was observed with dynamic contrast-enhanced magnetic resonance imaging. Best tumor response was stable disease, observed in 50.9% of patients. 
