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Annals of Oncology 2007 18(8):1400-1407; doi:10.1093/annonc/mdm140
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© 2007 European Society for Medical Oncology

phase I and pharmacokinetics

Assessment of the biological and pharmacological effects of the {alpha}{nu}ß3 and {alpha}{nu}ß5 integrin receptor antagonist, cilengitide (EMD 121974), in patients with advanced solid tumors

S Hariharan1, D Gustafson1, S Holden1, D McConkey2, D Davis3, M Morrow1, M Basche1, L Gore1, C Zang1, CL O'Bryant1, A Baron1, D Gallemann4, D Colevas5 and SG Eckhardt1,*

1 University of Colorado Cancer Center, Aurora, CO
2 Department of Cancer Biology, M.D. Anderson Cancer Center, Houston, TX
3 ApoCell, Inc., Houston, TX, USA
4 Merck KGaA, Darmstadt, Germany
5 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA

* Correspondence to: Dr S. G. Eckhardt, University of Colorado at Denver and Health Sciences Center, 12801 E. 17th Avenue Campus Box 8117, PO Box 6511, Aurora, CO 80045, USA. Tel: +1-303-724-3850; Fax: +1-303-724-3892; E-mail: gail.eckhardt{at}uchsc.edu

Background: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins {alpha}{nu}ß3 and {alpha}{nu}ß5 to the extracellular matrix, was studied at two dose levels in cancer patients to determine the optimal biological dose.

Patients and methods: The doses of cilengitide were 600 or 1200 mg/m2 as a 1-h infusion twice weekly every 28 days. A novel dose escalation scheme was utilized that relied upon the biological activity rate.

Results: Twenty patients received 50 courses of cilengitide with no dose-limiting toxic effects. The pharmacokinetic (PK) profile revealed a short elimination half-life of 4 h, supporting twice weekly dosing. Of the six soluble angiogenic molecules assessed, only E-selectin increased significantly from baseline. Analysis of tumor microvessel density and gene expression was not informative due to intrapatient tumor heterogeneity. Although several patients with evaluable tumor biopsy pairs did reveal posttreatment increases in tumor and endothelial cell apoptosis, these results did not reach statistical significance due to the aforementioned heterogeneity.

Conclusions: Cilengitide is a well-tolerated antiangiogenic agent. The biomarkers chosen in this study underscore the difficulty in assessing the biological activity of antiangiogenic agents in the absence of validated biological assays.

Key words: angiogenesis, cilengitide, integrins, phase I trials

Received for publication January 14, 2007. Revision received March 3, 2007. Accepted for publication March 23, 2007.


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