Journal
ANNALS OF ONCOLOGY
Volume 18, Issue 8, Pages 1400-1407Publisher
OXFORD UNIV PRESS
DOI: 10.1093/annonc/mdm140
Keywords
angiogenesis; cilengitide; integrins; phase I trials
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Funding
- NCI NIH HHS [U01 CA099176, K24 CA106349] Funding Source: Medline
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Background: Cilengitide, an antiangiogenic agent that inhibits the binding of integrins alpha(nu)beta(3) and alpha(nu)beta(5) 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 cilengiticle were 600 or 1200 mg/m(2) 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 cilengiticle 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 enclothelial 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.
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