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Oral presentation

Angiogenesis — the development of new blood vessels from the pre-existing vasculature — is necessary for tumor growth, tumor infiltration and the development of distant metastases. Preclinical studies have shown that the therapy with anti-angiogenic agents inhibits the growth of primary tumors as well as the formation of distant metastases.

More than 200 compounds with anti-angiogenic properties have been developed, and a large number of these agents are already in clinical evaluation [1]. The clinical testing of angiogenesis inhibitors in oncology however is challenging because these compounds differ from conventional cytotoxic chemotherapies by targeting primarily normal cells rather then tumor cells. Conventional study endpoints may not be useful in evaluating the activity of these agents as the response may be slow with little change in tumor volume and the effective dose may be considerably lower than maximal tolerated dose (MTD). Therefore in phase 1 clinical trials the main study objectives are not only to determine safety, tolerability and the pharmacokinetics of chronic administration but also to identify a biologically optimal dose using pre-clinical data as well as clinical efficacy, toxicity and surrogate markers. Additionally specific tumor types for future Phase II/III testing should be evaluated. The use of soluble biomarkers reflective for angiogenic activity and endothelial cells activation as well as innovative imaging methods like dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) should be introduced in the evaluation of clinical activity in a very early stage of the clinical development. Since the combination of angiogenic compounds with established cytotoxic agents may be the most effective therapeutic strategy, particularly in the more advanced disease setting, pilot phase I/II combination trials to evaluate the safety, tolerability and activity of potential combination partners should be considered.

References

1. H Verheul, H Pinedo: Anti-Angiogenic Drugs.

   Updates Principles and Practice of Oncology 2002, 16:1-15.

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