PHASE I STUDY OF CILENGITIDE (EMD 121974) IN CHILDREN WITH REFRATORY BRAIN TUMOR

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Angiogenesis, which is critical for tumor growth, is induced by tumor secretion of vascular growth factors that activate and promote endothelial cell proliferation, survival, and maturation. One of the consequences of this activation is the expression on endothelial cells of integrin receptors, whose presence appears to be crucial for continued survival and proliferation of and invasion by endothelial cells. Two specific integrins, the alpha v Beta 3 and alpha v beta 5 receptors, appear to be particularly important in the process of angiogenesis, and therefore represent logical targets for the development of anti-angiogenesis strategies for the treatment of malignancies. These receptors allow endothelial cells to attach to the extracellular matrix through their ability to bind to RGD sequences found on the matrix proteins. Thus, one approach to inhibiting angiogenesis is to use RGD-containing peptide antagonists. Specificity for the alpha v beta 3 and alpha v beta 5 receptors can be significantly enhanced by cyclizing RGD peptides. Cilengitide (EMD121974), the inner salt of a cyclized RGD pentapeptide (cyclo-[Arg-Gly-Asp-DPhe-(NMeVal)], is a potent and selective alpha v beta 3 and alpha v beta 5 vitronectin receptor antagonist. It has been shown to inhibit tumor growth in a dose dependent manner in a variety of in vivo systems. The treatment plan for children with refractory CNS tumors will consist of administration of cilengitide twice weekly as a 1-hour infusion for up to one year in the absence of unacceptable toxicity or tumor progression. Based on emerging data from ongoing studies with cilengitide, which continue to show acceptable toxicity profile at the higher dosing range and potential for clinical benefit even at the lower dosing range, this study will potentially investigate a broad range of doses.