Molecular therapies for malignant glioma may have a cytostatic mechanism of action and limited toxicity. The absence of toxicity as an endpoint requires a new approach for dose-finding and efficacy testing. AlphavBeta3 antagonists have shown significant efficacy in vitro, using assays of angiogenesis and invasion. Animal studies using these agents in vivo with corneal tumor implants and orthotopic primary gliomas have also shown promising efficacy. This glioma therapy project will be similar to a Phase 2 efficacy study in patients with malignant glioma, using the primary endpoints of time-to-tumor progression (TTP) (measured clinically or radiologically) and overall survival. In this study, the efficacy of alphavBeta3 antagonists will be compared with alterations in in vivo MR tissue perfusion, permeability and vascular maturity parameters using large molecular weight contrast agents. Targeted contrast agents capable of binding specifically to the alphavBeta3 integrin will also be explored and compared with these and conventional volumetric outcomes in standard use. It is intended that these assays will allow the accurate in vivo assessment of the bio-activity and efficacy of alphavBeta3 antagonists in this model system and support the use of these imaging and bio-assay endpoints in the clinical evaluation of these agents for which conventional toxicity cannot be used for dose-finding.
