EXTH-34. PHASE I TRIAL OF CONVECTION-ENHANCED DELIVERY OF IL13RA2 AND EPHA2 RECEPTOR TARGETED CYTOTOXINS IN DOGS WITH SPONTANEOUS INTRACRANIAL GLIOMAS

Abstract

Abstract The interleukin 13 receptor alpha 2 (IL13RA2) and ephrin type-A receptor 2 (EPHA2) receptors are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technical barriers associated with the convection enhanced delivery (CED) method. In this study, IL-13 mutant and Ephrin-A1 (EFNA1)-based bacterial cytotoxins targeted to IL13RA2 and EPHA2 receptors, respectively, were administered locoregionally by CED to dogs with intracranial gliomas to evaluate their safety and preliminary efficacy. In this Phase I, 3 + 3 dose escalation trial, cytotoxins were infused by CED in 17 dogs with gliomas expressing IL13RA2 or EPHA2 receptors. CED was performed using a shape-fitting therapeutic planning algorithm, reflux-preventing catheters, and real-time intraoperative MRI-monitoring. The primary end point was to determine the maximum tolerated dose of the cytotoxic cocktail in dogs with gliomas. Consistent intratumoral delivery of the cytotoxic cocktail was achieved, with a median target coverage of 70% (range, 40–94%). Cytotoxins were well tolerated over a dose range of 0.012–1.278 mg/mL delivered to the target volume (median, 0.099 mg/mL), with no dose limiting toxicities observed. Objective tumor responses, up to 94% tumor volume reduction, were observed in 50% (8/16) of dogs, including at least one dog in each dosing cohort >0.05 mg/mL. This study provides pre-clinical data fundamental to the translation of this multi-receptor targeted therapeutic approach to the human clinic.