PHASE 1 STUDY OF Ad-RTS-hIL-12+VELEDIMEX IN PEDIATRIC BRAIN TUMORS

Pediatric glioblastoma has an aggressive clinical course accounting for significant morbidity and mortality among children with brain tumors. Only 10% of children with DIPG survive for 2 years following diagnosis, and less than 1% survive for 5 years. The median survival is 9 months from diagnosis. New therapies are urgently needed. Ad-RTS-hIL-12 is a novel gene therapy expressing IL-12 under the control of an oral activator ligand, veledimex, via the RheoSwitch Therapeutic System® gene switch. Intratumoral administration of Ad-RTS-hIL-12 results in targeted tumor cytotoxicity and induction of systemic T-cell memory. Ad-RTS-hIL-12 + veledimex is a treatment strategy to extend the IL-12 therapeutic window. Based on encouraging data from an ongoing phase I dose escalation trial in adults with recurrent/progressive glioma and preclinical data in a GL-261 medullary glioma mouse model, we expect significant safety margins and tolerability profile in pediatric glioma. In a phase 1 adult study, subjects received intratumoral injections of Ad-RTS-hIL-12 2x1011 viral particles during resection or administered stereotactically. Daily oral veledimex began prior to surgery or following stereotactic injection. Overall, Ad-RTS-hIL-12 + veledimex in adults was well tolerated; toxicities were predictable and reversible upon discontinuing veledimex with a correlation between veledimex dose, BBB penetration and drug related AEs. The tolerability and encouraging survival observed warrants a dose escalation pediatric trial for subjects with recurrent/progressive brain tumors. Two groups of subjects receiving Ad-RTS-hIL-12 2x1011 viral particles are planned: Arm 1 receives Ad-RTS-hIL-12 intratumorally after resection of supratentorial tumors that are unresponsive to conventional treatment or for which there is no alternative curative therapy; Arm 2 consists of stereotactic injection in subjects with DIPG post prior standard focal radiotherapy and for which a diagnostic biopsy has previously been obtained. Subjects receive BSA adjusted escalating doses of 10 or 20mg veledimex. An update will be presented.