CTIM-34. JACOB: JOINT ADMINISTRATION OF CDNA FOR TP53, CHECKPOINT INHIBITION, AND BOOST/HYPO FRACTIONATED RADIATION. A PHASE 0/1 STUDY IN CHILDREN WITH RECURRENT, PROGRESSIVE, OR REFRACTORY CNS MALIGNANCIES

Abstract

Abstract BACKGROUND Pediatric patients with recurrent, progressive, or refractory brain tumors have dismal prognoses and few therapeutic options. Due to the complex biological mechanisms of resistance in these tumors, targeted agents and immunotherapeutic approaches in isolation have yielded disappointing results. The combination of SGT-53, anti-PD-1, and hypofractionated radiation has shown encouraging results in preclinical studies. SGT-53 is a novel nanoparticle carrying cDNA encoding human wild-type human TP53; the nanoparticle uses a single-chain antibody fragment recognizing the human transferrin receptor, leading to excellent blood-brain barrier penetrance and anti-tumor targeting. TP53 therapy work synergistically with immune checkpoint inhibitors like anti-PD-1. Hypofractionated radiation provides additional synergy, increasing vascular access, cytokine production and activating tumor-specific T-cells. METHODS JACOB is a prospective, phase 0/1 clinical trial to evaluate the safety and efficacy of SGT-53 in combination with hypofractionated radiation and anti-PD-1 in children with recurrent, progressive, or refractory CNS malignancies. Inclusion criteria: patients age ≥ 3 and ≤ 21 years, measurable disease, performance status >50 and adequate organ function. The 3 + 3 de-escalation design will be used to determine the maximum tolerated dose (MTD) of SGT-53 in combination with ICI and radiation. Dose limiting toxicities will be evaluated. SGT-53 will be administered two times per week. Hypofractionated radiation will be given in week 2, and anti-PD-1 (once in 2 weeks) will begin on the second week of treatment. A maintenance phase of SGT-53 and anti-PD-1 will be continued for up to 12 months. Primary endpoints evaluate toxicities related to SGT-53 and plasma pharmacokinetics. Secondary and exploratory endpoints include best radiological response, and immunobiological markers. Twelve patients will be treated in the phase I/dose de-escalation cohort. After the MTD has been identified, a target validation/ phase 0 cohort will include up to 4 patients receiving 2 doses of SGT-53 prior to undergoing surgical resection to determine tissue-specific response.