FINAL RESULTS OF CONTROLLED IL-12 MONOTHERAPY AND IN COMBINATION WITH PD-1 INHIBITOR IN ADULT SUBJECTS WITH RECURRENT GLIOBLASTOMA

Abstract Ad-RTS-hIL-12(Ad) is a gene therapy candidate conditionally expressing IL-12 under the transcriptional control of veledimex(V) acting via the RheoSwitch Therapeutic System® gene switch. Veledimex plasma and tumor PK demonstrated a dose-response relationship and crossing the BBB. PD-1+ T-cells were increased in tumor biopsy samples after treatment with Controlled-IL-12 in a phase-l study. This finding was the rationale for conducting 2 trials of Controlled-IL-12 in combination with PD-1-inhibitor to enhance T-cell-mediated anti-tumor effects. Data from two completed phase-I studies (presented in SNO2020), and an ongoing phase-II study of Controlled-IL-12 with cemiplimab study for the treatment of recurrent glioblastoma (rGBM) will be discussed. Ziopharm has conducted 3 phase-I (NCT02026271/NCT03679754 (monotherapy), NCT03636477 (combination with nivolumab)) and one phase-ll (NCT04006119) multicenter, open-label, single-arm trial in subjects with rGBM is evaluating Ad (single intratumoral injection, 2 x 1011-viral-particles, Day0) with oral V dosing (20mg, Days 0-14) with cemiplimab infusions (350 mg IV) on Days -7, 15, then Q3W. Systemic biomarkers (serum cytokines, and immune-activation-markers), local effects (tumor cytokines, T-cell immunobiology, pathology), neoepitope, and imaging will be assessed. Subject characteristics (Controlled IL-12 monotherapy (n=75); combination (Controlled IL-12 with anti-PD-1s) (n=61) were consistent across all 3 studies. Safety profiles were comparable between monotherapy and in combination with anti-PD-1s. Adverse reactions (ARs) after nivolumab or cemiplimab were consistent with labeling of anti-PD-1s. ARs related to Controlled IL-12 were all manageable and reversible with no synergistic toxicities in combination with anti-PD-1s. Increases in serum cytokine levels and pathology findings consistent with immune-mediated anti-tumor effect were observed in subjects who received Controlled-IL-12 monotherapy and in combination with anti-PD-1s. Final survival data and results from neoepitope analysis will be presented. Further investigation is warranted to understand the impact of monotherapy vs. combination, concurrent steroids use and unifocal vs. multifocal disease on overall survival in subjects with rGBM receiving Controlled-IL-12.