ATIM-15. A PHASE 1 STUDY OF Ad-RTS-hIL-12 + VELEDIMEX IN ADULTS WITH RECURRENT GLIOBLASTOMA: DOSE DETERMINATION WITH UPDATED OVERALL SURVIVAL. (5th November 2018)

• Record Type: Journal Article
• Authors: Chiocca, E Antonio; Lukas, Rimas; Yu, John; Oberheim Bush, Nancy Ann; Buck, Jill; Demars, Nathan; Barrett, John; Gelb, Arnold; Wang, Yunxia; Cooper, Laurence; Lebel, Francois
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi3
• Page End: vi4
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.010
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Ad-RTS-hIL-12 (Ad) is a novel gene therapy expressing IL-12 via the RheoSwitch Therapeutic System ® gene switch under control of an oral activator ligand, veledimex (V). We previously reported on an open label Phase I trial describing biological activity of recombinant IL-12 with downstream IFN-γ and activation of the immune system. We provide an update on the intratumoral injections of Ad (2x10 11 virus-particles) + V for patients with recurrent GBM (rGBM) in Group 1 (G1) (craniotomy, n=31) and initial results for Group 2 (G2) (stereotactic administration n=7). In G1, the V 20-mg cohort mOS increased to 12.7 months with mean follow-up of 12.9 months. 20-mg V in G1 showed fewer toxicities and higher V compliance (84%) compared with higher-doses of V (30 and 40-mg) with 75% and 67%, respectively. These data are encouraging compared to historical data that predict mOS of 5 to 8 months. An additional cohort at V 10-mg (n=6) was well tolerated, but subtherapeutic, with a mOS of 7.6 months (mean follow-up 6.7 months). There was an association between V dose level, blood-brain-barrier penetration, and drug-related adverse events (AEs) with increased TEAEs observed above V 20-mg. Subgroup analyses across all cohorts did not detect statistically significant differences including extent of resection or IDH mutation status. Subjects (20-mg V) who received a cumulative dose of ≤10mg of dexamethasone during the first 15 days of treatment showed improved OS versus >100mg of dexamethasone, suggesting corticosteroid-mediated blunting of the IL-12 dependent immune-mediated therapeutic effect. In the G2 20-mg V cohort, similar cytokine levels and reversible AEs were observed compared to G1; follow up is ongoing and mOS will be presented. Based on these results and the best risk-benefit profile, the 20-mg V dose level was chosen for further investigation. Combination with an immune checkpoint inhibitor in rGBM is underway.