CTNI-03. REPLICATION-COMPETENT ADENOVIRUS-MEDIATED DOUBLE SUICIDE GENE THERAPY WITH FRACTIONATED STEREOTACTIC RADIOSURGERY IN PROGRESSIVE GLIOBLASTOMA: A PHASE 1 TRIAL

Abstract Recurrent glioblastoma (rGBM) is marked by short median survival and there is no standard treatment. We conducted a single site, nonrandomized, dose-escalation phase 1 trial of a replication competent novel adenovirus harboring two suicide genes (HSV-TK, yCD) and ADP expression cassette for treatment of adult patients with rGBM undergoing repeat craniotomy followed by fractionated stereotactic radiosurgery (fSRS). The primary endpoints of this dose escalation study were to establish the maximum tolerated dose (MTD) and safety up to Day 90. Secondary endpoints were virus persistence, level of immunological cytokines, Quality of Life and overall survival(mOS). After maximal resection, the ADP adenovirus was injected into remaining tumor tissue and/or the adjacent brain tissue around the resection cavity. Patients received prodrug therapy consisting of 4 days of 5-fluorocytosine (150 mg/kg/day, orally) and valganciclovir (1800 mg/daily) for 13 days, 6-7 days post-surgery, patients received 4 doses of fSRS (32Gy total). Toxicity, virus persistence, immunological cytokines, and immune cell activation were measured up to day 30. The study followed a 3 + 3 design, with 3 doses of viral particles (1x1011, 3x1011, 1x1012). A total of 14 patients with rGBM, IDH1wt, were enrolled. After one patient in cohort 1 had a seizure, the cohort was extended to 6 patients prior to further dose escalation. The last cohort has not yet been completed. To date, Ad5-yCD/mutTKSR39rep-ADP adenovirus plus fSRS was safe and well tolerated in rGBM. MTD was not reached. The treatment was well tolerated as the majority of adverse events were grade 1 or 2. Grade 3 adverse events included one event of headache, nausea, vomiting, hyponatremia, seizure and were not attributed to study treatment. No grade 4 or 5 events were observed. Patients on Ad5-yCD/mutTKSR39rep-ADP gene therapy with combined fSRS had an mOS of 12.3 months. Complete study results will be reported.