240 - Replication-Competent Adenoviral Double-Suicide Therapy with fSRS in Progressive Glioblastoma (RAD-Gli): A Phase 1 Trial
Presenter(s)
T. Walbert1, I. Lee2, J. Snyder2, M. M. Shah2, S. Siddiqui2, A. Robin3, S. Thoidingjam3, S. L. Brown4, B. Movsas4, F. Siddiqui4, and S. Nyati3; 1Henry Ford Cancer Institute, Detroit, MI, United States, 2Henry Ford Health System, Detroit, MI, 3Henry Ford Health, Detroit, MI, 4Department of Radiation Oncology, Henry Ford Health, Detroit, MI
Purpose/Objective(s): 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 (OS).
Materials/Methods: 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 90. The study followed a 3+3 design, with 3 doses of viral particles (1x1011, 3x1011, 1x1012).
Results: 17 patients with rGBM, IDH1wt, were enrolled. 1 patient in cohort 1 had a seizure, the cohort was extended to 6 patients. The Ad5-yCD/mutTKSR39rep-ADP adenovirus plus fSRS was safe and well tolerated in rGBM in dose level 3x1011. MTD reached at the highest dose 1x1012 when one patient developed ischemic changes and another patient developed intracranial hemorrhage, both attributed to the combination of virus and fSRS. On the lower dose levels, 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. Median OS is 12.3 months.
Conclusion: MTD was reached at dose level 2, 1x1011. Median overall survival is promising at 12.3 months.