Phase II multicenter study of gene-mediated cytotoxic immunotherapy as adjuvant to surgical resection for newly diagnosed malignant glioma

BACKGROUND: Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a polyvalent anti-tumor immune response through local delivery of aglatimagene besadenovec (AdV-tk) which synergizes with standard of care (SOC). METHODS: A Phase II trial was designed to evaluate overall survival (OS) after GMCI + SOC compared to a concurrent matched control group meeting protocol criteria and SOC at an institution not active in the treatment trial. Primary efficacy analysis was planned on the null hypothesis of no improvement in the 2-yr survival over the SOC group with planned subset analysis of significant disease prognostic factors. RESULTS: From 2006 to 2010, 48 patients completed SOC + GMCI and 134 SOC in the matched cohort. There were no dose-limiting toxicities. Fever, fatigue and headache were the most common GMCI-related symptoms. Median OS was 17.1 and 13.5 months for GMCI + SOC and SOC, respectively (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.52-0.99, p = 0.0417). Median PFS was 8.1 and 6.5 months for GMCI + SOC and SOC, respectively (HR 0.66, 95% CI 0.48-0.91, p = 0.0100). OS at 1- 2- and 3-years increased from 57%, 22% and 8% to 67%, 35% and 19%, respectively. The improvement was mostly in patients that underwent gross total resection: median OS increased from 16.9 to 25 months (p = 0.0492); 1- 2- and 3-year survival rates from 64%, 28% and 6% to 90%, 53% and 32%. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival rates compared favorably to historical reports and a matched control group. Survival outcomes were significantly improved in patients with minimal residual disease after total resection. The 2-yr survival rate met the planned statistical threshold for significance. This is the first study to demonstrate a correlation between maximum debulking and a survival advantage using immunotherapy. These data strongly support further evaluation of GMCI for malignant gliomas.