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

Abstract

Background: Despite aggressive standard of care (SOC) treatment, survival of malignant gliomas remains very poor. This Phase II, prospective, matched controlled, multicenter trial was conducted to assess the safety and efficacy of aglatimagene besadenovec (AdV-tk) plus valacyclovir (gene-mediated cytotoxic immunotherapy [GMCI]) in combination with SOC for newly diagnosed malignant glioma patients.

Methods: Treatment cohort patients received SOC + GMCI and were enrolled at 4 institutions from 2006 to 2010. The preplanned, matched-control cohort included all concurrent patients meeting protocol criteria and SOC at a fifth institution. AdV-tk was administered at surgery followed by SOC radiation and temozolomide. Subset analyses were preplanned, based on prognostic factors: pathological diagnosis (glioblastoma vs others) and extent of resection.

Results: Forty-eight patients completed SOC + GMCI, and 134 met control cohort criteria. Median overall survival (OS) was 17.1 months for GMCI + SOC versus 13.5 months for SOC alone (P = .0417). Survival at 1, 2, and 3 years was 67%, 35%, and 19% versus 57%, 22%, and 8%, respectively. The greatest benefit was observed in gross total resection patients: median OS of 25 versus 16.9 months (P = .0492); 1, 2, and 3-year survival of 90%, 53%, and 32% versus 64%, 28% and 6%, respectively. There were no dose-limiting toxicities; fever, fatigue, and headache were the most common GMCI-related symptoms.

Conclusions: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival outcomes were most notably improved in patients with minimal residual disease after gross total resection. These data should help guide future immunotherapy studies and strongly support further evaluation of GMCI for malignant gliomas.

Clinical trial registry: ClinicalTrials.gov NCT00589875.

Keywords: gene therapy; glioblastoma; immuno-oncology; immunotherapy; malignant glioma.

Fig 1.

Enrollment. CONSORT diagram for the phase 1b/2 study-group patients treated with gene-mediated cytotoxic immunotherapy plus standard of care (GMCI + SOC) (left) and patients who received SOC therapy alone in the matched control cohort (right). Serious adverse events (SAEs) leading to mid-treatment dropout in the GMCI + SOC group were surgical complications and cardiac arrhythmia, deemed unlikely related to protocol treatment. Abbreviations: AdV-tk, aglatimagene besadenovec; SOC, standard of care; TMZ, temozolomide; XRT, radiation therapy.

Fig. 2.

Overall and progression-free survival outcomes. Kaplan-Meier curves of overall survival (OS) and progression-free survival (PFS) are presented for the study group (red) and matched control group (blue). The study group had significantly higher median OS (panel A) and PFS (panel B) compared with the matched control group (P = .0417 and P = .0100, respectively).

Fig. 3.

Overall survival (OS) outcomes by prognostic subgroups. Kaplan-Meier curves of OS by surgical extent groups: total resection (solid or dotted lines) and subtotal resection (dashed lines); and by diagnostic stage: all malignant gliomas (panel A) or glioblastoma multiforme (GBM)-only patients (panel B). Patients treated with gene-mediated cytotoxic immunotherapy plus standard of care (GMCI + SOC) were compared with those in the same matched control subgroups. There was no significant difference between the study and control groups in participants who had undergone subtotal surgical resections. However, in patients who underwent gross total resection, in both the all malignant gliomas and GBM-only subgroups, the GMCI + SOC-treated participants had significantly higher median OS compared with the respective matched control subgroups (P = .0492 and P = .0120, respectively).