ON-01, an engineered recombinant oncolytic herpes simplex virus type-1, in recurrent glioma: A single-arm, phase 1/2 study

BACKGROUND: The prognosis of patients with recurrent WHO grade 4 glioma is poor, particularly in glioblastoma, which has a median survival of approximately 6 months and no effective treatment options. We evaluated the short-term (28-day) safety and efficacy of ON-01, an engineered recombinant oncolytic herpes simplex virus type-1, in patients with recurrent WHO grade 4 glioma. METHODS: In this single-arm, phase 1/2 clinical trial, eligible patients received intratumoral injections of ON-01 under stereotactic guidance. The primary endpoint was to assess the short-term safety profile of ON-01 treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the 2-year OS rate. An exploratory objective was to identify tumor-related biomarkers predictive of treatment efficacy. RESULTS: Of the 30 patients treated with ON-01, 13 (43.3%) were male, and the median age was 50.0 years (range, 22-75). A total of 36 grade 1, 12 grade 2, and 2 grade 3 adverse events were reported. Among all treated patients, the median OS was 12.0 months (95% CI, 10.1-13.9), median PFS was 3.0 months (95% CI, 1.7-4.3), and 2-year OS rate was 27.7% (95% CI, 12.6%-45.0%). Seven patients with recurrent multifocal gliomas demonstrated regression of non-injection site lesions following ON-01 therapy. Furthermore, patients with elevated expression of herpesvirus entry mediator exhibited significantly prolonged survival (P = .015). CONCLUSIONS: Intratumoral infusion of ON-01 appeared safe and demonstrated efficacy in patients with recurrent malignant glioma, with no evidence of neurotoxicity. The therapeutic response to ON-01 may be associated with HVEM expression levels.