Randomized phase IIb trial of a CMV vaccine immunotherapeutic candidate (VBI-1901) in recurrent glioblastomas.

TPS2100 Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBMs. CD4 + and CD8 + T cells are most frequently directed against the gB and pp65 antigens, respectively, which are immunogenic targets in a CMV-based GBM immunotherapeutic. A total of 28 first-recurrent GBM subjects were enrolled in a trial, designed as a single arm, 3-dose escalation phase (n=18) followed by a dose-expansion phase (n=10), to receive VBI-1901 (a gB/pp65 enveloped virus-like particle vaccine immunotherapeutic adjuvanted with GM-CSF) given intradermally every 4 weeks until clinical disease progression (NCT03382977). In Phase I (Part A) of the study, 3 vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated. No DLTs or safety concerns with any of the doses. The 10µg dose was chosen for the dose-expansion phase. Injection site erythema was the most common adverse event. Vaccination with VB-1901 led to both humoral response with increase in CMV gB antibodies, and cellular response with increase in CD4+ effector memory T cells against CMV pp65 antigen; immunological responses were associated with MRI/clinical response. Among 16 subjects receiving the highest dose of VBI-1901, the disease control rate was 44%, including 2 durable partial responses, which translated into a mOS of 12.9 months. Based on these results, the study was amended into a randomized study. Methods: Approximately 60 adult subjects (18 years or older) with first recurrence of WHO 2016 grade IV Glioblastoma, IDH-wildtype will be randomized at a 1:1 ratio to two open-label cohorts to receive: VBI-1901 or standard of care (SOC) treatment with lomustine or carmustine. The contrast-enhancing lesion may not have an area measuring greater than 600 mm 2 (subjects with a resected first recurrence tumor, which may not be measurable after surgery, are eligible). Subjects must have a KPS ≥70, corticosteroid (dexamethasone or equivalent) dosage must be ≤ 2 mg daily that has been stable for at least 5 days before randomization into the study, and only subjects with a CD4/CD8 ratio ≥1 OR a CD4 count of ≥ 400/uL at screening are eligible, as people with a preserved immune system are more likely to respond to immunization with VBI-1901 based on the initial phase study. The primary endpoints are hierarchical. If the safety endpoint is achieved, then efficacy (overall survival) will be considered as a co-primary endpoint. Tumor response rate is a secondary endpoint with planned interim analyses. For a one-sided log rank test with an equal allocation of subjects in the two groups, 80% power and a 0.20 significance level, a total number of 47 events are needed to detect a hazard ratio for mortality of 0.6145 in the VBI-1901 cohort relative to the SOC cohort. This hazard ratio corresponds to a difference in the mOS observed previously with VBI-1901 and a historical mOS of 8 months in the SOC group. As of January 31 st 2024 , 12 of 60 patients have been randomized and dosed across 8 US sites. Clinical trial information: NCT03382977 .