Phase 2 study of VB-111, an anti-cancer gene therapy, as monotherapy followed by combination of VB-111 with bevacizumab, in patients with recurrent glioblastoma
Background: VB-111 is an anti-angiogenic agent consisting of a non-replicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a fas-chimera transgene in angiogenic endothelial cells. Safety and efficacy of VB-111 alone and in combination with bevacizumab (BEV) were evaluated for patients with recurrent Glioblastoma (rGBM) in this phase 1–2 dose-escalation study.
Methods: VB-111 was administered at doses of 3x1012 or 1x1013 every 2 months until progression, followed by bevacizumab as standard of care. The protocol was amended to add-on Bevacizumab 10mg/Kg every 2 weeks combined with VB-111 every 2 months, upon further progression. Assessments included safety, pharmacokinetics, overall survival (OS) based on Kaplan Meyer analysis and tumor response (RANO criteria).
Results: Forty-six patients at 4 recruiting medical centers in the US and Israel received up to 13 repeat doses of VB-111. Upon further progression, 24 received combination of VB-111 with bevacizumab, and 22 were treated with standard of care bevacizumab (SOC). There were 26 grade 3–4 adverse events. VB-111 was safe and well tolerated as monotherapy and in combination with BEV in patients with rGBM. The median OS was 15 months for patients who received combination therapy at progression versus 8 months for those who received SOC (p=0.05). OS of the study combination therapy cohort was superior to that reported in the historical controls BELOB trial bevacizumab arm, 15 versus 8 months (p=0.0278).
Conclusions: VB-111 was safe and well tolerated as monotherapy and in combination with BEV in patients with rGBM. Overall survival of patients who received VB-111 followed by VB-111 bevacizumab combination was almost doubled compared to historical rGBM bevacizumab data, and compared to patients who received VB-111 monotherapy. Toxicities were as expected in this patient population. A phase 3 randomized controlled trial is currently underway.
