Date: 2017-10-02
Type of
information: DSMB assessment
phase: 3
Announcement: DSMB assessment
Company: VBL Therapeutics (Israel)
Product: VB-111 (ofranergene obadenovec)
Action
mechanism:
- gene therapy. VB-111 is a dual-action, anti-angiogenic and Vascular Disruptive Agent (VDA) that utilizes VTS™, VBL’s proprietary platform technology for cancer therapy. VB-111 is an intravenously administered VDA that works in a manner akin to a “biological knife” to destroy tumor vasculature, thus cutting off the blood vessels feeding the tumor. Preclinical pharmacological and toxicology studies of VB-111 showed tissue specificity for the tumor tissue, no significant damage to normal non-cancerous tissues or to the normal vasculatures in the body, and a more than 90 percent reduction in metastatic lung cancer model with one injection, as well as similar efficacy in other tumor models. A Phase 1 “all-comers” study of VB-111 in 33 patients with advanced metastatic cancer demonstrated antitumor activity and no effects on liver function or major changes in complete blood count.
- About Ofranergene Obadenovec (VB-111)
Ofranergene obadenovec is a unique biologic agent that uses a dual mechanism to target solid tumors. Based on a non-integrating, non-replicating, Adeno 5 vector, ofranergene obadenovec utilizes VBL's proprietary Vascular Targeting System (VTS™) to target the tumor vasculature for cancer therapy. Unlike anti-VEGF or TKIs, ofranergene obadenovec does not aim to block a specific pro-angiogenic pathway; instead, it uses an angiogenesis-specific sensor (VBL's PPE-1-3x proprietary promoter) to specifically induce cell death in angiogenic endothelial cells in the tumor milieu. This mechanism retains activity regardless of baseline tumor mutations or the identity of the pro-angiogenic factors secreted by the tumor and shows activity even after failure of prior treatment with other anti-angiogenics. In addition, ofranergene obadenovec induces specific anti-tumor immune response, which is accompanied by recruitment of CD8 T-cells and apoptosis of tumor cells.
Ofranergene obadenovec completed a Phase 2 study in rGBM, which showed a statistically significant improvement in overall survival in patients treated with ofranergene obadenovec through progression, compared to either patients treated with ofranergene obadenovec followed by bevacizumab alone, or to historical bevacizumab data. In a Phase 2 trial for recurrent platinum-resistant ovarian cancer, ofranergene obadenovec demonstrated a statistically significant increase in overall survival and 60% durable response rate (as measured by reduction in CA-125), approximately twice the historical response with bevacizumab plus chemotherapy in ovarian cancer. In a Phase 2 study in recurrent, iodine-resistant differentiated thyroid cancer, ofranergene obadenovec met the primary endpoint and provided evidence of disease stabilization with a positive safety profile, along with a dose-response and evidence of an overall survival benefit. Ofranergene obadenovec has received Fast Track Designation for recurrent glioblastoma in the U.S. and orphan drug status for glioblastoma in both the U.S. and EU.
Disease: glioblastoma
Therapeutic
area: Cancer - Oncology
Country: Canada, Israel, USA
Trial
details:
- The Phase 3 GLOBE study is proceeding under a Special Protocol Assessment (SPA) granted by the FDA, with full endorsement by the Canadian Brain Tumor Consortium (CBTC). VB-111 has received orphan drug designation in the United States and Europe and was granted Fast Track designation by the FDA for promising and meaningful long-term survival in patients with glioblastoma that has recurred following treatment with standard chemotherapy and radiation. The study in recurrent GBM is comparing VB-111 in combination with Avastin® (bevacizumab) to Avastin alone and has recruited 256 patients in the US, Canada and Israel. (NCT02511405)
Latest
news:
- • On October 2, 2017, VBL Therapeutics announced that the independent Data Safety Monitoring Committee (DSMC) met on September 28, 2017 to conduct its third and final safety review of the Phase 3 GLOBE Study investigating ofranergene obadenovec (VB-111) in recurrent glioblastoma. The committee reviewed the GLOBE safety data, including mortality data, collected through a cutoff date in August 2017 and stated that they did not identify any safety concerns. The DSMC confirmed that no additional follow up will be necessary. Accordingly, the DSMC unanimously recommended that the study continue as planned, to completion. VBL Therapeutics currently expect stop-line results from the study to be available in Q1 2018.
- • On April 20, 2017, VBL Therapeutics announced that the DSMC met to conduct its second safety review of the Phase 3 GLOBE study investigating ofranergene obadenovec (VB-111) in recurrent glioblastoma. The committee reviewed the GLOBE safety data collected through a cutoff date in March 2017 and unanimously recommended that the study continue as planned.
- • On January 6, 2017, VBL Therapeutics announced that it has completed enrollment in the GLOBE Phase 3 study evaluating the efficacy of its lead candidate ofranergene obadenovec (VB-111) in patients with recurrent glioblastoma (rGBM). Enrollment in the study, 256 patients in total, has been completed five months ahead of schedule. VBL has also received FDA approval for adjustments in the GLOBE protocol. These major modifications relate to the triggers for the interim and final analyses. The SPA covering GLOBE remains in place. Originally, the interim analysis in GLOBE was to be conducted after 91 deaths. The modified protocol specifies that it will be conducted after 105 deaths, and after 50% of the patients have more than 12 months potential follow up, whichever occurs later. The final analysis will be conducted at 189 deaths (75% of events), versus the original planned for 151 deaths (60% of events).
These adjustments to the GLOBE protocol are intended to provide better powering and increase the probability for a clearer efficacy signal. Given the fast recruitment pace and completion of recruitment ahead of schedule, the company continues to expect that the interim analysis will occur in mid-2017 and that the top-line results from the full dataset will be available in early 2018.
- • On December 5, 2016, VBL Therapeutics announced that the independent Data Safety Monitoring Committee (DSMC) met to conduct its first safety review of the Phase 3 GLOBE Study investigating ofranergene obadenovec (VB-111) in recurrent glioblastoma. The DSMC reviewed the GLOBE safety data collected through a cutoff date in September 2016 , and did not find any adverse events that would be cause for concern. As a result, the DSMC recommended that the study continue as planned.
- The Phase 3 GLOBE study in rGBM is comparing VB-111 in combination with Avastin® (bevacizumab) to Avastin alone and is recruiting approximately 252 patients in the US, Canada and Israel . The study is proceeding under a Special Protocol Assessment (SPA) granted by the FDA , with full endorsement by the Canadian Brain Tumor Consortium (CBTC). VB-111 has received orphan drug designation in the United States and Europe and was granted Fast Track designation by the FDA for prolongation of survival in patients with glioblastoma that has recurred following treatment with standard chemotherapy and radiation.
Is
general: Yes
