CLINICAL TRIALS

VBL Therapeutics’ lead oncology product candidate, VB-111 (ofranergene obadenovec), is a targeted anti-cancer gene-based biologic agent that is positioned to potentially treat a wide range of solid tumors.  It is conveniently administered as an IV infusion once every two months.

 

Completed Clinical Trials

VBL conducted a Phase 1 “all comers” clinical trial of VB-111 in the United States as an open-label, dose-escalating trial to assess the safety and pharmacokinetics and pharmacodynamics of VB-111 in 56 patients with advanced metastatic cancer. In that trial, VB-111 was well-tolerated and showed a dose dependent extension in median overall survival across a range of tumor types [ClinicalTrials.gov Identifier: NCT00559117] .

Based on the Phase 1 results, VBL decided to proceed with the development of VB-111 for the lead indication of rGBM, as well as to investigate VB-111 as a monotherapy for the treatment of thyroid cancer and, in combination with chemotherapy, for ovarian cancer.

  • Phase 2 single-arm open-label multicenter trial of VB-111 in patients with recurrent Glioblastoma (rGBM) [ClinicalTrials.gov Identifier: NCT01260506]:

In September 2015 at the European Cancer Conference (ECC 2015), VBL Therapeutics reported full Phase 2 data from a multi-center clinical trial of VB-111 in rGBM, which met the primary endpoint of statistically significant increase in overall survival.

In June 2016, at the 2016 American Society of Clinical Oncology (ASCO) annual meeting, VBL reported new data comparing Phase 2 clinical outcomes with VB-111 with pooled data from 8 studies that investigated Avastin in recurrent glioblastoma (rGBM). In the Phase 2 VB-111 trial, the median overall survival of patients who received continuous exposure of VB-111 in combination with Avastin was 59 weeks. This is compared to 32 weeks in the pooled data from the 8 studies in the meta-analysis (p= 0.0295 Hazard Ratio 0.62, 95% CI: 0.40-0.96). Median survival ranged from 26.0 weeks to 45.7 weeks in the meta-analysis. Overall survival at 12 months for patients on continuous exposure of VB-111 was 57%, compared to 24% overall survival (range 16% – 38%) for the pooled data (p= 0.03).  See also the  VB-111 rGBM Poster at ASCO 2016 .

At ASCO 2017,  VBL presented additional analyses from the Phase 2 study, which demonstrate that tumor growth kinetics were significantly attenuated upon longer treatment with VB-111.  See also VB-111 data at ASCO 2017 and the ASCO 2017 Poster

The FDA granted fast track designation for the investigation of VB-111 for prolongation of survival in patients with glioblastoma that has recurred following treatment with temozolomide. VB-111 was also granted orphan designation for treatment of malignant glioma by the FDA, and for treatment of glioma in Europe.

  • GLOBE: Phase 3 pivotal, randomized, controlled trial of VB-111 in Patients with rGBM [ClinicalTrials.gov Identifier: NCT02511405]:

VBL’s pivotal Phase 3 GLOBE study in rGBM, comparing VB-111 in combination with Avastin to Avastin alone, was conducted in the US, Canada and Israel, and enrolled 256 patients in total. GLOBE was conducted under a Special Protocol Assessment (SPA) granted by the U.S. Food and Drug Administration (FDA), with full endorsement by the Canadian Brain Tumor Consortium (CBTC). 

In March 2018, we announced top-line results from the GLOBE study, which showed that the study did not meet its pre-specified primary endpoint of overall survival (OS) or the secondary endpoint of progression-free survival (PFS). The full study data were presented at the 2018 Society for Neuro-Oncology Annual Meeting by Dr. Timothy Cloughesy, MD, Professor of Clinical Neurology and Director of the Neuro-Oncology Program, UCLA School of Medicine and principal investigator of the GLOBE trial.

  • Data show that the baseline tumor volume, which is a significant prognostic factor in rGBM, was higher in the treatment arm compared to the control arm. Overall, the subjects in the study had relatively high tumor volume, as large-volume tumors were not an exclusion criterion. It is of interest that patients with smaller tumors (<15 cm3) appeared to respond better to the treatment arm, with numerically higher response rate and overall survival observed.  Furthermore, a trend towards greater survival was observed in patients treated with VB-111 who reported fever. VB-111 was well tolerated, with a similar early termination rate in both the treatment and control arms. Most frequent adverse event was self-limited fever, starting several hours post therapy and usually resolving by 24 hours. As expected, a higher rate of SAEs and grade >=3 AEs was reported in the combination treatment arm.
  • Subsequent analyses have focused on the potential reasons for the major differences in outcomes between the positive VB-111 Phase 2 clinical trial in rGBM and the unsuccessful GLOBE results. The Phase 2 trial of VB-111 met the primary endpoint of OS benefit with median OS (mOS) of 13.6 months upon treatment with VB-111 as a single drug (`priming`) followed by adding bevacizumab to VB-111 upon further progression, compared to mOS of 6.8 months for the treatment arm in GLOBE (co-administration of VB-111 and bevacizumab, without any VB-111 monotherapy `priming` period). 
  • Thorough analyses of the baseline risk factors of the Phase 2 and the Phase 3 treatment groups did not reveal any differences. Therefore, patient selection or different patient populations could not explain the difference between the results of the two studies. The only significant change between the Phase 2 and Phase 3 treatment cohorts was in the treatment regimen – the regimen for Phase 2 trial included priming with VB-111 whereas the regimen for GLOBE trial did not. 
  • Data suggest that concomitant treatment with bevacizumab may have a negative effect on VB-111 activity. The Company believes that priming with VB-111 without bevacizumab may be critical for the immune and vascular-disruptive/anti-angiogenic mechanism of VB-111 in rGBM. 

We do not think that results of the particular GLOBE study that investigated VB-111 in combination with bevacizumab in rGBM, will necessarily have implications on the prospects for VB-111 in other tumor types, in different patients populations, or in different regimens. 

The company is currently evaluating the path forward of VB-111 in rGBM, including the option of an investigator-initiated clinical trial.

  • Phase 1/2 clinical trial of VB-111 in Ovarian Cancer [ClinicalTrials.gov Identifier: NCT01711970]:

This is a Phase 1/2 investigator-initiated clinical trial under VBL’s IND, which was conducted as an open- label, dose-escalating trial to assess the safety and efficacy of bi-monthly doses of VB-111 in combination with weekly paclitaxel in patients with recurrent epithelial ovarian cancer.  In June 2016, at the 2016 ASCO meeting, VBL reported interim results from a Phase 1/2 trial of VB-111 in patients with recurrent platinum resistant ovarian cancer.  The interim data demonstrate a median overall survival of 810 days in the VB-111 therapeutic dose arm, versus 172 days in the low dose arm, a result that was statistically significant. There was also a durable doubling in the response rate, as measured by a reduction in the CA-125 biomarker, compared to historical rates of Avastin® (bevacizumab) plus chemotherapy in ovarian cancer. Durable RECIST responses and disease stabilizations were also observed. An immunotherapeutic effect was also observed in biopsies taken from patients.  The trial was conducted at Massachusetts General Hospital and Dana Farber Cancer Institute, Boston, MA. See also the  VB-111 Ovarian Cancer Poster at ASCO 2016 .  

  • Phase 2 clinical trial of VB-111 in Thyroid Cancer [ClinicalTrials.gov Identifier: NCT01229865]:

We conducted an exploratory Phase 2 clinical trial in the United States to assess the safety and efficacy of single or multiple doses of VB-111.  Our open-label dose-escalating study enrolled patients with advanced, recently-progressive, differentiated thyroid cancer that was unresponsive to radioactive iodine, in two cohorts. Most patients had tumors that had not responded to multiple therapies prior to enrollment, including radiation and kinase inhibitors. In the first cohort, thirteen patients received a single intravenous infusion of VB-111 at a sub-therapeutic dose of 3X1012 viral particles (VPs). The second cohort included seventeen patients, who received VB-111 at a therapeutic dose of 1013 VPs every two months until disease progression. One patient proceeded from a single low dose to receive later multiple high doses at progression and was included in both groups (for PFS only). VB-111 was well-tolerated in this study, with no signs of clinically significant safety issues.The primary endpoint of the trial, defined as 6-month progression-free-survival (PFS-6) of 25%, was met with a dose response. Forty-seven percent (47%; 8/17) of patients in the therapeutic-dose cohort reached PFS-6, versus 25% (4/12) in the sub-therapeutic cohort, both groups meeting the primary endpoint. Reduction in tumor measurement after the first dose was seen in 44% (7/16) of patients in the therapeutic-dose cohort, compared to 9% (1/11) in the sub-therapeutic-dose cohort. An overall survival benefit was seen with a tail of more than 40% at 3.7 years for the therapeutic-dose cohort (mOS 684 days). This is similar to historical data for pazopanib* (Votrient®), a tyrosine kinase inhibitor; however, most patients in the VB-111 study had tumors that previously had progressed on pazopanib or other kinase inhibitors.  The trial was conducted at Mayo Clinic and Massachusetts General Hospital, Boston, MA. Currently, VBL does not have an active clinical trial in Thyroid Cancer.

Ongoing Clinical Trial/s

 

  • OVAL – Phase 3 potential registration double-blind, placebo-controlled study of VB-111 in recurrent platinum-resistant ovarian cancer [ClinicalTrials.gov Identifier: NCT03398655]: 

    The OVAL Phase 3 study in recurrent platinum-resistant ovarian cancer has been designed to enroll up to 400 adult patients at approximately 70 clinical sites in the United States and Israel. Patients are randomized 1:1 to VB-111 in combination with chemotherapy, or chemotherapy alone. The OVAL study is conducted in collaboration with the GOG Foundation, Inc., a leading organization for research excellence in the field of gynecologic malignancies.

 

 Detailed information on the clinical trials can be found at www.clinicaltrials.gov