dm+d

Unassigned

New Medicines

Recurrent platinum-resistant ovarian cancer

Information

New molecular entity
VBL Therapeutics
VBL Therapeutics

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials
Yes
Mar 22VBL plans to seek initial marketing approval in Europe and Japan, in addition to the US. Its in-house gene therapy manufacturing plant in Israel has been certified by a European Union Qualified Person and is expected to be the first commercial facility for production of ofra-vec if it receives regulatory approval. VBL intends to bring on at least one additional manufacturing site to support long term scale up and label expansion activities for ofra-vec [11].
Mar 22OVAL top-line data for ofra-vec is expected H2 2022; with positive results, VBL anticipates submitting a Biologics License Application (BLA) in 1H 2023. They have established operations in the US [10].
Nov 21The Chemistry, Manufacturing, and Controls group of the FDA provided VBL clearance of VB-111 batches produced in its commercial-scale facility located in Modiin, Israel, for use in clinical trials in the US. Previously in Aug 21, VBL Therapeutics announced it plans file in the US within about a year [9].
Dec 19VBL summarises its development program for 2020; OVAL potential-registration study in ovarian cancer is recruiting patients in the US + Israel, with an interim analysis expected 1Q 20, which will include CA-125 analysis for efficacy [5].
Oct 17Has orphan drug status in EU [4].

Category

Anti-angiogenic agent. First-in-class, targeted gene therapy consists of a non-replicating adenovirus vector with a pre-proendothelin-1 (PPE-1-3x) promoter that encodes a Fas-Chimera transgene apoptotic receptor in tumour blood vessel endothelial cells
Crude ovarian cancer incidence rate in the UK in 2015 was 11.2 per 100,000 women. Incidence rates for ovarian cancer are projected to rise by 15% in the UK between 2014 and 2035, to 32 cases per 100,000 females by 2035 [1].
Recurrent platinum-resistant ovarian cancer
Intravenous infusion

Trial or other data

Nov 21More than 85% of the planned 400 patients have been enrolled in the registrational OVAL study. The independent Data Safety Monitoring Committee (DSMC) conducted its fifth pre-planned data review and provided clearance to proceed as planned with no changes to the protocol [9].
Dec 20VBL Therapeutics announced the expansion of the OVAL study into Europe, where the first patient has now been enrolled. The study continues to actively recruit patients in the U.S. and Israel, with over 200 patients enrolled to date. This is expected to accelerate the recruitment pace, diversify the patient population in the study and support dialogue with European regulatory authorities. Interim analysis from OVAL demonstrated significant response rate of 58% or higher in the first 60 patients. According to the Company update on November 16, 2020, the high response rate of >50% in the total evaluable patient population was still maintained with approximately 200 patients enrolled. The EU expansion follows two completed analyses by the independent Data Safety Monitoring Committee (DSMC) which recommended to continue the study as planned. The next DSMC review is expected in Q1 2021 [8].
Mar 20Positive outcome of interim analysis of PIII OVAL ovarian cancer pivotal study. The study met the interim pre-specified efficacy criterion, of an absolute % advantage of >10% CA-125 response rate for the VB-111 treatment arm. Assuming a balanced randomisation, the response rate in the treatment arm (VB-111 + weekly paclitaxel) is 58% or higher. In pts who had post-dosing fever (a marker for VB-111 treatment), the response rate is 69%. [7]
Dec 19PIII OVAL trial is recruiting; collection of primary outcome data on course to complete by Dec 22 [6].
Nov 18VBL expects an efficacy interim readout in Q4 2019 [3].
Mar 18VBL Therapeutics reports that modification in the OVAL protocol is underway to incorporate an efficacy interim readout [3].
Dec 17PIII OVAL trial to compare VB-111 and paclitaxel to placebo and paclitaxel in 400 women with recurrent platinum-resistant ovarian cancer starts (VB111-701/GOG3018; NCT03398655). Patients will be recruited in the US and Israel. The primary endpoint is overall survival; collection of these data is due to complete Dec 22 [2].

Recurrent glioblastoma multiforme

Information

Licence extension / variation
VBL Therapeutics
VBL Therapeutics

Development and Regulatory status

None
None
Phase III Clinical Trials
Nov 21Enrollment continues in the VB-111 investigator-sponsored PI trial with preliminary data expected H2 22 [15].
Mar 21Orphan drug status granted in both EU and US. PII study NCT04406272 starts [14].
Jan 21VBL notes that the new PII study implements lessons learnt from the GLOBE study. The study will enrol recurrent GBM patients undergoing a second surgery. VB-111 will be administrated either before (´neo-adjuvant´) and after the surgery (´adjuvant´), or just after the surgery. The primary endpoint of this new study is an immunological readout, increase in tumor infiltrating T lymphocyte (TIL) within the tumour. Secondary endpoints include progression free survival at 6 months (PFS-6) and overall survival (OS) [13].
Dec 19VBL announces that its development plan for 2020 is to begin an investigator-initiated randomised controlled PII study in rGBM in Q1 20, with readout expected 1H 2021 [10].
Feb 15US FDA announces that VBL may proceed with a pivotal PIII trial in rGBM and has removed the clinical hold previously imposed on the study. VBL plans to initiate this trial in mid-2015 under a special protocol assessment with the FDA [1].

Category

Anti-angiogenic agent. First-in-class, targeted gene therapy consists of a non-replicating adenovirus vector with a pre-proendothelin-1 (PPE-1-3x) promoter that encodes a Fas-Chimera transgene apoptotic receptor in tumour blood vessel endothelial cells
Neuroglial tumours account for 80% of primary brain tumours. Glioblastoma multiforme (GBM) is the most common glioma to occur. Primary brain tumours represent 1.6% of all tumours in the UK. It has been estimated that the lifetime risk of developing brain and other CNS cancer is 1/133 for men and 1/185 for women in the UK. The incidence of brain and CNS tumours in the UK in 2007 was 6.8 per 100,000 (male 8.1 per 100,000 and female 5.6 per 100,000) [2].
Recurrent glioblastoma multiforme
Intravenous infusion

Trial or other data

Oct 21PII trial (NCT04406272) is recruiting and now due to finish collecting primary outcome data in Feb 23 [16].
Aug 19PII investigator-initiated trial starts recruiting (NCT04406272) and is due to complete collection of primary outcome data in Aug 22 [12].
Jun 19VBL Therapeutics initiates an investigator-sponsored trial, investigating use of ofranergene obadenovec, in the treatment of recurrent glioblastoma. The primary endpoint of the study is to investigate whether administration of VB 111 prior to surgery can result in an increase in tumour infiltrating T lymphocyte within the rGBM tumor. Secondary endpoints include progression free survival at six months and overall survival. The randomised, controlled trial intends to enrol approximately 45 patients in the US. The study is designed to generate results that can be part of a future filing with the regulatory authorities [11].
Jun 19MRI comparison data from an analysis conducted by UCLA, from the PII VB-111-122 study and PIII GLOBE trial showed objective responses to VB-111 monotherapy. VB-111 responders showed a survival advantage [11].
Nov 18VBL presents further data from the GLOBE study at the 2018 Society for Neuro-Oncology Annual Meeting. Overall, subjects in the study had relatively high tumor volume, as large-volume tumors were not an exclusion criterion. Patients with smaller tumors (<15 cm3) appeared to respond better to the treatment arm, with numerically higher response rate and overall survival observed. Also a trend towards greater survival was seen in patients treated with VB-111 who reported fever. Subsequent analyses have focused on potential reasons for the major differences in outcomes between the positive VB-111 PII trial and the unsuccessful GLOBE results. The PII 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 PII and the PIII 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 PII and PIII treatment cohorts was in the treatment regimen – the regimen for PII trial included priming with VB-111 whereas the regimen for GLOBE trial did not. To test the hypothesis that concomitant treatment with bevacizumab may have a negative effect on VB-111 activity, VBL investigated this combination in a pre-clinical tumor model. The results indicate that treatment with VB-111 in combination with bevacizumab appears to block the anti-tumor the effect of VB-111 vs. VB-111 monotherapy. Plus, a retrospective analysis of a cohort of 10 patients treated concomitantly with VB-111 and bevacizumab for safety evaluation (no priming), was inferior to what was observed with VB-111 priming in the PII study. VBL plans to work with UCLA scientists in performing thorough analyses of MRI scans for VB-111-primed combination arm patients from the PII trial vs. un-primed combination arm patients in the GLOBE trial [9].
Sep 18PIII GLOBE study completes [8].
Mar 18VBL announces that the primary endpoint of overall survival was not met in the GLOBE study [7].
Dec 17Topline data from GLOBE study expected early 2018 [6].
Oct 17The Data Safety Monitoring Committee for the GLOBE study has carried out its third and final safety review and has identified no new concerns. The trial will therefore continue as planned to completion, expected at the end of 2017 [5].
Nov 16PIII GLOBE study in relapsed GBM (NCT02511405) is comparing VB-111 in combination with bevacizumab to bevacizumab alone and 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) [4].
Nov 16PII study in rGBM found 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 [4].
Jan 14PI/II (NCT01260506) study to evaluate the safety, tolerability, and efficacy of VB-111 in 90 patients with relapsed GBM in the US & Israel is currently recruiting pts. Collection of primary outcome data (progression-free survival) is expected to complete in Jan 15 [3].

Recurrent, iodine-resistant differentiated thyroid cancer

Information

Licence extension / variation
VBL Therapeutics
VBL Therapeutics

Development and Regulatory status

None
None
Phase II Clinical Trials
Oct 21VBL is still focussing on ovarian cancer, colorectal cancer and glioblastoma - thyroid cancer not listed amongst its current studies [8].
Dec 19VBL continues to focus on development of VB-111 for ovarian cancer and glioblastoma [7].
Nov 18No PIII development yet started in thyroid cancer. VBL is concentrating its finances on development of VB-111 for ovarian cancer and developing two independent platforms of proprietary monoclonal antibodies targeting MOSPD2 [6].
Dec 17Remains PII [5].

Category

Anti-angiogenic agent. First-in-class, targeted gene therapy consists of a non-replicating adenovirus vector with a pre-proendothelin-1 (PPE-1-3x) promoter that encodes a Fas-Chimera transgene apoptotic receptor in tumour blood vessel endothelial cells
UK age-standardised incidence rate of thyroid cancer is 3.2 per 100,000 population; anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid tumour & accounts for (<2% of all thyroid tumours [10]. Occurs in 800 to 1,000 patients each year in the US and a similar number in the EU with a reported median survival around 3-4 months; < 10% survive one year [2].
Recurrent, iodine-resistant differentiated thyroid cancer
Intravenous infusion

Trial or other data

Feb 17VBL Therapeutics presents more data from a PII trial of VB-111 monotherapy in thyroid cancer patients. The release adds evidence of dose response to support the previously reported difference in progression-free survival between the low- and high-dose cohorts. The tumor measurements of seven of the 16 patients in the high-dose cohort fell after one dose of the angiogenic drug, compared to a reduction in one of the 11 participants who received the low, sub-therapeutic dose. VBL sees the data as adding to evidence of dose-dependent responses. The data on the effect of one dose of VB-111 are in line with earlier results on the proportion of patients who went six months without progressing when given the drug every two months. In the 2015 release of top-line data, VBL reported six of the 17 patients in the high-dose arm—and three of 12 in the low-dose cohort—went six months or more without progressing. Those figures were repeated when VBL presented a look at overall survival results last year. In the latest release, VBL reported eight of the 17 patients in the high-dose cohort went six months or more without progressing, compared to six of 17 in previous publications. VBL also reported different numbers for the low-dose arm—four out of 12 versus three out of 12—but still said 25% of the subjects met the six-month progression-free survival endpoint. A spokesperson for VBL said the difference is because the original release featured top-line data, whereas the most recent update uses clean full data after data lock and analysis done by the independent biostatistician [4].
Oct 15VBL Therapeutics announced positive results from its multicohort open-label, dose-escalating trial, PII trial (n=29) of VB-111 in advanced radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). The pre-specified primary trial endpoint of 6-month Progression Free Survival (PFS) for at least 25% of enrolled pts was met (25% in the VB-111 high-dose cohort vs. 0% in the low-dose cohort), showing a dose response for VB-111. Several pts also had complete or partially resolution of metastatic lesions or lymph nodes. Pts in the trial have a median overall survival (OS) of 20 months (18 months in the low-dose cohort and 22 months in the high-dose cohort). Nine pts remain alive – one in the low-dose cohort (8%) and eight in the high-dose cohort (47%), all of whom are beyond 18 months and still being followed. VB-111 was well tolerated in the majority of pts with some pts reporting modest flu-like symptoms following infusion. Safety was consistent with the favourable safety and tolerability across more than 170 cancer pts across the whole VB-111 study program [3].
Dec 14VBL Therapeutics (VBLX) Announces Positive exploratory Phase 2a Data for VB-111 in 30 pts with recurrent, iodine-resistant differentiated thyroid cancer. Most of the included pts had failed on several therapeutic lines, including tyrosine kinase inhibitors, prior to enrolment. VB-111 demonstrated disease stabilisation and safety in the open label, dose-escalating study, which was designed to assess the compound´s safety and signal of efficacy. Thirteen pts received a sub-therapeutic single dose of VB-111 17 received VB-111 every 2 months until disease progression. Six pts (35%) in the therapeutic dose cohort (n=17) met the primary endpoint of 6-month progression-free survival using Response Evaluation Criteria in Solid Tumors (RECIST), compared to three pts (23%) in the low dose cohort (n=13). VB-111 was well-tolerated in both stages of this study, with no signs of clinically significant safety issues [1].