Phase 3 OVAL Trial With VB-111 in Platinum-Resistant Ovarian Cancer to Continue

The independent data safety monitoring committee (DMSC) has unanimously recommended that the phase 3 OVAL trial (NCT03398655) examining VB-111 (ofranergene obadenovec) in patients with platinum-resistant ovarian cancer continue as planned, according to an announcement from VBL Therapeutics.¹

The recommendation followed the completion of a second, prespecified interim analysis of the trial, in which the DMSC evaluated the unblinded overall survival (OS) data collected on the first 100 participants who underwent randomization and had follow up for at least 3 months. Data pertaining to response rates and safety were also examined.

“We are pleased by the DSMC recommendation to continue the OVAL study as planned,” Dror Harats, MD, chief executive officer of VBL Therapeutics, stated in a press release. “This is the second successful analysis in the OVAL study, which reviewed unblinded OS data comparing VB-111 with placebo.”

In March 2020, the investigational agent was reported to have met the prespecified efficacy criterion in the phase 3 trial. The combination of VB-111 and paclitaxel was found to have reached the predetermined benchmark of an absolute percentage advantage of 10% or more in CA-125 response versus paclitaxel alone.²

Specifically, the CA-125 response rate achieved with the combination in the first 60 randomized evaluable participants across both treatment arms was 53%. The response rate in the investigational arm, assuming a balanced randomization, was reported to be 58% or higher. Moreover, in those with post-dosing fever, the response rate with the treatment was 69%.

The international, double-blind, phase 3 trial has a target enrollment of 400 participants with recurrent platinum-resistant ovarian cancer. To be eligible to participate, patients had to be 18 years of age or older, have histologically confirmed epithelial ovarian cancer and have platinum-resistant disease that was also measurable per RECIST v1.1 criteria, which requires treatment with chemotherapy.³

Patients also had to have an ECOG performance status of 0 to 1 and acceptable hematologic functions. Notably, patients with BRCA-mutant disease who experienced disease progression on a PARP inhibitor were permitted to enroll, as well as those ineligible for or intolerant of PARP inhibition.

Those with non-epithelial tumors, ovarian tumors with low malignant potential clear cell carcinomas, grade 1 serous tumors, or mucinous cancers, were not eligible to participate. Patients who received previous treatment with over 5 regimens for their ovarian cancer or any previous radiotherapy to the pelvis or abdomen were also not permitted, among others.

In the trial, patients were randomized to receive VB-111 plus paclitaxel or placebo plus paclitaxel. In the experimental arm, VB-111 was given intravenously at a dose of 1 x 1013 viral particles bimonthly, and paclitaxel was also given intravenously but at a weekly dose of 80 mg/m².

The primary end point of the trial is OS, and key secondary end points include progression-free survival, combined CA-125 and RECIST v1.1 response, CA-125 response, and objective response rates per RECIST v1.1 criteria.

“The OVAL study continues to show strong recruitment despite the COVID-19 pandemic, and we are encouraged by the high remarkable response rate observed in our first interim efficacy analysis and the survival benefit seen in the phase 2 trial of VB-111 in patients with platinum-resistant ovarian cancer, support the confidence we have in OVAL,” Harats added. “We are excited to advance VB-111 for the potential benefit of [patients with] ovarian cancer.”

Previous data with VB-111 plus paclitaxel were reported from a prospective, open-label, dose-escalating phase 1/2 study (NCT01711970) in platinum-resistant ovarian cancer. Here, the median age of participants was 65 years and they had received a median of 3 prior lines of treatment. In the phase 2 portion of the research, the investigational agent was given at 1x1013 viral particles every 8 weeks plus paclitaxel at 80 mg/m² weekly.

Results showed that more than half, or 58% of evaluable participants experienced a CA-125 response with the combination, and the median OS was 498 days.⁴ Notably, efficacy with the approach was demonstrated, despite the unfavorable prognostic characteristics of the study population; half of the patients had platinum-refractory disease.

Moreover, a favorable OS trend was observed in patients who experienced over a 50% reduction in CA-125. Here, posttreatment fever was found to be associated with improved OS; those with fever following treatment had an OS of 808 days compared with 479 days in those without fever (P = .27).

With regard to safety, no dose-limiting toxicities were reported with the combination. Overall, the investigational agent was found to be well tolerated, although mild, flu-like symptoms had been observed in some participants.

References

1. VBL Therapeutics announces second successful pre-planned interim analysis with a positive data safety monitoring committee review looking at OS – the primary endpoint of the OVAL phase 3 potential registration study of VB-111 in ovarian cancer. News release. VBL Therapeutics. August 12, 2020. Accessed August 12, 2020. https://bit.ly/2XUno6J.
2. VBL Therapeutics announces positive outcome of the interim analysis in the OVAL phase 3 ovarian cancer pivotal study. News release. VBL Therapeutics. March 26, 2020. Accessed August 12, 2020. https://bit.ly/2Cm0Wfr.
3. A study of VB-111 with paclitaxel vs paclitaxel for treatment of recurrent platinum-resistant ovarian cancer (OVAL) (OVAL). ClinicalTrials.gov. Updated June 30, 2020. Accessed August 12, 2020. https://clinicaltrials.gov/ct2/show/NCT03398655.
4. VBL final phase 1/2 study results presented at ASCO demonstrate VB-111 dose dependent Increase in overall survival and 58% CA-125 response rate in platinum-resistant ovarian cancer. News release. VBL Therapeutics. June 3, 2019. Accessed August 12, 2020. https://bit.ly/3axNS2x.