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The combination of ofranergene obadenovec and paclitaxel failed to elicit a statistically significant improvement in progression-free survival or overall survival compared with paclitaxel alone in patients with platinum-resistant ovarian cancer, missing the coprimary end points of the OVAL trial.
The combination of ofranergene obadenovec (ofra-vec; VB-111) and paclitaxel failed to elicit a statistically significant improvement in progression-free survival (PFS) or overall survival (OS) compared with paclitaxel alone in patients with platinum-resistant ovarian cancer, missing the coprimary end points of the study, according to topline findings from the phase 3 OVAL trial (NCT03398655).1
The results showed that the median PFS was 5.29 months with the combination vs 5.36 months with paclitaxel alone (HR, 1.03). The interim OS analysis was also not significantly different between the study arms, with a median OS of 13.37 months and 13.14 months, respectively (HR, 0.97).
“Given the urgent unmet need for those fighting platinum-resistant ovarian cancer, we are deeply disappointed that the top-line data indicate that ofra-vec did not improve progression-free survival or overall survival,” Dror Harats, MD, chief executive officer of VBL Therapeutics, said in a news release. “Based on this outcome, we plan to discontinue the OVAL trial and will review the data from our ongoing phase 2 trials in metastatic colorectal cancer and recurrent glioblastoma multiforme to determine next steps with the ofra-vec program. We extend our deepest gratitude to all the patients, families and healthcare professionals who participated in this trial.”
Ofra-vec is a targeted anticancer viral gene therapy designed to use a dual mechanism to target several solid tumors, including ovarian cancer. The mechanism combines the inhibition of tumor vasculature with an antitumor immune response.
In April 2022, the FDA granted a fast track designation to the agent for use as a potential therapeutic option in patients with platinum-resistant ovarian cancer.2 Prior data from a phase 1/2 trial (NCT01711970) demonstrated that the combination of ofra-vec and paclitaxel was safe and effective in this patient population.3,4
OVAL was an international, phase 3, randomized, double-blind, placebo-controlled, trial that compared the combination of ofra-vec and paclitaxel with placebo plus paclitaxel in 409 adult patients with recurrent platinum-resistant ovarian cancer.
Eligible patients were at least 18 years of age with histologically confirmed epithelial ovarian cancer and platinum resistance. Additionally, patients had to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria that required chemotherapy treatment, and acceptable hematologic function.5
Patients were randomly assigned to ofra-vec plus paclitaxel or placebo plus paclitaxel. Investigators administered itravenous (IV) ofra-vec at 1 x 1013 viral particles every 2 months. Both treatment arms received 80 mg/m2 of IV paclitaxel weekly.
The primary end points of the trial were OS and PFS. Secondary end points included combined CA-125 and RECIST v1.1 response, CA-125 response, objective response rate per RECIST v1.1 criteria, and OS100 for a sensitivity analysis of OS.
In March 2020, OVAL was allowed to continue without modification after an independent data safety monitoring committee (DMSC) determined that the combination hit the prespecified benchmark of an absolute percentage advantage of at least 10% in CA-125 response vs placebo plus paclitaxel.6
Specifically, the combination led to a CA-125 response rate of 53% in the first 60 evaluable patients across both treatment arms. The response rate in the investigative arm, assuming a balanced randomization, was 58% or higher. Additionally, in those with post-dosing fever, a known marker for VB-111, the reported response rate with the regimen was 69%.
Subsequently, in August 2020, the DMSC evaluated the unblinded OS data collected on the first 100 participants who underwent randomization and had at least 3 months of follow up. Based on these findings, they unanimously recommended that the trial to continue.7 As of November 16, 2020, a high response rate of over 50% in evaluable patients was maintained with approximately 200 patients enrolled.
The following year, in February 2021, the trial received another green light to continue, after a review of unblinded data from 370 randomized patients did not reveal any safety issues.8