Periodic Reporting for period 1 - OVAL (The OVAL study for VB-111 treatment of platinum-resistant ovarian cancer)
Berichtszeitraum: 2022-04-01 bis 2023-03-31
VBL therapeutics is a late-stage clinical biopharmaceutical company focused on first in class treatments for cancer. VBL's lead oncology product candidate, VB-111, is an innovative targeted anti-cancer gene therapy with potential to treat a wide range of solid tumors. Most cancer therapies aim to target tumor cells while sparing normal cells, but tumors are heterogeneous and often develop resistance to treatment. Instead of targeting the tumor directly, VB-111 targets the tumor microenvironment by disrupting the blood vessels that supply blood to the tumor and by recruiting the immune system into the tumor. VBL is pursuing Ovarian Cancer as the first indication for VB-111. In the scope of this project, VBL will finalize the OVAL study, an international Phase 3, randomized, placebo-controlled registration-enabling clinical trial in platinum-resistant ovarian cancer (PROC). In addition, VBL will execute all the necessary steps towards final regulatory approvals and commercialization of VB-111.
Recruitment to the OVAL trial tool place between December 2017 and March 2022. During this time 537 patients were screened and 409 enrolled at 86 clinical sites in US, Israel, Spain, Poland and Japan. The trigger to perform the PFS primary analysis was reached in May 2022. After this time point intense activities took place in order to prepare the study for database lock and analysis of the primary endpoint.
The results that were presented to VBL by the DSMC on July 2022 indicated that the trial was negative and the final PFS and interim OS analysis were not met. With 42 patients ongoing on treatment, it was not considered likely that this result would change if the final OS readout would be performed as initially planned in 2023 after a longer duration of observation. Therefore, the study was terminated early according to the iDSMC recommendation after the first planned unblinded analysis.
Accordingly, VBL informed al Sites and Vendors regarding trial termination, and initiated all the trial closing activities including on-site close-out visits at each of the sites by the blinded and unblinded CRAs. Regulatory submissions for study close-out, generation of patient CSR and distribution to the sites.
Simultaneously, the statistical analyses were finalized and the Clinical Study Report was drafted and prepared for regulatory submission.
The results that were presented to VBL by the DSMC on July 2022 indicated that the trial was negative and the final PFS and interim OS analysis were not met. With 42 patients ongoing on treatment, it was not considered likely that this result would change if the final OS readout would be performed as initially planned in 2023 after a longer duration of observation. Therefore, the study was terminated early according to the iDSMC recommendation after the first planned unblinded analysis.
Accordingly, VBL informed al Sites and Vendors regarding trial termination, and initiated all the trial closing activities including on-site close-out visits at each of the sites by the blinded and unblinded CRAs. Regulatory submissions for study close-out, generation of patient CSR and distribution to the sites.
Simultaneously, the statistical analyses were finalized and the Clinical Study Report was drafted and prepared for regulatory submission.
At the cut-off date, 204 patients were randomized to the ofra-vec arm and 205 to the control arm. A similar number of patients in each of the treatment arms continued study treatment until disease progression by RECIST and were considered as having completed treatment per protocol; 143 (70.1%) completers in the ofra-vec arm compared to 146 (71.2%) in the control arm.
Exposure to study medications was similar in both arms.
Demographic variables and baseline disease characteristics were as expected for the patient population recruited, were well balanced between the treatment arms, and showed only minimal differences, which would not be expected to impact the validity or interpretation of the results. Patients in both arms were heavily pre-treated.
All patients were considered platinum resistant or refractory, (excluding 2 patients (1%) in each arm who were enrolled despite not meeting this eligibility criterion).
Efficacy
All 204 patients in the ofra-vec arm and 205 in the control arm were evaluable for efficacy. The PFS primary endpoint was not met.
The secondary endpoint of ORR was also not.
Exploratory analyses compared the primary efficacy endpoints in various patient subgroups. The most significant results were obtained for the post-randomization subgroup of patients who had a CA-125 response (CR or PR), which was associated with substantially improved PFS and OS in both treatment arms. See full report for more details.
Safety
The safety analysis set included 406 patients with 203 in each of the two treatment arms. Ofra-vec was well tolerated as evidenced by a low rate of treatment discontinuations due to AEs; In the ofra-vec arm 8 patients [3.9%] discontinued ofra-vec/placebo due to an AE compared to 14 [6.9%] in the control arm, and 14 [6.9%] discontinued paclitaxel due to an AE compared to 20 [9.9%] in the control arm.
Almost all patients experienced at least one AE. Seven patients reported AEs with fatal outcomes; 3 in the treatment arm (pneumonia, AML, and hypovolemic shock) and 4 in the control arm (sepsis in 1 patient, sepsis and general physical health deterioration in 1 patient, sepsis and necrotizing fasciitis in 1 patient, and intestinal perforation in 1 patient). None of the fatal AEs was considered related to study treatment.
Serious AEs (SAEs) were reported by 63 (31.0%) patients in the ofra-vec arm and 54 (26.6%) in the control arm. Some SAEs were more commonly reported in the ofra-vec than the control arm. SAEs related to ofra-vec were reported by 12 (5.9%) in the ofra-vec arm; pyrexia (4 patients), anemia (2 patients), and infusion related reaction, pneumonitis, duodenal perforation, pulmonary embolism, fatigue, dehydration, cerebrovascular accident, deep vein thrombosis (one patient each). This compared to 6 (3.0%) patients in the control arm reporting SAEs related to ofra-vec/placebo; one case each of enterovesical fistula, anemia, pneumonitis, sepsis, febrile neutropenia, pulmonary embolism.
Grade ≥ 3 AEs were reported by 123 (60.6%) patients and 109 (53.7%) in the ofra-vec and control arms, respectively. Of these, 52 (25.6%) in the ofra-vec arm were considered related to ofra-vec/placebo compared to 30 (14.8%) in the control arm.
AEs considered related to ofra-vec or placebo were more common in the ofra-vec arm (183 [90.1%] patients) than in the control arm (154 [75.9%] patients). These events were generally low grade, responded well to antipyretic treatment and resolved within 1-2 days. These differences are expected based on the viral vector nature of ofra-vec.
No new or unexpected safety findings arose during the study. There was no increased incidence of AEs known to be associated with anti-angiogenic agents such as hypertension, proteinuria, gastrointestinal perforation, bleeding, hemorrhage. The pattern of AEs observed reflected the product’s established safety profile and was as expected for an adenovirus based viral therapy. See full report for more details.
Conclusions:
Neither the final PFS or interim OS primary endpoints were met, and the study could not support an efficacy claim in the overall population of patients PROC.
The two treatment groups were well balanced for all relevant background and demographic characteristics. Patients in both treatment groups were heavily pre-treated with a mean of 3 prior lines of anti-cancer therapies, and 60%-70% in each of the groups previously being treated with anti-angiogenics and/or PARP inhibitors. The PFS and ORR results of the control group exceeded the results that were anticipated based on historic results of the AURELIA chemotherapy control group.
In both treatment groups a CA-125 response was associated with substantially improved PFS and OS indicating that CA-125 response is a prognostic biomarker for patients with platinum-resistant ovarian cancer treated with paclitaxel.
Exposure to study medications was similar in both arms.
Demographic variables and baseline disease characteristics were as expected for the patient population recruited, were well balanced between the treatment arms, and showed only minimal differences, which would not be expected to impact the validity or interpretation of the results. Patients in both arms were heavily pre-treated.
All patients were considered platinum resistant or refractory, (excluding 2 patients (1%) in each arm who were enrolled despite not meeting this eligibility criterion).
Efficacy
All 204 patients in the ofra-vec arm and 205 in the control arm were evaluable for efficacy. The PFS primary endpoint was not met.
The secondary endpoint of ORR was also not.
Exploratory analyses compared the primary efficacy endpoints in various patient subgroups. The most significant results were obtained for the post-randomization subgroup of patients who had a CA-125 response (CR or PR), which was associated with substantially improved PFS and OS in both treatment arms. See full report for more details.
Safety
The safety analysis set included 406 patients with 203 in each of the two treatment arms. Ofra-vec was well tolerated as evidenced by a low rate of treatment discontinuations due to AEs; In the ofra-vec arm 8 patients [3.9%] discontinued ofra-vec/placebo due to an AE compared to 14 [6.9%] in the control arm, and 14 [6.9%] discontinued paclitaxel due to an AE compared to 20 [9.9%] in the control arm.
Almost all patients experienced at least one AE. Seven patients reported AEs with fatal outcomes; 3 in the treatment arm (pneumonia, AML, and hypovolemic shock) and 4 in the control arm (sepsis in 1 patient, sepsis and general physical health deterioration in 1 patient, sepsis and necrotizing fasciitis in 1 patient, and intestinal perforation in 1 patient). None of the fatal AEs was considered related to study treatment.
Serious AEs (SAEs) were reported by 63 (31.0%) patients in the ofra-vec arm and 54 (26.6%) in the control arm. Some SAEs were more commonly reported in the ofra-vec than the control arm. SAEs related to ofra-vec were reported by 12 (5.9%) in the ofra-vec arm; pyrexia (4 patients), anemia (2 patients), and infusion related reaction, pneumonitis, duodenal perforation, pulmonary embolism, fatigue, dehydration, cerebrovascular accident, deep vein thrombosis (one patient each). This compared to 6 (3.0%) patients in the control arm reporting SAEs related to ofra-vec/placebo; one case each of enterovesical fistula, anemia, pneumonitis, sepsis, febrile neutropenia, pulmonary embolism.
Grade ≥ 3 AEs were reported by 123 (60.6%) patients and 109 (53.7%) in the ofra-vec and control arms, respectively. Of these, 52 (25.6%) in the ofra-vec arm were considered related to ofra-vec/placebo compared to 30 (14.8%) in the control arm.
AEs considered related to ofra-vec or placebo were more common in the ofra-vec arm (183 [90.1%] patients) than in the control arm (154 [75.9%] patients). These events were generally low grade, responded well to antipyretic treatment and resolved within 1-2 days. These differences are expected based on the viral vector nature of ofra-vec.
No new or unexpected safety findings arose during the study. There was no increased incidence of AEs known to be associated with anti-angiogenic agents such as hypertension, proteinuria, gastrointestinal perforation, bleeding, hemorrhage. The pattern of AEs observed reflected the product’s established safety profile and was as expected for an adenovirus based viral therapy. See full report for more details.
Conclusions:
Neither the final PFS or interim OS primary endpoints were met, and the study could not support an efficacy claim in the overall population of patients PROC.
The two treatment groups were well balanced for all relevant background and demographic characteristics. Patients in both treatment groups were heavily pre-treated with a mean of 3 prior lines of anti-cancer therapies, and 60%-70% in each of the groups previously being treated with anti-angiogenics and/or PARP inhibitors. The PFS and ORR results of the control group exceeded the results that were anticipated based on historic results of the AURELIA chemotherapy control group.
In both treatment groups a CA-125 response was associated with substantially improved PFS and OS indicating that CA-125 response is a prognostic biomarker for patients with platinum-resistant ovarian cancer treated with paclitaxel.