Safety Review for OVATION 2 Trial Examining GEN-1 in Advanced Ovarian Cancer Has Positive Results

Michael H. Tardugno

The Data Safety Monitoring Board (DSMB) for the ongoing phase 1/2 OVATION 2 trial (NCT033393884) has unanimously recommended that patients continue to receive treatment with the novel gene-mediated immunotherapy, GEN-1, at a dose of 100 mg/m².¹

The recommendation follows a preplanned interim safety review of 81 patients with newly diagnosed stage III/IV disease who underwent randomization on the trial and received treatment with the investigational agent plus standard-of-care (SOC) neoadjuvant chemotherapy (NACT).

The DSMB continued to find the safety of GEN-1 to be satisfactory, with an acceptable risk/benefit profile. Moreover, patients were found to be able to tolerate up to 17 doses of the immunotherapy during a treatment course that lasted for up to 6 months. Notably, no dose-limiting toxicities (DLTs) were observed in this population.

“We thank the DSMB members for their work and advice,” Michael H. Tardugno, chairman, president, and chief executive officer at Celsion Corporation, stated in a press release. “FDA fast track and orphan drug designations for GEN-1 in advanced ovarian cancer are important for our future commercialization efforts. In addition, under the Biologics Price Competition and Innovation Act of 2009, sponsors of new, licensed biological products like GEN-1 that are approved through a biologics license application receive 12 years of market exclusivity.”

GEN-1 was developed to produce safe and durable local levels of interleukin-12 (IL-12), which has been linked with the production of innate and adaptive immune responses against cancer. The nanoparticle is made up of a DNA plasmid that encodes the IL-12 gene and a synthetic polymer that enables the plasmid delivery vector. After cell transfection, the IL-12 protein is consistently locally secreted at therapeutic levels.

OVATION 2 enrolled patients with a suspected histologic diagnosis of epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.2 Patients needed to have FIGO grade III or IV disease, an ECOG performance status ranging from 0 to 2, and acceptable bone marrow, renal, hepatic, and neurologic function.

If patients previously received GEN-1, had a history of allergic reactions attributed to compounds with a similar chemical or biologic composition to GEN-1, previously received oral or parenteral corticosteroids within 2 weeks of study entry, or were receiving treatment for active autoimmune disease, they were excluded.

Those enrolled to the trial received NACT and then underwent interval debulking surgery. Thereafter, they received 3 adjuvant cycles of chemotherapy and up to 9 additional weekly treatments of GEN-1.

Patients randomized to the investigative arm were given intravenous paclitaxel at 175 mg/m², which was followed by carboplatin at area under the curve of 6 on day 1; this was repeated every 3 weeks for 6 treatment cycles. The immunotherapy was administered at a dose of 100 mg/m² on days 8 and 15 of the first cycle of NACT for a total of 17 treatments. Those in the control arm were given the same NACT regimen.

The trial was 80% powered to showcase the equivalent of a 33% improvement in progression-free survival (PFS; HR, 0.75), which was the primary end point, compared with the control arm of NACT only.

To date, more than 75% of the projected 110 patients have been enrolled to the trial, and interim clinical findings from the first 39 patients who have undergone surgery showed that those who received immunotherapy experienced a 27% improvement in R0 surgical resection rate vs those who received NACT alone.

Earlier data from OVATION 2 showed that among 22 patients who received GEN-1 at 0 mg/m², 36 mg/m², or 47 mg/m², in combination with chemotherapy, 50% experienced R0 resections.³ In 28 patients who received the immunotherapy at higher doses of 61 mg/m², 79 mg/m², or 100 mg/m², 82% achieved R0 resections.

Previously, findings from the phase 1 OVATION 1 trial (NCT02480374) demonstrated that the addition of GEN-1 to NACT had preliminary safety and clinical activity, with an impact on the tumor microenvironment, in patients with advanced epithelial ovarian cancer.⁴

Specifically, no DLTs were observed with the approach. Of the 14 evaluable patients, 85.7% had a radiological response before undergoing debulking. Of the 12 responders, 2 had a complete response and 10 achieved a partial response (PR). At the time of debulking, 9 patients achieved R0, and 1 had a pathological complete response.

Moreover, increased levels of IL-12 and interferon-g were observed in the peritoneal washings because of the immunotherapy. Increased levels of myeloid dendritic cells and T effector memory cells were also noted in the peritoneal fluid. Within the tumor microenvironment, elevated CD8-positive T cells and reduced immunosuppression were also reported.

“Findings from our OVATION 1 and OVATION 2 studies show a consistent dose-dependent clinical response in both surgical outcome and tumor response, which is further supported by translational data of the tumor microenvironment,” Nicholas Borys, MD, executive vice president and chief medical officer at Celsion, added in the press release. “We are encouraged by the current rate of patient recruitment and expect to complete enrollment by mid-2022. The primary end point for the study is PFS, which we expect to report approximately 12 months after patient enrollment is completed.”

In February 2021, the FDA granted a fast track designation to GEN-1 for use as a potential therapeutic option in patients with advanced ovarian cancer.⁵

Celsion Corporation shared plans to request a breakthrough therapy designation from the regulatory agency for the immunotherapy based on the clinical data produced in these trials.

References

1. Celsion reports Data Safety Monitoring Board unanimous recommendation to continue dosing patients in the phase II portion of the OVATION 2 study with GEN-1 in advanced ovarian cancer. News release. Celsion Corporation; February 17, 2022. Accessed February 22, 2022. https://bit.ly/3BFBV9h
2. Study of GEN-1 with NACT for treatment of ovarian cancer (OVATION 2) (OVATION 2). ClinicalTrials.gov. Updated June 28, 2021. Accessed February 22, 2022. https://clinicaltrials.gov/ct2/show/NCT03393884
3. Celsion reports Data Safety Monitoring Board recommendation to continue dosing patients in the phase II portion of the OVATION 2 study with GEN-1 in advanced ovarian cancer. News release. Celsion Corporation; July 19, 2021. Accessed February 22, 2022. https://bit.ly/3zgJh0j
4. Thaker PH, Bradley WH, Leath CA, et al. GEN-1 in combination with neoadjuvant chemotherapy for patients with advanced epithelial ovarian cancer: a phase I dose-escalation study. Clin Cancer Res. 2021;27(20):5536-5545. doi:10.1158/1078-0432.CCR-21-0360
5. Celsion Corporation receives FDA fast track designation for GEN-1 in advanced ovarian cancer. News release. Celsion Corporation; February 22, 2021. Accessed February 22, 2022. http://bit.ly/3dBCpTE