OVATION-3 Trial of IMNN-001 Seeks to Confirm Feasibility of Targeting IL-12 to Boost Immune Responses in Ovarian Cancer

Premal Thaker, MD, MS

Despite decades of research, the standard of care (SOC) for patients with advanced ovarian cancer has remained largely unchanged for the past 25 years, and women diagnosed with this malignancy continue to face high rates of recurrence and poor prognoses.1 Clinical progress has been particularly limited in the domain of immunotherapy, where checkpoint inhibitors have repeatedly failed to demonstrate consistent survival benefits.2 This has somewhat tempered initial interest in developing immunotherapy approaches in this space; nevertheless, investigators remain committed to identifying strategies that can successfully leverage patients’ innate immune responses to reduce recurrence and boost survival.

“Right now, we don't have many upfront phase 3 clinical trials for our ovarian cancer patients. All of us who are in drug development believe a lot in the immune system, but are just trying to figure out the best way to harness it,” Premal Thaker, MD, MS, explained in an interview with OncLive®. “I have patients every day come and ask, ‘Can I get some type of immune therapy?’ When patients have a virus, [they think], ‘My immune system needs to rev itself up and help me get over this.’ In the same way, we need to be able to augment that [immune response] with cancer treatment.” Thaker is the David G. and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology, director of Gynecological Oncology Clinical Research, and interim chief of the Division of Gynecologic Oncology at Washington University School of Medicine in St. Louis, Missouri.

One emerging strategy involves the investigational immunotherapy IMNN-001, a novel interleukin-12 (IL-12) DNA plasmid vector delivered via nanoparticle encapsulation.1 Historically, efforts to leverage IL-12 have been hampered by systemic toxicities and limited efficacy.3 However, intraperitoneal delivery of IMNN-001 has demonstrated promising antitumor activity and a manageable safety profile, reigniting interest in IL-12–based immunotherapy as a viable approach for the treatment of patients with ovarian cancer.

Findings from the phase 2 OVATION 2 trial (NCT03393884) showed that IMNN-001 in combination with chemotherapy led to a clinically meaningful improvement in overall survival (OS), making it the first and only immunotherapy to produce this outcome in women with advanced ovarian cancer.1,4 These data provide the rationale for the ongoing confirmatory phase 3 OVATION 3 trial (NCT06915025), which aims to validate the OS benefit and further define the role of IL-12–based immunotherapy in the frontline treatment setting.

Intraperitoneal Delivery of IL-12 Could Overcome Prior Challenges With Drug Development

A more robust immune response in patients with ovarian cancer has long been associated with improved survival outcomes, Thaker explained. However, the field has historically struggled with how best to therapeutically harness the immune system to elicit such outcomes. Additionally, prior efforts to use recombinant human IL-12 in patients with ovarian cancer were unsuccessful, primarily due to poor tolerability.3 Patients frequently experienced significant adverse effects (AEs), including high fevers and flu-like symptoms, which limited clinical utility.

“Up until now, all of the immunotherapies that we've looked at, predominantly with chemotherapy, have been immune checkpoint inhibitors. They [essentially] only activate the T-cell portion of ovarian cancer, and we know ovarian cancer is a tumor that relies a lot on the immune system. If you have a more robust immune response, we can see better survival, and we've known that for a long time, but we've never known how to get the immune system to parlay itself against the cancer. [IMNN-001] is a very novel agent because it has that ability.”

IMNN-001 targets IL-12, a potent cytokine that activates both the adaptive and innate arms of the immune system.5 The current treatment strategy involves the administration of IL-12 directly into the peritoneal cavity, which contains the primary tumor microenvironment, via a plasmid vector.1 This localized delivery method minimizes systemic exposure, thereby reducing treatment-related toxicities and enhancing the likelihood of achieving a meaningful antitumor response at the tumor site, Thaker detailed.

IMNN-001 is being investigated in combination with standard chemotherapy, which remains a cornerstone of ovarian cancer management. One rationale for investigating immunotherapy in the neoadjuvant setting is that patients who are not initially candidates for surgery often present with a higher disease burden and greater clinical acuity, making them more likely to benefit from intensified treatment approaches, Thaker noted. Additionally, emerging evidence suggests that the presence of active tumor tissue during immunotherapy administration may enhance immune priming.6

“One of the reasons we wanted to look at [synergizing IMNN-001] with neoadjuvant chemotherapy in particular is that those patients] need something to [improve] longitudinal outcomes, as they're too sick to go to surgery first and their disease burden is high,” Thaker said. “Sometimes, when we use immunotherapy, it is not as effective because patients don't have the tumor “neoantigens” to act upon. It seems to make more sense to give [immunotherapy] with the actual chemotherapy prior to surgery, hopefully inducing that more long-term [T-cell] memory afterwards.”

This approach aligns with the evolving understanding of cancer immunobiology and supports the hypothesis that neoadjuvant strategies may elicit more robust and lasting immune responses in appropriately selected patients, Thaker concluded.

OVATION 2: Phase 2 Data Support Further Development of IMNN-001

Initial early-phase data with IMNN-001 previously demonstrated a favorable safety profile and initial signals of efficacy when administered either as monotherapy or in combination with systemic therapy in patients with advanced peritoneally metastasized primary or recurrent ovarian cancer.1 Subsequent data from the phase 1b OVATION 1 trial (NCT02480374) established the feasibility of combining IMNN-001 with carboplatin and paclitaxel in the neoadjuvant setting for patients with newly diagnosed ovarian cancer through a completed dose-escalation study.

Based on these findings, the phase 2 OVATION 2 trial was designed to investigate the addition of IMNN-001 to standard chemotherapy in patients with advanced ovarian cancer in the neoadjuvant and adjuvant settings.4 A total of 112 patients were randomly assigned to receive either SOC chemotherapy alone or in combination with IMNN-001 administered intraperitoneally both before and after interval debulking surgery each week.

The study identified 100 mg/m² as the recommended dose of IMNN-001, which was found to be tolerable. Critically, the trial demonstrated both a progression-free survival (PFS) and OS benefit with the addition of IMNN-001 to chemotherapy.

Findings presented at the 2024 SITC Annual Meeting showed that, at a median follow-up of 24 months, patients treated with IMNN-001 plus chemotherapy (n = 58) achieved a median OS of 40.5 months (95% CI, 28.09-not estimable) compared with 29.4 months (95% CI, 24.94-45.60) in the chemotherapy-only group (n = 54; HR, 0.74; 95% CI, 0.42-1.30; P = .2963).7 Median PFS was 14.9 months (95% CI, 12.55-21.19) in the IMNN-001 group vs 11.9 months (95% CI, 10.09-14.92) in the control group (HR, 0.79; 95% CI, 0.51-1.23; P = .2933). Rates of complete response at the time of debulking surgery were comparable between arms (n = 1 patient in each arm; 1.7% vs 1.9%, respectively).

Additionally, a subgroup analysis showed that among patients who received PARP inhibitors during treatment (n = 74), the median OS was not reached in the IMNN-001 arm compared with 37.1 months in the control arm (HR, 0.41; 95% CI, 0.13-1.28).

In December 2024, IMUNON, the developer of IMNN-001, reported updated findings from OVATION 2.8 With an additional 7 months of follow-up, early OS data continued to favor the investigational arm, demonstrating a median OS of 13.0 months with IMNN-001 plus chemotherapy, representing a significant benefit vs chemotherapy alone (HR, 0.69). More than one-third of enrolled patients survived beyond 36 months, with 62% of those long-term survivors in the IMNN-001 arm and 38% in the control arm. Additionally, over 10% of trial participants reached survival landmarks of 48 months or longer.

“We haven't been able to see a substantive OS benefit with all of the previous immunotherapy or checkpoint inhibitor trials. That was telling to us and is what prompted us to proceed with the phase 3 [trial]. To date, we're seeing some improvements, but not the sort of improvements we'd hoped to see. That's why you always need a confirmatory trial.”

Updated OS data from OVATION 2 are scheduled to be presented at the 2025 ASCO Annual Meeting.

Additional translational data released in February 2025 reinforced the regimen’s dose-dependent pharmacodynamic effects, demonstrating a 20% increase in intraperitoneal IL-12 levels at 100 mg/m² compared with the 79 mg/m² dose.9 Cytokine analysis demonstrated that the increase in IL-12 was localized to the peritoneal cavity with minimal to no systemic circulation of IL-12. This local elevation in IL-12 was accompanied by increases in interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), key downstream cytokines associated with anti-tumor immune responses.

Regarding safety, gastrointestinal AEs were more frequent in the experimental arm, though pain management protocols were reported to be effective.4 No serious immune-related AEs, including cytokine release syndrome, occurred, and the overall safety profile of the combination was considered manageable.

Thaker emphasized that one of the primary concerns in delivering intraperitoneal therapy is the potential for port-site infections, as the delivery system requires the placement of a catheter on the abdominal wall for drug administration into the abdominal cavity. However, given the historical use of intraperitoneal chemotherapy in ovarian cancer, many gynecologic oncologists are familiar with the technique, and infection risk was found to be manageable in OVATION 2.

An additional insight from the trial was the benefit of proactive symptom management, Thaker noted. During the study, premedication with analgesics was introduced to mitigate anticipatory discomfort, improving overall tolerability. Moreover, a therapeutic effect appeared to be observed across all dose levels administered.

“Interestingly, even though we couldn't get all patients to get all the doses, there did seem to be a benefit regardless of how many doses they received. The importance of this is that it does show that we're changing the immune system. We're able to not only administer [IMNN-001 safely] but also be able to see an effect, which could be variable in terms of the number of cycles of IMNN-001. The phase 3 study will be [more] informative [about the efficacy and dosing patterns of this agent] because things are powered differently.”

OVATION-3 Trial Overview

OVATION 3 is an open-label study designed to evaluate the safety and efficacy of IMNN-001 in combination with perioperative chemotherapy vs standard neoadjuvant chemotherapy alone.1,10 The intent-to-treat (ITT) population will include women with newly diagnosed, high-grade stage IIIC or IV epithelial ovarian, fallopian tube, or primary peritoneal carcinoma who are candidates for neoadjuvant chemotherapy and have an ECOG performance status of 0 to 2.

Upon enrollment, patients will be randomly assigned 1:1 to receive 100 mg/m² of IMNN-001 intraperitoneally on a weekly schedule in combination with neoadjuvant chemotherapy interval debulking surgery and adjuvant chemotherapy; or neoadjuvant chemotherapy alone.

“I hope people understand that administering [IMNN-001] where the cancer is located is maximizing the effectiveness of the treatment while generating the best clinical results for patients,” Thaker noted.

The study’s primary end point is OS, with surgical response score, chemotherapy response score, clinical response, and time to second-line treatment serving as key secondary end points. The trial will also explore several translational and immunologic endpoints to better understand treatment-associated immune modulation in this population.

A predefined subgroup analysis will focus on patients who are homologous recombination deficiency (HRD)–positive, including those with germline or somatic BRCA1 or BRCA2 mutations. These patients will receive FDA-approved PARP inhibitors as standard maintenance therapy.

“OVATION 2 was performed at a time where PARP inhibitors were not standard maintenance [therapies], so we did not regulate what [patients] had to get as a maintenance therapy afterwards. We saw that patients who had an HRD signature seemed to have a more robust response [with IMNN-001 vs those without]. The phase 3 study will be powered to evaluate that because we're hoping that might give us an earlier signal of benefit. On top of that, we'll be looking at all comers…because now we have better guidance on how to manage ovarian cancer than when we had originally designed OVATION 2.”

Notably, the trial was designed with operational flexibility and incorporates 2 event-driven interim analyses.10 The study will initially enroll 250 patients with HRD, representing approximately 50% of the epithelial ovarian cancer population, before expanding to an all-comers cohort of 500 patients, encompassing the full population.

This adaptive statistical design enables an accelerated timeline for data readout—potentially up to 2 years earlier than traditional designs—and includes provisions for early stopping for efficacy, thereby supporting the possibility of an expedited regulatory filing.

“We're trying to pull out those HRD patients, because if we do see that early signal, we would love to then be able to receive accelerated approval. In the trials to date, when we look at…the HRD segment of this patient population, the OS [benefit with immunotherapy] is not statistically significant. If we could achieve a statistically significant P value [for IMNN-001], that could change how we would treat these patients. That's why we have 2 interim analyses: if we can’t get the first shot on goal, then hopefully maybe the second shot will make it. We want to try to get effective medications to our patients as soon as possible.”

On March 24, 2025, IMUNON announced that the final study design for the phase 3 OVATION 3 trial had been established in collaboration with the FDA.11 Subsequently, on May 8, 2025, the company reported the activation of the first trial site at Washington University School of Medicine.9 Additional trial sites are currently being initiated, and investigators are preparing to begin patient enrollment.

“After we [see the data from] our first interim analysis, [we’d next like to see] how [IMNN-001 could benefit] our HR-proficient patients and whether we need to add another drug in combination or not? Bevacizumab [Avastin] is also utilized quite a bit in this disease, [for example]. There are some other avenues that we will explore based on other trials that might be getting more data by the time we start getting into the thick of the trial.”

References

1. Imunon announces first site initiated in pivotal phase 3 OVATION 3 study of IMNN-001 in newly diagnosed advanced ovarian cancer. News Release. IMUNON. May 8, 2025. Accessed May 13, 2025. https://investor.celsion.com/news-releases/news-release-details/imunon-announces-first-site-initiated-pivotal-phase-3-ovation-3
2. Connor AE, Lyons PM, Kilgallon AM, et al. Examining the evidence for immune checkpoint therapy in high-grade serous ovarian cancer. Heliyon. 2024;10(20):e38888. doi:10.1016/j.heliyon.2024.e38888
3. Jia Z, Ragoonanan D, Mahadeo KM, et al. IL12 immune therapy clinical trial review: Novel strategies for avoiding CRS-associated cytokines. Front Immunol. 2022;13:952231. doi:10.3389/fimmu.2022.952231
4. IMUNON presents positive data from phase 2 OVATION 2 clinical trial of IMNN-001 in advanced ovarian cancer at SITC 39th Annual Meeting. News Release. IMUNON. November 7, 2024. Accessed May 13, 2025. https://www.globenewswire.com/news-release/2024/11/07/2976849/0/en/IMUNON-Presents-Positive-Data-from-Phase-2-OVATION-2-Clinical-Trial-of-IMNN-001-in-Advanced-Ovarian-Cancer-at-SITC-39th-Annual-Meeting.html
5. Tugues S, Burkhard SH, Ohs I, et al. New insights into IL-12-mediated tumor suppression. Cell Death Differ. 2015;22(2):237-246. doi:10.1038/cdd.2014.134
6. Xie N, Shen G, Gao W, Huang Z, Huang C, Fu L. Neoantigens: promising targets for cancer therapy. Signal Transduct Target Ther. 2023;8(1):9. doi:10.1038/s41392-022-01270-x
7. Thaker PH, Richardson DL, Hagemann AR, et al. Phase I/II study of safety and efficacy of intraperitoneal IMNN-001 with neoadjuvant chemotherapy of paclitaxel and carboplatin in patients newly diagnosed with advanced epithelial ovarian cancer. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 1505.
8. IMUNON announces continued strong improvement in overall survival data from randomized phase 2 OVATION 2 study of IMNN-001. News Release. IMUNON. December 10, 2024. Accessed May 13, 2025. https://investors.imunon.com/news-releases/news-release-details/imunon-announces-continued-strong-improvement-overall-survival
9. IMUNON reports first quarter 2025 financial results and provides business update. News Release. IMUNON. May 12, 2025. Accessed May 13, 2025. https://investors.imunon.com/news-releases/news-release-details/imunon-reports-first-quarter-2025-financial-results-and-provides
10. Investor call: OVATION-3, phase 3 study design. IMUNON. March 25, 2025. Accessed May 13, 2025. https://investors.imunon.com/static-files/7b95b8b5-40b2-434d-9656-c546751a7c39
11. IMUNON finalizes phase 3 study design with FDA for IMNN-001 in newly diagnosed advanced ovarian cancer. News release. IMUNON. March 24, 2025. Accessed May 13, 2025. https://investors.imunon.com/news-releases/news-release-details/imunon-finalizes-phase-3-study-design-fda-imnn-001-newly