Imunon Talks Passionate PIs, Endpoint Selection In Frontline Ovarian Cancer Trials

A conversation with Stacy Lindborg, Ph.D., CEO, IMUNON

Overall survival improvement is the gold standard in ovarian cancer clinical trials. But it’s not often chosen as the primary endpoint. Rather, sponsor companies tend to opt for progression-free survival because it’s faster and requires fewer participants. IMUNON is taking a bolder path.

IMUNON is developing a frontline treatment — a DNA plasmid vector encased in a nanoparticle delivery system to deliver a powerful cytokine locally to the tumor micro-environment — with the intent of improving overall survival rates despite the apparent challenges. Already, the Phase 2 data have shown a median overall survival increase of 13 months following treatment with IMNN-001 plus standard-of-care (SoC) chemotherapy versus SoC chemotherapy alone.

In a conversation with Clinical Leader’s Abby Proch, IMUNON CEO Stacy Lindborg, Ph.D., details their recent success and recounts the company’s transition from a successful Phase 2 trial. She shares lessons learned from one phase to the next, detailing site selection criteria and the importance of passionate PIs, as well as designing a fit-for-purpose trial that answers scientific questions and meets patient needs.

Clinical Leader: How did IMUNON select clinical research sites for the Phase 2 and 3 trials of IMNN-001, given the challenges of enrolling cancer clinical trials?

Stacy Lindborg: We know operations is so critical. Ultimately, you can have an innovative product, but if you can't deliver the trial, it's game over. In general, I'd say every disease I've worked in across my career has proven that recruitment is one of the biggest stumbling blocks. And that starts with your sites.

We have a Phase 2 trial that we recently completed. As we look at the sites we plan to activate this year for our Phase 3 pivotal trial — and we have a careful plan around onboarding and how it fits in with our patient enrollment strategy — we're starting with sites that participated in the Phase 2 trial.

Some of those early learnings we've pulled forward and made them part of how we're doing business. This includes, for example, making sure a gynecologic oncologist, not just a medical oncologist, is on-site as the PI. Right now, women either start chemotherapy followed by surgery or go directly to surgery and then have chemotherapy after. But what we are hearing, and this came up at the recent ASCO Annual Meeting just a few weeks ago, is that there seems to be consensus building around frontline chemotherapy, reducing the size of the tumors to allow for more effective surgery, and then chemotherapy afterward.

What becomes critical is engagement with the pharmacy staff at trial sites and making sure they understand how to reconstitute the product and get it ready for administration. A gyno-oncologist is central to making sure a site and pharmacy can handle the specifics of our product. Performance as a clinical site is important to the success of any study, so focusing initially on those Phase 2 sites that are experienced in clinical studies and performed well on our Phase 2, positions our Phase 3 study kick-off for success. Although this strategy of initially working with investigators and sites familiar with our product will give us the fastest start for our trial, it is important to note that most, if not all, gynecologic oncologists are already very familiar with the techniques used to administer our drug, and recruitments of sites outside of Ovation-2 is straightforward.

Were you only looking then for oncologists who have that same treatment paradigm in mind?

Our drug is positioned to be given in parallel to the current standard of care. Our initial focus, to target sites that have worked with our treatment in the Phase 2, is maximizing the efficiency of our kickoff. The sites that we plan to enroll in our Phase 3 trial this year were all part of our Phase 2 trial. There is a familiarity with our route of administration. They already understand our therapy’s mechanism of action and the clinical efficacy and safety data, so they understand the benefit-risk profile.

And when I think about some of the PIs I've interacted with and the community at ASCO, there's such an expression of hope in the Phase 3 trial; advanced ovarian cancer hasn't really seen a change in the standard of care for newly diagnosed women since the current standard of care was established over 25 years ago.

We've seen changes in second line and a maintenance treatment and advances that are all important. But with our therapy IMNN-001 in frontline treatment, we're now seeing what could and will be transformative for women if we replicate these findings in Phase 3.

In fact, we've had clinicians who have moved their academic appointment to a new institution, who were PIs in Phase 2, and now in their new institution, want to be in this Phase 3 trial. Our data so far will be our strongest asset in attracting new clinical sites to our Phase 3. There is very strong interest, and I think that it will translate into a medical recommendation when helping patients make decisions for their treatment.

During site selection for either Phase 2 or 3, did you rely on any AI-assisted tools or third parties? What were some of the tools in your toolbox?

I would say that we have not relied on tools, and there's a very good reason for that. Newly diagnosed women are literally getting a diagnosis and being faced with what to do. And there's an urgency because almost 80% of women diagnosed with ovarian cancer are being diagnosed in stage 3B and up. The time from diagnosis to treatment is very tight and needs to be acted on very quickly. We don't have the benefit of a dataset, but that comes with a strength.

You're seeing these women who have fully intact, relatively speaking, immune systems compared to those who’ve had surgery and chemotherapy. We believe, and I heard this at ASCO as well, that the immune system and treatment interact best when the body has a heavy burden of tumor; it's being trained on what we want the immune system to fight. Having it present during the neoadjuvant chemotherapy treatment period, we believe, is a strength.

Across diseases like cancer and neurodegenerative conditions, we've seen that faster diagnoses and faster treatment often lead to better outcomes. We don't have the luxury of databases to mine, but we do have a network and a great set of PIs who are dedicated to helping fight for new treatments and advancing the ovarian cancer treatment landscape, and we are using a CRO partner to help us identify new sites.  

You mentioned that you don't have the luxury of time or of relying on databases. Have you had any challenges to overcome from the patient perspective of trials or the product? And if you had them, how did you overcome that?

I've been in my job here for a year. I was on the board during the last trial but didn't get as many operational insights. But in talking with PIs, I understand that in the ovarian cancer landscape, the percentage of women who will consider a trial is increasing. That’s because the standard of care is three cycles of chemotherapy before interval debulking surgery and then three more cycles of chemotherapy. It's been the standard of care for 25 years.

On top of that, we've never had a trial in the newly diagnosed patient population that has shown an overall survival benefit. We have now shown more than a year's prolongation over that standard of care. We're taking the combination chemotherapy before and after interval debulking surgery as the control arm, and we are adding IMNN-001 immunotherapy to this standard of care. What's really critical is that these gynecologic oncologists engaging with these patients have familiarity with our data and the ability to now talk about the options. Our option is a well-designed controlled clinical trial that shows we've extended the standard of care over a year in an all-comers population. So, we think that our recent Phase 2 data and the reception from the medical community will aid in that discussion.

How did you take the insights from the OVATION Phase 2 trial into Phase 3?

Phase 3 is a registrational trial, meaning we're confirming the clinically meaningful results we've just seen in Phase 2. The dose and the dosing scheme are the same for IMNN-001, we're targeting the same patient population, and the control arm, the standard of care, has remained unchanged.

We did find opportunities for enhancements, and that's really where the changes occur. Number one: We're choosing to focus on overall survival as the primary endpoint in Phase 3. This is the definitive endpoint for approval that we believe we need to show.

Progression-free survival (PFS), in some cancers, may be a surrogate and may be predictive of overall survival. However, the literature has been increasingly clear with immunotherapies that PFS doesn't necessarily give you confidence that if you have an effect in progression-free survival, you're going to see an overall survival benefit. We think it's critical just to answer the ultimate question of a benefit to survival. So, overall survival will be our primary endpoint. It also turns out to be the endpoint required for European regulatory approval, and there's added strength in including it in our Phase 3.

From that perspective, we've chosen to implement two areas of stratification in the Phase 3 trial. Women who have BRCA mutations and other HR deficiencies have seen an even larger therapeutic effect. In our Phase 2 OVATION 2 Study, we’ve seen an effect in the intent-to-treat population of all comers, but an even more substantial reduction in the hazard ratio in women whose tumors were HRD-positive, including those with BRCA mutations. We saw a drop in the hazard ratio that was substantial, to the point where we still haven't observed the time to median overall survival in the experimental arm as we have in the control arm. HRD status is a biomarker-defined stratification, which we know from the literature is likely to increase the probability of success of the trial. And then we're also going to stratify by stage of cancer diagnosis, so that we're bringing balance across the treatment arms and can ensure findings are interpretable and that a successful outcome from the Phase 3 trial comes from the one difference — IMNN-001 being added to the standard of care.

The other things are relatively more minor but are important from a patient perspective. In the Phase 2 trial, some women experienced abdominal pain after surgery and infusion, so we began using prophylactic pain medicine that worked extremely well. Now that prophylaxis will be done at the very beginning, and has been implemented in another ongoing trial. And then we've defined a maintenance therapy in the protocol. So again, there's consistency that's aligned with the current standard of care, and we'll collect a little bit more information around quality of life, with added endpoints that will help with pricing and reimbursement discussions.

How would you characterize your communication with the FDA?

I describe it as a very smooth set of interactions with the FDA. Leading up to our end-of-Phase 2 meeting, we were invited to the White Oak campus. Of course, these interactions are very formal. You submit a briefing document, you submit the questions you want to go through, and what was really fabulous walking into that discussion is that you always get feedback a day or two before the meeting. The preliminary feedback was that they agreed with our patient population, our primary endpoint, and the overall trial design for Phase 3. And nothing was ever a major point of disagreement; it is probably one of the smoother processes I've been through. A lot of that comes down to the major medical need for women with advanced ovarian cancer and the lack of concern regarding safety issues for IMNN-001.

Given recent staffing reductions and new leadership, did you encounter any challenges, or even differences, in how you’ve historically interacted with the FDA?

We haven't. We ended up with only one more substantial interaction with the FDA after the protocol review and approval, which was around moving manufacturing the active pharmaceutical ingredient within IMUNON. Once you get your core elements in place, your interactions are relatively limited. Our interactions have gone smoothly, and questions have been answered very, very efficiently. So, I'd say it's continued to be quite smooth.

About The Expert:

Stacy R. Lindborg, Ph.D., was appointed president and chief executive officer of IMUNON, Inc. in May 2024. She has served on the company’s board of directors since June 2021. Dr. Lindborg has nearly 30 years of pharmaceutical and biotechnology industry experience with a particular focus on R&D, regulatory affairs, executive management, and strategy development. She has designed, hired, and led global teams, guiding long-term vision for growth through analytics and stimulating innovative development platforms to increase productivity.