DNX-2440 Shows Promise in CRC and Other Cancers With Liver Metastasis as Phase 1 Trial Begins

Investigation into a novel oncolytic adenovirus as a treatment option for patients with colorectal cancer and other cancers with liver metastasis is underway. The biotech company, DNAtrix, recently announced the treatment of the first patient enrolled to a phase 1 dose-escalation and dose-expansion study of DNX-2440 (NCT04714983) in patients with resectable liver metastasis.

DNX-2240 is a replication competent, potent, oncolytic adenovirus expressing human OX40 ligand. Expression of OX40 ligand on the surface of tumor cells is expected to enhance antitumor immune responses by providing costimulatory signals to T cells within the tumor microenvironment.¹

“[DNX-2440] will infect, replicate, and kill cells,” Brett Ewald, senior vice president of development for DNAtrix explained in an interview with OncLive^®. “As it does [this], DNX-2440 will release inflammatory cytokines and viral and tumor-associated antigens which will trigger both an innate and adaptive immune response. We know from our preclinical and clinical work across all of our programs that this helps drive durable clinical activity.”

DNX-2440 demonstrated an effect on both injected and noninjected tumors in preclinical models, including those that are distanced, Ewald explained. The agent also facilitated immune memory, displaying an impact in mice that were rechallenged with new tumors.

In the phase 1 study, DNX-2240 will be evaluated in approximately 24 to 30 patients with resectable multifocal liver metastasis, who are scheduled to have liver resection with curative-intent. The primary end point of the study is to establish safety and identify a maximum tolerated dose. Secondary end points include evaluating tumor cell killing of injected and uninjected tumors, determining viral replication in the injected tumor, and measuring local and systemic anti-tumor immune responses.²

“In this study, patients will mostly have more than 1 lesion and we’ll inject 1 lesion but not inject the other lesions with DNX-2440, 2 times, 2 weeks apart,” Ewald said. “Then, they’ll have their scheduled surgery. That will allow us to remove the treated tumors, the nontreated tumors, and healthy tissue and really evaluate the mechanism of DNX-2440 from a detailed standpoint. The idea is that you give exposure to this powerful immunotherapy the month before surgery, allow the immune system to kick into gear, and, after the tumors are removed, that will have an impact on the tumor coming back.”

Ewald said that DNX-2440 has the potential to fulfill an unmet need in this disease setting because many of these tumors have not previously had typical responses to other immunotherapies, such as checkpoint inhibitors.

“We think that this unique immunotherapy might provide that kind of immune spark, that stimulation, needed to really have an impact in these tumors,” Ewald said. “We’re really just adding on to the standard of care. Patients are already getting scheduled surgery to remove these tumors, if you can add on a dose or 2 of DNX-2440 before that scheduled surgery and that impacts the disease in a positive manner, you can see why that would be very beneficial for the patients and their families.”

If the phase 1 study is successful, the agent will be tested in other patient populations in the neoadjuvant and other settings. DNX-2440 would also be evaluated in combination with checkpoint inhibitors and other agents.

“I think the design of this trial is what’s especially exciting,” Ewald concluded. “It’s really focused on a patient population with a need, but it is also focused on scientifically understanding more about the drug and its mechanism within the tumors themselves. I think we’re going to learn a lot, get a lot of bang for our buck, in a fairly small study.”

References

1. DNAtrix announces first patient dosed in clinical study of DNX-2440, an OX40 ligand expressing immunotherapy, in colorectal cancer and other cancers with liver metastasis. News release. DNAtrix. March 4, 2021. Accessed March 12, 2021. https://www.dnatrix.com/view.cfm/140/2021-press-release
2. DNX-2440 for resectable colorectal liver metastasis. Updated March 10, 2021. Accessed March 12, 2021. https://clinicaltrials.gov/ct2/show/NCT04714983?term=DNX-2440&draw=2&rank=2