At the 65th American Society of Hematology (ASH) Annual Meeting, Shernan G Holtan, MD, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota, discusses a phase 1 dose escalation portion of a first-in-human clinical trial of post-transplant cyclophosphamide (PTCy) plus sirolimus and selective oral AURKA inhibitor VIC-1911 for graft-versus-host disease (GVHD) and relapse prophylaxis after myeloablative allogeneic hematopoietic cell transplantation (alloHCT).

Transcript:

I am Shernan Holton, [an] Associate Professor of Medicine from the University of Minnesota. At ASH 2023, it was my pleasure to present the phase 1 results of our study [on] post-transplant cyclophosphamide, tacrolimus, and Aurora kinase A (AURKA) inhibitor VIC-1911 (VIC) for GVHD and relapse prophylaxis. I'd like you to hear the story about how this clinical trial was developed. You probably read about post-transplant cyclophosphamide really changing the landscape of GVHD prophylaxis over the past several years, especially in the well-matched setting. Now we're extending this beyond [haploidentical transplant] (HAPLO) and ever since the [BMT CTN 1703 study], post-transplant cyclophosphamide has really become the standard of care for GVHD prophylaxis across the country and in several countries around the world. We have studied post-transplant cyclophosphamide, tacrolimus, and [mycophenolate mofetil] (MMF) in the matched myeloablative setting and publish those results this summer in [Transplantation and Cellular Therapy] (TCT). We have very low rates of acute and chronic graft versus host disease with that regimen, [with] approximately 5.5% for each. The major barrier that we see to the success of that regimen was relapse. 

At about 1 year, approximately ¼ of patients relapsed, and by 2 years about 35% of adults had relapsed post-transplant. So, that really remains, in our view, the unmet need in transplantation. We developed a novel regimen that we think can help improve immune function and potentially have direct anti-leukemia effect to target relapse as well. The concept is that we want to use the post-transplant cyclophosphamide backbone, but we've changed tacrolimus to sirolimus, which allows for more immune function, it's less immunosuppressive and supports [regulatory T cells] (Treg). We've taken out mycophenolate mofetil, which we don't think probably adds that much to the regimen. Instead, we've substituted VIC-1911, which is a novel oral Aurora kinase A inhibitor. 

The way we use VIC-1911 is day plus 5 through day plus 45 post-transplant. So similar, [a] little longer than what you might do with MMF, but otherwise fairly similar. And what we are publishing with the ASH abstract is our phase 1 results where we found the dose. Through a series of dose escalations, we determined that VIC-1911 at a dose of 75 milligrams twice daily effectively suppresses Aurora kinase A activity. We found that when we've added this to post-transplant cyclophosphamide and sirolimus, that the regimen is overall well tolerated, [with] no dose-limiting toxicities. Importantly, even though this is just a phase 1 study, the clinical outcomes are very encouraging. We've had no grade 3 to 4 acute GVHD and with about a year of follow-up, we've had 1 relapse and we've had 1 patient with chronic GVHD requiring immunosuppression; in fact, that wasn't even starting new agents, it was just a continuation of sirolimus. Again, this is just a phase 1 [study]. We've found the dose, but we're already really encouraged by what we're seeing clinically. This has not added a lot of toxicities to what we would typically see in myeloablative transplantation [and they are] very, very encouraging early results. Now the plan is to take this dose forward to a phase 1 extension. In the future, we envision potentially doing a randomized phase 3 study comparing [post-transplant cyclophosphamide and sirolimus] MMF to [post-transplant cyclophosphamide and sirolimus] and VIC-1911 specifically seeing if we can improve upon the relapse rates with a [post-transplant cyclophosphamide] based regimen.

Source:

Holtan S, Walton K, Jurdi N, et al. Aurora kinase a inhibition for gvhd and relapse prevention after allogeneic HCT: phase I trial in combination with Ptcy/Sirolimus. Presented at the 2023 ASH Annual Meeting: December 9-12, 2023. San Diego, CA. Abstract 4925