Early Data for Orca-T Cellular Therapy Provides Basis for Phase 3 Study in AML

The use of the precision cellular therapy Orca-T demonstrated promising efficacy effects at a median follow-up of 1 year in patients with acute leukemia or high-risk myelodysplastic syndrome (MDS) in an early analysis of a phase 1b and 2 study that have yet to be reported, according to data presented at the 2023 Tandem Transplantation and Cellular Therapy Meetings.¹

“Granted, this is still early data, it's a lot of patients, and there might be a number of different factors that could affect these promising outcomes, but it provided a very strong rationale for a phase 3 trial,” explained Caspian Oliai, MD, MS, medical director of the Bone Marrow Transplantation & Cellular Therapies Processing Center, UCLA Health, in a presentation of the study.

Data from the overall phase 1b/2 cohort of patients on Orca-T (n = 151) compared to a control arm of patients treated at the Center for International Blood and Marrow Transplant Research (CIBMTR) Center on standard of care (n = 375) favored those on the cellular therapy. At 1 year, the graft-vs-host-disease (GVHD) and relapse survival rate was higher in the Orca-T cohort at 70% vs 21% in the control arm, and 1-year overall survival (OS) rate was 88% vs 68%, respectively; however, the non-relapse mortality rate favored the control arm at 10% vs 4% in the treatment arm.

According to Oliai, the outcomes of patients given Orca-T appeared to be enhanced with further condition with a regimen consisting of busulfan, fludarabine, and thiotepa (BFT).

While Oliai cautioned these results were considered early, the 71 patients on Orca-T plus BFT showed a relapse-free survival (RFS) rate of 87%. Moreover, 27% of this cohort had positive minimal residual disease (MRD) status before treatment compared to 19% in the original Orca-T arm.

The 1-year RFS and OS rates were 81% and 94%, respectively.

At the time of the presentation, at a median follow-up of 413 days, there is no non-relapse mortality rate and researchers did not see a high incidence of severe infections or complications when compared to patients on CD34 depleted grafts. Moreover, patients did well with infections and there were no notable issues with rates of Epstein-Barr virus or cytomegalovirus. Lastly, researchers observed a low incidence of grade 3 acute GVHD that was similar to the overall trial cohort at 5%.

The Orca-T and control arms comprised similar disease states, including acute myeloid leukemia (AML; 44% vs 47%, respectively), acute lymphocytic leukemia (ALL; 31% vs 20%), and myelodysplastic syndrome (MDS; 15% vs 33%). Fifty-seven percent of patients in both groups were male, and 52% and 48% of patients in the Orca-T arm had a related and unrelated HLA matched donor, respectively, compared to 45% and 55% of patients in the CIBMTR control arm.

Patients treated with the BFT conditioning regimen had baseline characteristics with 51% and 49% of patients having a related and unrelated HLA matched donor, respectively. Fifty-nine percent of patients in the Orca-T and BFT arm had AML, followed by 11% with ALL, 23% with MDS, 6% with CML and 1% had mixed phenotype acute leukemia.

While the phase 1b and 2 trials had met their study end points, Orca-T was also successfully manufactured in a single centralized facility that allowed the therapy to be distributed nationally. On Orca-T, after MA conditioning, vein-to-vein time for the therapy was less than 72 hours and by day +3 of treatment, patients were given 5 ng/mL to 10 ng/mL of single agent tacrolimus compared with the standard-of-care methotrexate prophylaxis at days +1, +3, +6, and +11 after infusion.

Oliai elaborated that there have been no manufacturing failures of Orca-T so far, but there were a few products delivered over 72 hours on the phase 2 portion of the study, but not the phase 1B portion.

“This is now underway at 15 participating centers, and more hopefully to come, in which patients who are high risk for all sorts of hematologic malignancies undergoing transplantation,” he added.

The ongoing phase 3 study (NCT05316701) has a primary end point of chronic GVHD-free survival and a secondary end point of RFS, graft RFS, and rates of moderate to severe chronic GVHD. The study will again look at patients with AML, ALL, and mixed phenotype acute leukemia along with patients who have high-risk MDS active disease at the time of their transplantation. Patients are planned to undergo MA-allogenic HSCT followed by either BFT, TBI/etoposide, or TBI/Cy. The experimental arm will include patients on Orca-T plus single agent tacrolimus compared with the standard of care for this patient population.

^Reference

^{Oliai C, Pavlova A, Muffly L, et al. Precision-Engineered Cell Therapy Orca-T Demonstrates High Relapse-Free Survival at 1 Year While Reducing Graft-Versus-Host Disease and Toxicity. Presented at: 2023 Transplantation & Cellular Therapy Meetings of ASCT and CIBMTR; February 15-19, 2023; Orlando, FL. Abstract 54.}