Updated results from a phase Ib and phase I/II trial of Orca-T

During the 27th Congress of the European Hematology Association (EHA2022), Caspian Oliai¹ presented updated results of a multicenter phase Ib trial (NCT04013685) and single-center phase I/II trial (NCT01660607) studying Orca-T, an engineered Treg donor product, for use in patients with hematologic malignancies. In comparison with traditional hematopoietic stem cell transplantation, the use of Orca-T may reduce the incidence of graft-versus-host disease (GvHD).¹ The GvHD Hub has previously reported on the initial results of these trials. The Phase III trial is now open and enrolling patients across more than 20 clinical trial sites.² 

Study design¹

The data includes 137 patients who have been dosed with Orca-T, with ≥100 days of follow-up, in comparison to a historical control Center for International Blood and Marrow Transplant Research (CIBMTR) cohort. The primary objective of these studies was to evaluate the safety of Orca-T, with primary endpoints measured by incidence and severity of acute GvHD (aGvHD; Grade 3 or 4), and incidence of primary graft failure. Key eligibility criteria for enrollment in the studies included using an 8/8-matched related or unrelated donor, a hematopoietic cell transplant comorbidity index of ≤4, a Karnofsky performance status score of ≥70, adequate organ function, and an age of 18–65 years (18–72 years for patients with non-Hodgkin lymphoma). Patient characteristics are shown in Table 1.

Table 1. Key patient characteristics of NCT04013685 and NCT01660607, compared with a CIBMTR historical control cohort*

ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CIBMTR, Center for International Blood and Marrow Transplant Research; CML, chronic myeloid leukemia; HLA, human leukocyte antigen; MDS, myelodysplastic syndrome. *Adapted from Oliai. 2022.1
Characteristic, % (unless otherwise stated)	Multicenter phase Ib (NCT04013685) n = 103	Single-center phase I/II (NCT01660607) n = 34		CIBMTR control cohort n = 375
Median age, years (range)	51 (19–65)	42 (19–71)		52 (18–65)
Male	52	71		57
Primary disease
AML	43	41		47
ALL	32	17		20
MDS	13	2		33
Myelofibrosis	7	7		0
CML	3	12		0
Non-Hodgkin lymphoma	0		10		0
Other	2		11		0
Graft source
HLA-matched siblings	54		74		45
HLA-matched unrelated donor	46		26		55

Safety and efficacy¹

Outcomes in patients post infusion, compared with the CIBMTR control cohort, are shown in Table 2. All outcomes are at 1 year, apart from time to neutrophil and time to platelet engraftment, which were at days posttransplant.

Table 2. Outcomes after infusion of Orca-T, compared with a CIBMTR historical control cohort*

CI, confidence interval; GvHD, graft-versus-host disease. *Adapted from Oliai, 2022. †As defined in the Blood & Marrow Transplant Clinical Trials Network Manual of Procedures.
Outcome, % (unless otherwise stated)	Orca-T cohort	CIBMTR control cohort
Median time to neutrophil engraftment, days posttransplant	13	—
Median time to platelet engraftment, days posttransplant	16	—
Grade 3 infections† (range)	10 (95% CI, 2–26)	—
Severe acute GvHD (range)	4 (95%CI, 0–20)	16 (95%CI, 12–19)
Moderate to severe (≥Grade 2 chronic GvHD, (range)	5 (95% CI, 0–21)	38 (95% CI, 33–44)
Relapse (range)	20 (8–34)	35 (30–40)
GvHD relapse-free survival (range)	71 (95% CI, 60–78)	21 (95% CI, 17–25)
Overall survival (range)	90 (95% CI, 82–95)	68 (95% CI, 63–73)

These studies also highlighted that the choice of conditioning regimen used alongside Orca-T may improve relapse-free survival. Patients given a conditioning regimen of busulfan with either cyclophosphamide or fludarabine had an average relapse-free survival of 72% compared with 91% in patients who received a regimen of busulfan with fludarabine and thiotepa. This may be due to improved lymphodepletion with use of thiotepa, allowing for a more favorable immune reconstitution in patients.

Conclusion

Following these phase Ib and phase I/II trials, a multicenter phase III trial (NCT05316701) of Orca-T is now opening at centers in the US, investigating Orca-T plus tacrolimus versus unmanipulated allograft plus tacrolimus and methotrexate. Results from these initial studies are promising, with Orca-T resulting in lower rates of GvHD, improved GvHD relapse-free survival, and low rates of infection when compared with a historical traditional hematopoietic stem cell transplantation control group. The phase III study will provide further insight into the safety and efficacy of Orca-T compared with the current standard of care.