Orca-T after reduced-intensity or nonmyeloablative conditioning for adults with AML or MDS

A Phase 2 Trial of Orca-T Following Reduced Intensity or Nonmyeloablative Conditioning in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

This trial will test whether Orca-T, a donor-derived stem cell and T-cell therapy, is safe and helps adults with acute myeloid leukemia or myelodysplastic syndrome who are receiving reduced-intensity or nonmyeloablative allogeneic stem cell transplants.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 80 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Orca Biosystems, Inc. (Industry-sponsored)
• Drugs / interventions: cyclophosphamide, fludarabine, immunotherapy
• Locations: 5 sites (Los Angeles, California and 4 other locations)
• Trial ID: NCT07216443 on ClinicalTrials.gov

What this trial studies

This is a multicenter, open-label phase 2 trial of Orca-T given to adults with acute myeloid leukemia (AML) in remission or to patients with myelodysplastic syndrome (MDS) who are eligible for reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) allogeneic hematopoietic cell transplantation (alloHCT). Orca-T is a donor-manufactured product composed of purified hematopoietic stem and progenitor cells (HSPCs), regulatory T cells (Tregs), and conventional T cells (Tcons) derived from an 8/8 HLA-matched related or unrelated donor. Participants receive the investigator-chosen RIC or NMA preparative regimen, Orca-T infusion from the matched donor, and single-agent graft-versus-host disease prophylaxis with tacrolimus. The trial further characterizes safety and tolerability and provides an initial look at efficacy in this lower-intensity transplant population, building on earlier phase 1 and ongoing phase 1b/3 experiences.

Who should consider this trial

Good fit: Adults (≥18 years) with AML in complete remission (CR/CRi) or MDS appropriate for alloHCT who are planned for RIC or NMA conditioning and have an identified 8/8 HLA-matched related or unrelated donor are ideal candidates.

Not a fit: Patients who need myeloablative conditioning, lack an 8/8 HLA-matched donor, have active uncontrolled disease or significant organ dysfunction are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, Orca-T could lower graft-versus-host disease while preserving graft function and anti-leukemia activity, potentially improving survival and quality of life after lower-intensity transplants.

How similar studies have performed: Early-phase work, including a phase 1 study and ongoing phase 1b/3 trials of Orca-T in different conditioning settings, produced encouraging safety and preliminary efficacy signals that prompted this phase 2 evaluation.

Eligibility criteria

Inclusion Criteria:

1. Age ≥18 years at the time of enrollment
2. Diagnosed with 1 of the following diseases:

   1. Acute myeloid, or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi), with or without the presence of known minimal residual disease.
   2. Myelodysplastic syndrome that is indicated for alloHCT per the 2017 International Expert Panel recommendations and/or therapy-related/secondary MDS as defined by the World Health Organization (WHO) classification of myeloid malignancies, with ≤10% blast burden in the bone marrow.
3. Planned to undergo 1 of the following preparative regimens as per Investigator discretion:

   1. RIC cohort: Planned RIC-alloHCT including RIC regimen with TBI/thiotepa/fludarabine
   2. NMA cohort: Planned NMA-alloHCT including NMA regimen with fludarabine/cyclophosphamide/TBI
4. Identified related or unrelated donor who is an 8/8 match for HLA-A, -B, -C, and -DRB1
5. Estimated glomerular filtration rate ≥30 mL/minute
6. Cardiac ejection fraction at rest ≥40% or shortening fraction of ≥22% by echocardiogram or radionuclide scan (MUGA)
7. Diffusing capacity of the lung for carbon monoxide (adjusted for hemoglobin) ≥40%
8. Negative serum or urine β-HCG test in persons of childbearing potential
9. Alanine transaminase (ALT)/aspartate transaminase (AST) \<5 times the upper limit of normal (ULN)
10. Total bilirubin \<3 × ULN
11. Deemed ineligible for a fully myeloablative alloHCT per assessment of the principal investigator

Exclusion Criteria:

1. Prior alloHCT
2. Currently receiving corticosteroids or other immunosuppressive therapy. Topical corticosteroids or oral systemic corticosteroid doses less than or equal to 10 mg/day are allowed.
3. Planned donor lymphocyte infusion (DLI)
4. Planned pharmaceutical in vivo or ex vivo T-cell depletion
5. Recipient-positive antidonor HLA antibodies against a mismatched allele in the selected donor
6. Karnofsky performance score \<60%
7. For RIC cohort only: HCT-Specific Comorbidity Index (HCT-CI) ≥6
8. Uncontrolled bacterial, viral, or fungal infection (currently taking antimicrobial therapy and with progression or no clinical improvement) at the time of enrollment
9. Seropositive for HIV-1 or -2, HTLV-1 or -2, hepatitis B surface antigen, or HCV antibody unless previously treated with curative therapy and are HCV NAT negative
10. Known allergy or hypersensitivity to or intolerance of tacrolimus
11. Documented allergy or hypersensitivity to iron dextran or bovine, murine, algal, or Streptomyces avidinii proteins
12. Any uncontrolled autoimmune disease requiring active immunosuppressive treatment
13. Concurrent malignancy within 1 year except nonmelanoma skin cancer that has been curatively resected
14. Psychosocial circumstances that preclude the participant being able to go through transplantation or participate responsibly in follow-up care
15. Persons who are pregnant or breastfeeding
16. Person of childbearing potential (POCBP) or men who have sexual contact with POCBP who are unwilling to use effective forms of birth control or abstinence for 1 year after transplantation.
17. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's or medical monitor's judgment, precludes the recipient's safe participation in and completion of the trial or which could affect compliance with the protocol or interpretation of results

Where this trial is running

Los Angeles, California and 4 other locations

• UCLA Department of Medicine — Los Angeles, California, United States (Recruiting)
• Moffitt Cancer Center — Tampa, Florida, United States (Not_yet_recruiting)
• John Theurer Cancer Center at Hackensack University Medical Center — Hackensack, New Jersey, United States (Recruiting)
• Oregon Health and Science University — Portland, Oregon, United States (Recruiting)
• Vanderbilt University, Ingram Cancer Center — Nashville, Tennessee, United States (Recruiting)

Study contacts

• Study coordinator: Chief Medical Officer

Conditions Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Mixed Phenotype Acute Leukemia; Therapy-Related Myelodysplastic Syndrome; Hematopoietic Stem Cell Transplantation; Humans; Graft vs Host Disease; SERENE-T