Orca-T with myeloablative allogeneic stem cell transplant for advanced leukemias and MDS

Phase I Trial for Patients With Advanced Hematologic Malignancies Undergoing Allogeneic Hematopoietic Cell Transplantation From an HLA-Mismatched Donor (7/8) With Orca-T

This Phase I study tests whether giving Orca-T alongside standard dual‑agent graft‑versus‑host disease prevention is safe in adults (18–70) receiving a myeloablative allogeneic stem cell transplant for acute leukemias or myelodysplastic syndromes.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 18 Years to 70 Years
• Sex: All
• Sponsor: Stanford University (Academic / other)
• Drugs / interventions: alemtuzumab, cyclophosphamide, fludarabine
• Locations: 1 site (Palo Alto, California)
• Trial ID: NCT06551584 on ClinicalTrials.gov

What this trial studies

This is a Phase I, single‑center safety trial combining Orca‑T cellular therapy with dual‑agent GVHD prophylaxis in adults with acute myeloid, lymphoid, mixed phenotype leukemias in CR/CRi, or eligible myelodysplastic syndromes. Eligible patients must be 18–70 years old, suitable for myeloablative conditioning (TBI/cyclophosphamide or busulfan/fludarabine/thiotepa), and have a 7/8 HLA‑matched related or unrelated donor. The primary focus is to characterize safety and tolerability of the combination around allogeneic hematopoietic cell transplantation, with prospective monitoring for transplant‑related complications including GVHD and engraftment. The trial is led by Stanford University and involves on‑site treatment and follow‑up at the Palo Alto center.

Who should consider this trial

Good fit: Adults aged 18–70 with AML, ALL, mixed phenotype acute leukemia in CR/CRi, or transplant‑eligible MDS with ≤10% blasts who are candidates for myeloablative alloHCT and have a 7/8 HLA‑matched donor and adequate organ function are ideal candidates.

Not a fit: Patients older than 70, those not in remission, with >10% blasts, inadequate organ function, no suitable 7/8 matched donor, or those needing non‑myeloablative conditioning are unlikely to qualify or benefit from this protocol.

Why it matters

Potential benefit: If successful, this approach could lower rates or severity of graft‑versus‑host disease and improve outcomes after allogeneic transplant.

How similar studies have performed: Early‑phase studies of Orca‑T and related cellular approaches have shown promising reductions in acute GVHD in small cohorts, but larger confirmatory trials are still needed.

Eligibility criteria

Inclusion Criteria:

1. Eligible diseases:

   * Acute myeloid, lymphoid or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi) as defined in Section 6.1.3; with or without the presence of known minimal residual disease, or
   * Myelodysplasic syndrome (MDS) myelodysplastic syndromes eligible for alloHSCT and/or treatment-related MDS \<10% blasts
2. Age ≥ 18 and ≤ 70 years at the time of enrollment.
3. Eligible for myeloablative alloHCT including one of two the myeloablative conditioning regimens (fractionated total body irradiation plus cyclophosphamide or busulfan, fludarabine, and thiotepa)
4. Has a related or unrelated donor available who is 7/8 match (single allele mismatched) at HLA-A, -B, -C, and -DRB1, all typed using DNA-based high-resolution methods.
5. Estimated glomerular filtration rate (eGFR) ≥ 50 mL/minute or creatinine \< 2 mg/dL.
6. Cardiac ejection fraction at rest ≥ 45% or shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA).
7. Diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥ 50%.
8. Total bilirubin \< 2 times upper limit of normal (ULN) (patients with Gilbert's syndrome may be included once hemolysis has been excluded).
9. Ability to understand and the willingness to provide written informed consent.
10. Negative serum or urine beta-HCG test in females of childbearing potential (FCBP) within 3 weeks of enrollment.

    A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
11. Able to give informed consent. Legal authorized representative (LAR) is permitted if subject is cognitively able to provide verbal assent.
12. Karnofsky Performance Score ≥70%

Exclusion Criteria:

1. Prior allogeneic HCT.
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, e.g., post-transplant cyclophosphamide (Cy), peri-transplant anti-thymocyte globulin (ATG), or alemtuzumab. For patients that have previously been exposed to a T cell-depleting agent, a 5 half-life washout of the agent must occur prior to planned Day 0 (day of infusion of Orca-T HSPC and Tregs ).
5. Recipient positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either:

   1. Positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing), or
   2. Presence of anti-donor HLA antibody to any of the following HLA loci: HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1, or -DPA1, with mean fluorescence intensity (MFI) \>1000 by solid phase immunoassay.
6. Uncontrolled bacterial, viral, or fungal infections (currently taking antimicrobial therapy and with progression or no clinical improvement) at time of enrollment including known, active tuberculosis infection.
7. Seropositive for HIV-1 or -2, HTLV-1 or -2, Hepatitis B sAg, and/or Hepatitis C antibody.

   \*History of hepatitis B or hepatitis C is permitted if viral load is undetectable per quantitative PCR and/or NAT. In this case, monitoring for hepatitis B or hepatitis C by PCR at 3, 6, and 12 months is recommended.
8. Known allergy or hypersensitivity to, or intolerance of, any investigational agent or ingredient therein, or planned GVHD prophylactic medications.
9. Documented allergy or hypersensitivity to iron dextran or bovine, murine, algal or Streptomyces avidinii proteins.
10. Any uncontrolled autoimmune disease requiring active immunosuppressive treatment.
11. Concurrent malignancy diagnosed within 12 months of enrollment, except non-melanoma skin cancers that have been curatively resected.
12. Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation.

    (FCBP definition: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).
13. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or other clinically significant cardiac disease within 12 months of enrollment. History of stroke or pulmonary embolism within 6 months of enrollment.
14. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the recipient's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results.

Where this trial is running

Palo Alto, California

• Stanford University — Palo Alto, California, United States (Recruiting)

Study contacts

• Principal investigator: Lori Muffly — Stanford University
• Study coordinator: Alyssa Kanegai

Conditions Acute Myeloid Leukemia; Acute Lymphoid Leukemia; Mixed Phenotype Acute Leukemia; Myelodysplastic Syndromes; Orca-T; Hematopoietic Cell Transplantation; Advanced Hematologic Malignancies