Precision-T: A Randomized Phase III Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies

Study Overview
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Brief Summary
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This study will compare the safety and efficacy between patients receiving an engineered donor graft (Orca-T, a T-cell-Depleted Graft With Additional Infusion of Conventional T Cells and Regulatory T Cells) or standard-of-care (SOC) control in participants undergoing myeloablative allogeneic hematopoietic cell transplant transplantation (MA-alloHCT) for hematologic malignancies. This posting represents the Phase III component of Precision-T. The Precision-T Ph1b component is described under NCT04013685.

Detailed Description
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Cross reference NCT04013685

Official Title
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A Randomized Phase III Trial of Patients With Advanced Hematologic Malignancies Undergoing Allogeneic Hematopoietic Cell Transplantation With Either Orca-T, a T-cell-Depleted Graft With Additional Infusion of Conventional T Cells and Regulatory T Cells, or Standard-of-Care Allogeneic Graft

Conditions
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Acute Myeloid Leukemia, Acute Lymphoid Leukemia, Mixed Phenotype Acute Leukemia, Undifferentiated Leukemia, High-risk Myelodysplastic Syndrome, Acute Leukemia, Therapy-Related Myelodysplastic Syndrome, MDS

Intervention / Treatment
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* Biological: Orca-T
* Biological: Standard-of-Care


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Matched to a related or unrelated donor who is an 8/8 match for HLA-A, -B, -C, and DRB1 Diagnosed with one of the following diseases: Acute myeloid, lymphoid 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 Myelodysplastic syndromes (MDS) that are indicated for alloHSCT per 2017 International Expert Panel recommendations and/or have therapy-related/secondary MDS, with ≤ 10% blast burden in the bone marrow Planned to undergo MA-alloHCT including one of the following myeloablative conditioning regimens: TBI/Cy TBI/Etoposide BFT Cardiac ejection fraction at rest ≥ 45% or shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA) Diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥ 50% Negative serum or urine beta-HCG test in females of childbearing potential ALT/AST < 3 times ULN Recipients in screening must screen negative for SARS-CoV-2 RNA using a PCR-based test Disease Risk Index (DRI) overall risk categorization of intermediate or high Total bilirubin ≤ upper limit of normal (ULN) Estimated glomerular filtration rate (eGFR) ≥ 60 mL/minute Key Exclusion Criteria: Prior allogeneic HCT Currently receiving corticosteroids or other immunosuppressive therapy. Topical corticosteroids or oral systemic corticosteroid doses less than or equal to 10 mg/day are allowed. Planned donor lymphocyte infusion (DLI) Planned pharmaceutical in vivo or ex vivo T cell depletion Recipient positive anti-donor HLA antibodies against a mismatched allele in the selected donor Karnofsky performance score < 70% Hematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) > 4 Uncontrolled bacterial, viral or fungal infections at time of enrollment Seropositive for HIV-1 or -2, HTLV-1 or -2, Hepatitis B sAg, Hepatitis C antibody Known allergy or hypersensitivity to, or intolerance of, tacrolimus Documented allergy or hypersensitivity to iron dextran or bovine, murine, algal or Streptomyces avidinii proteins Any uncontrolled autoimmune disease requiring active immunosuppressive treatment Concurrent malignancies or active disease within 1 year, except non-melanoma skin cancers that have been curatively resected Psychosocial circumstances that preclude the patient being able to go through transplant or participate responsibly in follow up care Women who are pregnant or breastfeeding Women of childbearing potential (WOCBP) or men who have sexual contact with WOCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The Phase III is a randomized, open-label, multicenter study comparing outcomes between patients receiving Orca-T followed by single-agent tacrolimus or standard-of-care (SOC) control followed by dual agent, tacrolimus-based Graft-versus-Host-Disease (GVHD) prophylaxis regimen
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Orca-T<br>For patients randomized to the Orca-T arm, Orca-T will be administered after myeloablative conditioning regimen. Single-agent GVHD prophylaxis with tacrolimus will be administered following Tcon infusion (generally Day +3). | Biological: Orca-T<br>* engineered donor allograft<br>* Other names: TregGraft;|
| Active Comparator: Standard of Care alloHCT Control<br>For patients randomized to the standard-of-care control arm, an unmanipulated allograft derived from the peripheral blood of a matched donor will be administered after a myeloablative conditioning regimen. Dual-agent prophylaxis consisting of tacrolimus plus methotrexate will be administered starting on Day -3. | Biological: Standard-of-Care<br>* unmanipulated donor allograft<br>* Other names: SOC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chronic Graft-versus-Host-Disease-free Survival | An event for this time-to-event outcome is defined as death by any cause or moderate to severe cGVHD as defined by NIH consensus criteria | Randomization through 730 days post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Graft-versus-Host-Disease and Relapse-free survival (GRFS) | An event for this time-to-event outcome is defined as survival free of death from any cause, relapse, Grade 3-4 aGVHD (graded per MAGIC), and moderate to severe cGVHD (graded per NIH consensus criteria). | Day 0 through 365 days post-transplant | 
| Moderate to severe chronic graft-versus-host-disease | An event for this time-to-event outcome is defined as moderate to severe cGVHD as defined by NIH consensus criteria. | Day 0 through 365 days post-transplant | 
| Relapse-free survival | Survival free of death from relapse. | Day 0 through 730 days post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematopoietic stem cell transplantation, acute leukemia, Myelodysplastic syndromes, matched related donor, matched unrelated donor, myelodysplastic syndrome