A Phase 1 Study of Engineered Donor Grafts (Orca-Q) in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, and efficacy of engineered donor grafts (OrcaGraft/Orca-Q) in participants undergoing myeloablative allogeneic hematopoietic cell transplant transplantation for hematologic malignancies.

Official Title
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A Phase 1, Dose Escalation and Expansion Study of Engineered Donor Grafts Derived From Mobilized Peripheral Blood (Orca-Q, Formerly OrcaGraft), With Single Agent Graft Versus-host Disease Prophylaxis, in Recipients Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancies

Conditions
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Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, Acute Leukemia

Intervention / Treatment
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* Biological: OrcaGraft (Orca-Q)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 and ≤ 65 years at the time of enrollment Diagnosed acute myeloid, lymphoid or mixed phenotype leukemia, or high or very high risk myelodysplasic syndrome (MDS) or Myelofibrosis Planned to undergo myeloablative allogeneic hematopoietic stem cell transplant (HCT) Matched to a 8/8 or 7/8 related or unrelated donor, or to a related haploidentical donor Estimated glomerular filtration rate (eGFR) > 50 mL/minute 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% Total bilirubin < 1.5 times upper limit of normal (ULN) (< 3 times if attributed to Gilbert's syndrome) and ALT/AST < 3 times ULN 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) Positive anti-donor HLA antibodies against a mismatched allele in the selected donor Karnofsky performance score < 70% (Appendix 12.7) Hematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) > 4 (Appendix 12.8) Uncontrolled bacterial, viral or fungal infections (currently taking antimicrobial therapy and with progression or no clinical improvement) at time of enrollment Seropositive for HIV-1 or -2, HTLV-1 or -2 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 History of idiopathic or secondary myelofibrosis Women who are pregnant or breastfeeding

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Recipients with HLA-identical or 1-allele mismatched (7/8 alleles) related or unrelated donor; with single-agent GVHD prophylaxis given | Biological: OrcaGraft (Orca-Q)<br>* engineered donor allograft<br>|
| Experimental: Arm B<br>Recipients with haploidentical-related donors; with single-agent GVHD prophylaxis given | Biological: OrcaGraft (Orca-Q)<br>* engineered donor allograft<br>|
| Experimental: Arm C<br>Recipients with an HLA-identical related or unrelated donor; no GVHD prophylaxis given | Biological: OrcaGraft (Orca-Q)<br>* engineered donor allograft<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose Limiting Toxicities | Safety and tolerability of Orca-Q (formerly OrcaGraft) in adults undergoing myeloablative allogeneic hematopoietic cell transplantation (MA-alloHCT) will be evaluated by identification of the following dose limiting toxicities: Grade ≥ 3 infusion-related reaction or cytokine release syndrome, Grade ≥ 3 acute GVHD, Any Grade ≥ 3 treatment-related non-hematologic event not clearly related to the underlying malignancy, intercurrent infection, the HCT conditioning regimen, or other pre-existing medical condition, and by instance of primary graft failure, defined as being alive without recovery of neutrophils during the evaluation period | 28 Days after administration of Orca-Q/OrcaGraft | 
| Primary Graft failure through Day +28 (dose expansion) | Primary graft failure in the dose expansion phase, defined as being alive without recovery of neutrophils during the evaluation period | 28 Days after administration of Orca-Q/OrcaGraft | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neutrophil Engraftment through Day +28 | Neutrophil engraftment defined as an absolute neutrophil count of >/=500/mm3 for 3 consecutive days | 28 days after administration of Orca-Q/OrcaGraft | 
| Platelet engraftment through Day +50 | Platelet engraftment is defined as achieving a platelet count > 20,000/mm3 for 3 consecutive days without platelet transfusion in the preceding 7 days, by Day +50 | 50 days after administration of Orca-Q/OrcaGraft | 
| Secondary graft failure through Day +100 | Secondary graft failure is defined as neutrophil engraftment followed by subsequent decline in absolute neutrophil counts < 500 cells/μL, unresponsive to growth factor therapy, by Day +100 | 100 days after administration of Orca-Q/OrcaGraft | 
| Treatment-emergent adverse events (TEAEs) through the safety reporting period | TEAEs categorized by System Organ Lass and graded according to the CTCAE v5.0 | 100 days after administration of Orca-Q/OrcaGraft | 
| Acute GVHD through Day +100 | Acute GVHD will be staged and graded per Mount Sinai Acute GvHD International Consortium (MAGIC) Standardization criteria | 100 days after administration of Orca-Q/OrcaGraft | 
| Steroid-refractory acute GVHD through Day +100 | Steroid-refractory acute GVHD will be defined as per the EBMT-NIH-CIBMTR Task Force position statement | 100 days after administration of Orca-Q/OrcaGraft | 
| Chronic GVHD through Day +365 | Chronic GVHD will be diagnosed per 2014 International NIH Chronic GVHD Diagnosis and Staging Consensus Working Group criteria | 365 days after administration of Orca-Q/OrcaGraft | 
| Post-Transplant Lymphoproliferative Disorder (PTLD) through Day +365 | PTLD is defined as a biopsy consistent with the 2017 World Health Organization (WHO) classification of PTLD | 365 days after administration of Orca-Q/OrcaGraft | 
| Incidence of non-relapse mortality (NRM) through Day +365 | NRM is defined as death without evidence of disease recurrence | 365 days after administration of Orca-Q/OrcaGraft | 
| Incidence of disease relapse through Day +365 | Recurrence of primary disease for transplant | 365 days after administration of Orca-Q/OrcaGraft | 
| GVHD-free and relapse-free survival (GRFS) through Day +365 | Survival free from GVHD and relapse | 365 days after administration of Orca-Q/OrcaGraft | 
| Disease-free survival (DFS) through Day +365 | Disease-free survival is the time from date of transplant to death or relapse, whichever comes first. | 365 days after administration of Orca-Q/OrcaGraft | 
| Overall survival through Day +365 | OS is defined as the time from the date of transplant to the date of death from any cause or, for surviving patients, to the date of last follow-up. | 365 days after administration of Orca-Q/OrcaGraft |