Orca-T Following Chemotherapy and Total Marrow and Lymphoid Irradiation for the Treatment of Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia or Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. Describe toxicities attributable to total marrow and lymphoid irradiation (TMLI) by dose level in patients with high-risk acute leukemias or MDS, in the context of partially engineered T-regulatory cell donor graft TRGFT-201 (Orca-T) from a matched or haploidentical donor.

II. Determine the recommended phase II dose (RP2D) of TMLI with an Orca-T for allogeneic hematopoietic cell transplantation (HCT).

SECONDARY OBJECTIVES:

I. Determine incidence of acute and late HCT-related immune complications (infections, etc.) at 100 days and 1 year.

II. To evaluate the safety of the regimen, at each dose level, by assessing the following: type, frequency, severity, attribution, time course and duration of adverse events in dose limiting toxicity (DLT) window of 28 days at each dose level, including acute graft-versus-host disease (GVHD), infection and delayed engraftment within the first 100 days and chronic GVHD incidence at 1 year.

III. Measure incidence of acute and chronic GVHD at 100 days and 1-year post-HCT, respectively.

IV. Measure GVHD-free and relapse-free survival (GRFS) at 1-year post-HCT.

EXPLORATORY OBJECTIVES:

I. Estimate overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of relapse/progression, and non-relapse mortality (NRM) at 100 days, 1 year and 2 years.

II. Evaluate the effect of TMLI as conditioning for Orca-T HCT on immune reconstitution at 1, 3, 6, 9 and 12 months after alloHCT.

III. Evaluate GVHD biomarkers and inflammatory cytokines on days +7, +14, and +30, (all patients) and upon GVHD onset/resolution.

IV. Investigate the temporal effect and bone marrow residual damage and regeneration on days +30, +100, and 1-year post-alloHCT by using longitudinally collected biological samples and imaging.

V. Monitor effects of TMLI as conditioning on gastrointestinal (GI) toxicity and T cell signaling pathways.

VI. Monitor effects of TMLI on GI microbiome diversity.

OUTLINE: This is a dose-escalation study of TMLI followed by a dose-expansion study.

PREPARATIVE REGIMEN: Patients undergo TMLI twice a day (BID) on days -8 to -5, followed by fludarabine intravenously (IV) on days -4 to -2 and melphalan IV on day -2. Patients receiving the lowest dose of TMLI also receive thiotepa IV on days -4 and -3.

HCT: Patients receive Orca-T CD34+hematopoietic stem and progenitor cells (HSPC) and T-regulatory cell (Treg) products IV on day 0, followed by the Orca-T conventional t-cell (tcon) product IV on day 2.

GVHD PROPHYLAXIS: Patients undergoing haploidentical (haplo)-HCT receive tacrolimus starting on day 14 and continuing until day 90 with a taper per treating physician's discretion.

Patients also undergo echocardiogram (ECHO) or multigated acquisition (MUGA) scans, dual energy computed tomography (DECT)/magnetic resonance imaging (MRI) scans, bone marrow biopsies/aspirates, and blood sample collection throughout the study.

After completion of study treatment, patients are followed for up to 2 years from enrollment.