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HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide

About

Brief Summary

This is a prospective, multi-center, Phase II study of hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-mismatched unrelated donors (MMUD) for peripheral blood stem cell transplant in adults and bone marrow stem cell transplant in children. Post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil (MMF) will be used for for graft versus host disease (GVHD) prophylaxis. This trial will study how well this treatment works in patients with hematologic malignancies.

Primary Purpose

Treatment

Study Type

Interventional

Phase

Phase 2

Eligibility

Gender

All

Healthy Volunteers

Minimum Age

1 Year

Maximum Age

N/A

Stratum 1 Recipient Inclusion Criteria:

Age > 18 years and < 66 years (chemotherapy-based conditioning) or < 61 years (total body irradiation [TBI]-based conditioning) at the time of signing informed consent
Planned MAC regimen as defined per protocol
Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age < 35 years
Product planned for infusion is PBSC
HCT Comorbidity Index (HCT-CI) < 5
One of the following diagnoses:
- Acute myeloid leukemia (AML) acute lymphoblastic leukemia (ALL), or other acute leukemia in 1st remission or beyond with ≤ 5% marrow blasts and no circulating blasts or evidence of extra-medullary disease. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
- Patients with myelodysplastic syndrome (MDS) with no circulating blasts and with < 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with < 5% or 5-10% blasts in MDS). Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
Cardiac function: Left ventricular ejection fraction > 45% based on most recent echocardiogram or multigated acquisition scan (MUGA) results
Estimated creatinine clearance > 60 mL/min calculated by equation
Pulmonary function: diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for hemoglobin > 50% and forced expiratory volume in first second (FEV1) predicted > 50% based on most recent pulmonary function test results
Liver function acceptable per local institutional guidelines
Karnofsky performance status (KPS) of > 70%
Subjects ≥ 18 years of age or legally authorized representative must have the ability to give informed consent according to applicable regulatory and local institutional requirements.

Stratum 2 Recipient Inclusion Criteria

Age > 18 years at the time of signing informed consent
Planned NMA/RIC regimen as defined per protocol
Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age < 35 years
Product planned for infusion is PBSC
One of the following diagnoses:
- Patients with acute leukemia or chronic myeloid leukemia (CML) with no circulating blasts, no evidence of extramedullary disease, and with < 5% blasts in the bone marrow. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
- Patients with MDS with no circulating blasts and with < 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with < 5% or 5-10% blasts in MDS.) Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
- Patients with chronic lymphocytic leukemia (CLL) or other leukemias (including prolymphocytic leukemia) with chemosensitive disease at time of transplantation
- Patients with lymphoma with chemosensitive disease at the time of transplantation
Cardiac function: Left ventricular ejection fraction > 45% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure
Estimated creatinine clearance > 60 mL/min calculated by equation
Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted > 50% based on most recent pulmonary function test results
Liver function acceptable per local institutional guidelines
KPS of > 60%
Subjects ≥ 18 years of age or legally authorized representative must have the ability to give informed consent according to applicable regulatory and local institutional requirements.

Stratum 3 Recipient Inclusion Criteria

Age > 1 years and < 21 years at the time of signing informed consent
Partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age < 35 years
Product planned for infusion is BM
Planned MAC regimen as defined per protocol
One of the following diagnosis:
- AML in 1st remission or beyond with ≤ 5% marrow blasts, no circulating blasts or evidence of extra-medullary disease. Pre-transplant MRD testing will be performed as per standard of practice at the treating institution. Patients with any MRD status are eligible and should be enrolled at the discretion of provider. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
- Patients MDS with no circulating blasts and less than 10% blasts in the bone marrow. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
- ALL in 1st remission or beyond with ≤ 5% marrow blasts, no circulating blasts, or evidence of extra-medullary disease. Pre-transplant MRD testing will be performed as standard practice at the treating institution with the goal of achieving MRD of <0.01%. Patients with any MRD status are eligible and should be enrolled at the discretion of provider. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
- Other leukemia (mixed-phenotype acute leukemia [MPAL], CML, or other leukemia) in morphologic remission with ≤ 5% marrow blasts and no circulating blasts or evidence of extramedullary disease. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
- Chemotherapy sensitive lymphoma in at least partial remission (PR)
KPS or Lansky performance score ≥ 70%
Cardiac function: Left ventricular ejection fraction of ≥ 50% and shortening fraction of ≥ 27% based on most recent echocardiogram
Glomerular Filtration Rate (GFR) of ≥ 60ml/min/1.73m2 measured by nuclear medicine scan or calculated from a 24 hour urine collection
Pulmonary function: DLCO corrected for hemoglobin, FEV1, and Forced Vital Capacity (FVC) of ≥50% if able to perform pulmonary function tests. If unable to perform pulmonary function tests, must have a resting pulse oximetry of >92% without supplemental oxygen.
Hepatic: Total bilirubin ≤ 2.5 mg/dL and alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3x the upper limit of normal
Legal guardian permission must be obtained for subjects < 18 years of age. Pediatric subjects will be included in age appropriate discussion in order to obtain assent.
Subjects ≥ 18 years of age or legally authorized representative must have the ability to give informed consent according to applicable regulatory and local institutional requirements.

Donor Inclusion Criteria:

Must be unrelated to the subject and high-resolution HLA-matched at 4/8, 5/8, 6/8, or 7/8 (HLA-A, -B, -C, and -DRB1)
Donor must be typed at high-resolution for a minimum of HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1
Age > 18 years and < 35 years at the time of signing informed consent
Meet the donor registries' medical suitability requirements for PBSC or BM donation
Must undergo eligibility screening according to current Food and Drug Administration (FDA) requirements. Donors who do not meet one or more of the donor screening requirements may donate under urgent medical need.
Must agree to donate PBSC (or BM for stratum 3)
Must have the ability to give standard (non-study) informed consent according to applicable donor regulatory requirements

Recipient Exclusion Criteria (Strata 1, 2 and 3):

Suitable HLA-matched related or 8/8 high-resolution matched unrelated donor available
Subject unwilling or unable to give informed consent, or unable to comply with the protocol including required follow-up and testing
Primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia, polycythemia vera, or MDS with grade 4 marrow fibrosis
Subjects with a prior allogeneic HSC transplant
Subjects with an autologous HSC transplant within the past 3 months
Females who are breast-feeding or pregnant
Uncontrolled bacterial, viral or fungal infection at the time of the transplant preparative regimen
Concurrent enrollment on other interventional GVHD clinical trial (enrollment on supportive care trials may be allowed after discussion with Principal Investigators)
Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant.
Patients who are HIV+ with persistently positive viral load. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

Donor Exclusion Criteria:

Donor unwilling or unable to donate
Recipient positive anti-donor HLA antibodies against a mismatched HLA in the selected donor determined by the presence of donor specific HLA antibodies (DSA) to any mismatched HLA allele/antigen at any of the following loci (HLA-A, -B, -C, -DRB1, DRB3, DRB4, DRB5, -DQA1, -DQB1, -DPA1, -DPB1) with median fluorescence intensity (MFI) >3000 by microarray-based single antigen bead testing. In patients receiving red blood cell or platelet transfusions, DSA evaluation must be performed or repeated post-transfusion and prior to donor mobilization and initiation of recipient preparative regimen.

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