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

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Brief Title

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

Official Title

A Multi-Center, Phase II Trial of HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide for Patients With Hematologic Malignancies

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.
    


Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Overall Survival

Secondary Outcome

 Event-free survival

Condition

Acute Lymphoblastic Leukemia

Intervention

Busulfan

Study Arms / Comparison Groups

 Regimen A (MAC: busulfan and fludarabine, PBSC HCT)
Description:  Patients receive:
Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3
Fludarabine (150 mg/m2 total dose) IV on days -6 to -2
Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

180

Start Date

August 2021

Completion Date

July 2024

Primary Completion Date

July 2024

Eligibility Criteria

        Stratum 1 Recipient Inclusion Criteria:

          1. 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

          2. Planned MAC regimen as defined per protocol

          3. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with
             age < 35 years

          4. Product planned for infusion is PBSC

          5. HCT Comorbidity Index (HCT-CI) < 5

          6. One of the following diagnoses:

               1. Acute myelogenous leukemia (AML) 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.

               2. Acute lymphoblastic leukemia (ALL) 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.

               3. 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.

          7. Cardiac function: Left ventricular ejection fraction > 45% based on most recent
             echocardiogram or multigated acquisition scan (MUGA) results

          8. Estimated creatinine clearance > 60 mL/min calculated by equation

          9. 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 DLCO results

         10. Liver function acceptable per local institutional guidelines

         11. Karnofsky performance status (KPS) of > 70%

         12. Subjects ≥ 18 years of age must have the ability to give informed consent according to
             applicable regulatory and local institutional requirements.

        Stratum 2 Recipient Inclusion Criteria

          1. Age > 18 years at the time of signing informed consent

          2. Planned NMA/RIC regimen as defined per protocol

          3. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with
             age < 35 years

          4. Product planned for infusion is PBSC

          5. One of the following diagnoses:

               1. Patients with acute leukemia or chronic myelogenous 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.

               2. 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.

               3. Patients with relapsed chronic lymphocytic leukemia (CLL) with chemosensitive
                  disease at time of transplantation

               4. Patients with lymphoma with chemosensitive disease at the time of transplantation

          6. Cardiac function: Left ventricular ejection fraction > 45% based on most recent
             echocardiogram or MUGA results with no clinical evidence of heart failure

          7. Estimated creatinine clearance > 60 mL/min calculated by equation

          8. Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted > 50% based
             on most recent DLCO results

          9. Liver function acceptable per local institutional guidelines

         10. KPS of > 60%

         11. Subjects ≥ 18 years of age must have the ability to give informed consent according to
             applicable regulatory and local institutional requirements.

        Stratum 3 Recipient Inclusion Criteria

          1. Age > 1 years and < 21 years at the time of signing informed consent

          2. Partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age < 35
             years

          3. Product planned for infusion is BM

          4. Planned MAC regimen as defined per protocol

          5. One of the following diagnosis:

               1. 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.

               2. 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.

               3. 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.

               4. Other leukemia (mixed-phenotype acute leukemia [MPAL], CML) 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.

               5. Chemotherapy sensitive lymphoma in at least partial remission (PR)

          6. KPS or Lansky performance score ≥ 70%

          7. Cardiac function: Left ventricular ejection fraction of ≥ 50% and shortening fraction
             of ≥ 27% based on most recent echocardiogram

          8. Glomerular Filtration Rate (GFR) of ≥ 60ml/min/1.73m2 measured by nuclear medicine
             scan or calculated from a 24 hour urine collection

          9. Pulmonary function: DLCO corrected for hemoglobin, FEV1, 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.

         10. Hepatic: Total bilirubin ≤ 2.5 mg/dL and alanine aminotransferase (ALT), aspartate
             aminotransferase (AST) < 3x the upper limit of normal

         11. 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.

         12. Subjects ≥ 18 years of age must have the ability to give informed consent according to
             applicable regulatory and local institutional requirements.

        Donor Inclusion Criteria:

          1. 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)

          2. Donor must be typed at high-resolution for a minimum of HLA-A, -B, -C, -DRB1, -DQB1,
             and -DPB1

          3. Age > 18 years and < 35 years at the time of signing informed consent

          4. Meet the donor registries' medical suitability requirements for PBSC or BM donation

          5. 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.

          6. Must agree to donate PBSC (or BM for stratum 3)

          7. 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):

          1. Suitable HLA-matched related or 8/8 high-resolution matched unrelated donor available

          2. Subject unwilling or unable to give informed consent, or unable to comply with the
             protocol including required follow-up and testing

          3. Primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia,
             polycythemia vera, or MDS with grade 4 marrow fibrosis

          4. Subjects with a prior allogeneic transplant or autologous transplant within the past 3
             months

          5. Females who are breast-feeding or pregnant

          6. Uncontrolled bacterial, viral or fungal infection at the time of the transplant
             preparative regimen

          7. Concurrent enrollment on other interventional GVHD clinical trial (enrollment on
             supportive care trials may be allowed after discussion with Principal Investigators)

        Donor Exclusion Criteria:

          1. Donor unwilling or unable to donate

          2. Recipient positive anti-donor HLA antibodies against a mismatched HLA in the selected
             donor determined by either:

               1. a positive crossmatch test of any titer (by complement-dependent cytotoxicity or
                  flow cytometric testing) or

               2. the presence of anti-donor HLA antibody to any HLA locus (HLA-A, -B, -C, -DRB1,
                  -DQB1, -DQA1, -DPB1, -DPA1) with mean fluorescence intensity (MFI) >3000 by solid
                  phase immunoassay
      

Gender

All

Ages

1 Year - N/A

Accepts Healthy Volunteers

No

Contacts

Steven Devine, MD, 763-406-8147, [email protected]



Administrative Informations


NCT ID

NCT04904588

Organization ID

ACCESS


Responsible Party

Sponsor

Study Sponsor

Center for International Blood and Marrow Transplant Research

Collaborators

 National Marrow Donor Program

Study Sponsor

Steven Devine, MD, Principal Investigator, NMDP/Be The Match


Verification Date

May 2021