Clinical trial NCT04904588: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Mixed Phenotype Acute Leukemia
Acute Leukemia
Myelodysplastic Syndromes
Chronic Myelogenous Leukemia
Chronic Lymphocytic Leukemia
Lymphoma
Keywords: Lymphoma
Leukemia
Hematologic Diseases
Myelodysplastic Syndromes
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Myeloid, Acute
Leukemia, Biphenotypic, Acute
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Bone Marrow Diseases
Precancerous Conditions
Leukemia, Lymphoid
Leukemia, B-Cell
Leukemia, Myeloid
Cyclophosphamide
Mesna
Tacrolimus
Busulfan
Fludarabine
Total Body Irradiation
Melphalan
Mycophenolate mofetil
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Hematopoietic Stem Cell Transplantation
Unrelated Donors
Lead sponsor: Center for International Blood and Marrow Transplant Research
Sponsor class: NETWORK
Collaborators: name: National Marrow Donor Program
First posted: 2021-05-27
Enrollment: 300
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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 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.
   2. 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 pulmonary function test results
10. Liver function acceptable per local institutional guidelines
11. Karnofsky performance status (KPS) of \> 70%
12. 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

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 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.
   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 chronic lymphocytic leukemia (CLL) or other leukemias (including prolymphocytic leukemia) 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 pulmonary function test results
9. Liver function acceptable per local institutional guidelines
10. KPS of \> 60%
11. 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

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, 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.
   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, 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.
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 or legally authorized representative 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 HSC transplant
5. Subjects with an autologous HSC transplant within the past 3 months
6. Females who are breast-feeding or pregnant
7. Uncontrolled bacterial, viral or fungal infection at the time of the transplant preparative regimen
8. Concurrent enrollment on other interventional GVHD clinical trial (enrollment on supportive care trials may be allowed after discussion with Principal Investigators)
9. Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant.
10. 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:

1. Donor unwilling or unable to donate
2. 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.

Primary outcomes:
measure: Overall Survival
timeFrame: 1 year post HCT
Secondary outcomes:
measure: Event-free survival
timeFrame: 1 year post-HCT
measure: GVHD, relapse free survival
timeFrame: 1 year post-HCT
measure: Modified GVHD, relapse free survival
timeFrame: 1 year post-HCT
measure: Progression-free survival
timeFrame: 1 year post-HCT
measure: Cumulative incidence of nonrelapse mortality
timeFrame: Day +100 and 1 year post-HCT
measure: Event-Free Survival based on donor HLA match grade and donor age (7/8 versus <7/8)
timeFrame: 1 year post-HCT
measure: Overall Survival based on donor HLA match grade and donor age (7/8 versus <7/8)
timeFrame: 1 year post-HCT
measure: Cumulative incidence of neutrophil recovery
timeFrame: Day +100 post-HCT
measure: Kinetics of neutrophil recovery
timeFrame: Day +100 post-HCT
measure: Cumulative incidence of platelet recovery
timeFrame: Day +100 post-HCT
measure: Kinetics of platelet recovery
timeFrame: Day +100 post-HCT
measure: Cumulative incidence of primary graft failure
timeFrame: Day +28 post-HCT
measure: Donor chimerism
timeFrame: Day +100 post-HCT
measure: Cumulative incidence of acute GVHD
timeFrame: Day +100 post-HCT
measure: Cumulative incidence of chronic GVHD
timeFrame: 1 year post-HCT
measure: Cumulative incidence of BK and cytomegalovirus (CMV) viral infections
timeFrame: Days +100 and +180 post-HCT
measure: Cumulative incidence of relapse/progression
timeFrame: 1 year post-HCT
measure: Incidence of cytokine release syndrome (CRS)
timeFrame: Day +14 post-HCT
measure: Cumulative incidence of secondary graft failure
timeFrame: 1 year post-HCT
measure: Overall Toxicity
timeFrame: 1 year post-HCT
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Gainesville
country: United States
facility: University of Florida Health Shands Hospital
state: Florida
city: Miami
country: United States
facility: University of Miami Sylvester Cancer Center
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Atlanta
country: United States
facility: Emory University Medical Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Medical Center - Mott Children's Hospita
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Rochester
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University/Barnes Jewish Hospital
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Comprehensive Cancer Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Chapel Hill
state: North Carolina
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Ohio State Medical Center, James Cancer Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Sidney Kimmel Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: TriStar BMT
state: Tennessee
city: Nashville
country: United States
facility: TriStar Medical Group Children's Specialists
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Austin
country: United States
facility: St. David's South Austin Medical Center
state: Texas
city: Houston
country: United States
facility: -Baylor College of Medicine - Texas Children's Hospital and Houston Methodist
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert & the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: NMDP/Be The Match
name: Steven Devine, MD
role: PRINCIPAL_INVESTIGATOR
References: