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

Lymphoma Clinical Trial

— ACCESS  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04904588
• Other study ID #: ACCESS
• Status: Recruiting
• Phase: Phase 2
• Start date: September 30, 2021
• Est. completion date: July 2024

Study information

• Verified date: May 2024
• Source: Center for International Blood and Marrow Transplant Research
• Contact: Sarah Smith, RN, BSN
• Phone: 763-406-5397
• Email: ssmith23[@]nmdp.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: July 2024
• Est. primary completion date: July 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Disease
• Acute Leukemia
• Acute Lymphoblastic Leukemia
• Acute Myelogenous Leukemia
• Chronic Lymphocytic Leukemia
• Chronic Myelogenous Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Lymphoma
• Mixed Phenotype Acute Leukemia
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia

Intervention

Drug:
• Busulfan
Given IV or PO pre-transplant as part of conditioning regimen
• Busulfan
Given IV pre-transplant as part of conditioning regimen
• Fludarabine
Given IV pre-transplant as part of conditioning regimen

Radiation:
• Total-body irradiation
Administered pre-transplant as part of conditioning regimen

Drug:
• Cyclophosphamide
Given IV pre-transplant as part of conditioning regimen
• Melphalan
Given IV pre-transplant as part of conditioning regimen

Procedure:
• PBSC Hematopoietic Stem Cell Transplantation (HSCT)
Peripheral blood stem cell graft is infused from a mismatched unrelated donor on Day 0.
• Bone Marrow Hematopoietic Stem Cell Transplantation
Bone marrow graft is infused from a mismatched unrelated donor on Day 0.

Drug:
• Post-transplant Cyclophosphamide
Cyclophosphamide (50 mg/kg) is administered on Day +3 and on Day +4 post-transplant as an IV infusion over 1-2 hours.
• Mesna
Mesna is given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide.
• Tacrolimus
Tacrolimus is given at a dose of 0.05 mg/kg PO or an IV dose of 0.03 mg/kg of ideal body weight (IBW) starting on Day +5 post-transplant with taper recommended at 90-100 days post HCT.
• Mycophenolate Mofetil
Mycophenolate mofetil (MMF) is given at a dose of 15 mg/kg three times daily IV or PO from Day +5 to Day +35 post-transplant.

Other:
• Patient-Reported Outcomes
Survey assessments will be administered to study participants pre- and post-transplant.

Locations

Country	Name	City	State
United States	University of Michigan Medical Center - Mott Children's Hospita	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Emory University Medical Center	Atlanta	Georgia
United States	St. David's South Austin Medical Center	Austin	Texas
United States	The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	University of North Carolina Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	The University of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Ohio State Medical Center, James Cancer Center	Columbus	Ohio
United States	Colorado Blood Cancer Institute	Denver	Colorado
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	University of Florida Health Shands Hospital	Gainesville	Florida
United States	-Baylor College of Medicine - Texas Children's Hospital and Houston Methodist	Houston	Texas
United States	University of Wisconsin Hospital and Clinic	Madison	Wisconsin
United States	University of Miami Sylvester Cancer Center	Miami	Florida
United States	Froedtert & the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	TriStar BMT	Nashville	Tennessee
United States	TriStar Medical Group Children's Specialists	Nashville	Tennessee
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Thomas Jefferson University Sidney Kimmel Cancer Center	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Mayo Clinic Rochester	Rochester	Minnesota
United States	Washington University/Barnes Jewish Hospital	Saint Louis	Missouri
United States	Texas Transplant Institute	San Antonio	Texas
United States	University of California San Francisco	San Francisco	California
United States	Stanford University	Stanford	California
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Center for International Blood and Marrow Transplant Research	National Marrow Donor Program

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival		1 year post HCT
Secondary	Event-free survival	Defined as graft failure, relapse or progression of underlying disease, death, grade 3-4 acute GVHD, or NIH-severe chronic GVHD.	1 year post-HCT
Secondary	GVHD, relapse free survival	Defined as relapse or progression of underling disease, graft failure, grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, or death by any cause.	1 year post-HCT
Secondary	Modified GVHD, relapse free survival	Defined as relapse or progression of underling disease, graft failure, grade III-IV acute GVHD, NIH moderate or severe chronic GVHD, or death by any cause.	1 year post-HCT
Secondary	Progression-free survival		1 year post-HCT
Secondary	Cumulative incidence of nonrelapse mortality		Day +100 and 1 year post-HCT
Secondary	Event-Free Survival based on donor HLA match grade and donor age (7/8 versus <7/8)		1 year post-HCT
Secondary	Overall Survival based on donor HLA match grade and donor age (7/8 versus <7/8)		1 year post-HCT
Secondary	Cumulative incidence of neutrophil recovery	Defined as neutrophil count =500/mm^3 for 3 consecutive days post-HCT.	Day +100 post-HCT
Secondary	Kinetics of neutrophil recovery	Defined as the evaluation of the time it takes for neutrophil count recovery to occur in the study subjects.	Day +100 post-HCT
Secondary	Cumulative incidence of platelet recovery	Defined as platelet count =20,000/mm^3 or =50,000/mm^3 with no platelet transfusions within seven days.	Day +100 post-HCT
Secondary	Kinetics of platelet recovery	Defined as the evaluation of the time it takes for platelet count recovery to occur in the study subjects.	Day +100 post-HCT
Secondary	Cumulative incidence of primary graft failure		Day +28 post-HCT
Secondary	Donor chimerism	Strata 2 and 3 only. Percent of donor chimerism via peripheral blood	Day +100 post-HCT
Secondary	Cumulative incidence of acute GVHD		Day +100 post-HCT
Secondary	Cumulative incidence of chronic GVHD		1 year post-HCT
Secondary	Cumulative incidence of BK and cytomegalovirus (CMV) viral infections		Days +100 and +180 post-HCT
Secondary	Cumulative incidence of relapse/progression		1 year post-HCT
Secondary	Incidence of cytokine release syndrome (CRS)	Overall incidence of CRS of any grade and grade 3 or 4 CRS post-transplant	Day +14 post-HCT
Secondary	Cumulative incidence of secondary graft failure		1 year post-HCT
Secondary	Overall Toxicity	To tabulate adverse events (AEs) experienced by recipients, defined as grade 3-5 unexpected and Grade 5 expected AEs, according to CTCAE version 5.0.	1 year post-HCT