Clinical trial NCT06001385: HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Prophylaxis
Official title: A Phase II Study of Reduced Dose Post Transplantation Cyclophosphamide as GvHD Prophylaxis in Adult Patients With Hematologic Malignancies Receiving HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Acute Leukemia
Myelodysplastic Syndromes
Chronic Myeloid Leukemia
Chronic Lymphocytic Leukemia
Myeloproliferative Neoplasm
Lymphoma
Chronic Myelomonocytic Leukemia
Pro-Lymphocytic Leukemia
Myelofibrosis
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 Disorders
Bone Marrow Diseases
Precancerous Conditions
Leukemia, Lymphoid
Leukemia, B-Cell
Leukemia, Myeloid
Cyclophosphamide
Mesna
Tacrolimus
Busulfan
Fludarabine
Total Body Irradiation
Melphalan
Mycophenolate mofetil
Reduced Dose Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Hematopoietic Stem Cell Transplantation
Peripheral Blood Stem Cells
Unrelated Donors
Lead sponsor: Center for International Blood and Marrow Transplant Research
Sponsor class: NETWORK
Collaborators: name: National Marrow Donor Program
First posted: 2023-08-21
Enrollment: 313
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to determine the effectiveness of Reduced Dose Post-Transplant Cyclophosphamide (PTCy) in patients with hematologic malignancies after receiving an HLA-Mismatched Unrelated Donor (MMUD) . The main question\[s\] it aims to answer are:

* Does a reduced dose of PTCy reduce the occurrence of infections in the first 100 days after transplant?
* Does a reduced dose of PTCy maintain the same level of protection against Graft Versus Host Disease (GvHD) as the standard dose of PTCy?


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. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and institutional requirements.
3. Stated willingness to comply with all study procedures and availability for the duration of the study.
4. Planned MAC regimen as defined per study protocol
5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred).
6. Product planned for infusion is MMUD T-cell replete PBSC allograft
7. HCT-CI \< 5. The presence of prior malignancy will not be used to calculate HCT-CI for this trial to allow for the inclusion of patients with secondary or therapy-related AML or MDS.
8. 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 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.
9. Cardiac function: Left ventricular ejection fraction ≥ 45% based on most recent echocardiogram or multi-gated acquisition scan (MUGA) results.
10. Estimated creatinine clearance ≥ 45mL/min calculated by equation.
11. 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 (PFT) results
12. Liver function acceptable per local institutional guidelines
13. KPS of ≥ 70%

Stratum 2 Recipient Inclusion Criteria:

1. Age ≥18 years at the time of signing informed consent
2. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and local institutional requirements.
3. Stated willingness to comply with all study procedures and availability for the duration of the study.
4. Planned NMA/RIC regimen per study protocol
5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred).
6. Product planned for infusion is MMUD T-cell replete PBSC allograft
7. 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. Higher risk CMML according to CMML-specific prognostic scoring system or high risk MDS/MPN not otherwise specified are eligible, provided there is no evidence of high-grade bone marrow fibrosis or massive splenomegaly at the time of enrollment.
   5. Patients with lymphoma with chemosensitive disease at the time of transplantation
8. Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure
9. Estimated creatinine clearance ≥ 45mL/min calculated by equation
10. Pulmonary function: DLCO corrected for hemoglobin \> 50% and FEV1 predicted \>50% based on most recent PFT results
11. Liver function acceptable per local institutional guidelines
12. KPS of ≥ 60%

Stratum 3 Recipient Inclusion Criteria:

1. Age ≥18 years at the time of signing informed consent
2. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and local institutional requirements.
3. Stated willingness to comply with all study procedures and availability for the duration of the study.
4. Planned NMA/RIC regimen per study protocol
5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred).
6. Product planned for infusion is MMUD T-cell replete PBSC allograft
7. Diagnosis of primary myelofibrosis with risk features making them eligible for HCT. Myelofibrosis secondary to essential thrombocythemia, polycythemia vera, or MDS with grade 4 fibrosis are also eligible. Patients with a myelofibrosis diagnosis require sponsor approval before enrolling.
8. Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure
9. Estimated creatinine clearance ≥ 45 mL/min calculated by equation
10. Pulmonary function: DLCO corrected for hemoglobin \> 50% and FEV1 predicted \>50% based on most recent PFT results
11. Liver function acceptable per local institutional guidelines
12. KPS of ≥ 60%

Donor Inclusion Criteria (note: donors are not research subjects):

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, -DQB1, and -DPB1.
3. Age ≥ 18 years and ≤ 40 years at the time of signing informed consent for PBSC donation. Note: donors are preferred to be ≤ 35.
4. Meet the donor registries' medical suitability requirements for PBSC 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.
7. Must have the ability to give informed consent according to 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. Subjects with a prior allogeneic transplant
4. Subjects with an 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 a preventative GvHD and/or infectious disease prevention clinical trial.
8. Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant.
9. Patients who are HIV+ with persistently positive viral load. HIV-infected patients on effective anti-retroviral therapy (ART) with undetectable viral load within 6 months are eligible for this trial. Patients with well controlled HIV are eligible provided resistance panels are negative, the patient is compliant with ART, and their disease remains well controlled.

Donor Exclusion Criteria:

1. Donor unwilling or unable to donate.
2. Recipient positive for 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: Infection Free Survival
timeFrame: 100 days post-HCT
Secondary outcomes:
measure: Overall Survival
timeFrame: 1-year post-HCT
measure: Progression-free survival
timeFrame: 1-year post-HCT
measure: Infection-free survival
timeFrame: 1-year post-HCT
measure: Graft versus host disease relapse free survival
timeFrame: 1-year post-HCT
measure: Non-relapse mortality
timeFrame: 1-year post-HCT
measure: Cumulative incidence of neutrophil recovery
timeFrame: Day 28 post-HCT
measure: Cumulative incidence of platelet recovery
timeFrame: Day 28 post-HCT
measure: Cumulative incidence of primary and secondary graft failure
timeFrame: Day 28 and 1-year post-HCT
measure: Donor T-Cell Chimerism
timeFrame: Day 28, 100 and 365 post-HCT
measure: Cumulative incidence of acute GvHD
timeFrame: Day 100 and Day 180 post-HCT
measure: Cumulative incidence of chronic GvHD
timeFrame: 1-year post-HCT
measure: Cumulative incidence of grade 2-3 bacterial, fungal, and viral infections
timeFrame: Day 100 and 1-year post-HCT
measure: Cumulative incidence of grades 2-3 BK virus hemorrhagic cystitis
timeFrame: 1-year post-HCT
measure: Cumulative incidence of relapse/progression
timeFrame: 1-year post-HCT
measure: Overall Toxicity
timeFrame: 1-year post-HCT
measure: Incidence and Severity of cytokine release syndrome
timeFrame: within 14 days post-HCT
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Scottsdale
country: United States
facility: Honor Health
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Duarte
country: United States
facility: City of Hope
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 at Presbyterian St. Luke's
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Miami
country: United States
facility: University of Miami Sylvester Cancer Center
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Baltimore
country: United States
facility: Greenbaum Cancer Center University of Maryland
state: Maryland
city: Boston
country: United States
facility: Tufts University
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital / Washington University
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - Adults
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Columbus
country: United States
facility: Ohio State Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Danville
country: United States
facility: The Center for Bone Marrow Transplantation at Geisinger
state: Pennsylvania
city: Philadelphia
country: United States
facility: Abramson Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: TriStar Centennial
state: Tennessee
city: Austin
country: United States
facility: St. David's South Austin Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Hospital San Antonio
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Center
state: Washington
city: Milwaukee
country: United States
facility: Froedtert & the Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: NMDP
name: Steven Devine, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NMDP
name: Jeffery Auletta, MD
role: STUDY_CHAIR
References: