HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Prophylaxis

Lymphoma Clinical Trial

— OPTIMIZE  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06001385
• Other study ID #: OPTIMIZE
• Status: Recruiting
• Phase: Phase 2
• Start date: December 8, 2023
• Est. completion date: June 30, 2026

Study information

• Verified date: June 2024
• Source: Center for International Blood and Marrow Transplant Research
• Contact: Brandan Butler, MBA
• Phone: 763-406-3280
• Email: bbutler[@]nmdp.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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?

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 190
• Est. completion date: June 30, 2026
• Est. primary completion date: February 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years 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. 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.

Related Conditions & MeSH terms

• Acute Leukemia
• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Chronic Lymphocytic Leukemia
• Chronic Myeloid Leukemia
• Chronic Myelomonocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Leukemia, Prolymphocytic
• Lymphoma
• Myelodysplastic Syndromes
• Myelofibrosis
• Myeloproliferative Disorders
• Myeloproliferative Neoplasm
• Neoplasms
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia

Intervention

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

Drug:
• Post-Transplant Cyclophosphamide
Cyclophosphamide (25mg/kg) is administered on Day 3 and Day 4 post-transplant as an IV infusion over 1-2 hours. First 20 subjects with a 4-6/8 HLA mismatched unrelated donor will receive an intermediate dose of post-transplant cyclophosphamide of 37.5 mg/kg Day 3 and Day 4 post-transplant.
• 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 Day + 90 and finished by Day +180.
• 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 transplant, at Day + 100, Day + 180, and Day +365 post transplant.

Drug:
• Melphalan
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

Locations

Country	Name	City	State
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	University of Miami Sylvester Cancer Center	Miami	Florida
United States	Froedtert & the Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Memorial Sloan Kettering Cancer Center - Adults	New York	New York
United States	Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Barnes Jewish Hospital / Washington University	Saint Louis	Missouri
United States	Fred Hutchinson Cancer Center	Seattle	Washington
United States	Stanford University	Stanford	California
United States	Moffitt Cancer Center	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	Infection Free Survival	Survival at 100 days without grades 2-3 infections (per BMT CTN grading criteria)	100 days post-HCT
Secondary	Overall Survival	Defined as time interval between date of transplant and death from any cause	1-year post-HCT
Secondary	Progression-free survival	Defined as disease relapse or progression, or death by any cause	1-year post-HCT
Secondary	Infection-free survival	Defined as death and grades II-III infection (per BMT CTN criteria)	1-year post-HCT
Secondary	Graft versus host disease relapse free survival	Defined as relapse or progression of underling disease (by 1 year), grade III-IV acute GvHD (by 6 months), chronic GvHD requiring systemic immune suppression (by 1 year), or death by any cause (by 1 year).	1-year post-HCT
Secondary	Non-relapse mortality	Defined as death without evidence of disease progression or recurrence	1-year post-HCT
Secondary	Cumulative incidence of neutrophil recovery	Defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/mm3 for three consecutive measurements on three different days	Day 28 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 28 post-HCT
Secondary	Cumulative incidence of primary and secondary graft failure	Primary graft failure is defined as no neutrophil recovery to = 500 cells/mm3 by Day 28 post HCT.; Secondary graft failure is defined as as initial neutrophil count recovery followed by subsequent decline in absolute neutrophil counts <500 cells/mm3, unresponsive to growth factor therapy, but cannot be explained by infection, disease relapse, or medications.	Day 28 and 1-year post-HCT
Secondary	Donor T-Cell Chimerism	Defined as percent of donor chimerism via peripheral blood	Day 28, 100 and 365 post-HCT
Secondary	Cumulative incidence of acute GvHD	Defined as cumulative incidence of grades II-IV acute GvHD	Day 100 and Day 180 post-HCT
Secondary	Cumulative incidence of chronic GvHD		1-year post-HCT
Secondary	Cumulative incidence of grade 2-3 bacterial, fungal, and viral infections	Defined as grades 2-3 infection as defined by BMT CTN grading criteria.	Day 100 and 1-year post-HCT
Secondary	Cumulative incidence of grades 2-3 BK virus hemorrhagic cystitis	Defined as incidence of BK virus hemorrhagic cystitis per BMT CTN grading criteria	1-year post-HCT
Secondary	Cumulative incidence of relapse/progression	Defined as disease relapse or progression from Day 0 to 1-year post-HCT	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 v5	1-year post-HCT
Secondary	Incidence and Severity of cytokine release syndrome	Defined and graded using the ASTCT grading criteria.	within 14 days post-HCT