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

NCT06001385 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: OPTIMIZE
• Study Type: interventional
• Target: 313
• Locations: 1 country
• Sites: 32

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?

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes; Chronic Myeloid Leukemia; Chronic Lymphocytic Leukemia; Myeloproliferative Neoplasm; Lymphoma; Chronic Myelomonocytic Leukemia; Pro-Lymphocytic Leukemia; Myelofibrosis; Acute Lymphoblastic Leukemia; Acute Leukemia

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

Outcome Measures

Primary Outcomes (1)

• Infection Free Survival

  Survival at 100 days without grades 2-3 infections (per BMT CTN grading criteria)

  100 days post-HCT

Secondary Outcomes (16)

• Overall Survival

  1-year post-HCT

• Progression-free survival

  1-year post-HCT

• Infection-free survival

  1-year post-HCT

• Graft versus host disease relapse free survival

  1-year post-HCT

• Non-relapse mortality

  1-year post-HCT

Study Arms (5)

Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy

EXPERIMENTAL

Patients Receive: 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Drug: Busulfan; Drug: Fludarabine; Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT); Drug: Post-Transplant Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Other: Patient Reported Outcomes

Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy

EXPERIMENTAL

Patients receive: Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Drug: Fludarabine; Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT); Drug: Post-Transplant Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Other: Patient Reported Outcomes; Radiation: Total-body irradiation

Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy

EXPERIMENTAL

Patients receive: Fludarabine (150-180 mg/m2 total dose) IV on days -6 to -2 Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Drug: Busulfan; Drug: Fludarabine; Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT); Drug: Post-Transplant Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Other: Patient Reported Outcomes

Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy

EXPERIMENTAL

Patients receive: Fludarabine (125-150 mg/m2 total dose) IV on days -7 to -3 Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Drug: Fludarabine; Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT); Drug: Post-Transplant Cyclophosphamide; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Other: Patient Reported Outcomes; Drug: Melphalan

Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

EXPERIMENTAL

Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Drug: Fludarabine; Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT); Drug: Post-Transplant Cyclophosphamide; Drug: Mesna; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Other: Patient Reported Outcomes; Radiation: Total-body irradiation; Drug: Cyclophosphamide

Interventions

PBSC Hematopoietic Stem Cell Transplantation (HSCT) PROCEDURE

Peripheral blood stem cell graft is infused from a mismatched unrelated donor on Day 0

Also known as: PBSC HSCT, PBSC HCT, PBSC Transplantation, PBSCT

Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy; Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy; Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy; Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy; Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Mesna DRUG

Mesna is given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post cyclophosphamide.

Also known as: Mesnex®

Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Tacrolimus DRUG

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.

Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy; Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy; Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy; Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy; Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Mycophenolate Mofetil DRUG

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.

Also known as: MMF, Cellcept®

Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy; Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy; Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy; Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy; Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Patient Reported Outcomes OTHER

Survey assessments will be administered to study participants pre transplant, at Day + 100, Day + 180, and Day +365 post transplant.

Also known as: PRO

Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy; Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy; Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy; Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy; Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Melphalan DRUG

Given IV pre transplant as part of conditioning regimen

Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy

Total-body irradiation RADIATION

Administered pre-transplant as part of conditioning regimen

Also known as: TBI

Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy; Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Cyclophosphamide DRUG

Given IV pre-transplant as part of conditioning regimen

Also known as: Cytoxan®

Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Busulfan DRUG

Given IV or PO pre-transplant as part of conditioning regimen

Also known as: Busulfex®

Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy; Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy

Fludarabine DRUG

Given IV pre-transplant as part of conditioning regimen

Also known as: Fludara®

Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy; Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy; Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy; Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy; Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Post-Transplant Cyclophosphamide DRUG

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.

Also known as: Cytoxan®, PTCy

Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy; Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy; Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy; Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy; Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and institutional requirements.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Planned MAC regimen as defined per study protocol
• 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).
• Product planned for infusion is MMUD T-cell replete PBSC allograft
• One of the following diagnoses:
• 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.
• 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.
• Cardiac function: Left ventricular ejection fraction ≥ 45% based on most recent echocardiogram or multi-gated acquisition scan (MUGA) results.
• Estimated creatinine clearance ≥ 45mL/min calculated by equation.
• 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
• Liver function acceptable per local institutional guidelines
• KPS of ≥ 70%
• Age ≥18 years at the time of signing informed consent

You may not qualify if:

• Suitable HLA-matched related or 8/8 high-resolution matched unrelated donor available
• Subject unwilling or unable to give informed consent, or unable to comply with the protocol including required follow-up and testing
• Subjects with a prior allogeneic transplant
• Subjects with an autologous transplant within the past 3 months
• Females who are breast-feeding or pregnant
• Uncontrolled bacterial, viral, or fungal infection at the time of the transplant preparative regimen
• Concurrent enrollment on a preventative GvHD and/or infectious disease prevention clinical trial.
• Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant.
• 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 unwilling or unable to donate.
• 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.

Sponsors & Collaborators

• Center for International Blood and Marrow Transplant Research: lead
• National Marrow Donor Program: collaborator

Study Sites (32)

Mayo Clinic Arizona

Phoenix, Arizona, 85054, United States

Location

Honor Health

Scottsdale, Arizona, 85258, United States

Location

University of Arkansas for Medical Sciences

Little Rock, Arkansas, 72205, United States

Location

City of Hope

Duarte, California, 91010, United States

Location

University of California San Francisco

San Francisco, California, 94158, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

Colorado Blood Cancer Institute at Presbyterian St. Luke's

Denver, Colorado, 80218, United States

Location

Mayo Clinic Jacksonville

Jacksonville, Florida, 32224, United States

Location

University of Miami Sylvester Cancer Center

Miami, Florida, 33136, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Greenbaum Cancer Center University of Maryland

Baltimore, Maryland, 21201, United States

Location

Tufts University

Boston, Massachusetts, 02155, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Mayo Clinic

Rochester, Minnesota, 55902, United States

Location

Barnes Jewish Hospital / Washington University

St Louis, Missouri, 63110, United States

Location

Memorial Sloan Kettering Cancer Center - Adults

New York, New York, 10065, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

Ohio State Medical Center

Columbus, Ohio, 43210, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

The Center for Bone Marrow Transplantation at Geisinger

Danville, Pennsylvania, 17822, United States

Location

Abramson Cancer Center

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15232, United States

Location

TriStar Centennial

Nashville, Tennessee, 37203, United States

Location

St. David's South Austin Medical Center

Austin, Texas, 78704, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Methodist Hospital San Antonio

San Antonio, Texas, 78229, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

Location

Froedtert & the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloproliferative Disorders; Lymphoma; Leukemia, Myelomonocytic, Chronic; Leukemia, Prolymphocytic; Primary Myelofibrosis; Leukemia; Hematologic Diseases; Preleukemia; Leukemia, B-Cell; 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, Myeloid

Interventions

Busulfan; fludarabine; fludarabine phosphate; Peripheral Blood Stem Cell Transplantation; Cyclophosphamide; Mesna; Tacrolimus; Mycophenolic Acid; Patient Reported Outcome Measures; Melphalan; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Myelodysplastic-Myeloproliferative Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Sulfhydryl Compounds; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Health Care Surveys; Surveys and Questionnaires; Data Collection; Epidemiologic Methods; Investigative Techniques; Health Services Research; Health Planning; Health Care Economics and Organizations; Patient Outcome Assessment; Outcome Assessment, Health Care; Outcome and Process Assessment, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Health Care Evaluation Mechanisms; Public Health; Environment and Public Health; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Radiotherapy

Study Officials

• Steven Devine, MD

  NMDP

  PRINCIPAL INVESTIGATOR

• Jeffery Auletta, MD

  NMDP

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 14, 2023
• First Posted: August 21, 2023
• Study Start: December 8, 2023
• Primary Completion: February 1, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: February 5, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (32)