Treosulfan-Based Conditioning Regimen Before a Blood or Bone Marrow Transplant for the Treatment of Bone Marrow Failure Diseases (BMT CTN 1904)

NCT04965597 | Completed Phase 2 DMC FDA Drug

• 5 other identifiers: BMTCTN19042U10HL069294-11RG112182010840NCI-2021-13862
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 24

Brief Summary

This phase II trial tests whether treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) work when given before a blood or bone marrow transplant (conditioning regimen) to cause fewer complications for patients with bone marrow failure diseases. Chemotherapy drugs, such as treosulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Fludarabine may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. rATG is used to decrease the body's immune response and may improve bone marrow function and increase blood cell counts. Adding treosulfan to a conditioning regimen with fludarabine and rATG may result in patients having less severe complications after a blood or bone marrow transplant.

Conditions

Bone Marrow Failure Syndrome; Congenital Amegakaryocytic Thrombocytopenia; Diamond-Blackfan Anemia; Hereditary Sideroblastic Anemia; Paroxysmal Nocturnal Hemoglobinuria; Shwachman-Diamond Syndrome; Hematologic Neoplasm With Germline GATA2 Mutation; Hematologic Neoplasm With Germline SAMD9 Mutation; Hematologic Neoplasm With Germline SAMD9L Mutation

Keywords

Bone Marrow Failure Disorders; HSCT; Treosulfan; Unrelated donor; Matched donor; mismatched donor; transplant

Outcome Measures

Primary Outcomes (1)

• Graft-Versus Host-Disease (GVHD)-Free Event-Free Survival (EFS)

  The primary endpoint is the incidence of 1-year GVHD free, EFS (GEFS). An event is defined as death due to any cause, primary or secondary graft failure/rejection, or 2nd HCT whichever occurs first. Grade III-IV acute GVHD and chronic GVHD (using National Institutes of Health \[NIH\] consensus criteria) requiring systemic immune suppression will be considered in this estimate.

  1 year post-HCT

Secondary Outcomes (20)

• Overall Survival

  Day 100 post-HCT

• Overall Survival

  6 months post-HCT

• Overall Survival

  1 year post-HCT

• Event-Free Survival

  1 year post-HCT

• Hematologic Recovery: Neutrophil recovery

  Assessed up to 1 year post-HCT

Study Arms (1)

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

EXPERIMENTAL

CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2. TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.

Drug: Treosulfan; Drug: Fludarabine Phosphate; Drug: Tacrolimus; Drug: Methotrexate; Biological: Lapine T-Lymphocyte Immune Globulin; Procedure: Peripheral Blood Stem Cell Transplantation; Procedure: Allogeneic Bone Marrow Transplantation; Other: Quality-of-Life Assessment; Procedure: Echocardiography; Procedure: Multigated Acquisition Scan; Procedure: Bone Marrow Biopsy; Procedure: Bone Marrow Aspiration; Procedure: Biospecimen Collection; Procedure: X-Ray Imaging; Procedure: Computed Tomography

Interventions

Treosulfan DRUG

Given IV

Also known as: Dihydroxybusulfan, Ovastat, Treosulphan, Tresulfon, Trecondi

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, 9H-purin-6-amine, 2-fluoro-9-(5-O-phosphono-beta-D-arabinofuranosyl), Beneflur, Fludara, Fludarabine-5'-Monophosphate, SH T 586

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Tacrolimus DRUG

Given IV and PO

Also known as: FK 506, Fujimycin, Hecoria, Prograf, Protopic

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Methotrexate DRUG

Given IV

Also known as: Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate, Emthexat, Emtexate, Farmitrexat, Methotrexate LPF, Methylaminopterin, Methotrexatum, Metotrexato, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Lapine T-Lymphocyte Immune Globulin BIOLOGICAL

Given IV

Also known as: Anti-Thymocyte Globulin Rabbit, Grafalon, Rabbit Anti-Human Thymocyte Globulin (RATG), Rabbit Anti-Thymocyte Globulin, Rabbit Antithymocyte Globulin, Rabbit ATG, rATG, Thymoglobulin, Antithymocyte globulin rabbit ATG, Imtix

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo PBSC

Also known as: PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, PERIPHERAL BLOOD STEM CELL TRANSPLANT, peripheral stem cell support, Peripheral Stem Cell Transplant, peripheral stem cell transplantation

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Allogeneic Bone Marrow Transplantation PROCEDURE

Undergo bone marrow transplant

Also known as: Allo BMT, Allogeneic Blood and Marrow Transplantation, Allogeneic BMT

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Echocardiography PROCEDURE

Undergo ECHO

Also known as: EC

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Multigated Acquisition Scan PROCEDURE

Undergo MUGA

Also known as: Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, Multi-Gated Acquisition Scan, MUGA Scan, Radionuclide Ventriculogram Scan, Radionuclide ventriculography, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Bone Marrow Biopsy PROCEDURE

Undergo bone marrow biopsy and aspiration

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow biopsy and aspiration

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

X-Ray Imaging PROCEDURE

Undergo chest x-ray

Also known as: Conventional X-Ray, Diagnostic Radiology

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Computed Tomography PROCEDURE

Undergo chest CT

Also known as: Computed Axial Tomography, CAT Scan, CT Scan

Treatment (conditioning regimen; transplant; GVHD prophylaxis)

Eligibility Criteria

• Age: 1 Year - 49 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patient must be \>= 1.0 year of age and less than 50.0 years of age at the time of enrollment (i.e. patient must have celebrated their 1st birthday when enrolled and must NOT have celebrated their 50th birthday when enrolled; 49.99 years)
• Underlying BMFD treatable by allogenic HCT
• Shwachman-Diamond syndrome
• Criteria for Diagnosis:
• A pathogenic mutation(s) for Shwachman-Diamond syndrome
• For those patients tested but lacking a genetic mutation they must meet both \*\*\* criteria below:
• Exocrine pancreatic dysfunction as defined by at least one of the following:
• Pancreatic isoamylase below normal (age \>= 3 years old), OR
• Fecal elastase \< 200, AND
• Bone marrow failure as evidence by at least one of the following:
• Intermittent or persistent neutropenia (absolute neutrophil count \< 1,500/uL), OR
• Hypo-productive anemia with a hemoglobin concentration below the age-related adjusted norms, OR
• Unexplained macrocytosis, OR
• Platelet count \< 150,000/uL without alternative etiology, OR
• Hypocellular bone marrow

You may not qualify if:

• Patients with idiopathic aplastic anemia, Fanconi anemia, dyskeratosis congenita, and congenital neutropenia
• Patients with MDS as defined by the World Health Organization (WHO) or leukemia
• Prior allogeneic HCT
• Patient's weight =\< 10.0 kg (actual body weight and adjusted body weight) at time of study enrollment
• Lansky (patients \< 16 years of age) or Karnofsky (patients \>= 16 years of age) performance \< 70%
• Left ventricular ejection fraction \< 50% by echocardiogram or multi-gated acquisition (MUGA) scan
• \* For patients unable to obtain a left ventricular ejection fraction, left ventricular shortening fraction of \< 26%
• Diffusing capacity of the lungs for carbon monoxide (DLCO) (corrected/adjusted for hemoglobin) \< 50%, forced expiratory volume (FEV)1 \< 50% predicted, and forced vital capacity (FVC) \< 50% predicted
• For patients unable to perform pulmonary function tests (PFTs) due to age or developmental delay: oxygen (O2) saturation \< 92% on room air
• On supplemental oxygen
• Estimated creatinine clearance \< 60 mL/minute/1.73m\^2 (estimated per institutional practice)
• Dialysis dependent
• Conjugated bilirubin \> 2 x upper limit of normal for age (ULN, unless attributable to Gilbert's syndrome)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 4 x ULN for age, or
• Fulminant liver failure or cirrhosis

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• Blood and Marrow Transplant Clinical Trials Network: collaborator
• National Cancer Institute (NCI): collaborator
• National Marrow Donor Program: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (24)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Rady Children's Hospital/UCSD

San Diego, California, 92123, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30329, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21231, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48109, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

St. Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Roswell Park Comprehensive Cancer Center

Buffalo, New York, 14203, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cohen Children's Hospital of NY

Queens, New York, 11040, United States

Location

Duke University Medical Center

Durham, North Carolina, 27705, United States

Location

Cincinnati Children's Hospital

Cincinnati, Ohio, 45229, United States

Location

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Oregon Health & Science University

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Primary Children's/University of Utah

Salt Lake City, Utah, 84113, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Medical College of Wisconsin/Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Bone Marrow Failure Disorders; Congenital amegakaryocytic thrombocytopenia; Anemia, Diamond-Blackfan; Anemia, Hypochromic; Hemoglobinuria, Paroxysmal; Shwachman-Diamond Syndrome

Interventions

treosulfan; fludarabine phosphate; Tacrolimus; Methotrexate; Antilymphocyte Serum; thymoglobulin; Peripheral Blood Stem Cell Transplantation; Bone Marrow Transplantation; X-Rays

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Anemia; Red-Cell Aplasia, Pure; Congenital Bone Marrow Failure Syndromes; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Anemia, Hemolytic; Myelodysplastic Syndromes; Exocrine Pancreatic Insufficiency; Pancreatic Diseases; Digestive System Diseases; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipomatosis

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Tissue Transplantation; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing

Study Officials

• Lauri Burroughs, MD

  Fred Hutch/University of Washington Cancer Consortium

  STUDY CHAIR

• Margaret MacMillan, MD

  University of Minnesota

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 21, 2021
• First Posted: July 16, 2021
• Study Start: April 19, 2022
• Primary Completion: February 18, 2026
• Study Completion: February 18, 2026
• Last Updated: March 9, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (24)