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

Active:	Yes
Cancer Type:	Cancer-Related Syndrome Hematopoietic Malignancies Leukemia Unknown Primary	NCT ID:	NCT04965597
Trial Phases:	Phase II	Protocol IDs:	RG1121820 (primary) NCI-2021-13862 BMT CTN 1904
Eligibility:	1 - 49 Years, Male and Female	Study Type:	Treatment
Study Sponsor:	Fred Hutch/University of Washington/Seattle Children's Cancer Consortium
NCI Full Details:	http://clinicaltrials.gov/show/NCT04965597

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.

Objectives

PRIMARY OBJECTIVE:
I. To assess the 1-year graft-versus-host disease (GVHD)-free, event-free survival (EFS) in patients with bone marrow failure diseases (BMFD) undergoing hematopoietic cell transplantation (HCT) using treosulfan-based conditioning.

SECONDARY OBJECTIVES:
I. Overall survival at day 100, 6 months, and 1-year post-HCT.
II. EFS at 1-year post-HCT.
III. Neutrophil recovery at day 42 and platelet recovery at day 100 post-HCT.
IV. Donor chimerism (CD3 and myeloid) at day 28, 100, and 1-year post-HCT.
V. Primary graft failure/rejection at day 42 and secondary graft failure/rejection post-HCT.
VI. Incidence of grade II-IV and grade III-IV GVHD at day 100 and chronic GVHD requiring systemic immune suppression at 1-year post-HCT.
VII. Acute GVHD will be defined as grade II-IV and grade III-IV.
VIII. Chronic GVHD will be defined as chronic GVHD (using National Institutes of Health [NIH] consensus criteria) requiring systemic immune suppression.
IX. Incidence of grade 3-5 toxicities at day 30 and day 100 post-HCT.
X. Incidence of grade 2-3 systemic infections by day 180 post-HCT.
XI. Incidence of Epstein-Barr virus (EBV)-reactivation requiring therapy and the incidence of EBV-associated lymphoproliferative disorder by day 180 post-HCT.
XII. Incidence of cytomegalovirus (CMV) reactivation requiring therapy by day 180 post-HCT.

EXPLORATORY OBJECTIVES:
I. Treosulfan Pharmacokinetic Studies: Treosulfan pharmacokinetic (PK) characteristics to determine the optimal dose of treosulfan and evaluate whether the exposure to treosulfan determined by area under the curve (AUC) for patients with BMFD impacts engraftment, transplant-related mortality, and overall and event-free survival.
II. Biological Studies: Collect blood and marrow samples (cells, deoxyribonucleic acid [DNA], serum) and establish fibroblast cell cultures as a source of germline DNA to investigate: 1) somatic mutations, 2) T cell phenotypes, and 3) cytokine levels.
III. Mutational Testing: Collect peripheral blood on patients who lack a known genetic mutation responsible for their bone marrow failure phenotype in order to perform whole exome or whole genome sequencing with the goal of identifying new mutations for patients with BMFD.
IV. Health-related quality of life using Patient Reported Outcomes Measurement Information System (PROMIS) at baseline, day +180 and day +365 post-HCT.

OUTLINE:
CONDITIONING REGIMEN: Patients receive treosulfan intravenously (IV) over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and lapine T-lymphocyte immune globulin (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 orally (PO). Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Patients undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients may optionally undergo blood sample collection throughout the trial.

After completion of study treatment, patients are followed up at 1 year from transplant.

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