Treosulfan and Fludarabine Phosphate With or Without Total Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01894477
First received: July 1, 2013
Last updated: June 16, 2014
Last verified: June 2014
  Purpose

This randomized phase II trial studies how well treosulfan and fludarabine phosphate with or without total body irradiation before donor stem cell transplant works in treating patients with myelodysplastic syndrome. Giving chemotherapy, such as treosulfan and fludarabine phosphate, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus before and mycophenolate mofetil after the transplant may stop this from happening.


Condition Intervention Phase
Childhood Myelodysplastic Syndromes
Chronic Myelomonocytic Leukemia
de Novo Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
Previously Treated Myelodysplastic Syndromes
Drug: treosulfan
Drug: fludarabine phosphate
Radiation: total-body irradiation
Procedure: peripheral blood stem cell transplantation
Procedure: allogeneic bone marrow transplantation
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Multi-Center Study of Treosulfan, Fludarabine and Low-Dose TBI as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With Myelodysplastic Syndrome (MDS)

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Progression free survival (PFS) [ Time Frame: At 6 months post-transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in gene expression profiles [ Time Frame: Baseline and at day 0 within 6 hours of conditioning prior to transplant ] [ Designated as safety issue: No ]
    Differences between arms in the changes in gene expression will be compared. 80% power to detect mean differences between arms in the change in gene expression equal in magnitude to 1.08 standard deviation (SD) units will be done using a two-sample t-test, at the 2-sided 0.05 Bonferroni-corrected level of significance (assuming correction for 100 genes).

  • Relapse risk as measured by degree of change in gene expression profiles [ Time Frame: Baseline and at day 0 within 6 hours of conditioning prior to transplant ] [ Designated as safety issue: No ]
    Among genes identified whose expression is modified by conditioning, the degree of change in expression in these genes will be evaluated to determine whether it is correlated with relapse risk and offers improved prediction of relapse risk over that obtained with standard clinical parameters (cytogenetics, blast count, International Prognostic Scoring System [IPSS] score). To account for censoring and the competing risk of NRM, the analysis will be a time-to-event analysis of relapse using Cox regression, with change in expression as a continuous covariate (on a log scale).

  • Incidence of relapse/progression [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Non-relapse mortality (NRM) [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
  • Overall Survival (OS) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Incidence of acute GVHD, graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 84 days ] [ Designated as safety issue: Yes ]
  • Incidence of chronic GVHD graded by the NCI CTCAE version 4.0 [ Time Frame: Up to 5 years after HCT ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 80
Study Start Date: November 2013
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (treosulfan, fludarabine phosphate)

CONDITIONING REGIMEN:

Patients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine phosphate IV over 30 minutes on days -6 to -2.

TRANSPLANT: Patients in both arms undergo allogeneic PBSC transplant or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients with a related donor receive tacrolimus PO every 8 or 12 hours on days -3 to 56 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 12 hours to day 28. Patients with an unrelated donor receive tacrolimus PO every 8 or 12 hours on days -3 to 100 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 8 hours to day 40 with taper to day 96.

Drug: treosulfan
Given IV
Other Names:
  • dihydroxybusulfan
  • Ovastat
  • tresulfon
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic PBSC transplant
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm B (treosulfan, fludarabine phosphate, TBI)

CONDITIONING REGIMEN:

Patients receive treosulfan and fludarabine phosphate as in Arm A and undergo low-dose TBI on day 0.

TRANSPLANT: Patients in both arms undergo allogeneic PBSC transplant or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients with a related donor receive tacrolimus PO every 8 or 12 hours on days -3 to 56 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 12 hours to day 28. Patients with an unrelated donor receive tacrolimus PO every 8 or 12 hours on days -3 to 100 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 8 hours to day 40 with taper to day 96.

Drug: treosulfan
Given IV
Other Names:
  • dihydroxybusulfan
  • Ovastat
  • tresulfon
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: peripheral blood stem cell transplantation
Undergo allogeneic PBSC transplant
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the better of two treosulfan-based conditioning regimens in patients with myelodysplastic syndrome (MDS), by comparing 6-month progression-free survival.

SECONDARY OBJECTIVES:

I. Determine the effects of two conditioning regimens on changes in gene expression profiles, and evaluate the association of gene expression profiles and disease relapse.

II. Determine the incidence of progression-free survival at 1 year and 2 years after hematopoietic cell transplantation (HCT).

III. Evaluate overall survival (OS) at 6 months, at 1 year and at 2 years after HCT.

IV. Determine the incidence of grades II-IV acute graft-versus-host disease (GVHD).

V. Determine the incidence of chronic GVHD.

VI. Determine donor chimerism around days +28 and +84.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

CONDITIONING REGIMEN:

ARM A: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 30 minutes on days -6 to -2.

ARM B: Patients receive treosulfan and fludarabine phosphate as in Arm A and undergo low-dose total-body irradiation (TBI) on day 0.

TRANSPLANT: Patients in both arms undergo allogeneic peripheral blood stem cell (PBSC) transplant or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients with a related donor receive tacrolimus orally (PO) every 8 or 12 hours on days -3 to 56 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 12 hours to day 28. Patients with an unrelated donor receive tacrolimus PO every 8 or 12 hours on days -3 to 100 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 8 hours to day 40 with taper to day 96.

After completion of study treatment, patients are followed up periodically.

  Eligibility

Ages Eligible for Study:   up to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • MDS, myelodysplastic syndrome/myeloproliferative neoplasia overlap disorders (including chronic myelomonocytic leukemia (CMML), and MDS/myeloproliferative neoplasm (MPN) unclassifiable syndromes)
  • With Karnofsky index or Lansky Play-Performance scale > 70% on pre-transplant evaluation
  • Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)
  • Patients with previous autologous or allogeneic HCT are allowed to enroll
  • DONOR: Human leukocyte antigen (HLA)-identical related donors or
  • DONOR: Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 as defined by high resolution deoxyribonucleic acid (DNA) typing; mismatch for one HLA allele is allowed
  • DONOR: Donors able to undergo peripheral blood stem cell collection or bone marrow harvest
  • DONOR: Donors in good general health, with a Karnofsky or Lansky play performance score > 90%
  • DONOR: Donors able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)

Exclusion Criteria:

  • Receiving umbilical cord blood
  • With impaired cardiac function as evidenced by ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease; patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist
  • With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) < 70 mm Hg and diffusing capacity of the lungs for carbon monoxide (DLCO) < 70% of predicted or pO2 < 80 mm Hg and DLCO < 60% of predicted; or receiving supplementary continuous oxygen
  • With impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2 x upper limit of normal or dialysis-dependent
  • With hepatic dysfunction as evidenced by total bilirubin > 2.0 x upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis
  • With hepatic dysfunction as evidenced by aspartate aminotransferase (AST) > 2.0 x upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis
  • With active infectious disease requiring deferral of conditioning, as recommended by an infectious disease specialist
  • With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis
  • With central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy, cranial irradiation or both prior to initiating conditioning (day -6)
  • With life expectancy severely limited by diseases other than malignancy
  • Women who are pregnant or lactating
  • With known hypersensitivity to treosulfan or fludarabine
  • Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6)
  • Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent
  • DONOR: Individuals deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis
  • DONOR: Individuals who are HIV-positive
  • DONOR: Individuals with active infectious hepatitis
  • DONOR: Females with a positive pregnancy test
  • DONOR: Persons unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01894477

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: H. Joachim J. Deeg    206-667-5985      
Principal Investigator: H. Joachim J. Deeg         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: H. Joachim Deeg Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01894477     History of Changes
Other Study ID Numbers: 2524.00, NCI-2013-01261, 2524.00, P30CA015704, K12HL087165
Study First Received: July 1, 2013
Last Updated: June 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Neoplasms
Leukemia
Leukemia, Myelomonocytic, Chronic
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Acute
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Neoplasms by Histologic Type
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Fludarabine
Fludarabine monophosphate
Treosulfan
Vidarabine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Antineoplastic Agents, Alkylating
Alkylating Agents

ClinicalTrials.gov processed this record on July 23, 2014