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

July 1, 2013
June 16, 2014
November 2013
November 2018   (final data collection date for primary outcome measure)
Progression free survival (PFS) [ Time Frame: At 6 months post-transplant ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT01894477 on ClinicalTrials.gov Archive Site
  • 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 ]
  • 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 2 years ] [ Designated as safety issue: No ]
  • Non-relapse mortality (NRM) [ Time Frame: Up to 2 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 2 years after HCT ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Treosulfan and Fludarabine Phosphate With or Without Total Body Irradiation Before Donor Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome
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)

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.

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Childhood Myelodysplastic Syndromes
  • Chronic Myelomonocytic Leukemia
  • de Novo Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Previously Treated Myelodysplastic Syndromes
  • 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
  • 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.

    Interventions:
    • Drug: treosulfan
    • Drug: fludarabine phosphate
    • Procedure: peripheral blood stem cell transplantation
    • Procedure: allogeneic bone marrow transplantation
    • Other: laboratory biomarker analysis
  • 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.

    Interventions:
    • Drug: treosulfan
    • Drug: fludarabine phosphate
    • Radiation: total-body irradiation
    • Procedure: peripheral blood stem cell transplantation
    • Procedure: allogeneic bone marrow transplantation
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
80
Not Provided
November 2018   (final data collection date for primary outcome measure)

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
Both
up to 70 Years
No
United States
 
NCT01894477
2524.00, NCI-2013-01261, 2524.00, P30CA015704, K12HL087165
Yes
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
  • National Heart, Lung, and Blood Institute (NHLBI)
  • National Cancer Institute (NCI)
Principal Investigator: H. Joachim Deeg Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Fred Hutchinson Cancer Research Center
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP