Clinical Trials /

Treo/Flu/TBI With Donor Stem Cell Transplant for Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

NCT01894477

Description:

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 or acute myeloid leukemia. 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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
  • Myelodysplastic/Myeloproliferative Neoplasm
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Treo/Flu/TBI With Donor Stem Cell Transplant for Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia
  • Official Title: A Randomized Phase II Study of Treosulfan, Fludarabine and Low-Dose TBI as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Clinical Trial IDs

  • ORG STUDY ID: 2524.00
  • SECONDARY ID: NCI-2013-01261
  • SECONDARY ID: 2524
  • SECONDARY ID: 2524.00
  • SECONDARY ID: K12HL087165
  • SECONDARY ID: P30CA015704
  • NCT ID: NCT01894477

Conditions

  • Acute Myeloid Leukemia in Remission
  • Chronic Myelomonocytic Leukemia
  • Minimal Residual Disease
  • Myelodysplastic Syndrome
  • Myelodysplastic/Myeloproliferative Neoplasm
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Interventions

DrugSynonymsArms
Fludarabine Phosphate2-F-ara-AMP, Beneflur, Fludara, SH T 586Arm A
Treosulfan1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-, Dihydroxybusulfan, Ovastat, Treosulphan, TresulfonArm A

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 or acute myeloid leukemia. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the better of two treosulfan-based conditioning regimens in patients with
      myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), 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.

      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.

      NOTE: Patients with related donors eligible for FHCRC protocol 2545 may receive cyclosporine
      IV, instead of tacrolimus, beginning on day -3 to day 50 with a taper to day 180.

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

Trial Arms

NameTypeDescriptionInterventions
Arm AExperimentalArm A: Treosulfan, Fludarabine Phosphate Treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 30 minutes on days -6 to -2.
  • Fludarabine Phosphate
  • Treosulfan
Arm BExperimentalArm B: Treosulfan, Fludarabine Phosphate, TBI Treosulfan and fludarabine phosphate as in Arm A and undergo low -dose total-body irradiation (TBI) on day 0
  • Fludarabine Phosphate
  • Treosulfan

Eligibility Criteria

        Inclusion Criteria:

          -  MDS, myelodysplastic syndrome/myeloproliferative neoplasia overlap disorders
             (including chronic myelomonocytic leukemia [CMML], and MDS/myeloproliferative neoplasm
             [MPN] unclassifiable syndromes)

          -  AML, other than acute promyelocytic leukemia (APL), in first or second remission or
             with minimal residual disease

          -  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 carbon monoxide diffusing capability test (DLCO) < 70% of predicted or pO2 <
             80 mm Hg and DLCO < 60% of predicted; (or, for pediatric patients unable to perform
             pulmonary function tests, then oxygen (O2) saturation < 92% on room air), 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)

          -  Patients with active non-hematological malignancies (except non-melanoma skin cancers)
             or those with non-hematological malignancies who have been rendered with no evidence
             of disease, but have a greater than 20% chance of having disease recurrence within 5
             years; this exclusion does not apply to patients with non-hematologic malignancies
             that do not require therapy

          -  With life expectancy severely limited by diseases other than malignancy

          -  Women who are pregnant or lactating

          -  With known hypersensitivity to treosulfan or fludarabine (fludarabine phosphate)

          -  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
      
Maximum Eligible Age:70 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants That Did Not Progress Within 6 Months
Time Frame:At 6 months post-transplant
Safety Issue:
Description:Progression is defined as relapse

Secondary Outcome Measures

Measure:Number of Participants With 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
Safety Issue:
Description:
Measure:Incidence of Chronic GVHD Graded by the NCI CTCAE Version 4.0
Time Frame:Up to 5 year
Safety Issue:
Description:
Measure:Incidence of Relapse/Progression
Time Frame:Up to 5 year
Safety Issue:
Description:
Measure:NRM
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:Up to 2 year
Safety Issue:
Description:
Measure:Change in Gene Expression Profiles
Time Frame:Baseline and at day 0 within 6 hours of conditioning prior to transplant
Safety Issue:
Description:Differences between arms in the changes in gene expression will be compared. 80% power to detect mean differences of approximately 1.4 standard deviation units, at the 2-sided 0.05 level of significance (with Bonferroni correction for 50 genes).
Measure: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
Safety Issue:
Description:Among genes identified whose expression is modified by conditioning, degree of change in expression will be evaluated to determine if 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 score, minimal residual disease. To account for censoring and the competing risk of non-relapse mortality (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). 8

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Fred Hutchinson Cancer Research Center

Last Updated