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

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ClinicalTrials.gov Identifier: NCT01894477
Recruitment Status : Active, not recruiting
First Posted : July 10, 2013
Results First Posted : May 21, 2018
Last Update Posted : May 21, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Joachim Deeg, Fred Hutchinson Cancer Research Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia in Remission Chronic Myelomonocytic Leukemia Minimal Residual Disease Myelodysplastic Syndrome Myelodysplastic/Myeloproliferative Neoplasm Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable Procedure: Allogeneic Bone Marrow Transplantation Drug: Fludarabine Phosphate Procedure: Peripheral Blood Stem Cell Transplantation Radiation: Total-Body Irradiation Drug: Treosulfan Other: Laboratory Biomarker Analysis Phase 2

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Study Start Date : November 2013
Actual Primary Completion Date : January 9, 2017
Estimated Study Completion Date : January 2022


Arm Intervention/treatment
Experimental: Arm A

Arm 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.

Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • Allo BMT
  • Allogeneic BMT
Drug: Fludarabine Phosphate
Intravenously administered Fludarabine Phosphate
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
  • SH T 586
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSC transplant
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation
Drug: Treosulfan
Intravenously administered Treosulfan
Other Names:
  • 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-
  • Dihydroxybusulfan
  • Ovastat
  • Treosulphan
  • Tresulfon
Other: Laboratory Biomarker Analysis
Correlative Studies
Experimental: Arm B

Arm B: Treosulfan, Fludarabine Phosphate, TBI

Treosulfan and fludarabine phosphate as in Arm A and undergo low -dose total-body irradiation (TBI) on day 0

Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • Allo BMT
  • Allogeneic BMT
Drug: Fludarabine Phosphate
Intravenously administered Fludarabine Phosphate
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
  • SH T 586
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo allogeneic PBSC transplant
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation
Drug: Treosulfan
Intravenously administered Treosulfan
Other Names:
  • 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-
  • Dihydroxybusulfan
  • Ovastat
  • Treosulphan
  • Tresulfon
Other: Laboratory Biomarker Analysis
Correlative Studies



Primary Outcome Measures :
  1. Number of Participants That Did Not Progress Within 6 Months [ Time Frame: At 6 months post-transplant ]
    Progression is defined as relapse


Secondary Outcome Measures :
  1. 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 ]
  2. Incidence of Chronic GVHD Graded by the NCI CTCAE Version 4.0 [ Time Frame: Up to 5 year ]
  3. Incidence of Relapse/Progression [ Time Frame: Up to 5 year ]
  4. NRM [ Time Frame: Up to 5 years ]
  5. Overall Survival (OS) [ Time Frame: Up to 2 year ]
  6. Change in Gene Expression Profiles [ Time Frame: Baseline and at day 0 within 6 hours of conditioning prior to transplant ]
    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).

  7. 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 ]
    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



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Ages Eligible for Study:   up to 70 Years   (Child, Adult, Senior)
Sexes Eligible for Study:   All
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)
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01894477


Locations
United States, Washington
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: H. Joachim Deeg Fred Hutch/University of Washington Cancer Consortium

Responsible Party: Joachim Deeg, Principal Investigator, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01894477     History of Changes
Other Study ID Numbers: 2524.00
NCI-2013-01261 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2524
2524.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
K12HL087165 ( U.S. NIH Grant/Contract )
P30CA015704 ( U.S. NIH Grant/Contract )
First Posted: July 10, 2013    Key Record Dates
Results First Posted: May 21, 2018
Last Update Posted: May 21, 2018
Last Verified: February 2018

Additional relevant MeSH terms:
Syndrome
Leukemia
Neoplasms
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Chronic
Leukemia, Myelomonocytic, Juvenile
Myeloproliferative Disorders
Myelodysplastic-Myeloproliferative Diseases
Neoplasm, Residual
Disease
Pathologic Processes
Neoplasms by Histologic Type
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplastic Processes
Fludarabine
Fludarabine phosphate
Treosulfan
Busulfan
Vidarabine
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors