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Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Peripheral Blood Stem Cell Transplant, Tacrolimus, and Methotrexate in Treating Patients With Myeloid Malignancies

This study has been completed.
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01056614
First received: January 22, 2010
Last updated: May 4, 2016
Last verified: May 2016
  Purpose
This phase II trial is studying the side effects and how well giving fludarabine phosphate, busulfan, anti-thymocyte globulin followed by donor peripheral blood stem cell transplant, tacrolimus, and methotrexate works in treating patients with myeloid malignancies. Giving chemotherapy, such as fludarabine phosphate and busulfan, before a donor peripheral blood 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. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving anti-thymocyte globulin before transplant and tacrolimus and methotrexate after transplant may stop this from happening.

Condition Intervention Phase
Accelerated Phase Chronic Myelogenous Leukemia Adult Acute Myeloid Leukemia in Remission Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities Adult Acute Myeloid Leukemia With Del(5q) Adult Acute Myeloid Leukemia With Inv(16)(p13;q22) Adult Acute Myeloid Leukemia With t(15;17)(q22;q12) Adult Acute Myeloid Leukemia With t(16;16)(p13;q22) Adult Acute Myeloid Leukemia With t(8;21)(q22;q22) Blastic Phase Chronic Myelogenous Leukemia Childhood Acute Myeloid Leukemia in Remission Childhood Chronic Myelogenous Leukemia Childhood Myelodysplastic Syndromes Chronic Phase Chronic Myelogenous Leukemia de Novo Myelodysplastic Syndromes Hematopoietic/Lymphoid Cancer Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable Previously Treated Myelodysplastic Syndromes Recurrent Adult Acute Myeloid Leukemia Recurrent Childhood Acute Myeloid Leukemia Relapsing Chronic Myelogenous Leukemia Drug: fludarabine phosphate Drug: busulfan Biological: anti-thymocyte globulin Drug: tacrolimus Drug: methotrexate Procedure: peripheral blood stem cell transplantation Procedure: allogeneic hematopoietic stem cell transplantation Other: laboratory biomarker analysis Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Conditioning for Hematopoietic Cell Transplantation With Fludarabine Plus Targeted IV Busulfan and GVHD Prophylaxis With Thymoglobulin, Tacrolimus and Methotrexate in Patients With Myeloid Malignancies

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Incidence of acute GvHD [ Time Frame: Day 100 post-transplant ]
    Maximum grade of acute GVHD and the number of therapies required to treat GVHD will be determined.


Secondary Outcome Measures:
  • Pharmacokinetics of IV busulfan including interdose variability and evaluation of a limited sampling strategy [ Time Frame: At 3.25, 4.5, 6, 8, 11, and 24-hours after the beginning of infusion on days -5, -4, and -3 ]
  • Thymoglobulin pharmacokinetics [ Time Frame: On day -3 prior to the first dose, on day -1 one hour after completion of infusion and on day 1 at 0900 ]
  • Incidence of donor cell engraftment [ Time Frame: By day 100 ]
  • Incidence of system toxicities >= grade 3 as graded per CTCAE v.3 [ Time Frame: Up to day 100 after transplantation ]
  • Incidence of chronic GvHD [ Time Frame: Day 100 ]
  • Incidence of non-relapse mortality defined as death without history of post-transplant relapse [ Time Frame: At day 100 ]
  • Incidence of non-relapse mortality defined as death without history of post-transplant relapse [ Time Frame: At 1 year ]
  • Incidence of relapse [ Time Frame: At 1 year ]
    Defined by either morphological or cytogenetic evidence of chronic myelogenous leukemia (CML), AML, MDS or other myeloproliferative disease in marrow, blood, or other sites, or laboratory evidence of residual disease.

  • Relapse-free survival [ Time Frame: At 1 year ]
  • Incidence of EBV activation defined as an increase in plasma EBV DNA to >= 1000 copies/mL as determined by quantitative polymerase chain reaction (PCR) [ Time Frame: Up to 1 year ]

Enrollment: 23
Study Start Date: September 2004
Study Completion Date: April 2016
Primary Completion Date: August 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemotherapy, PBSC transplant)
Patients receive fludarabine phosphate IV over 30 minutes on days -9 to -6, busulfan IV over 3 hours on days -5 to -2, and anti-thymocyte globulin IV over 6 hours on days -3 and -2 and over 4 hours on day -1. Patients undergo allogeneic PBSC transplant on day 0. Patients then receive tacrolimus IV continuously or PO every 12 hours beginning on day -1 and taper to day 180 and methotrexate IV on days 1, 3, 6, and 11.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: busulfan
Given IV
Other Names:
  • BSF
  • BU
  • Misulfan
  • Mitosan
  • Myeloleukon
Biological: anti-thymocyte globulin
Given IV
Other Names:
  • ATG
  • ATGAM
  • lymphocyte immune globulin
  • Thymoglobulin
Drug: tacrolimus
Given IV and orally
Other Names:
  • FK 506
  • Prograf
Drug: methotrexate
Given IV
Other Names:
  • amethopterin
  • Folex
  • methylaminopterin
  • Mexate
  • MTX
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 hematopoietic stem cell transplantation
Undergo allogeneic PBSC transplant
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVE:

I. Determine the incidence and severity of acute graft-versus-host disease (GvHD).

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of intravenous (IV) busulfan including interdose variability and evaluation of a limited sampling strategy.

II. Determine thymoglobulin (anti-thymocyte globulin) pharmacokinetics.

III. Determine the incidence of donor engraftment.

IV. Determine system toxicities >= grade 3 per Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 3.

V. Determine the incidence and severity of chronic GvHD.

VI. Determine the incidence of non-relapse mortality at day +100 and at 1 year (yr).

VII. Determine the incidence of relapse.

VIII. Determine relapse-free survival.

IX. Determine the incidence of Epstein-Barr virus (EBV) activation.

OUTLINE:

Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days -9 to -6, busulfan IV over 3 hours on days -5 to -2, and anti-thymocyte globulin IV over 6 hours on days -3 and -2 and over 4 hours on day -1. Patients undergo allogeneic peripheral blood stem cell (PBSC) transplant on day 0. Patients then receive tacrolimus IV continuously or orally (PO) every 12 hours beginning on day -1 and taper to day 180 and methotrexate IV on days 1, 3, 6, and 11.

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

  Eligibility

Ages Eligible for Study:   up to 60 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Chronic myelogenous leukemia in chronic phase, accelerated phase and treated blast phase (CP2)
  • Acute myeloid leukemia (AML) in remission or early relapse (< 10% marrow blasts)
  • Myelodysplastic syndromes (MDS) ( all risk groups)
  • Other myeloproliferative disorders
  • DONOR: related or unrelated donors matched for human leukocyte antigen (HLA)-A, B, C, DRB1, and DQB1 defined by high resolution deoxyribonucleic acid (DNA) typing or mismatched for a single HLA-A, B, C, DRB1 or DQB1 allele
  • DONOR: donor must consent to peripheral blood stem cell (PBSC) mobilization with granulocyte colony-stimulating factor (G-CSF) and leukapheresis; related donors will be collected at Fred Hutchinson Cancer Research Center (FHCRC), while unrelated donors will be collected through the National Marrow Donor Program (NMDP) or other donor centers
  • DONOR: Age 12-75 yrs

Exclusion Criteria:

  • Cardiac insufficiency requiring treatment or symptomatic coronary artery disease
  • Hepatic disease, with aspartate aminotransferase (AST) > 2 times normal
  • Severe hypoxemia, oxygen partial pressure (pO2) < 70 mm Hg, with decreased diffusion capacity of carbon monoxide (DLCO) < 70% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 60% of predicted
  • Impaired renal function (creatinine > 2 times normal or estimated creatinine clearance < 60 ml/min)

    • MALE: ([140 -age in years] x ideal body weight [kg])/72 x serum creatinine (SCr) (mg/dL)
    • FEMALE: .85 x ([140-age in years] x ideal body weight [kg])/72 x SCr (mg/dL)
  • Human immunodeficiency virus (HIV)-positive patients due to risk of reactivation or acceleration of HIV replication
  • Female patients who are pregnant or breast feeding
  • Life expectancy severely limited by diseases other than malignancy
  • DONOR: donors who for any reason are unable to tolerate the mobilization and leukapheresis procedure
  • DONOR: donors who are HIV-positive, or hepatitis B or C antigen-positive
  • DONOR: female donors who have a positive pregnancy test
  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: NCT01056614

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

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01056614     History of Changes
Other Study ID Numbers: 1913.00
NCI-2009-01785 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
1913.00 ( Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
P01HL036444 ( U.S. NIH Grant/Contract )
Study First Received: January 22, 2010
Last Updated: May 4, 2016

Additional relevant MeSH terms:
Pathologic Processes
Cell Transformation, Neoplastic
Neoplastic Processes
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Myeloproliferative Disorders
Leukemia, Myeloid, Chronic-Phase
Blast Crisis
Leukemia, Myeloid, Accelerated Phase
Myelodysplastic-Myeloproliferative Diseases
Disease
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Carcinogenesis
Methotrexate
Fludarabine phosphate
Tacrolimus
Busulfan
Antilymphocyte Serum
Vidarabine
Fludarabine
Abortifacient Agents, Nonsteroidal

ClinicalTrials.gov processed this record on August 21, 2017