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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

Primary Purpose

Accelerated Phase Chronic Myelogenous Leukemia, Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
fludarabine phosphate
busulfan
anti-thymocyte globulin
tacrolimus
methotrexate
peripheral blood stem cell transplantation
allogeneic hematopoietic stem cell transplantation
laboratory biomarker analysis
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Accelerated Phase Chronic Myelogenous Leukemia

Eligibility Criteria

undefined - 60 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (chemotherapy, PBSC transplant)

Arm Description

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.

Outcomes

Primary Outcome Measures

Incidence of acute GvHD
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
Thymoglobulin pharmacokinetics
Incidence of donor cell engraftment
Incidence of system toxicities >= grade 3 as graded per CTCAE v.3
Incidence of chronic GvHD
Incidence of non-relapse mortality defined as death without history of post-transplant relapse
Incidence of non-relapse mortality defined as death without history of post-transplant relapse
Incidence of relapse
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
Incidence of EBV activation defined as an increase in plasma EBV DNA to >= 1000 copies/mL as determined by quantitative polymerase chain reaction (PCR)

Full Information

First Posted
January 22, 2010
Last Updated
May 4, 2016
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01056614
Brief Title
Fludarabine Phosphate, Busulfan, and Anti-Thymocyte Globulin Followed By Donor Peripheral Blood Stem Cell Transplant, Tacrolimus, and Methotrexate in Treating Patients With Myeloid Malignancies
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
September 2004 (undefined)
Primary Completion Date
August 2005 (Actual)
Study Completion Date
April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI), National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (chemotherapy, PBSC transplant)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
BSF, BU, Misulfan, Mitosan, Myeloleukon
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
anti-thymocyte globulin
Other Intervention Name(s)
ATG, ATGAM, lymphocyte immune globulin, Thymoglobulin
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
tacrolimus
Other Intervention Name(s)
FK 506, Prograf
Intervention Description
Given IV and orally
Intervention Type
Drug
Intervention Name(s)
methotrexate
Other Intervention Name(s)
amethopterin, Folex, methylaminopterin, Mexate, MTX
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Intervention Description
Undergo allogeneic PBSC transplant
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo allogeneic PBSC transplant
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Incidence of acute GvHD
Description
Maximum grade of acute GVHD and the number of therapies required to treat GVHD will be determined.
Time Frame
Day 100 post-transplant
Secondary Outcome Measure Information:
Title
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
Title
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
Title
Incidence of donor cell engraftment
Time Frame
By day 100
Title
Incidence of system toxicities >= grade 3 as graded per CTCAE v.3
Time Frame
Up to day 100 after transplantation
Title
Incidence of chronic GvHD
Time Frame
Day 100
Title
Incidence of non-relapse mortality defined as death without history of post-transplant relapse
Time Frame
At day 100
Title
Incidence of non-relapse mortality defined as death without history of post-transplant relapse
Time Frame
At 1 year
Title
Incidence of relapse
Description
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.
Time Frame
At 1 year
Title
Relapse-free survival
Time Frame
At 1 year
Title
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

10. Eligibility

Sex
All
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
H. Joachim Deeg
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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