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Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

Primary Purpose

Adult Acute Myeloid Leukemia in Remission, Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q)

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
cyclophosphamide
busulfan
tacrolimus
methotrexate
cytogenetic analysis
flow cytometry
pharmacological study
pharmacogenomic studies
peripheral blood stem cell transplantation
allogeneic hematopoietic stem cell transplantation
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Myeloid Leukemia in Remission

Eligibility Criteria

undefined - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Idiopathic myelofibrosis (CIMF)
  • Myelofibrosis developing with polycythemia vera or essential thrombocythemia
  • Acute myeloid leukemia with or without antecedent hematologic disorder, at any disease stage (complete remission, minimal residual disease, or relapsed leukemia)
  • Myelodysplastic syndrome of any World Health Organization (WHO) or French-American-British (FAB) category, at any disease stage
  • Less than 61 years of age if transplanted from an unrelated donor, or less than 66 years of age if transplanted from a related donor
  • Receiving unmanipulated peripheral blood stem cells from an human leukocyte antigen (HLA)-identical or 1-allele-mismatched related or unrelated donor, or receiving G-CSF-stimulated bone marrow if co-enrolled on Fred Hutchinson Cancer Research Center (FHCRC) protocol 2250
  • With a Karnofsky Performance score of > 70% at the time of pre-transplant evaluation
  • Able to give informed consent (if >= 18 years of age), or with a legal guardian capable of giving consent (if < 18 years of age)
  • DONOR: HLA-identical or 1-allele-mismatched related or unrelated donors (by high resolution typing)
  • DONOR: Undergoing peripheral blood stem cell harvest or G-CSF-stimulated bone marrow harvest (bone marrow permitted only as part of FHCRC protocol 2250)
  • DONOR: In good general health, with a Karnofsky performance score of > 80%
  • DONOR: Able to give informed consent (if >= 18 years of age), or with a legal guardian able to give informed consent (if < 18 years of age and donating for a related transplant)

Exclusion Criteria:

  • Without an HLA-identical or 1-allele-mismatched related or unrelated donor
  • With human immunodeficiency virus (HIV) positivity or active infectious hepatitis
  • Receiving a medication known to strongly inhibit enzymes in the CYP450 pathway, and which, in the judgment of the consenting provider, cannot be safely discontinued for the duration of conditioning
  • Whose life expectancy is severely limited by diseases other than the hematologic disorder for which they are undergoing HCT (HCT-comorbidity index [CI] > 3)
  • Women who are pregnant or lactating
  • With known hypersensitivity to BU or CY
  • With hepatic dysfunction as evidenced by total bilirubin or AST > 2x the upper limit of normal, or evidence of synthetic dysfunction or cirrhosis
  • With impaired renal function, as evidenced by creatinine clearance < 50% of expected, creatinine > 2x the upper limit of normal, or dialysis dependence
  • With impaired pulmonary function, as evidenced by pO2 < 70 mm Hg and diffusing capacity of carbon monoxide (DLCO) < 70% predicted or by pO2 < 80 mm Hg and DLCO < 60%, or receiving continuous supplementary oxygen
  • With impaired cardiac function, as evidenced by ejection fraction < 35% or active coronary artery disease
  • Unable to give informed consent
  • DONOR: Deemed unable to undergo stem cell collection, for any reason
  • DONOR: HIV-positive, or hepatitis B or C antigen-positive
  • DONOR: Women with a positive pregnancy test
  • DONOR: Unable to give informed consent (if >= 18 years of age), or without a legal guardian able to give informed consent (if <18 years of age)

Sites / Locations

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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (cyclophosphamide, busulfan, transplant)

Arm Description

CONDITIONING REGIMEN: Patients receive cyclophosphamide IV on days -7 and -6 and busulfan IV over 3 hours on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplant on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV or PO twice daily on days -1 to 200 with taper on day 56 and methotrexate on days 1, 3, 6, and 11.

Outcomes

Primary Outcome Measures

Effectiveness of Cyclophosphamide/Busulfan Regimen in Reducing Regimen-related Liver Toxicity
Number of patients with regimen-related liver toxicity. Diagnoses will be made according to the established criteria initially proposed in 1984 by McDonald et al.
Non-relapse Mortality (NRM) (Patients With AML/MDS)
Cumulative incidence rate with death as a competing risk, assessed at day 100.

Secondary Outcome Measures

Full Information

First Posted
March 7, 2007
Last Updated
December 1, 2017
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
NCT00445744
Brief Title
Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome
Official Title
Cyclophosphamide Followed by Intravenous Busulfan as Conditioning for Hematopoietic Cell Transplantation in Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome.
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
December 2006 (undefined)
Primary Completion Date
June 2011 (Actual)
Study Completion Date
June 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
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 trial is studying the side effects and how well giving cyclophosphamide and busulfan followed by donor stem cell transplant works in treating patients with myelofibrosis, acute myeloid leukemia, or myelodysplastic syndrome. Giving chemotherapy, such as cyclophosphamide and busulfan, before a donor stem cell transplant helps stops the growth of cancer cells. It also helps 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 and methotrexate after the transplant may stop this from happening
Detailed Description
PRIMARY OBJECTIVES: I. To estimate the incidence of hepatotoxicity with a conditioning regimen of CY (cyclophosphamide)/tBU (busulfan) in patients receiving hematopoietic cell transplant (HCT). SECONDARY OBJECTIVES: I. To determine overall and non-relapse mortality at day +200 after HCT. II. To determine the peak bilirubin levels through day +20 after HCT. III. To determine the incidence of pulmonary toxicity in the form of idiopathic pulmonary syndrome (IPS). IV. To determine the rate of graft failure. V. To determine the time to engraftment. VI. To determine the rate of relapse. VII. To determine the incidence and severity of graft-versus-host disease (GVHD). VIII. To evaluate the pharmacokinetics/dynamics of BU and CY. X. To evaluate the pharmacogenomics of response, toxicity and pharmacokinetics of CY/tBU. OUTLINE: CONDITIONING REGIMEN: Patients receive cyclophosphamide intravenously (IV) on days -7 and -6 and busulfan IV over 3 hours on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplant on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV or orally (PO) twice daily on days -1 to 200 with taper on day 56 and methotrexate on days 1, 3, 6, and 11. After completion of study treatment, patients are followed periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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), Childhood Acute Myeloid Leukemia in Remission, Childhood Myelodysplastic Syndromes, de Novo Myelodysplastic Syndromes, Essential Thrombocythemia, Myelodysplastic Syndrome With Isolated Del(5q), Polycythemia Vera, Previously Treated Myelodysplastic Syndromes, Primary Myelofibrosis, Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia, Secondary Myelodysplastic Syndromes, Secondary Myelofibrosis, Untreated Adult Acute Myeloid Leukemia, Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (cyclophosphamide, busulfan, transplant)
Arm Type
Experimental
Arm Description
CONDITIONING REGIMEN: Patients receive cyclophosphamide IV on days -7 and -6 and busulfan IV over 3 hours on days -5 to -2. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplant on day 0. POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive tacrolimus IV or PO twice daily on days -1 to 200 with taper on day 56 and methotrexate on days 1, 3, 6, and 11.
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CPM, CTX, Cytoxan, Endoxan, Endoxana
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
Drug
Intervention Name(s)
tacrolimus
Other Intervention Name(s)
FK 506, Prograf
Intervention Description
Given IV or PO
Intervention Type
Drug
Intervention Name(s)
methotrexate
Other Intervention Name(s)
amethopterin, Folex, methylaminopterin, Mexate, MTX
Intervention Description
Given IV
Intervention Type
Genetic
Intervention Name(s)
cytogenetic analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacogenomic studies
Other Intervention Name(s)
Pharmacogenomic Study
Intervention Description
Correlative studies
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 PBPC transplantation
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo allogeneic transplantation
Primary Outcome Measure Information:
Title
Effectiveness of Cyclophosphamide/Busulfan Regimen in Reducing Regimen-related Liver Toxicity
Description
Number of patients with regimen-related liver toxicity. Diagnoses will be made according to the established criteria initially proposed in 1984 by McDonald et al.
Time Frame
Up to day +20
Title
Non-relapse Mortality (NRM) (Patients With AML/MDS)
Description
Cumulative incidence rate with death as a competing risk, assessed at day 100.
Time Frame
Up to day 200

10. Eligibility

Sex
All
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Idiopathic myelofibrosis (CIMF) Myelofibrosis developing with polycythemia vera or essential thrombocythemia Acute myeloid leukemia with or without antecedent hematologic disorder, at any disease stage (complete remission, minimal residual disease, or relapsed leukemia) Myelodysplastic syndrome of any World Health Organization (WHO) or French-American-British (FAB) category, at any disease stage Less than 61 years of age if transplanted from an unrelated donor, or less than 66 years of age if transplanted from a related donor Receiving unmanipulated peripheral blood stem cells from an human leukocyte antigen (HLA)-identical or 1-allele-mismatched related or unrelated donor, or receiving G-CSF-stimulated bone marrow if co-enrolled on Fred Hutchinson Cancer Research Center (FHCRC) protocol 2250 With a Karnofsky Performance score of > 70% at the time of pre-transplant evaluation Able to give informed consent (if >= 18 years of age), or with a legal guardian capable of giving consent (if < 18 years of age) DONOR: HLA-identical or 1-allele-mismatched related or unrelated donors (by high resolution typing) DONOR: Undergoing peripheral blood stem cell harvest or G-CSF-stimulated bone marrow harvest (bone marrow permitted only as part of FHCRC protocol 2250) DONOR: In good general health, with a Karnofsky performance score of > 80% DONOR: Able to give informed consent (if >= 18 years of age), or with a legal guardian able to give informed consent (if < 18 years of age and donating for a related transplant) Exclusion Criteria: Without an HLA-identical or 1-allele-mismatched related or unrelated donor With human immunodeficiency virus (HIV) positivity or active infectious hepatitis Receiving a medication known to strongly inhibit enzymes in the CYP450 pathway, and which, in the judgment of the consenting provider, cannot be safely discontinued for the duration of conditioning Whose life expectancy is severely limited by diseases other than the hematologic disorder for which they are undergoing HCT (HCT-comorbidity index [CI] > 3) Women who are pregnant or lactating With known hypersensitivity to BU or CY With hepatic dysfunction as evidenced by total bilirubin or AST > 2x the upper limit of normal, or evidence of synthetic dysfunction or cirrhosis With impaired renal function, as evidenced by creatinine clearance < 50% of expected, creatinine > 2x the upper limit of normal, or dialysis dependence With impaired pulmonary function, as evidenced by pO2 < 70 mm Hg and diffusing capacity of carbon monoxide (DLCO) < 70% predicted or by pO2 < 80 mm Hg and DLCO < 60%, or receiving continuous supplementary oxygen With impaired cardiac function, as evidenced by ejection fraction < 35% or active coronary artery disease Unable to give informed consent DONOR: Deemed unable to undergo stem cell collection, for any reason DONOR: HIV-positive, or hepatitis B or C antigen-positive DONOR: Women with a positive pregnancy test DONOR: Unable to give informed consent (if >= 18 years of age), or without a legal guardian able to give informed consent (if <18 years of age)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Rezvani
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

Cyclophosphamide and Busulfan Followed by Donor Stem Cell Transplant in Treating Patients With Myelofibrosis, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

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