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Busulfan, Cyclophosphamide, & Antithymocyte Globulin Followed by Stem Cell Transplant in Treating Hematologic Cancer

Primary Purpose

Graft Versus Host Disease, Leukemia, Lymphoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
anti-thymocyte globulin
busulfan
cyclophosphamide
mycophenolate mofetil
tacrolimus
polymerase chain reaction
polymorphism analysis
flow cytometry
laboratory biomarker analysis
pharmacogenomic studies
pharmacological study
allogeneic bone marrow transplantation
allogeneic hematopoietic stem cell transplantation
peripheral blood stem cell transplantation
Sponsored by
University of Nebraska
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graft Versus Host Disease focused on measuring graft versus host disease, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, 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), recurrent adult acute myeloid leukemia, untreated adult acute myeloid leukemia, untreated adult acute lymphoblastic leukemia, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, stage III multiple myeloma, refractory multiple myeloma, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative disease, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, secondary myelofibrosis, secondary acute myeloid leukemia, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, recurrent adult acute lymphoblastic leukemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, adult nasal type extranodal NK/T-cell lymphoma, stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, stage III adult T-cell leukemia/lymphoma, stage IV adult T-cell leukemia/lymphoma, stage III adult Burkitt lymphoma, stage IV adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage IV adult lymphoblastic lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, atypical chronic myeloid leukemia, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, refractory hairy cell leukemia, stage I multiple myeloma, stage II multiple myeloma

Eligibility Criteria

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

DISEASE CHARACTERISTICS:

  • Pathologically confirmed diagnosis of 1 of the following:

    • Acute myeloid leukemia
    • Acute lymphocytic leukemia
    • Chronic myelogenous leukemia beyond first chronic phase (i.e., 2nd chronic phase, accelerated phase, or blast crisis)
    • Multiple myeloma
    • Myelodysplastic syndromes
    • Malignant lymphoma
    • Myelofibrosis
  • Requirement for myeloablative conditioning regimen confirmed by attending physician

  • Available donor must meet the following criteria:

    • HLA phenotypically identical unrelated donor by low, intermediate, or high resolution for HLA class I antigens, and by high resolution for HLA class II antigens

      • Matched at the A, B, and DRβ1 loci
      • Single HLA-A or HLA-B antigen mismatch allowed
    • Meets all National Marrow Donor Program or foreign registry criteria for allogeneic bone marrow/stem cell donors
    • Peripheral blood stem cells are the preferred product on this study but bone marrow is allowed

PATIENT CHARACTERISTICS:

  • Karnofsky performance status 70-100%
  • DLCO ≥ 50% predicted
  • LVEF ≥ 45%
  • Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 65 mL/min
  • Serum total bilirubin ≤ 2.0 mg/dL
  • No active uncontrolled infection
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No HIV infection
  • No chronic active hepatitis B or C or evidence of cirrhosis on liver biopsy

PRIOR CONCURRENT THERAPY:

  • Not specified

Sites / Locations

  • Unversity of Nebraska Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Unrelated Donor Allogeneic

Arm Description

Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.

Outcomes

Primary Outcome Measures

Transplantation-related Mortality at 100 Days Post-transplantation

Secondary Outcome Measures

Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD)
Overall Survival
Event-free Survival

Full Information

First Posted
February 7, 2008
Last Updated
October 5, 2023
Sponsor
University of Nebraska
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00611351
Brief Title
Busulfan, Cyclophosphamide, & Antithymocyte Globulin Followed by Stem Cell Transplant in Treating Hematologic Cancer
Official Title
Matched Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation With a Conditioning Regimen of Targeted Busulfan, Cyclophosphamide, and Thymoglobulin
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Completed
Study Start Date
June 7, 2005 (Actual)
Primary Completion Date
February 1, 2008 (Actual)
Study Completion Date
September 17, 2008 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Nebraska
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
RATIONALE: Giving chemotherapy before a donor bone marrow transplant or peripheral stem cell transplant helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When certain 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 tacrolimus and mycophenolate mofetil after the transplant may stop this from happening. PURPOSE: This phase II trial is studying how well giving busulfan together with cyclophosphamide and antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer.
Detailed Description
OBJECTIVES: Primary To determine the incidence of grade II-IV acute graft-versus-host disease in patients with hematologic cancer or other diseases treated with a myeloablative conditioning regimen comprising targeted (steady-state concentration of 800-1,000 ng/mL) busulfan, cyclophosphamide, and anti-thymocyte globulin followed by matched unrelated donor allogeneic hematopoietic stem cell transplantation. To determine the day +100 transplantation-related mortality in these patients. Secondary To determine the effect of cyclophosphamide pharmacokinetic parameters on day +100 transplantation-related mortality in these patients. To determine the ability of low-dose anti-thymocyte globulin administered on day +5 to induce activation-induced cell death of activated donor lymphocytes. To determine the incidence of chronic graft-versus-host disease in patients treated with this regimen. To determine event-free and overall survival of patients treated with this regimen. To evaluate pharmacogenomic associations between genetic polymorphisms in drug disposition enzymes with the pharmacokinetics of busulfan and cyclophosphamide. OUTLINE: Myeloablative conditioning regimen: Patients receive busulfan IV over 2 hours on days -8 to -5; cyclophosphamide IV over 4 hours on days -3 to -2; and anti-thymocyte globulin IV over 6 hours on day -3 and then over 4 hours on days -2, -1, and 5. Allogeneic hematopoietic stem cell transplantation: Patients undergo allogeneic bone marrow or peripheral blood stem cell infusion on day 0. Graft-versus-host-disease prophylaxis: Patients receive tacrolimus IV continuously or orally on days 6 to150, followed by an even taper to day 180 in the absence of graft-versus-host-disease. Patients also receive mycophenolate mofetil IV or orally beginning on day 6 and continuing to day 28. Patients undergo blood collection periodically during study for pharmacokinetic, pharmacogenomic, and other translational studies. Genomic DNA extracted from blood samples is analyzed by polymerase chain reaction for genetic polymorphisms in cyclophosphamide/busulfan disposition enzymes. Activated donor lymphocytes are assessed using flow cytometry to measure activation-induced cell death, as reflected by apoptosis in activated T cells. Chimerism on or around day 100 is also assessed using fluorescence in situ hybridization analysis and DNA fingerprinting. 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
Graft Versus Host Disease, Leukemia, Lymphoma, Multiple Myeloma and Plasma Cell Neoplasm, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Diseases, Secondary Myelofibrosis
Keywords
graft versus host disease, adult acute myeloid leukemia with 11q23 (MLL) abnormalities, 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), recurrent adult acute myeloid leukemia, untreated adult acute myeloid leukemia, untreated adult acute lymphoblastic leukemia, accelerated phase chronic myelogenous leukemia, blastic phase chronic myelogenous leukemia, chronic phase chronic myelogenous leukemia, relapsing chronic myelogenous leukemia, stage III multiple myeloma, refractory multiple myeloma, de novo myelodysplastic syndromes, myelodysplastic/myeloproliferative disease, unclassifiable, previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes, secondary myelofibrosis, secondary acute myeloid leukemia, recurrent adult Burkitt lymphoma, recurrent adult diffuse large cell lymphoma, recurrent adult diffuse mixed cell lymphoma, recurrent adult diffuse small cleaved cell lymphoma, recurrent adult Hodgkin lymphoma, recurrent adult immunoblastic large cell lymphoma, recurrent adult lymphoblastic lymphoma, recurrent adult T-cell leukemia/lymphoma, recurrent cutaneous T-cell non-Hodgkin lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, recurrent mantle cell lymphoma, recurrent marginal zone lymphoma, recurrent small lymphocytic lymphoma, recurrent adult acute lymphoblastic leukemia, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone B-cell lymphoma, splenic marginal zone lymphoma, adult nasal type extranodal NK/T-cell lymphoma, stage III adult Hodgkin lymphoma, stage IV adult Hodgkin lymphoma, stage III adult T-cell leukemia/lymphoma, stage IV adult T-cell leukemia/lymphoma, stage III adult Burkitt lymphoma, stage IV adult Burkitt lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, stage III adult diffuse mixed cell lymphoma, stage IV adult diffuse mixed cell lymphoma, stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, stage III adult lymphoblastic lymphoma, stage IV adult lymphoblastic lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, stage III adult diffuse small cleaved cell lymphoma, stage IV adult diffuse small cleaved cell lymphoma, adult acute lymphoblastic leukemia in remission, adult acute myeloid leukemia in remission, atypical chronic myeloid leukemia, noncontiguous stage II adult Burkitt lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse mixed cell lymphoma, noncontiguous stage II adult diffuse small cleaved cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult lymphoblastic lymphoma, noncontiguous stage II grade 1 follicular lymphoma, noncontiguous stage II grade 2 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, noncontiguous stage II mantle cell lymphoma, noncontiguous stage II marginal zone lymphoma, noncontiguous stage II small lymphocytic lymphoma, refractory hairy cell leukemia, stage I multiple myeloma, stage II multiple myeloma

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Unrelated Donor Allogeneic
Arm Type
Experimental
Arm Description
Matched unrelated donor allogeneic stem cell transplantation with a conditioning regimen of targeted busulfan, cyclophosphamide and thymoglobulin.
Intervention Type
Biological
Intervention Name(s)
anti-thymocyte globulin
Other Intervention Name(s)
immunosuppressant
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
Busulfex, Myleran
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
cytophosphane
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
CellCept
Intervention Type
Drug
Intervention Name(s)
tacrolimus
Other Intervention Name(s)
Protopic, Envarsus XR, Astagraf XL
Intervention Type
Genetic
Intervention Name(s)
polymerase chain reaction
Intervention Type
Genetic
Intervention Name(s)
polymorphism analysis
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Type
Other
Intervention Name(s)
pharmacogenomic studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Intervention Type
Procedure
Intervention Name(s)
allogeneic bone marrow transplantation
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Primary Outcome Measure Information:
Title
Transplantation-related Mortality at 100 Days Post-transplantation
Time Frame
at the 100 days post-transplant
Secondary Outcome Measure Information:
Title
Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD)
Time Frame
at day 100 post transplantation
Title
Overall Survival
Time Frame
2 years post transplant
Title
Event-free Survival
Time Frame
2 years post transplant

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Pathologically confirmed diagnosis of 1 of the following: Acute myeloid leukemia Acute lymphocytic leukemia Chronic myelogenous leukemia beyond first chronic phase (i.e., 2nd chronic phase, accelerated phase, or blast crisis) Multiple myeloma Myelodysplastic syndromes Malignant lymphoma Myelofibrosis Requirement for myeloablative conditioning regimen confirmed by attending physician Available donor must meet the following criteria: HLA phenotypically identical unrelated donor by low, intermediate, or high resolution for HLA class I antigens, and by high resolution for HLA class II antigens Matched at the A, B, and DRβ1 loci Single HLA-A or HLA-B antigen mismatch allowed Meets all National Marrow Donor Program or foreign registry criteria for allogeneic bone marrow/stem cell donors Peripheral blood stem cells are the preferred product on this study but bone marrow is allowed Karnofsky performance status 70-100% DLCO ≥ 50% predicted LVEF ≥ 45% Serum creatinine ≤ 1.5 mg/dL or creatinine clearance ≥ 65 mL/min Serum total bilirubin ≤ 2.0 mg/dL Fertile patients must use effective contraception Exclusion Criteria: No active uncontrolled infection Not pregnant or nursing/negative pregnancy test No HIV infection No chronic active hepatitis B or C or evidence of cirrhosis on liver biopsy
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marcel Devetten, MD
Organizational Affiliation
University of Nebraska
Official's Role
Principal Investigator
Facility Information:
Facility Name
Unversity of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Busulfan, Cyclophosphamide, & Antithymocyte Globulin Followed by Stem Cell Transplant in Treating Hematologic Cancer

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