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Reduced-Intensity Busulfan and Fludarabine With or Without Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Disease

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ClinicalTrials.gov Identifier: NCT00448201
Recruitment Status : Completed
First Posted : March 16, 2007
Results First Posted : May 30, 2017
Last Update Posted : May 30, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE March 14, 2007
First Posted Date  ICMJE March 16, 2007
Results First Submitted Date  ICMJE April 17, 2017
Results First Posted Date  ICMJE May 30, 2017
Last Update Posted Date May 30, 2017
Actual Study Start Date  ICMJE January 7, 2011
Actual Primary Completion Date January 11, 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 23, 2017)
Treatment-related Mortality [ Time Frame: 6 months ]
Treatment related mortality for first 6 months. Defined as the number of treatment related deaths excluding deaths due to disease relapse.
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00448201 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 23, 2017)
  • Complete Response at 6 and 12 Months Post-transplant [ Time Frame: 6 and 12 months ]
  • Complete or Mixed Donor Chimerism at 30, 60, and 90 Days Post-transplant [ Time Frame: Days 30, 60, and 90 ]
    Complete chimerism is defined as 100% donor cells detected, suggesting complete hematopoietic replacement. Mixed donor chimerism means host cells are detected in particular cells like lymphocytes. Five to 90% donor cells set the criteria for mixed chimerism (MC). Chimerism was not tabulated on day 30.
  • 5-year Disease-free Survival [ Time Frame: Year 5 ]
    The length of time post-transplant that the patient survives without any signs or symptoms of that cancer.
  • Graft-vs-host Disease at 6 Months Post-transplant [ Time Frame: 6 Months ]
    Graft-vs-host disease (GVHD) can be mild, moderate or severe depending on the differences in tissue type between patient and donor. Its symptoms can include:
    • Rashes, which include burning and redness, that erupt on the palms or soles and may spread to the trunk and eventually to the entire body
    • Blistering, causing the exposed skin surface to flake off in severe cases
    • Nausea, vomiting, abdominal cramps, diarrhea and loss of appetite, which can indicate that the gastrointestinal (digestive) tract is affected
    • Jaundice, or a yellowing of the skin, which can indicate liver damage
    • Excessive dryness of the mouth and throat, leading to ulcers
    • Dryness of the lungs, vagina and other surfaces
    Acute GVHD - Can occur soon after the transplanted cells begin to appear in the recipient. Acute GVHD ranges from mild, moderate or severe, and can be life-threatening if its effects are not controlled. Extensive chronic GVHD - Usually occurs at about three months post-transplant.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Reduced-Intensity Busulfan and Fludarabine With or Without Antithymocyte Globulin Followed by Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Disease
Official Title  ICMJE Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment With a More Intensive Therapeutic Regimen
Brief Summary

RATIONALE: Giving low doses of chemotherapy, such as busulfan and fludarabine, before a donor stem cell transplant helps stop the growth of cancer and abnormal 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 or abnormal cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Immunosuppressive therapy may improve bone marrow function and may be an effective treatment for hematologic cancer or other disease.

PURPOSE: This clinical trial is studying the side effects and how well giving busulfan and fludarabine with or without antithymocyte globulin followed by donor stem cell transplant works in treating patients with hematologic cancer or other disease.

Detailed Description

OBJECTIVES:

Primary

  • Determine the clinical efficacy and toxicity profiles of a nonmyeloablative preparative regimen comprising busulfan and fludarabine with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation in patients with hematologic cancers or other diseases.
  • Determine the feasibility of this regimen in these patients.
  • Establish a treatment-related mortality during the first 6 months that is less than 20% in patients treated with this regimen.

Secondary

  • Determine the response rates (disease-specific partial response and complete response) in patients treated with this regimen.
  • Determine overall and progression-free survival of patients treated with this regimen.
  • Determine the percent donor chimerism and immunologic recovery, including dendritic cell recovery, in patients treated with this regimen.
  • Determine the risk of acute and chronic graft-versus-host disease and other toxicities in patients treated with this regimen.
  • Assess the overall nonhematologic grades 3 and 4 toxicity of this regimen, including the incidence of veno-occlusive disease and pulmonary toxicity, in these patients.

OUTLINE: Patients are assigned to 1 of 4 treatment groups according to disease type and donor type.

  • Preparative regimen:

    • Group 1 (patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), IPSS (International Prognostic Scoring System score) high-risk myelodysplastic syndromes (HR MDS), or chronic myelogenous leukemia (CML) with an human leukocyte antigen (HLA)-matched related donor (MRD): Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV continuously over 48 hours on days -6 and -5.
    • Group 2 (patients with AML, ALL, IPSS HR MDS, or CML with an HLA-matched unrelated donor (MUD) or mismatched related donor (MMRD)): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on day -8.
    • Group 3 (patients with all other diseases with a MRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin as in group 2.
    • Group 4 (patients with all other disease with a MUD or MMRD): Patients receive fludarabine phosphate and busulfan as in group 1 and anti-thymocyte globulin IV over 4 hours on days -8 and -7.
  • Allogeneic stem cell transplantation: All patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously once daily beginning on day 5 (groups 1 and 2) or day 7 (groups 3 and 4) and continuing until blood counts recover.
  • Graft-vs-host disease (GVHD) prophylaxis: All patients receive oral tacrolimus twice daily on days -1 to 120 followed by a taper until day 180. Patients in groups 1 and 2 also receive methotrexate IV on days 1, 3, and 6.
  • Donor lymphocyte infusion (DLI): After day 120, patients with progressive disease or stable disease while off immunosuppression and with no evidence of active GVHD may receive DLI. Treatment with DLI may repeat every 8 weeks for up to 3 total infusions in the absence of disease response or GVHD.

Peripheral blood and/or bone marrow samples are collected at baseline and then at 30, 60, 90, 120, and 180 days post-transplantation. Chimerism (including the following subsets: whole blood, T-cells as defined by cluster of differentiation 3 (CD3) positivity, B-cells as defined by Cluster of Differentiation 19 (CD19) positivity, and myeloid cells as defined by Cluster of Differentiation 14 (CD14) and Cluster of Differentiation 15 (CD15) positivity is analyzed by polymerase chain reaction technology.

After restaging between Days 90 and 100 and between Days 150 to 180, patients are followed every 6 months for 1 years and then yearly for a maximum of 5 years from study entry.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Myeloproliferative Disorders
  • Leukemia
  • Lymphoma
  • Multiple Myeloma and Plasma Cell Neoplasm
  • Myelodysplastic Syndromes
Intervention  ICMJE
  • Biological: anti-thymocyte globulin
    0.5 mg/kg on day -3, 2.5 mg/kg on day -2 (groups 2, 3 and 4) and 3 mg/kg on day -1 (group 4 only)
  • Biological: sargramostim
    GM-CSF 500 ug everyday (QD) subcutaneously will be given to recipients who remain with an Absolute neutrophil count (ANC) < 1000/microliter (uL) past day 20
  • Biological: therapeutic allogeneic lymphocytes
    A minimum total cluster of differentiation 34 (CD34)+ cell dose of 3 x 10^6 cells/kg and a maximum 8 x 10^6 cells/kg will be infused on day 0
  • Drug: busulfan
    6.4 mg/kg by continuous IV infusion over 48 hours on Days -6 and -5
  • Drug: fludarabine phosphate
    fludarabine 30 mg/m^2/day x 5 days IV piggyback (IVPB) over 30 minutes on Days -7 through -3
  • Drug: methotrexate
    Methotrexate 5 mg/m^2 per day on days +1, +3 and +6
  • Drug: tacrolimus
    Suggested starting dose is 0.03 mg/kg po bid starting on Day -1
  • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
  • Procedure: peripheral blood stem cell transplantation
    Minimum total CD34+ cells of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on Day 0
Study Arms  ICMJE
  • Active Comparator: Methotrexate Only Arm
    GVHD Prophylaxis with Methotrexate
    Interventions:
    • Biological: sargramostim
    • Biological: therapeutic allogeneic lymphocytes
    • Drug: busulfan
    • Drug: fludarabine phosphate
    • Drug: methotrexate
    • Drug: tacrolimus
    • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: 2 Doses ATG + Methotrexate
    GVHD prophylaxis with antithymocyte globulin (ATG) + Methotrexate
    Interventions:
    • Biological: anti-thymocyte globulin
    • Biological: sargramostim
    • Biological: therapeutic allogeneic lymphocytes
    • Drug: busulfan
    • Drug: fludarabine phosphate
    • Drug: methotrexate
    • Drug: tacrolimus
    • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: 2 Doses ATG
    GVHD prophylaxis with 2 doses ATG
    Interventions:
    • Biological: anti-thymocyte globulin
    • Biological: sargramostim
    • Biological: therapeutic allogeneic lymphocytes
    • Drug: busulfan
    • Drug: fludarabine phosphate
    • Drug: tacrolimus
    • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: 3 Doses ATG
    GVHD prophylaxis with 3 doses ATG
    Interventions:
    • Biological: anti-thymocyte globulin
    • Biological: sargramostim
    • Biological: therapeutic allogeneic lymphocytes
    • Drug: busulfan
    • Drug: fludarabine phosphate
    • Drug: tacrolimus
    • Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 23, 2017)
71
Original Enrollment  ICMJE
 (submitted: March 15, 2007)
35
Actual Study Completion Date  ICMJE May 23, 2012
Actual Primary Completion Date January 11, 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

  • Histologically confirmed diagnosis of 1 of the following:

    • Chronic lymphocytic leukemia (CLL), meeting the following criteria:

      • Absolute lymphocyte count > 5,000/mm³
      • Lymphocytes must appear morphologically mature with < 55% prolymphocytes
      • Lymphocyte phenotype with expression of CD19 and cluster of differentiation 5 (CD5)
    • Prolymphocytic leukemia (PLL), meeting the following criteria:

      • Absolute lymphocyte count > 5,000/mm³
      • More than 55% prolymphocytes
      • Morphologically diagnosed
    • Chronic myelogenous leukemia (CML), meeting the following criteria:

      • Diagnosis of CML or similar myeloproliferative disorders based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated white blood cell (WBC) counts in peripheral blood or bone marrow
      • In first chronic phase CML and a candidate for treatment with reduced-dose busulfan
      • Patients with other cytogenetic abnormalities, such as t(9;12), that are associated with an aggressive clinical course are eligible
    • Non-Hodgkin's lymphoma (NHL), meeting the following criteria:

      • Any World Health Organization (WHO) class histologic subtype allowed
      • Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping
      • Bone marrow biopsies as sole means of diagnosis are not allowed for follicular lymphoma
    • Hodgkin's lymphoma, meeting the following criteria:

      • Any WHO class histologic subtype allowed
      • Core biopsies are acceptable provided they contain adequate tissue for primary diagnosis and immunophenotyping
    • Multiple myeloma, meeting the following criteria:

      • Active disease requiring treatment (Durie-Salmon stages I, II, or III)
    • Acute myeloid leukemia with documented control, defined as < 10% bone marrow blasts and no circulating blasts
    • Acute lymphoblastic leukemia, meeting the following criteria:

      • In early first relapse or beyond OR in first complete remission and has 1 of the following high-risk features:

        • t(9;22) or t(4;11)
        • WBC count > 30,000/mm³ at presentation
        • Non-T-cell phenotype
        • More than 30 years of age
    • Agnogenic myeloid metaplasia/myelofibrosis

      • Patients who are transfusion dependent or who have evolving myelodysplastic or leukemic features or high-risk cytogenetic abnormalities are eligible
    • Myelodysplastic syndromes (MDS) as defined by WHO criteria
  • Meets 1 of the following criteria:

    • Over 55 years of age
    • Ineligible for busulfan-based therapy based on diminished organ function or poor performance status
    • Indolent and chemotherapy-responsive CLL, low-grade NHL, small lymphocytic lymphoma, or PLL
  • Patients who have undergone prior autologous stem cell transplantation are preferentially enrolled on clinical trial CALGB-100002, if available and patient is eligible
  • HLA-matched or mismatched related donor or HLA-matched unrelated donor available

    • HLA-identical sibling (6/6 or 9/10) (minimal serologic typing required for class I [A, B]; molecular typing required for class II (DRB1))
    • 9/10 matched unrelated donor (MUD) (molecular analysis at HLA A, B, C, DRB1, and DQB1 by high resolution typing required)
    • 5/6 MUD (molecular analysis at HLA A, B, and DRB1 required)
    • No syngeneic donors

PATIENT CHARACTERISTICS:

  • Creatinine clearance ≥ 40 mL/min
  • Bilirubin ≤ 3 times upper limit of normal (ULN)
  • aspartate aminotransferase (AST) ≤ 3 times ULN
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) > 40% with no symptomatic pulmonary disease
  • Left ventricular ejection fraction (LVEF) ≥ 30% by multigated acquisition scan (MUGA)
  • No uncontrolled diabetes mellitus or active serious infection
  • No known hypersensitivity to Escherichia coli-derived products
  • No HIV infection
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • More than 4 weeks since prior chemotherapy, radiotherapy (except prophylactic cranial x-ray therapy), or surgery
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 10 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00448201
Other Study ID Numbers  ICMJE LCCC 0306
P30CA016086 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party UNC Lineberger Comprehensive Cancer Center
Study Sponsor  ICMJE UNC Lineberger Comprehensive Cancer Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Thomas C. Shea, MD UNC Lineberger Comprehensive Cancer Center
PRS Account UNC Lineberger Comprehensive Cancer Center
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP