Fludarabine and PK-Directed Busulfan With or Without ATG Followed By Donor Peripheral Stem Cell Transplant in Treating Patients With Hematologic Cancer or Other Diseases (LCCC 0510)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00448357
First received: March 14, 2007
Last updated: January 13, 2014
Last verified: January 2014
  Purpose

RATIONALE: Giving chemotherapy, such as fludarabine and busulfan, before a donor peripheral stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps 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 a monoclonal antibody, alemtuzumab, before the transplant and tacrolimus after the transplant may stop this from happening.

PURPOSE: The phase I portion of this trial identified the maximum tolerated dose of busulfan after treating 40 patients on a dose-escalation scheme. We are now treating an additional 26 patients on the phase II portion of the trial at a PK-directed dose of total AUC 6912 uM-min/24 hours. We transitioned to the Phase II portion of the study in October 2009.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Biological: rabbit anti-thymocyte globulin
Biological: therapeutic allogeneic lymphocytes
Drug: busulfan
Drug: fludarabine phosphate
Drug: tacrolimus
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Drug: methotrexate
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Allogeneic Hematopoietic Cell Transplantation for Patients With Hematologic Disorders Who Are Undergoing Dose-Adjusted Treatment With A Maximally Intensive Busulfex-Based Therapeutic Regimen

Resource links provided by NLM:

Genetic and Rare Diseases Information Center resources: Lymphoma, Small Cleaved-cell, Diffuse Leukemia, Myeloid Chronic Myeloid Leukemia Myelodysplastic Syndromes Acute Lymphoblastic Leukemia Multiple Myeloma Chronic Myeloproliferative Disorders Hodgkin Lymphoma Waldenstrom Macroglobulinemia Acute Myelocytic Leukemia Acute Non Lymphoblastic Leukemia Acute Myeloid Leukemia, Adult Follicular Lymphoma B-cell Lymphomas Myelofibrosis Burkitt Lymphoma Lymphoma, Large-cell Lymphomatoid Granulomatosis Lymphoma, Large-cell, Immunoblastic Lymphoblastic Lymphoma Chronic Lymphocytic Leukemia Leukemia, B-cell, Chronic Chronic Neutrophilic Leukemia Hypereosinophilic Syndrome Mantle Cell Lymphoma Cutaneous T-cell Lymphoma Essential Thrombocythemia Mycosis Fungoides Sezary Syndrome Polycythemia Vera Anaplastic Plasmacytoma
U.S. FDA Resources

Further study details as provided by UNC Lineberger Comprehensive Cancer Center:

Primary Outcome Measures:
  • One-year disease-free survival (DFS) rate at the maximum tolerated dose identified during phase I of the trial (target AUC 6912) [ Time Frame: One year post-transplant ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall and disease-free survival [ Time Frame: Five years post-transplant ] [ Designated as safety issue: No ]
  • Dose-limiting toxicities of busulfan [ Time Frame: 6 weeks post-transplant ] [ Designated as safety issue: Yes ]
  • Capacity of test dosing of busulfan that would result in the desired area under the curve concentration exposure of patients receiving a full-dose busulfan regimen [ Time Frame: Day -15 to Day -11 ] [ Designated as safety issue: No ]
  • To assess the incidence of graft vs host disease and DNA chimerism in patients between one month and two years post transplant [ Time Frame: 1 Month to 2 Years post-transplant ] [ Designated as safety issue: No ]

Enrollment: 60
Study Start Date: October 2005
Estimated Study Completion Date: August 2015
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Methotrexate Only
GVHD prophylaxis with Methotrexate alone
Biological: therapeutic allogeneic lymphocytes
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
Drug: busulfan
PK-targeted continuous IV infusion over 90 hours on Days -7 to -4.
Drug: fludarabine phosphate
30 mg/m^2/day x 5 days IVPB over 30 minutes on Days -7 through -3
Drug: tacrolimus
The suggested starting dose is 0.03 mg/kg po bid starting on day -1
Procedure: allogeneic hematopoietic stem cell transplantation
A minimum total CD34+ cell dose of 3 x 10^6 cells/kg and maximum of 8 x 10^6 cells/kg will be infused on day 0
Procedure: peripheral blood stem cell transplantation
minimum total CD34+ cell dose of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on day 0
Drug: methotrexate
5 mg/m^2 on days +1, +3 and +6
Active Comparator: 2 Doses ATG + Methotrexate
GVHD prophylaxis with ATG + Methotrexate
Biological: rabbit anti-thymocyte globulin
.5 mg/kg on day -3 and 2.5 mg/kg on day -2
Biological: therapeutic allogeneic lymphocytes
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
Drug: busulfan
PK-targeted continuous IV infusion over 90 hours on Days -7 to -4.
Drug: fludarabine phosphate
30 mg/m^2/day x 5 days IVPB over 30 minutes on Days -7 through -3
Drug: tacrolimus
The suggested starting dose is 0.03 mg/kg po bid starting on day -1
Procedure: allogeneic hematopoietic stem cell transplantation
A minimum total CD34+ cell dose of 3 x 10^6 cells/kg and maximum of 8 x 10^6 cells/kg will be infused on day 0
Procedure: peripheral blood stem cell transplantation
minimum total CD34+ cell dose of 3 x 10^6 cells/kg and a maximum of 8 x 10^6 cells/kg will be infused on day 0
Drug: methotrexate
5 mg/m^2 on days +1, +3 and +6

Detailed Description:

OBJECTIVES:

Primary

  • Phase I Objective: To identify the maximum tolerated dose of continuous infusion IV busulfan based on blood levels derived from a test dose in conjunction with fludarabine, ATG and methotrexate plus tacrolimus for GVHD prophylaxis
  • Phase II Objective: To determine the one-year disease-free survival (DFS) rate at the maximum tolerated dose identified during Phase I of the trial (target AUC 6912)

Secondary

  • Determine the overall and disease-free survival of patients treated with this regimen.
  • Determine the dose-limiting toxicities of this regimen in these patients.
  • Determine the capacity of test dosing of busulfan that would result in the desired area under the curve concentration exposure of patients receiving a full-dose busulfan regimen.
  • Determine the incidence of graft-vs-host disease and DNA chimerism between 1 month and 2 years post-transplantation in these patients.
  • Compare the overall survival (OS) and disease-free survival (DFS) rates for patients treated with Campath vs. patients treated with ATG/Methotrexate for GVHD control

OUTLINE: This is a non-randomized, open-label, parallel group study of busulfan. Patients are stratified according to donor relationship (matched related donor [MRD] vs matched unrelated donor [MUD]).

  • Conditioning regimen: Patients receive fludarabine phosphate IV over 30 minutes on days -7 to -3 and busulfan IV over 2 hours once within days -15 to -10 and then IV continuously over 90 hours on days -7 to -4. Patients with a MRD also receive Methotrexate (MTX) on Days +1, +3, and +6. Patients with a MUD receive ATG on Days -3 and -2 and MTX on Days +1, +3 and +6.

Phase I portion only: Cohorts of 3-6 patients receive escalating doses of busulfan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

  • Allogeneic peripheral blood stem cell transplantation: Patients undergo allogeneic peripheral blood stem cell transplantation on day 0. Patients then receive sargramostim (GM-CSF) subcutaneously beginning on day 5 and continuing until blood counts recover.
  • Graft-vs-host disease (GVHD) prophylaxis: Patients receive oral tacrolimus twice daily on days -1 to 180 or days -1 to 240.
  • Donor lymphocyte infusion (DLI): Patients who do not achieve CR, do not have GVHD, and have been off immunosuppressants for at least 30 days may receive up to 3 DLIs, at least 8 weeks apart, after completion of tacrolimus.

After the completion of study treatment, patients are followed periodically for up to 5 years.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Histologically confirmed diagnosis of any of the following:

    • Chronic lymphocytic leukemia or prolymphocytic leukemia

      • Chemotherapy-refractory or advanced disease after ≥ 3 prior treatments
    • Chronic myelogenous leukemia

      • Diagnosis based on t(9;22) or related t(9;12) cytogenetic abnormalities AND characterized by elevated WBC counts in peripheral blood or marrow
      • Patients with progressive disease on imatinib mesylate or other protein tyrosine kinase inhibitors; less than a major cytogenetic or fluorescent in situ hybridization (FISH) complete response (CR) after a minimum of 6 months of targeted therapy; or less than a complete FISH or cytogenetic response after 12 months of targeted therapy are eligible
      • 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) or Hodgkin's lymphoma

      • Any WHO classification histologic subtype allowed
      • Must have advanced disease as defined by relapse after initial CR or failure to achieve CR OR deemed to have less than a 30% likelihood of durable response with an autologous stem cell transplant
      • Refractory low-grade NHL histologies or any intermediate or aggressive large cell or mantle cell lymphoma allowed
    • Acute myeloid leukemia (AML)

      • High-risk disease in first CR (CR1) OR evidence of any recurrent disease beyond CR1

        • High-risk individuals are those requiring more than 1 course of induction therapy to achieve remission; those with extra-medullary disease at presentation; or those with high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3) or > 2 cytogenetic abnormalities
    • Multiple myeloma
    • Myelodysplastic syndromes (MDS)

      • Must have MDS defined by WHO criteria with > 5% blasts or high-risk cytogenetic abnormalities (abnormalities of chromosomes 5, 7, 2, trisomy 8, or 3)
    • Acute lymphoblastic leukemia (ALL)

      • High-risk disease in CR1 OR beyond CR1

        • High-risk disease includes the following: t(9;22) or t(4;11); WBC > 30,000/mm³ at presentation; non-T-cell phenotype; or more than 30 years of age
    • Myelofibrosis/agnogenic myeloid metaplasia

      • Patients must be transfusion dependant or have evidence of evolving AML as evidenced by an excess of blasts or a state of marrow failure/fibrosis
      • Myeloproliferative disorders with advanced disease (e.g., progressive or spent phase polycythemia vera, myelofibrosis, or essential thrombocythemia)
  • Any of the following categories of donors are acceptable*:

    • HLA-identical or 1 antigen-mismatched sibling (5/6, 6/6, or 8/10) donor

      • Minimal serologic typing required for class I (A, B); molecular typing required for class II (DRB1)
    • 8/10 matched unrelated donor (MUD)

      • Molecular analysis at HLA-A, -B, -C, -DRB1 and -DQB1 (8/10 match) by high resolution typing is required
    • 5/6 MUD

      • Molecular analysis at HLA-A, -B, and -DRB1 required NOTE: *No syngeneic donors

PATIENT CHARACTERISTICS:

  • Performance status 0-2
  • Bilirubin ≤ 2 times upper limit of normal (ULN)
  • AST ≤ 2 times ULN
  • Creatinine clearance ≥ 50 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • DLCO > 60% with no symptomatic pulmonary disease
  • LVEF ≥ 50% by MUGA
  • No uncontrolled or severe cardiovascular disease, pulmonary disease, or infection that, in the opinion of the treating physician, would make this study unreasonably hazardous to the patient
  • No other serious illness that would limit survival to < 2 years
  • No psychiatric condition that would preclude study compliance
  • No uncontrolled diabetes mellitus or active serious infection
  • No active second malignancy except for nonmelanomatous skin cancer
  • No known hypersensitivity to E. coli-derived products
  • No HIV positivity

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • More than 4 weeks since prior chemotherapy, radiotherapy, or surgery

    • Cranial radiotherapy or intrathecal therapy as prophylaxis against CNS recurrence within the past 4 weeks allowed (in high-risk patients)
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00448357

Locations
United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States, 27599-7295
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
Principal Investigator: Thomas C. Shea, MD UNC Lineberger Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00448357     History of Changes
Obsolete Identifiers: NCT00618306
Other Study ID Numbers: LCCC 0510, P30CA016086, CDR0000550145
Study First Received: March 14, 2007
Last Updated: January 13, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
United States: Federal Government

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
refractory multiple myeloma
relapsing chronic myelogenous leukemia
secondary acute myeloid leukemia
stage II multiple myeloma
stage III multiple myeloma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV adult Hodgkin lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
Waldenstrom macroglobulinemia
accelerated phase chronic myelogenous leukemia
adult acute myeloid leukemia in remission
blastic phase chronic myelogenous leukemia
chronic eosinophilic leukemia
chronic neutrophilic leukemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma

Additional relevant MeSH terms:
Neoplasms
Leukemia
Lymphoma
Lymphoma, Non-Hodgkin
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Myelodysplastic Syndromes
Preleukemia
Myeloproliferative Disorders
Lymphoma, Large-Cell, Immunoblastic
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Bone Marrow Diseases
Precancerous Conditions
Antilymphocyte Serum
Busulfan
Methotrexate
Fludarabine monophosphate
Tacrolimus

ClinicalTrials.gov processed this record on April 23, 2014