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Fludarabine, Cyclophosphamide, and Total-Body Irradiation in Treating Patients Who Are Undergoing a Donor Bone Marrow Transplant for Hematologic Cancer

This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), September 2006

Sponsors and Collaborators: Sidney Kimmel Comprehensive Cancer Center
National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00134004
  Purpose

RATIONALE: Giving low doses of chemotherapy, such as fludarabine and cyclophosphamide, and radiation therapy before a donor bone marrow transplant helps stop the growth of cancer cells. Giving chemotherapy or radiation therapy before or after transplant also stops the patient's immune system from rejecting the donor's bone marrow stem cells. The donated stem cells may replace the patient's immune system 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 mycophenolate mofetil after the transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving fludarabine and cyclophosphamide together with total-body irradiation works in treating patients who are undergoing a donor bone marrow transplant for hematologic cancer.


Condition Intervention Phase
Chronic Myeloproliferative Disorders
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Drug: cyclophosphamide
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Drug: tacrolimus
Procedure: allogeneic bone marrow transplantation
Procedure: radiation therapy
Phase II

Genetics Home Reference related topics:   aceruloplasminemia    hemophilia   

MedlinePlus related topics:   Bone Marrow Transplantation    Cancer    Hodgkin's Disease    Leukemia, Adult Acute    Leukemia, Adult Chronic    Leukemia, Childhood    Lymphoma    Multiple Myeloma   

ChemIDplus related topics:   Cyclophosphamide    Fludarabine    Fludarabine monophosphate    Tacrolimus    Mycophenolate Mofetil    Mycophenolate mofetil hydrochloride    Tacrolimus anhydrous   

U.S. FDA Resources

Study Type:   Interventional
Study Design:   Treatment, Open Label
Official Title:   A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched Bone Marrow for Patients With Hematologic Malignancies

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Transplant-related mortality at 60 days, 6 months, 1 and 2 years [ Designated as safety issue: No ]
  • Relapse at 60 days, 6 months, 1 and 2 years [ Designated as safety issue: No ]
  • Progression-free survival at 60 days, 6 months, 1 and 2 years [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Peripheral blood donor chimerism as measured by polymerase chain reaction (PCR) of variable nucleotide tandem repeats at 30 days, 60 days, and 6 months [ Designated as safety issue: No ]
  • Hematologic and non-hematologic toxicities as measured by NCI Common Toxicity Criteria for Adverse Events, v 3.0 weekly until day 60 after transplantation [ Designated as safety issue: Yes ]

Estimated Enrollment:   100
Study Start Date:   October 2004
Estimated Primary Completion Date:   December 2009 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

  • Determine transplant-related mortality, risk of relapse, and progression-free survival of patients with standard- or high-risk hematologic malignancies undergoing nonmyeloablative conditioning comprising fludarabine, cyclophosphamide, and total-body irradiation followed by HLA-haploidentical allogeneic bone marrow transplantation.
  • Determine donor hematopoietic chimerism in patients' peripheral blood at 30, 60, and 180 days after transplantation.
  • Determine hematologic and nonhematologic toxic effects of this regimen in these patients.
  • Determine, when feasible, surface expression of HLA molecules and death receptors, sensitivity to cytotoxic lymphocytes, and expression of anti-apoptotic genes (e.g., Bcl-2, Bcl-xL, X-IAP, and c-FLIP) in cancer cells from patients who relapse after treatment with this regimen.

OUTLINE: This is a multicenter study. Patients are stratified according to risk of relapse (standard [defined as ≤ 30% risk] vs high [defined as ≥ 70% risk]).

  • Nonmyeloablative conditioning regimen: Patients receive fludarabine IV over 30 minutes on days -6 to -2 and cyclophosphamide IV over 1-2 hours on days -6 and -5. Patients undergo total body irradiation on day -1.
  • Allogeneic bone marrow transplantation: Patients undergo donor bone marrow infusion on day 0.
  • Post-transplantation therapy: Patients receive cyclophosphamide IV over 1-2 hours on days 3 and 4.
  • Graft-vs-host disease prophylaxis: Beginning on day 5, patients receive oral mycophenolate mofetil 3 times daily until day 35 and tacrolimus IV (then changing to orally) twice daily until day 180.

Treatment continues in the absence of disease progression.

After completion of study transplantation, patients are followed on days 30, 60, 100, and 180; at 1 year; and then annually for 4 additional years.

PROJECTED ACCRUAL: A total of 75-100 patients will be accrued for this study within 3-4 years.

  Eligibility
Ages Eligible for Study:   up to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of 1 of the following hematologic malignancies:

    • Acute leukemia

      • In second or subsequent complete remission (CR), as defined by absence of abnormal blast population by flow cytometry
      • In first CR with any of the following poor-risk cytogenetic features:

        • Alteration of chromosome 5 or 7
        • Multiple abnormalities
        • Philadelphia chromosome positive
    • Chronic phase chronic myelogenous leukemia (CML)

      • In first chronic phase and refractory to interferon alfa or imatinib mesylate
      • In second or subsequent chronic phase
    • Chronic lymphocytic leukemia, meeting 1 of the following criteria:

      • Received prior chemotherapy with a nucleoside analog and had remission lasting < 6 months
      • Received 1 prior therapy and has any of the following high-risk features:

        • Cytogenetic abnormalities of 17p, 11q
        • Mutations of the Zap70 gene
        • Somatically unmutated immunoglobulin heavy chain variable region genes
    • Hodgkin's lymphoma

      • Ineligible for autologous stem cell transplantation (SCT) due to any of the following exclusion factors:

        • LVEF < 45%
        • FEV_1 or FVC < 50% of predicted (75% of predicted in patients with prior thoracic or mantle radiotherapy)
        • Total bilirubin > 2.0 mg/dL (unless documented Gilbert's disease)
        • Creatinine > 2.0 mg/dL
    • Non-Hodgkin's lymphoma (NHL)

      • Low-grade NHL allowed provided patient had a remission duration of < 1 year after administration of any established, multi-agent chemotherapy regimen (e.g., CVP, CHOP, or rituximab in combination with CHOP)
      • Intermediate- or high-grade NHL allowed provided patient is ineligible for autologous SCT according to the criteria listed above
    • Multiple myeloma
    • Myelodysplastic syndromes
    • Paroxysmal nocturnal hemoglobinuria
    • Chronic myeloproliferative disorders other than CML, including any of the following:

      • Chronic myelomonocytic leukemia
      • Agnogenic myeloid metaplasia (or myeloid metaplasia with myelofibrosis), with hemoglobin < 10 g/dL OR WBC < 4,000/mm^3 or > 30,000/mm^3
      • Polycythemia vera or essential thrombocythemia in "spent" phase, with a history of 2 of the following:

        • Marrow fibrosis
        • Splenomegaly
        • Cytopenia (i.e., absolute neutrophil count < 1,500/mm^3, platelet count < 100,000/mm^3, hemoglobin < 10 g/dL)
      • Polycythemia vera or essential thrombocythemia with transformation to myelodysplastic syndromes or acute myeloid leukemia (requires treatment to achieve < 20% blasts in marrow)
  • No smoldering myeloma
  • Patients with acute myeloid leukemia or myelodysplastic syndromes must have had comprehensive cytogenetic evaluation of bone marrow specimen during active disease
  • Ineligible for or refused bone marrow transplantation from an HLA-matched sibling or unrelated donor
  • Ineligible for or refused autologous SCT
  • Must have an HLA mismatched (i.e., 3/6, 4/6, or 5/6) related (first-degree relative)* donor available

    • Donor ≥ 18 years of age NOTE: *Patients with an inherited recombinant HLA haplotype may receive marrow from the parent in whose gamete the recombination occurred

NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

Age

  • 6 months to 70 years

Performance status

  • ECOG 0-1

Life expectancy

  • Not specified

Hematopoietic

  • See Disease Characteristics

Hepatic

  • See Disease Characteristics
  • Bilirubin < 3.1 mg/dL

Renal

  • See Disease Characteristics

Cardiovascular

  • See Disease Characteristics
  • LVEF ≥ 35%

Pulmonary

  • See Disease Characteristics
  • FEV_1 or FVC ≥ 40% of predicted in patients without prior thoracic or mantle radiotherapy (60% of predicted in patients with prior thoracic or mantle radiotherapy)

Other

  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • HIV negative
  • Geographically accessible
  • No debilitating medical or psychiatric illness that would preclude giving informed consent or receiving optimal treatment or follow-up

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • See Disease Characteristics
  • No prior transfusions from donor

Chemotherapy

  • See Disease Characteristics

Endocrine therapy

  • Not specified

Radiotherapy

  • See Disease Characteristics

Surgery

  • Not specified
  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00134004

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins     Recruiting
      Baltimore, Maryland, United States, 21231-2410
      Contact: Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce     410-955-8804     jhcccro@jhmi.edu    

Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
National Cancer Institute (NCI)

Investigators
Study Chair:     Ephraim J. Fuchs, MD     Sidney Kimmel Comprehensive Cancer Center    
  More Information

Clinical trial summary from the National Cancer Institute's PDQ® database  This link exits the ClinicalTrials.gov site
 

Study ID Numbers:   CDR0000440990, JHOC-J0457, JHOC-04072704
First Received:   August 22, 2005
Last Updated:   July 23, 2008
ClinicalTrials.gov Identifier:   NCT00134004
Health Authority:   Unspecified

Keywords provided by National Cancer Institute (NCI):
adult acute lymphoblastic leukemia in remission  
adult acute myeloid leukemia in remission  
childhood acute lymphoblastic leukemia in remission  
childhood acute myeloid leukemia in remission  
childhood chronic myelogenous leukemia  
chronic phase chronic myelogenous leukemia  
refractory chronic lymphocytic leukemia  
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue  
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)  
chronic idiopathic myelofibrosis  
chronic myelomonocytic leukemia  
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
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
recurrent adult Burkitt lymphoma

Study placed in the following topic categories:
Polycythemia
Chronic myelogenous leukemia
Chronic myelomonocytic leukemia
Hodgkin lymphoma, adult
Lymphoma, Mantle-Cell
Lymphoma, small cleaved-cell, diffuse
Tacrolimus
Small non-cleaved cell lymphoma
Lymphoma, large-cell, immunoblastic
Preleukemia
Hemorrhagic Disorders
Multiple myeloma
Hemorrhagic thrombocythemia
Mycophenolate mofetil
Neoplasm Metastasis
Thrombocythemia, Hemorrhagic
Acute myeloid leukemia, adult
Hodgkin Disease
Essential thrombocytosis
Chronic lymphocytic leukemia
Myelodysplastic syndromes
Lymphoma, Large B-Cell, Diffuse
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immunoproliferative Disorders
Hematologic Diseases
Leukemia, B-cell, chronic
Leukemia, Myelomonocytic, Chronic
Blood Coagulation Disorders
Acute myelogenous leukemia
Myeloproliferative Disorders

Additional relevant MeSH terms:
Antimetabolites
Antimetabolites, Antineoplastic
Neoplasms by Histologic Type
Disease
Molecular Mechanisms of Pharmacological Action
Immune System Diseases
Immunologic Factors
Antineoplastic Agents
Blood Protein Disorders
Physiological Effects of Drugs
Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Pathologic Processes
Therapeutic Uses
Syndrome
Myeloablative Agonists
Cardiovascular Diseases
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Alkylating Agents

ClinicalTrials.gov processed this record on August 28, 2008




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