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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00134004
First received: August 22, 2005
Last updated: April 16, 2013
Last verified: April 2013
  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
Radiation: radiation therapy
Phase 2

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

Resource links provided by NLM:

Genetic and Rare Diseases Information Center resources: Acute Lymphoblastic Leukemia Lymphoma, Small Cleaved-cell, Diffuse Leukemia, Myeloid Chronic Myeloid Leukemia Myelodysplastic Syndromes Multiple Myeloma Chronic Myeloproliferative Disorders Hodgkin Lymphoma Acute Myelocytic Leukemia Acute Non Lymphoblastic Leukemia Acute Myeloid Leukemia, Adult Follicular Lymphoma Hodgkin Lymphoma, Childhood B-cell Lymphomas Myelofibrosis Burkitt Lymphoma Lymphoma, Large-cell Lymphoma, Large-cell, Immunoblastic Lymphoblastic Lymphoma Small Non-cleaved Cell Lymphoma Chronic Lymphocytic Leukemia Leukemia, B-cell, Chronic Chronic Myelomonocytic Leukemia Acute Lymphoblastic Leukemia, Childhood Acute Myeloid Leukemia, Childhood Mantle Cell Lymphoma Essential Thrombocythemia Polycythemia Vera Anaplastic Plasmacytoma
U.S. FDA Resources

Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

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

Estimated Enrollment: 100
Study Start Date: October 2004
Estimated Primary Completion Date: December 2014 (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, Georgia
Blood and Marrow Transplant Program at Northside Hospital
Atlanta, Georgia, United States, 30342
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
United States, Pennsylvania
Hahnemann University Hospital
Philadelphia, Pennsylvania, United States, 19102-1192
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Study Chair: Ephraim J. Fuchs, MD Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00134004     History of Changes
Other Study ID Numbers: J0457 CDR0000440990, P01CA015396, P30CA006973, JHOC-J0457, JHOC-04072704
Study First Received: August 22, 2005
Last Updated: April 16, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
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

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
Cyclophosphamide
Mycophenolate mofetil
Fludarabine monophosphate
Tacrolimus
Fludarabine

ClinicalTrials.gov processed this record on April 15, 2014