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Total-Body Irradiation With Or Without Fludarabine Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer
This study is currently recruiting participants.
Verified by National Cancer Institute (NCI), July 2009
First Received: January 9, 2004   Last Updated: July 7, 2009   History of Changes
Sponsor: Fred Hutchinson Cancer Research Center
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00075478
  Purpose

RATIONALE: Giving low doses of chemotherapy, such as fludarabine, and radiation therapy before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's 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 cyclosporine and mycophenolate mofetil after transplant may stop this from happening. It is not yet known whether total-body irradiation followed by donor stem cell transplant is more effective with or without fludarabine in treating hematologic cancer.

PURPOSE: This randomized phase III trial is studying total-body irradiation and fludarabine to see how it works compared with total-body irradiation alone followed by donor stem cell transplant in treating patients with hematologic cancer.


Condition Intervention Phase
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Drug: fludarabine phosphate
Radiation: radiation therapy
Phase III

Study Type: Interventional
Study Design: Treatment, Randomized, Active Control
Official Title: A Multi-Center Phase III Study Comparing Nonmyeloablative Conditioning With TBI Versus Fludarabine/TBI for HLA-Matched Related Hematopoietic Cell Transplantation for Treatment of Hematologic Malignancies

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Nonrelapse mortality 1 year post-transplant [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Overall survival 1 year post-transplant [ Designated as safety issue: No ]
  • Incidence of graft rejection [ Designated as safety issue: No ]
  • Incidence of acute graft-vs-host disease (GVHD) and chronic extensive GVHD [ Designated as safety issue: Yes ]
  • Compare rates of disease progression and/or relapse-related mortality 1 year post-transplant [ Designated as safety issue: No ]
  • Compare immune reconstitution and the risks of infections [ Designated as safety issue: Yes ]

Estimated Enrollment: 200
Study Start Date: October 2003
Estimated Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Conditioning arm I: Experimental
Patients receive fludarabine IV on days -4 to -2. Patients then undergo low-dose total body irradiation (TBI) on day 0.
Drug: fludarabine phosphate
Given IV
Radiation: radiation therapy
Patients undergo low-dose total body irradiation on day 0
Conditioning arm II: Experimental
Patients undergo low-dose TBI on day 0.
Radiation: radiation therapy
Patients undergo low-dose total body irradiation on day 0

Detailed Description:

OBJECTIVES:

Primary

  • Compare the nonrelapse mortality 1 year after nonmyeloablative conditioning comprising low-dose total body irradiation (TBI) with vs without fludarabine followed by HLA-matched related allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies at low or moderate risk for graft rejection.

Secondary

  • Compare the 1-year overall survival of patients after treatment with these regimens.
  • Compare the incidence of graft rejection in patients treated with these regimens.
  • Compare the incidence of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD in patients treated with these regimens.
  • Compare the rates of disease progression and/or relapse-related mortality in patients treated with these regimens.
  • Compare the immune reconstitution and risk of infection in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, disease risk (indolent vs aggressive), and prior conventional hematopoietic stem cell transplantation (yes vs no).

  • Nonmyeloablative conditioning regimen: Patients are randomized to 1 of 2 treatment arms.

    • Arm I: Patients receive fludarabine IV on days -4 to -2. Patients then undergo low-dose total body irradiation (TBI) on day 0.
    • Arm II: Patients undergo low-dose TBI on day 0.
  • Allogeneic peripheral blood stem cell transplantation (PBSCT): After TBI, patients undergo PBSCT on day 0.
  • Immunosuppression: Patients receive oral cyclosporine twice daily on days -3 to 56 in the absence of graft-versus-host disease (GVHD). Patients with no evidence of GVHD at day 56 begin a cyclosporine taper and continue the taper until day 180. Patients with evidence of disease progression and no evidence of GVHD prior to day 56 receive tapered doses of cyclosporine for 2 weeks. Patients also receive oral mycophenolate mofetil (MMF) twice daily on days 0-27 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.

Patients are followed periodically for 1.5 years and then annually for 5 years post-transplantation.

PROJECTED ACCRUAL: A total of 200 patients (100 per treatment arm) will be accrued for this study within 3 years.

  Eligibility

Ages Eligible for Study:   up to 74 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of a hematologic malignancy treatable with hematopoietic stem cell transplantation (HSCT) OR a B-cell malignancy, including any of the following:

    • Aggressive non-Hodgkin's lymphoma (NHL) and other histologies, such as diffuse large B-cell non-Hodgkin's lymphoma (NHL)

      • Not eligible for conventional myeloablative HSCT OR failed autologous HSCT
      • No rapidly progressive aggressive NHL, unless in minimal disease state
    • Low-grade NHL with less than 6 months duration of complete remission (CR) between courses of conventional therapy
    • Mantle cell lymphoma

      • In first CR
    • Chronic lymphocytic leukemia

      • Meets 1 of the following criteria:

        • Failed to meet NCI Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine (FLU) (or another nucleoside analog, e.g., 2-CDA, pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog)
        • Failed FLU-CY-Rituximab (FCR) combination chemotherapy at any time point
        • Have "17p deletion" cytogenetic abnormality (patients should have received induction chemotherapy but could be transplanted in first CR)
    • Hodgkin's lymphoma

      • Received and failed front-line therapy
      • Failed or were not eligible for autologous transplantation
    • Multiple myeloma

      • Chemosensitive disease after failed autografting
      • No autografting prior (within 6 months) to nonmyeloablative hematopoietic cell transplantation (HCT)
    • Acute myeloid leukemia

      • Less then 5% marrow blasts at the time of transplantation and beyond first CR
      • No circulating leukemic blasts in the peripheral blood
    • Acute lymphoblastic leukemia

      • Less than 5% marrow blasts at the time of transplantation and beyond first CR
      • No circulating leukemic blasts in the peripheral blood
    • Chronic myelogenous leukemia

      • Chronic phase (CP) beyond CP1 allowed provided the patient is beyond the first CP and was previously treated with myelosuppressive chemotherapy or HSCT and has less than 5% marrow blasts at time of transplantation
      • No circulating leukemic blasts in the peripheral blood
    • Myelodysplastic syndromes

      • Received prior myelosuppressive chemotherapy or HSCT and less than 5% marrow blasts at time of transplantation
  • Not eligible for conventional allogeneic HSCT AND must have disease that is expected to be stable for at least 100 days without chemotherapy

    • Not curable with an autologous transplantation
    • Patients who refused to be treated on a conventional HSCT study are eligible
  • Not eligible for a high priority curative autologous transplantation
  • No chronic myelomonocytic leukemia or myeloproliferative disorder
  • No concurrent CNS involvement with disease refractory to intrathecal chemotherapy
  • Available HLA-matched related donor

    • Genotypically identical in at least 1 haplotype
    • Phenotypically or genotypically identical donor at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1 allowed
    • No identical twin 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

  • Under 75

    • Patients under 12 must be approved by the principal investigator

Performance status

  • Karnofsky 50-100% (adult patients)
  • Lansky 50-100% (pediatric patients)

Life expectancy

  • Not severely limited by disease other than malignancy

Hematopoietic

  • Not specified

Hepatic

  • No fulminant liver failure
  • No cirrhosis of the liver with evidence of portal hypertension
  • No alcoholic hepatitis
  • No esophageal varices
  • No history of bleeding esophageal varices
  • No hepatic encephalopathy
  • No uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the PT
  • No ascites related to portal hypertension
  • No bacterial or fungal liver abscess
  • No biliary obstruction
  • No chronic viral hepatitis with bilirubin greater than 3 mg/dL
  • No symptomatic biliary disease

Renal

  • Not specified

Cardiovascular

  • Ejection fraction at least 35%*
  • No poorly controlled hypertension despite multiple hypertensive drugs
  • No symptomatic coronary artery disease*
  • No other cardiac failure requiring therapy* NOTE: *For patients with a history of cardiac disease or anthrocycline use

Pulmonary

  • DLCO at least 30%
  • Total lung capacity at least 30%
  • FEV_1 at least 30%
  • No concurrent supplementary continuous oxygen
  • No fungal pneumonia with radiological progression after receiving amphotericin formulation or mold-active azoles for more than 1 month

Other

  • Not pregnant or nursing
  • Fertile patients must use effective contraception during and for up to 12 months after study participation
  • HIV negative
  • No active nonhematologic malignancy except localized nonmelanoma skin cancer
  • No nonhematologic malignancy not in complete remission with > 20% risk of disease recurrence except nonmelanoma skin cancer

PRIOR CONCURRENT THERAPY:

Biologic therapy

  • See Disease Characteristics
  • More than 6 months since prior autograft immediately before nonmyeloablative HSCT (tandem approach)
  • More than 3 weeks (from the initiation of conditioning) since prior cytotoxic agents for "cytoreduction, " except tyrosine kinase inhibitors (e.g., imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan

Chemotherapy

  • See Disease Characteristics
  • See Biologic therapy
  • More than 3 weeks since prior myelosuppressive chemotherapy

Endocrine therapy

  • Not specified

Radiotherapy

  • Not specified

Surgery

  • Not specified
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00075478

Locations
United States, Oregon
Knight Cancer Institute at Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239-3098
Contact: Clinical Trials Office - Knight Cancer Institute at Oregon Hea     503-494-1080     trials@ohsu.edu    
United States, Utah
LDS Hospital Recruiting
Salt Lake City, Utah, United States, 84143
Contact: Finn B. Petersen, MD     801-408-1818     ldfpeter@ihc.com    
United States, Washington
Fred Hutchinson Cancer Research Center Recruiting
Seattle, Washington, United States, 98109-1024
Contact: Brenda Sandmaier, MD     206-667-4961        
Seattle Cancer Care Alliance Recruiting
Seattle, Washington, United States, 98109-1023
Contact: Clinical Trials Office - Seattle Cancer Care Alliance     800-804-8824        
Veterans Affairs Medical Center - Seattle Recruiting
Seattle, Washington, United States, 98108
Contact: Thomas R. Chauncey, MD, PhD     206-764-2709        
United States, Wisconsin
Medical College of Wisconsin Cancer Center Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Clinical Trials Office - Medical College of Wisconsin Cancer C     414-805-4380        
Germany
Medizinische Universitaetsklinik I at the University of Cologne Recruiting
Cologne, Germany, D-50924
Contact: Kai Huebel, MD     49-221-478-3583     kai.huebel@uni-koeln.de    
Universitaet Leipzig Recruiting
Leipzig, Germany, D-04103
Contact: Dietger Niederwieser, MD     49-341-971-3050     dietger@medizin.uni_leipzig.de    
Universitaetsklinikum Tuebingen Recruiting
Tuebingen, Germany, D-72076
Contact: Wolfgang Bethge, MD     49-4707-1298-2711        
Italy
Azienda Sanitaria Ospedale San Giovanni Battista Molinette di Torino Recruiting
Turin, Italy, 10126
Contact: Benedetto Bruno, MD, PhD     39-339-112-9064     benedetto.bruno@unito.it    
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Brenda Sandmaier, MD Fred Hutchinson Cancer Research Center
  More Information

Additional Information:
No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center ( Brenda Sandmaier )
Study ID Numbers: CDR0000346618, FHCRC-1813.00
Study First Received: January 9, 2004
Last Updated: July 7, 2009
ClinicalTrials.gov Identifier: NCT00075478     History of Changes
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):
refractory multiple myeloma
recurrent childhood acute lymphoblastic leukemia
recurrent childhood acute myeloid leukemia
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
recurrent/refractory childhood Hodgkin lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult Hodgkin lymphoma
recurrent adult lymphoblastic lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
refractory chronic lymphocytic leukemia
relapsing chronic myelogenous leukemia
previously treated myelodysplastic syndromes
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
chronic phase chronic myelogenous leukemia
childhood chronic myelogenous leukemia
recurrent adult Burkitt lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma

Additional relevant MeSH terms:
Antimetabolites
Anti-Infective Agents
Vidarabine
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Precancerous Conditions
Antineoplastic Agents
Blood Protein Disorders
Physiological Effects of Drugs
Paraproteinemias
Hemostatic Disorders
Leukemia
Preleukemia
Hemorrhagic Disorders
Pathologic Processes
Therapeutic Uses
Syndrome
Cardiovascular Diseases
Lymphoma
Immunoproliferative Disorders
Neoplasms by Histologic Type
Disease
Immune System Diseases
Hematologic Diseases
Myelodysplastic Syndromes
Vascular Diseases
Fludarabine monophosphate
Antiviral Agents
Immunosuppressive Agents

ClinicalTrials.gov processed this record on November 27, 2009