Total-Body Irradiation (TBI) With Or Without Fludarabine Phosphate Followed By Donor Stem Cell Transplant in Treating Patients With Hematologic Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Brenda Sandmaier, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00075478
First received: January 9, 2004
Last updated: July 14, 2014
Last verified: July 2014
  Purpose

This randomized phase III trial is studying total-body irradiation (TBI) and fludarabine phosphate to see how it works compared with TBI alone followed by donor stem cell transplant in treating patients with hematologic cancer. Giving low doses of chemotherapy, such as fludarabine phosphate, 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 TBI followed by donor stem cell transplant is more effective with or without fludarabine phosphate in treating hematologic cancer.


Condition Intervention Phase
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
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)
Childhood Chronic Myelogenous Leukemia
Childhood Myelodysplastic Syndromes
Chronic Phase Chronic Myelogenous Leukemia
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Nodal Marginal Zone B-cell Lymphoma
Previously Treated Myelodysplastic Syndromes
Recurrent Adult Acute Lymphoblastic Leukemia
Recurrent Adult Acute Myeloid Leukemia
Recurrent Adult Burkitt Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Adult Diffuse Mixed Cell Lymphoma
Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
Recurrent Adult Hodgkin Lymphoma
Recurrent Adult Immunoblastic Large Cell Lymphoma
Recurrent Adult Lymphoblastic Lymphoma
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 Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Recurrent Small Lymphocytic Lymphoma
Recurrent/Refractory Childhood Hodgkin Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Multiple Myeloma
Relapsing Chronic Myelogenous Leukemia
Splenic Marginal Zone Lymphoma
Procedure: total-body irradiation
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Drug: cyclosporine
Procedure: peripheral blood stem cell transplantation
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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 Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Overall Survival [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]
    Percentage of patients surviving as estimated by Kaplan-Meier.


Secondary Outcome Measures:
  • Incidence of Non-relapse Mortality [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]
    Percentage of NRM as estimated by cumulative incidence methods with competing risks

  • Incidence of Relapse/Progression [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]
    Percentage of relapse estimated by cumulative incidence methods

  • Incidence of Relapse-related Mortality [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]
    Percentage of death following relapse/progression, estimated by cumulative incidence methods

  • Incidence of Grades II-IV Acute GVHD [ Time Frame: 120 days after transplant ] [ Designated as safety issue: No ]
    Percentage patients with grades II-IV GHVD, estimated by cumulative incidence methods

  • Incidence of Chronic Extensive GVHD [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]
    Percentage patients with chronic extensive GVHD, estimated by cumulative incidence methods

  • Incidence of Graft Rejection [ Time Frame: 1 year after transplant ] [ Designated as safety issue: No ]
    Donor CD3 chimerism less than 5%

  • Progression-free Survival [ Time Frame: 3 years after transplant ] [ Designated as safety issue: No ]
    Percentage of patients with progression-free survival, estimated by cumulative incidence methods


Enrollment: 87
Study Start Date: October 2003
Primary Completion Date: February 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (chemotherapy, TBI, transplant, GVHD prophylaxis)
Patients receive fludarabine phosphate IV on days -4 to -2. Patients then undergo low-dose TBI on day 0. After TBI, patients undergo PBSCT on day 0. Patients receive cyclosporine PO BID on days -3 to 56 in the absence of 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 MMF PO BID on days 0-28 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.
Procedure: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: cyclosporine
Given PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: peripheral blood stem cell transplantation
Undergo transplantation
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell
Active Comparator: Arm II (TBI, transplant, GVHD prophylaxis)
Patients undergo low-dose TBI on day 0. After TBI, patients undergo PBSCT on day 0. Patients receive cyclosporine PO BID on days -3 to 56 in the absence of 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 MMF PO BID on days 0-28 in the absence of GVHD. If treatment for GVHD is required before day 28, MMF is continued until a steroid taper begins.
Procedure: total-body irradiation
Undergo TBI
Other Name: TBI
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: cyclosporine
Given PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: peripheral blood stem cell transplantation
Undergo transplantation
Other Names:
  • PBPC transplantation
  • PBSC transplantation
  • peripheral blood progenitor cell transplantation
  • transplantation, peripheral blood stem cell

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare overall survival at 3 years after conditioning with 200 centigray (cGy) TBI alone vs. fludarabine (fludarabine phosphate)/200 cGy TBI in heavily pretreated patients with hematologic malignancies at low/moderate risk for graft rejection.

SECONDARY OBJECTIVES:

I. To compare the non-relapse mortality 1-year after conditioning in patients who received TBI alone vs. fludarabine/TBI.

II. To compare the incidences of graft rejection in patients who received TBI alone vs. fludarabine/TBI.

III. To compare the incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic extensive GVHD.

IV. To compare rates of disease progression and/or relapse-related mortality.

V. To compare the immune reconstitution and the risks of infections.

OUTLINE:

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2. Patients then undergo low-dose 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 cyclosporine orally (PO) twice daily (BID) on days -3 to 56 in the absence of 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 mycophenolate mofetil (MMF) PO BID on days 0-28 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 up periodically for 1.5 years and then annually for 5 years post-transplantation.

  Eligibility

Ages Eligible for Study:   up to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be not eligible for conventional allogeneic hematopoietic cell transplantation (HCT) and must have disease expected to be stable for at least 100 days without chemotherapy
  • An autograft immediately prior (less than 6 months) to nonmyeloablative HCT (tandem approach) is not permitted
  • Patients with hematologic malignancies treatable with HCT or with a B cell malignancy except those curable with autologous transplant will be included
  • Aggressive non-Hodgkin lymphomas (NHLs) and other histologies such as diffuse large B cell NHL: patients are eligible IF they are not eligible for autologous hematopoietic stem cell transplantation (HSCT), not eligible for conventional myeloablative HSCT, or have failed an autologous HSCT
  • Low grade NHL with < 6 month duration of complete remission (CR) between courses of conventional therapy
  • Mantle cell NHL; may be treated in first CR
  • Chronic lymphocytic leukemia (CLL) must have either:

    • Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine phosphate (FLU) (or another nucleoside analog, e.g. cladribine [2-CDA], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog)
    • Failed FLU-cyclophosphamide [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 1st CR
    • Or patients with a diagnosis of CLL (or small lymphocytic lymphoma) or diagnosis of CLL that progresses to prolymphocytic leukemia (PLL), or T-cell CLL or PLL
  • Hodgkin lymphoma (HL): must have received and failed frontline therapy; patients must have failed or were not eligible for autologous transplant
  • Multiple myeloma (MM): must have chemosensitive disease after failed autografting (an autografting immediately prior [within 6 months] to nonmyeloablative HCT [tandem approach] is not permitted)
  • Acute myeloid leukemia (AML): must have < 5% marrow blasts at the time of transplant and be beyond first CR
  • Acute lymphocytic leukemia (ALL): must have < 5% marrow blasts at the time of transplant and be beyond first CR
  • Chronic myelogenous leukemia (CML): patients will be accepted in chronic phase (CP) beyond CP1 if they have received previous myelosuppressive chemotherapy or HCT, < 5% marrow blasts at time of transplant
  • Myelodysplastic syndromes (MDS)/myeloproliferative disorders (MPD): must have received previous myelosuppressive chemotherapy or HCT, < 5% marrow blasts at time of transplant
  • Waldenstroms Macroglobulinemia: must have failed 2 courses of therapy
  • Patients will not be allowed to receive myelosuppressive chemotherapy for three weeks prior to conditioning
  • Patients < 12 years old must be approved by both the participating institutions' patient review committee such as the Patient Care Conference (PCC) at the Fred Hutchinson Cancer Research Center (FHCRC) and the FHCRC principal investigator
  • Patients who refused to be treated on a conventional HCT protocol; for this inclusion criterion, transplants must be approved by both the participating institution's patient review committee such as the Patient Care Conference (PCC) at the FHCRC and the FHCRC principal investigator
  • Patients with human leukocyte antigen (HLA)-matched related donors
  • DONOR: Related donor who is HLA genotypically identical at least at one haplotype and may be phenotypically or genotypically identical at the allele level at HLA-A, -B, -C, -DRB1, and -DQB1
  • DONOR: Donor must consent to filgrastim (G-CSF) administration and leukapheresis
  • DONOR: Donor must have adequate veins for leukapheresis or agree to placement of central venous catheter (femoral, subclavian)
  • DONOR: For females of child bearing age, serum pregnancy qualitative (PGSTAT) within 72 hours prior to initial dose of filgrastim (G-CSF); results must be available prior to filgrastim

Exclusion Criteria:

  • Eligible for a high priority curative autologous transplant
  • Patients with rapidly progressive, aggressive NHL unless in minimal disease state
  • Patients with chronic myelomonocytic leukemia
  • Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
  • Life expectancy severely limited by diseases other than malignancy
  • Any current central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
  • Fertile men or women unwilling to use contraceptives during and for up to 12 months post treatment
  • Female patients who are pregnant or breastfeeding
  • Human immunodeficiency virus (HIV) positive patients
  • Patients with active non-hematological malignancies (except localized non-melanoma skin malignancies)
  • Patients with a history of non-hematologic malignancies (except non-melanoma skin cancers) currently in a complete remission, who are less than 5 years from the time of complete remission, and have a > 20% risk of disease recurrence
  • Fungal infections with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month
  • Patients with active bacterial or fungal infections unresponsive to medical therapy
  • Karnofsky score < 50 for adult patients
  • Lansky-Play performance score < 50 for pediatric patients
  • The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine kinase inhibitors (imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or rituxan will not be allowed within three weeks of the initiation of conditioning
  • Patients with the following organ dysfunction:

    • Symptomatic coronary artery disease or ejection fraction < 35% or other cardiac failure requiring therapy (required for patients with history of cardiac disease or anthracycline use); ejection fraction is required if age > 50 years or there is a history of anthracycline exposure or history of cardiac disease
    • Poorly controlled hypertension on multiple antihypertensives
    • Pulmonary: diffusion capacity of carbon monoxide (DLCO) < 30%, total lung capacity (TLC) < 30%, forced expiratory volume in one second (FEV1) < 30% and/or receiving supplementary continuous oxygen; the FHCRC study principal investigator (PI) must approve enrollment of all patients with pulmonary nodules
    • Liver function abnormalities: patients with clinical or laboratory evidence of liver disease would be evaluated for the cause of liver disease, its clinical severity in terms of liver function, bridging fibrosis, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, and symptomatic biliary disease
  • DONOR: Age less than 12 years
  • DONOR: Identical twin
  • DONOR: Pregnancy
  • DONOR: Infection with HIV
  • DONOR: Known allergy to filgrastim
  • DONOR: Current serious systemic illness that would result in increased risk for filgrastim mobilization and harvest of PBSC
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00075478

Locations
United States, Oregon
OHSU Cancer Institute-Southern Region
Medford, Oregon, United States, 97504
United States, Utah
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, United States, 84112
LDS Hospital
Salt Lake City, Utah, United States, 84143
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
VA Puget Sound Health Care System
Seattle, Washington, United States, 98101
United States, Wisconsin
Froedtert and the Medical College of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Germany
Medizinische Univ Klinik Koln
Koln, Germany, 50924
Universitaet Leipzig
Leipzig, Germany, D-04103
University of Tuebingen-Germany
Tuebingen, Germany, D-72076
Italy
University of Torino
Torino, Italy, 10126
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Brenda Sandmaier Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

Publications:
Responsible Party: Brenda Sandmaier, Principal Investigator, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00075478     History of Changes
Other Study ID Numbers: 1813.00, NCI-2009-01532, 1813.00, P01CA078902, P30CA015704
Study First Received: January 9, 2004
Results First Received: April 16, 2014
Last Updated: July 14, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Burkitt Lymphoma
Hodgkin Disease
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Myeloid, Chronic-Phase
Lymphoma
Lymphoma, B-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Follicular
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Large-Cell, Immunoblastic
Lymphoma, Mantle-Cell
Lymphoma, Non-Hodgkin
Multiple Myeloma
Myelodysplastic Syndromes
Neoplasms, Plasma Cell
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Preleukemia
Syndrome
Blood Protein Disorders
Bone Marrow Diseases
Cardiovascular Diseases
Disease
DNA Virus Infections
Epstein-Barr Virus Infections
Hematologic Diseases

ClinicalTrials.gov processed this record on October 23, 2014