Overview

This trial is active, not recruiting.

Conditions 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
Treatments total-body irradiation, fludarabine phosphate, mycophenolate mofetil, cyclosporine, peripheral blood stem cell transplantation
Phase phase 3
Sponsor Fred Hutchinson Cancer Research Center
Collaborator National Heart, Lung, and Blood Institute (NHLBI)
Start date October 2003
End date February 2014
Trial size 87 participants
Trial identifier NCT00075478, 1813.00, NCI-2009-01532, P01CA078902, P30CA015704

Summary

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
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.
total-body irradiation TBI
Undergo TBI
fludarabine phosphate 2-F-ara-AMP
Given IV
mycophenolate mofetil Cellcept
Given PO
cyclosporine ciclosporin
Given PO
peripheral blood stem cell transplantation PBPC transplantation
Undergo transplantation
(Active Comparator)
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.
total-body irradiation TBI
Undergo TBI
mycophenolate mofetil Cellcept
Given PO
cyclosporine ciclosporin
Given PO
peripheral blood stem cell transplantation PBPC transplantation
Undergo transplantation

Primary Outcomes

Measure
Overall Survival
time frame: At 3 years after transplant

Secondary Outcomes

Measure
Non-relapse Mortality
time frame: At 1 year after transplant
Relapse/Progression
time frame: Up to 5 years
Relapse-related Mortality
time frame: Up to 5 years
Incidence of Grades II-IV Acute GVHD
time frame: 3/18/14
Incidence of Chronic Extensive GVHD
time frame: 3/18/2014
Graft Rejection
time frame: Day 84

Eligibility Criteria

Male or female participants up to 75 years old.

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

Additional Information

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
Principal investigator Brenda Sandmaier
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.
Trial information was received from ClinicalTrials.gov and was last updated in April 2014.
Information provided to ClinicalTrials.gov by Fred Hutchinson Cancer Research Center.