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Donor Stem Cell Transplant in Treating Patients With Fanconi's Anemia - NCT00453388-98109B(Clinical Trial 166759)



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City:  Seattle
State:  
WA
Zip Code: 98109
Conditions: Fanconi Anemia - Graft Versus Host Disease - Leukemia - Myelodysplastic Syndromes
Purpose: RATIONALE: Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide, mycophenolate mofetil, and tacrolimus after transplant may stop this from happening. PURPOSE: This phase I/II trial is studying the side effects and best dose of total-body irradiation and cyclophosphamide and to see how well they work in treating patients with Fanconi's anemia undergoing donor stem cell transplant.
Study summary: OBJECTIVES: Primary - Determine the doses of total-body irradiation and cyclophosphamide that lead to sufficient probability of donor engraftment (> 5% donor CD3 chimerism) by day 200 in patients with Fanconi anemia undergoing allogeneic hematopoietic stem cell transplantation. - Determine the probability of severe acute graft-versus-host disease in patients treated with this regimen. Secondary - Determine the overall survival, regimen-related toxicity, and recurrent hematopoietic malignancy in these patients. - Evaluate cyclophosphamide, fludarabine phosphate, and mycophenolate mofetil metabolism in these patients. - Examine the degree to which mixed chimerism provides for amelioration of symptoms (i.e., infections due to neutropenia, hemorrhage due to thrombocytopenia) associated with bone marrow failure in these patients. - Determine if the Fanconi anemia complementation group and percent initial mosaicism predict engraftment and toxicity outcomes in patients treated with this regimen. OUTLINE: This is a prospective, multicenter, dose-finding study of total-body irradiation (TBI) and cyclophosphamide. Patients are stratified according to diagnosis of hematologic malignancy (yes vs no). - Conditioning regimen: Patients with a hematologic malignancy are treated in group I while those without hematologic malignancy are treated in group II. - Group I: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide* IV over 1 hour on days -6 and -5. Patients also undergo TBI on day -1. Cohorts of 5 patients receive escalating doses of TBI and cyclophosphamide* until at least 2 of 5 patients achieve engraftment. - Group II: Patients receive fludarabine phosphate as in group I and cyclophosphamide* IV over 1 hour on days -6 to -4. Patients also undergo TBI on day -1. Cohorts of 5 patients receive escalating doses of cyclophosphamide* until at least 2 of 5 patients experience engraftment. NOTE: *Patients will no longer receive cyclophosphamide as of 4/9/2009) - Transplantation: In both groups, patients undergo allogeneic bone marrow transplantation (aBMT) on day 0. Patients receive filgrastim (G-CSF) IV or subcutaneously beginning on day 5 and continuing until blood counts recover. - Post-transplant immunosuppression and graft-vs-host disease (GVHD) prophylaxis: In both groups, patients receive cyclophosphamide IV over 1 hour on days 3-4, oral mycophenolate mofetil on days 5-35, and tacrolimus IV over 2-24 hours (or orally) on days 5-180 (taper starts at day 84). Patients with mixed chimerism and persistent life-threatening disease may undergo a second aBMT. After completion of study therapy, patients are followed periodically for up to 5 years. PROJECTED ACCRUAL: A total of 36 patients will be accrued for this study.
Criteria: DISEASE CHARACTERISTICS: - Diagnosis of Fanconi anemia confirmed by chromosomal fragility using diepoxybutane or mitomycin C - Patients must meet 1 of the following criteria: - Bone marrow failure, defined by any 2 of the following 3 criteria: - Granulocyte count < 500/mm³ - Platelet count < 20,000/mm³ - Hemoglobin < 8 g/dL - Red blood cell or platelet transfusion requirement as a result of marrow failure - Pre-existing cytogenetic abnormality, including hematopoietic malignancy (acute myeloid leukemia [AML] or myelodysplastic syndromes [MDS]) in remission - Remission defined as absence of circulating blasts and bone marrow blasts < 5% as assessed by morphology - Hematopoietic recovery is not required for remission status - No AML or MDS in relapse - Life-threatening bone marrow failure involving a single hematopoietic lineage - No HLA-matched related or unrelated donor available - Related, HLA-haploidentical donors meeting the following criteria: - Identical for 1 HLA-haplotype and mismatched for any number of HLA-A, -B, -C, DRB1, or DQB1 loci of the unshared haplotype - Bone marrow only hematopoietic stem cell source - No Fanconi anemia based on chromosomal breakage analysis - Not cross-match positive with recipient PATIENT CHARACTERISTICS: - Karnofsky performance status (PS) 50-100% OR Lansky PS 40-100% - No significant organ dysfunction that would prevent compliance with study therapy or severely limit the probability of survival including, but not limited to, any of the following: - Liver disease or failure (active hepatitis, moderate to severe portal fibrosis/cirrhosis confirmed by biopsy, or uncorrectable hepatic synthetic dysfunction) - Cardiac disease (ejection fraction < 35%) - Lung disease - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 12 months after completion of study treatment - No HIV positivity - No active infectious disease PRIOR CONCURRENT THERAPY: - Not specified
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Data Source: ClinicalTrials.gov
Date Processed: September 22, 2010
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