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Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant, Mycophenolate Mofetil, and Cyclosporine in Treating Patients With Fanconi Anemia

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Hans-Peter Kiem, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00453388
First received: March 27, 2007
Last updated: April 18, 2017
Last verified: April 2017
  Purpose
This phase II trial studies how well total-body irradiation (TBI) works when given together with fludarabine phosphate and cyclophosphamide followed by donor bone marrow transplant, mycophenolate mofetil, and cyclosporine in treating patients with Fanconi anemia (FA). Giving low doses of chemotherapy, such as fludarabine phosphate and cyclophosphamide, and TBI before or after a donor bone marrow transplant helps stop the growth of abnormal cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune 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 mycophenolate mofetil and cyclosporine after the transplant may stop this from happening.

Condition Intervention Phase
Acute Myeloid Leukemia in Remission
de Novo Myelodysplastic Syndrome
Fanconi Anemia
Previously Treated Myelodysplastic Syndrome
Procedure: Allogeneic Bone Marrow Transplantation
Drug: Cyclophosphamide
Drug: Cyclosporine
Drug: Fludarabine Phosphate
Other: Laboratory Biomarker Analysis
Drug: Mycophenolate Mofetil
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Radiation: Total-Body Irradiation
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Nonmyeloablative Hematopoietic Cell Transplantation for Patients With Fanconi Anemia Using Alternative Marrow Donors: A Phase II Dose-Finding Study

Resource links provided by NLM:


Further study details as provided by Hans-Peter Kiem, Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Number of Patients Who Engraft at Each Dose of TBI Used [ Time Frame: Up to Day 200 ]
    Number of subjects who engrafted. Engraftment defined as greater than 95% donor chimerism.

  • Incidence of Grades III-IV Acute GVHD [ Time Frame: Up to Day 100 ]

    Number of subjects who developed maximum grade acute graft-vs-host disease

    aGVHD Stages

    Skin:

    1. - a maculopapular eruption involving < 25% BSA
    2. - a maculopapular eruption involving 25 - 50% BSA
    3. - generalized erythroderma
    4. - generalized erythroderma with bullous formation and often with desquamation

    Liver:

    1. - bilirubin 2.0 - 3.0 mg/100 mL
    2. - bilirubin 3 - 5.9 mg/100 mL
    3. - bilirubin 6 - 14.9 mg/100 mL
    4. - bilirubin > 15 mg/100 mL

    Gut:

    Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients with visible bloody diarrhea are at least stage 2 gut and grade 3 overall.

    aGVHD Grades Grade III: Stage 2 - 4 gastrointestinal involvement and/or +2 to +4 liver involvement, with or without a rash Grade IV: Pattern and severity of GVHD similar to grade 3 with extreme constitutional symptoms or death



Secondary Outcome Measures:
  • Incidence of Transplant-related Mortality [ Time Frame: Up to Day 200 ]
    Number of subjects who expired due to transplant-related mortality

  • Incidence of Adverse Events [ Time Frame: Up to 6 years ]
    Number of subjects who developed reportable AEs, assessed using adapted version of the Common Toxicity Criteria


Enrollment: 6
Study Start Date: February 2007
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (2 vs 2.5 vs 3 Gy TBI dose-escalation)
Patients with a history of hematologic malignancy and HLA-haploidentical donor receive fludarabine phosphate (FLU) intravenously (IV) over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF orally (PO) thrice daily (TID) on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • Allo BMT
  • Allogeneic BMT
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Oforta
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant
Other Names:
  • Non-myeloablative allogeneic transplant
  • Nonmyeloablative Stem Cell Transplantation
  • NST
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation
Experimental: Arm II (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)
Patients with no history of hematological malignancy and HLA-haploidentical donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • Allo BMT
  • Allogeneic BMT
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Oforta
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant
Other Names:
  • Non-myeloablative allogeneic transplant
  • Nonmyeloablative Stem Cell Transplantation
  • NST
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation
Experimental: Arm III (2 vs 2.5 vs 3 Gy TBI dose-escalation)
Patients with history of hematologic malignancy and HLA-matched unrelated donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • Allo BMT
  • Allogeneic BMT
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Oforta
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant
Other Names:
  • Non-myeloablative allogeneic transplant
  • Nonmyeloablative Stem Cell Transplantation
  • NST
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation
Experimental: Arm IV (2 vs 2.5 vs 3 vs 1 vs 0 Gy TBI de-escalation)
Patients with no history of hematological malignancy and HLA-matched unrelated donors receive FLU IV over 1 hour on days -6 to -2, and undergo TBI on day -1 and allogeneic bone marrow transplant on day 0. Patients then receive CY IV over 1 hour on days 3 and 4, MMF PO TID on days 5-35, and CSP IV or PO on days 5-84, with taper until day 180, in the absence of GVHD.
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • Allo BMT
  • Allogeneic BMT
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-Cyclophosphamide
  • 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate
  • Carloxan
  • Ciclofosfamida
  • Ciclofosfamide
  • Cicloxal
  • Clafen
  • Claphene
  • CP monohydrate
  • CTX
  • CYCLO-cell
  • Cycloblastin
  • Cycloblastine
  • Cyclophospham
  • Cyclophosphamid monohydrate
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Cyclosporine
Given IV or PO
Other Names:
  • 27-400
  • Ciclosporin
  • CsA
  • Cyclosporin
  • Cyclosporin A
  • Neoral
  • OL 27-400
  • Sandimmun
  • Sandimmune
  • SangCya
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
  • Beneflur
  • Fludara
  • Oforta
  • SH T 586
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Mycophenolate Mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic stem cell transplant
Other Names:
  • Non-myeloablative allogeneic transplant
  • Nonmyeloablative Stem Cell Transplantation
  • NST
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TOTAL BODY IRRADIATION
  • Whole-Body Irradiation

Detailed Description:

PRIMARY OBJECTIVES:

I. Identify doses of total-body irradiation (TBI) that lead to sufficient probability of donor engraftment (> 5% donor cluster of differentiation [CD]3 chimerism) by day +200.

II. Evaluate the probability of severe acute graft-versus-host disease.

SECONDARY OBJECTIVES:

I. Evaluate the probabilities of overall survival, regimen-related toxicity (RRT), and recurrent hematopoietic malignancy in those patients with a prior underlying history of such.

II. 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.

III. Determine if the FA complementation group and % initial mosaicism predict engraftment and RRT outcomes.

OUTLINE: Patients are assigned to 1 of 4 treatment arms.

NOTE: Patients no longer receive pre-transplant cyclophosphamide as of February 2009.

After completion of study treatment, patients are followed up at 6 months and then annually thereafter.

  Eligibility

Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Any patient with FA and bone marrow (BM) failure involving 2 of the following 3 lineages: granulocyte count < 0.5 x 10^9/L, platelet count < 20 x 10^9/L, or hemoglobin < 8 g/dL
  • Any patient with FA who requires red blood cell or platelet transfusions because of marrow failure
  • Any patient with FA who has a life-threatening BM failure involving a single hematopoietic lineage
  • Any patient with FA and pre-existing cytogenetic abnormality including hematopoietic malignancy (acute myeloid leukemia [AML] or myelodysplastic syndrome [MDS]) in morphological remission (defined as absence of circulating blasts and bone marrow blasts < 5% as assessed by morphology); Note that hematopoietic recovery is not required for remission status
  • Patients must have a negative cytotoxic cross match with donor
  • DONOR: Related, human leukocyte antigen (HLA)-haploidentical donors must be identical for one HLA haplotype and mismatched for any number of HLA-A, -B, -C, DRB1 or DQB1 loci of the unshared haplotype
  • DONOR: Unrelated, HLA-matched donors must be matched at HLA-A, B, C, DRB1 and DQB1 by deoxyribonucleic acid (DNA) typing at the highest resolution routinely available at the time of donor selection; a single allele mismatch at HLA-A, B, or C is allowed OR a single DQB1 mismatch is allowed
  • DONOR: Bone marrow will be the only allowed hematopoietic stem cell source
  • DONOR: Haploidentical donor selection will be based on standard institutional criteria, otherwise no specific prioritization will be made amongst the suitable available donors

Exclusion Criteria:

  • Patients having available HLA-matched related donors
  • Significant organ dysfunction that would prevent compliance with conditioning, graft-versus-host disease (GVHD) prophylaxis, or would severely limit the probability of survival, such as liver disease/failure (active hepatitis, moderate to severe portal fibrosis/cirrhosis confirmed by biopsy or uncorrectable hepatic synthetic dysfunction), lung disease, or cardiac disease (ejection fraction < 35%, or if unable to obtain ejection fraction, shortening fraction of < 26%; if shortening is < 26% a cardiology consult is required with principal investigator [PI] having final approval of eligibility)
  • Human immunodeficiency virus (HIV) seropositive patients
  • Fertile females who are unwilling to use contraceptive techniques during and for the twelve months following treatment, as well as females who are pregnant or actively breast feeding
  • Fertile males who are unwilling to use contraceptive techniques during and for the twelve months following treatment
  • AML/MDS in morphological relapse, defined as having circulating blasts or bone marrow blasts >= 5% as assessed by morphology
  • Active infectious disease concerns
  • Karnofsky performance score < 50 or Lansky performance score < 40
  • DONOR: Donors found to have Fanconi anemia based on chromosomal breakage analysis
  • DONOR: Donors who are not expected to meet the minimum target dose of marrow cells (1 x 10^8 nucleated cells/kg recipient ideal body weight [IBW]) or who are unwilling to be bone marrow donors
  • DONOR: HIV-positive donors
  • DONOR: Donors who are cross-match positive with recipient
  • DONOR: Recipient homozygous at mismatched locus; if the recipient is homozygous at HLA-A, B, or C and the donor is mismatched at that locus, the donor should be avoided; exceptions must be discussed with the PI
  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: NCT00453388

Locations
United States, California
Children's Hospital and Research Center at Oakland
Oakland, California, United States, 94609-1809
United States, Tennessee
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
United States, Wisconsin
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53201
Brazil
Universidade Federal do Paraná
Curitiba, Paraná, Brazil, 80060-000
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Hans-Peter Kiem Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

Responsible Party: Hans-Peter Kiem, Principal Investigator, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00453388     History of Changes
Other Study ID Numbers: 2064.00
NCI-2010-00238 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2064.00 ( Other Identifier: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium )
P30CA015704 ( US NIH Grant/Contract Award Number )
Study First Received: March 27, 2007
Results First Received: April 10, 2017
Last Updated: April 18, 2017

Additional relevant MeSH terms:
Syndrome
Leukemia, Myeloid, Acute
Anemia
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myeloid
Fanconi Anemia
Fanconi Syndrome
Disease
Pathologic Processes
Leukemia
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
Metabolism, Inborn Errors
Fludarabine
Fludarabine phosphate
Cyclophosphamide
Mycophenolic Acid
Cyclosporins

ClinicalTrials.gov processed this record on May 25, 2017