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:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00453388
First received: March 27, 2007
Last updated: August 27, 2014
Last verified: August 2014
  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
Adult Acute Myeloid Leukemia in Remission
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 Acute Myeloid Leukemia in Remission
Childhood Myelodysplastic Syndromes
de Novo Myelodysplastic Syndromes
Fanconi Anemia
Previously Treated Myelodysplastic Syndromes
Drug: fludarabine phosphate
Drug: cyclophosphamide
Radiation: total-body irradiation
Procedure: allogeneic bone marrow transplantation
Drug: mycophenolate mofetil
Drug: cyclosporine
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Other: laboratory biomarker analysis
Phase 2

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

Primary Outcome Measures:
  • Doses of TBI associated with acceptable levels of engraftment without excess GVHD [ Time Frame: By day 200 ] [ Designated as safety issue: No ]
  • Grades III-IV acute GVHD [ Time Frame: Up to day 100 ] [ Designated as safety issue: No ]
  • Transplant-related mortality [ Time Frame: By day 200 ] [ Designated as safety issue: No ]
  • Incidence of adverse events assessed using adapted version of the Common Toxicity Criteria [ Time Frame: Up to 6 years ] [ Designated as safety issue: Yes ]

Enrollment: 1
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) trice 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.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: cyclosporine
Given IV or PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic stem cell transplant
Other: laboratory biomarker analysis
Correlative studies
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.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: cyclosporine
Given IV or PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic stem cell transplant
Other: laboratory biomarker analysis
Correlative studies
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.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: cyclosporine
Given IV or PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic stem cell transplant
Other: laboratory biomarker analysis
Correlative studies
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.
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Radiation: total-body irradiation
Undergo TBI
Other Name: TBI
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplant
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: cyclosporine
Given IV or PO
Other Names:
  • ciclosporin
  • cyclosporin
  • cyclosporin A
  • CYSP
  • Sandimmune
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic stem cell transplant
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Identify doses of 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 (GVHD).

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

Genders Eligible for Study:   Both
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, 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-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
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Hans-Peter Kiem Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT00453388     History of Changes
Other Study ID Numbers: 2064.00, NCI-2010-00238, 2064.00, P30CA015704
Study First Received: March 27, 2007
Last Updated: August 27, 2014
Health Authority: United States: Institutional Review Board

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

ClinicalTrials.gov processed this record on October 22, 2014