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Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00258427
Recruitment Status : Completed
First Posted : November 24, 2005
Results First Posted : December 2, 2021
Last Update Posted : December 2, 2021
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Study Description
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Brief Summary:

RATIONALE: A bone marrow or umbilical cord blood transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Giving combination chemotherapy before a donor stem cell transplant may make the transplant more likely to work. This may be an effective treatment for patients with high risk Fanconi's anemia.

PURPOSE: This clinical trial is studying how well combination chemotherapy works in treating high risk patients who are undergoing a donor stem cell transplant for Fanconi's anemia.


Condition or disease Intervention/treatment Phase
Fanconi Anemia Biological: anti-thymocyte globulin Biological: filgrastim Drug: busulfan Drug: cyclophosphamide Drug: fludarabine phosphate Drug: methylprednisolone Biological: Hematopoietic stem cell transplantation Phase 2

Detailed Description:

OBJECTIVES:

Primary

  • Determine whether the incidence of neutrophil engraftment is acceptable in high-risk patients with Fanconi's anemia treated with busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin followed by allogeneic hematopoietic stem cell transplantation.

Secondary

  • Determine the tolerability of mycophenolate mofetil in these patients.
  • Determine the incidence of acute and chronic graft-vs-host disease in patients treated with this regimen.
  • Determine the incidence of major infections in patients with a history of major infections treated with this regimen.
  • Determine the incidence of relapse in patients with refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia treated with this regimen
  • Determine the probability of 1-year survival of patients treated with this regimen.

OUTLINE: Patients are stratified according to donor/recipient HLA type (identical vs other).

  • Cytoreductive combination chemotherapy: Patients receive busulfan intravenously (IV) over 2 hours twice daily on days -7 and -6 and cyclophosphamide IV over 2 hours and fludarabine IV over 30 minutes once daily on days -5 to -2.
  • Graft failure prophylaxis: Patients receive methylprednisolone IV twice daily on days -5 to 30 and anti-thymocyte globulin IV over 4-6 hours twice daily on days -5 to -1.
  • Graft-vs-host disease prophylaxis: Patients receive cyclosporine IV over 2 hours twice daily on days -3 to 100 (if patient has a matched sibling donor) or days -3 to 180 (if patient has another donor type). Patients also receive mycophenolate mofetil orally or IV twice daily on days -3 to 45.
  • Allogeneic hematopoietic stem cell transplantation (HSCT): Patients undergo allogeneic HSCT (using bone marrow or umbilical cord blood) on day 0. Patients receive filgrastim (G-CSF) subcutaneously beginning on day 1 and continuing until blood counts recover.

After completion of study treatment, patients are followed periodically for 3 years.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hematopoietic Stem Cell Transplantation in High Risk Patients With Fanconi Anemia MT2002-02
Actual Study Start Date : March 26, 2002
Actual Primary Completion Date : October 10, 2020
Actual Study Completion Date : October 10, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anemia

Arms and Interventions
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Arm Intervention/treatment
Experimental: Marrow Isolex
Bone marrow processed using Isolex300i
 Biological: anti-thymocyte globulin
Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.
Other Name: ATG

Biological: filgrastim
given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L)
Other Name: G-CSF

Drug: busulfan
Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old)
Other Name: Busulfex

Drug: cyclophosphamide
10 mg/kg intravenously (IV) on Days -5 through -2.
Other Name: Cytoxan

Drug: fludarabine phosphate
35 mg/m^2 intravenously (IV) on Days -5 through -2.
Other Name: Fludara

Drug: methylprednisolone
1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.
Other Name: Medrol

Biological: Hematopoietic stem cell transplantation
Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.
Other Name: HSCT
Experimental: USB arm
No processing
 Biological: anti-thymocyte globulin
Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.
Other Name: ATG

Biological: filgrastim
given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L)
Other Name: G-CSF

Drug: busulfan
Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old)
Other Name: Busulfex

Drug: cyclophosphamide
10 mg/kg intravenously (IV) on Days -5 through -2.
Other Name: Cytoxan

Drug: fludarabine phosphate
35 mg/m^2 intravenously (IV) on Days -5 through -2.
Other Name: Fludara

Drug: methylprednisolone
1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.
Other Name: Medrol

Biological: Hematopoietic stem cell transplantation
Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.
Other Name: HSCT
Experimental: Marrow Clinimacs
Bone marrow processed using CliniMACS system
 Biological: anti-thymocyte globulin
Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.
Other Name: ATG

Biological: filgrastim
given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L)
Other Name: G-CSF

Drug: busulfan
Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old)
Other Name: Busulfex

Drug: cyclophosphamide
10 mg/kg intravenously (IV) on Days -5 through -2.
Other Name: Cytoxan

Drug: fludarabine phosphate
35 mg/m^2 intravenously (IV) on Days -5 through -2.
Other Name: Fludara

Drug: methylprednisolone
1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.
Other Name: Medrol

Biological: Hematopoietic stem cell transplantation
Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.
Other Name: HSCT
Experimental: Sibling without CliniMacs
Sibling donor without the use of CliniMACS system
 Biological: anti-thymocyte globulin
Given 15 mg/kg/day intravenously every 12 hours on Days -5 through -1.
Other Name: ATG

Biological: filgrastim
given 5 mcg/kg/day intravenously on Day 1 (continue until absolute neutrophil count (ANC) ≥2.5 x 10^9/L)
Other Name: G-CSF

Drug: busulfan
Busulfan 0.8 mg/kg intravenously (IV) every 12 hours on Days -7 and -6 (1.0 mg/kg IV if <4 years old)
Other Name: Busulfex

Drug: cyclophosphamide
10 mg/kg intravenously (IV) on Days -5 through -2.
Other Name: Cytoxan

Drug: fludarabine phosphate
35 mg/m^2 intravenously (IV) on Days -5 through -2.
Other Name: Fludara

Drug: methylprednisolone
1 mg/kg intravenously (IV) every 12 hours on Days -5 through -1.
Other Name: Medrol

Biological: Hematopoietic stem cell transplantation
Infused on Day 0 - Donor bone marrow or umbilical cord blood will be collected in the usual sterile manner using established parameters determined by the National Marrow Donor Program.
Other Name: HSCT


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants Experiencing Graft Failure [ Time Frame: Day 30 ]
    Graft failure is defined as absolute neutrophil count( ANC ) <5 x 10^8/L by day 30.


Secondary Outcome Measures :
  1. Number of Participants Experiencing Chronic Graft-Versus-Host Disease [ Time Frame: Day 42 ]
    Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host.

  2. Number of Participants Experiencing Chronic Graft-Versus-Host Disease [ Time Frame: 1 year ]
    Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cellsinto a foreign host.

  3. Number of Participants Experiencing Acute Graft-Versus-Host Disease [ Time Frame: 1 year ]
    Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

  4. Number of Participants Experiencing Acute Graft-Versus-Host Disease [ Time Frame: Day 42 ]
    Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

  5. Number of Participants Experiencing Relapse [ Time Frame: 1 Year ]
    Patients with leukemia will have this done by BM biopsy and additional special studies such as cytogenetics or flow cytometry as appropriate.

  6. Number of Participants Experiencing Overall Survival [ Time Frame: 1 Year ]
    Overall Survival - Number of patients alive at 1 year post transplant

  7. Number of Participants Experiencing Major Infections [ Time Frame: Day 1 through 1 year post-transplant ]
    Number of participants experiencing Major Infections by the end of treatment


Eligibility Criteria
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Ages Eligible for Study:   up to 44 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must be <45 years of age with a diagnosis of Fanconi anemia with:

    • Biallelic BRCA2 mutations, or
    • Aplastic anemia, or advanced myelodysplastic syndrome (MDS) (MDS with ≥5% blasts), or acute leukemia who are ineligible for total body irradiation. Aplastic anemia is defined as having at least one of the following (with or without cytogenetic abnormalities): platelet count <20 * 10^9, - absolute neutrophil count (ANC) <5 * 10^8/L, - Hgb <8 g/dL
  • Patients must have an HLA-A, B, DRB1 identical or 1 antigen mismatched related or unrelated BM donor or have an HLA-A, B, DRB1 identical, 1 antigen or 2 antigen mismatched related or unrelated umbilical cord blood (UCB) donor. Patients and donors will be typed for HLA-A and B using serological level typing and for DRB1 using high resolution molecular typing.

  • Adequate major organ function including:

    • Cardiac: ejection fraction >45%
    • Hepatic: no clinical evidence of hepatic failure (e.g. coagulopathy, ascites, no cirrhosis)
    • Karnofsky performance status >70% or Lansky >50%
  • Women of child bearing potential must be using adequate birth control and have a negative pregnancy test.

Exclusion Criteria:

  • Active CNS leukemia at time of HSCT.
  • Active uncontrolled infection within one week of hematopoietic stem cell transplant (HSCT).
  • Pregnant or lactating female.

Donor Inclusion Criteria:

  • Donor must be in good health based on review of systems and results of physical examination.
  • Donor must have a normal hemoglobin, white count, platelet count and partial thromboplastin time (PTT), and a negative diepoxybutane (DEB) test.
  • HIV-NAT negative, HTLV-1, HTLV-2 negative, Hepatitis B and C negative.
  • Female donors of childbearing potential must have a negative pregnancy test.
  • Unrelated donors must agree to peripheral blood stem cell (PBSC) donation

Donor Exclusion Criteria:

  • Donor is a lactating female.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00258427


Locations
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United States, Minnesota
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
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Principal Investigator: Margaret MacMillan, MD Masonic Cancer Center, University of Minnesota
  Study Documents (Full-Text)

Documents provided by Masonic Cancer Center, University of Minnesota:
Study Protocol and Statistical Analysis Plan  [PDF] September 4, 2019

More Information
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Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00258427    
Other Study ID Numbers: 2002LS014
MT2002-02 ( Other Identifier: Blood and Marrow Transplantation Program )
0202M18741 ( Other Identifier: IRB, University of Minnesota )
First Posted: November 24, 2005    Key Record Dates
Results First Posted: December 2, 2021
Last Update Posted: December 2, 2021
Last Verified: November 2021
Keywords provided by Masonic Cancer Center, University of Minnesota:
Fanconi anemia
Additional relevant MeSH terms:
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Fanconi Syndrome
Anemia
Fanconi Anemia
Hematologic Diseases
Anemia, Hypoplastic, Congenital
Anemia, Aplastic
Congenital Bone Marrow Failure Syndromes
Bone Marrow Failure Disorders
Bone Marrow Diseases
Genetic Diseases, Inborn
DNA Repair-Deficiency Disorders
Metabolic Diseases
Renal Tubular Transport, Inborn Errors
Kidney Diseases
Urologic Diseases
 Methylprednisolone
Cyclophosphamide
Busulfan
Fludarabine
Fludarabine phosphate
Antilymphocyte Serum
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists