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Fludarabine-based Conditioning for Severe Aplastic Anemia (BMT CTN 0301)

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: NCT00326417
Recruitment Status : Completed
First Posted : May 16, 2006
Results First Posted : October 4, 2016
Last Update Posted : October 27, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
The purpose of the current study is to continue to optimize conditioning regimens in high-risk patients with severe aplastic anemia transplanted with marrow from HLA-compatible unrelated donors. Specifically, the study will determine whether the addition of fludarabine to the conditioning regimen previously described by Deeg et al. will permit a reduction in the CY dose, to a point where sustained hematopoietic engraftment and survival are maintained (or improved), while the frequency of major regimen-related toxicity (RRT) and early deaths is reduced.

Condition or disease Intervention/treatment Phase
Anemia, Aplastic Drug: Fludarabine Drug: Cyclophosphamide 150mg Drug: Cyclophosphamide 100mg Drug: Cyclophosphamide 50mg Phase 1 Phase 2

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Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 97 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Fludarabine-based Conditioning for Allogeneic Marrow Transplantation From HLA-compatible Unrelated Donors in Severe Aplastic Anemia (BMT CTN #0301)
Study Start Date : January 2006
Primary Completion Date : September 2015
Study Completion Date : January 2016

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Cyclophosphamide 150mg
Fludarabine plus 150 mg/kg Cyclophosphamide (total dose)
Drug: Fludarabine
Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)
Other Name: Fludara
Drug: Cyclophosphamide 150mg
A total dose of 150 mg/kg will be given as 50 mg/kg per day for 3 days (Days -4, -3, -2)
Other Name: Cytoxan®
Experimental: Cyclophosphamide 100mg
Fludarabine plus 100 mg/kg Cyclophosphamide (total dose)
Drug: Fludarabine
Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)
Other Name: Fludara
Drug: Cyclophosphamide 100mg
A total dose of 100 mg/kg will be given as 50 mg/kg per day for 2 days (Days -3, -2)
Other Name: Cytoxan®
Experimental: Cyclophosphamide 50mg
Fludarabine plus 50 mg/kg Cyclophosphamide (total dose)
Drug: Fludarabine
Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)
Other Name: Fludara
Drug: Cyclophosphamide 50mg
A total dose of 50 mg/kg will be given once at 50 mg/kg per day on Day -2
Other Name: Cytoxan®
Experimental: Fludarabine
Fludarabine only (no Cyclophosphamide administered)
Drug: Fludarabine
Doses of 30 mg/m^2 IV will be given for no less than 30 minutes daily for 4 days (Days -5 to -2)
Other Name: Fludara

Outcome Measures

Primary Outcome Measures :
  1. Disease-free Survival (DFS) [ Time Frame: Day 100 ]
    DFS includes graft failure, regimen-related toxicity (RRT), and early death. Graft Failure is defined by lack of neutrophil engraftment (ANC less than 0.5 x 10^9/L for 3 consecutive days on different days). Major RRT is defined as severity of grade 4 in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal or hepatic. Early death is defined as death prior to Day 100 post-transplant.

Secondary Outcome Measures :
  1. Cumulative Incidence of Graft Failure [ Time Frame: Day 365 ]
    Primary and secondary graft failure are included, secondary graft failure is defined by initial neutrophil engraftment followed by subsequent decline in the ANC to less than 0.5 x 10^9/L for three consecutive measurements on different days, unresponsive to growth factor.

  2. Acute Graft vs Host Disease (GVHD) [ Time Frame: Day 100 ]
    All GVHD grades 2-4 will be graded according to the BMT CTN Manual of Procedures (MOP)

  3. Chronic GVHD [ Time Frame: Day 365 ]
    Chronic GVHD is scored according to the BMT CTN MOP. The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.

  4. Overall Survival (OS) [ Time Frame: Day 365 ]
    OS is defined as alive at 1 year, the event is death from any cause. Patients alive at the time of last observation, for statistical purposes, will have a survival time which is censored.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 65 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients up to 65 years of age at time of registration with a diagnosis of SAA; SAA is defined as follows:

    1. Bone marrow cellularity less than 25% or marrow cellularity less than 50% but with less than 30% residual hematopoietic cells
    2. Two out of three of the following (in peripheral blood): neutrophils less than 0.5 x 10^9/L; platelets less than 20 x 10^9/L; reticulocytes less than 20 x 10^9/L
  • Patient must have an available unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1 antigen; typing is by DNA techniques: intermediate resolution for A, B, and C, and high resolution for DRB1; HLA-DQ typing is recommended but will not count in the match
  • Patient and/or legal guardian able to provide signed informed consent
  • Matched unrelated donor must consent to provide a marrow allograft
  • Patients with adequate organ function as measured by:

    1. Cardiac: left ventricular ejection fraction at rest must be greater than 40% or shortening fraction greater than 20%
    2. Hepatic: serum bilirubin less than 2x upper limit of normal for age as per local laboratory) (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome), alanine transaminase (ALT) and aspartate transaminase (AST) less than 4x upper limit of normal for age (as per local laboratory)
    3. Renal: serum creatinine less than 2x upper limit of normal for age (as per local laboratory)
    4. Pulmonary: Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) (corrected for Hb) greater than 50% predicted; for patients in which pulse oxymetry is performed, O2 saturation greater than 92%
  • Diagnosis of Fanconi anemia must be excluded in patients younger than 18 years of age by diepoxybutane testing on peripheral blood or comparable testing on marrow.

Exclusion Criteria:

  • Clonal cytogenetic abnormalities associated with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) on marrow examination
  • Diagnosis of other "congenital" aplastic anemias such as: Diamond-Blackfan; Shwachman-Diamond; congenital amegakaryocytosis
  • Symptomatic or uncontrolled cardiac failure or coronary artery disease
  • Karnofsky performance status less than 60% or Lansky less than 40% for patients younger than 16 years old
  • Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms)
  • Seropositive for the human immunodeficiency virus (HIV)
  • Pregnant (positive total HCG) or breastfeeding
  • Presence of large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for GVHD prophylaxis
  • Known severe or life-threatening allergy or intolerance to ATG or cyclosporine/ tacrolimus
  • Planned administration of alemtuzumab (Campath-1H) or other investigational agents as alternative agent for GVHD prophylaxis
  • Concomitant enrollment in a Phase I study
  • Positive patient anti-donor lymphocyte crossmatch in HLA-A or B mismatched transplants; the definition of match is in Section 2.2.1; the crossmatch would only apply to mismatches at HLA-A or B, not DRB1 or HLA-C
  • Prior allogeneic marrow or stem cell transplantation
  • Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in-situ; cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair; cancer treated with curative intent more than 5 years previously will be allowed
Contacts and Locations

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): NCT00326417

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United States, Arizona
Phoenix Children's Hospital
Phoenix, Arizona, United States, 85016
United States, California
City of Hope National Medical Center
Duarte, California, United States, 91010
Children's Hospital Los Angeles
Los Angeles, California, United States, 90027
Mattel Children's Hospital at UCLA
Los Angeles, California, United States, 90095
Stanford Hospital and Clinics
Stanford, California, United States, 94305
United States, Florida
H. Lee Moffitt Cancer Center
Tampa, Florida, United States, 33624
United States, Georgia
Children's Healthcare of Atlanta
Atlanta, Georgia, United States, 30322
BMT Program at Northside Hospital
Atlanta, Georgia, United States, 30342
United States, Massachusetts
DFCI/Brigham & Women's Hospital
Boston, Massachusetts, United States, 02114
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10021
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Oregon
Oregon Health & Science University
Portland, Oregon, United States, 97239-3098
United States, Texas
Cook Children's Medical Center
Fort Worth, Texas, United States, 76104
University of Texas, MD Anderson CRC
Houston, Texas, United States, 77030
Texas Transplant Institute
San Antonio, Texas, United States, 78229
United States, Virginia
Virginia Commonwealth University, MCV Hospital
Richmond, Virginia, United States, 23298
United States, Washington
Fred Hutchinson Cancer Research Center
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
National Marrow Donor Program
Study Director: Mary Horowitz, MD Center for International Blood and Marrow Transplant Research
More Information

Additional Information:

Responsible Party: Medical College of Wisconsin
ClinicalTrials.gov Identifier: NCT00326417     History of Changes
Obsolete Identifiers: NCT00335608
Other Study ID Numbers: BMTCTN0301
U01HL069294 ( U.S. NIH Grant/Contract )
5U01HL069294-05 ( U.S. NIH Grant/Contract )
5U24CA076518 ( U.S. NIH Grant/Contract )
First Posted: May 16, 2006    Key Record Dates
Results First Posted: October 4, 2016
Last Update Posted: October 27, 2017
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Findings will be published in a manuscript.
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: Within 6 months of official study closure at participating sites.
Access Criteria: Available to the public.
URL: https://biolincc.nhlbi.nih.gov/home/

Keywords provided by Medical College of Wisconsin:
Severe Aplastic Anemia

Additional relevant MeSH terms:
Anemia, Aplastic
Hematologic Diseases
Bone Marrow Diseases
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antiviral Agents
Anti-Infective Agents