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Fludarabine Phosphate, Cyclophosphamide, and Total-Body Irradiation Followed by Donor Bone Marrow Transplant and Cyclophosphamide, Mycophenolate Mofetil, Tacrolimus, and Sirolimus in Treating Patients With Primary Immunodeficiency Disorders or Noncancerous Inherited Disorders

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. Identifier: NCT00358657
Recruitment Status : Active, not recruiting
First Posted : August 1, 2006
Last Update Posted : January 31, 2020
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center

Brief Summary:
This phase I/II trial studies the side effects of fludarabine phosphate, cyclophosphamide and total-body irradiation followed by donor bone marrow transplant and cyclophosphamide, mycophenolate mofetil, tacrolimus, and sirolimus in treating patients with primary immunodeficiency disorders or noncancerous inherited disorders. Giving low doses of chemotherapy and total-body irradiation before a bone marrow transplant helps prepare the patient's body to accept the incoming donor's bone marrow and decrease the risk that the patient's immune system will reject 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 called graft versus host disease. Giving cyclophosphamide, mycophenolate mofetil, tacrolimus, and sirolimus after the transplant may help decrease this from happening.

Condition or disease Intervention/treatment Phase
Immunodeficiency Syndrome Non-Cancer Diagnosis Severe Aplastic Anemia Donor Procedure: Allogeneic Bone Marrow Transplantation Drug: Cyclophosphamide Drug: Fludarabine Phosphate Other: Laboratory Biomarker Analysis Drug: Mycophenolate Mofetil Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation Drug: Sirolimus Drug: Tacrolimus Radiation: Total-Body Irradiation Phase 2

Detailed Description:


I. Determine safety of nonmyeloablative conditioning and hematopoietic cell transplantation (HCT) from human leukocyte antigen (HLA)-haploidentical related donors for patients with nonmalignant inherited disorders who do not have an HLA-matched related or unrelated donor.


I. Determine whether nonmyeloablative conditioning and HCT from an HLA-haploidentical related donor graft can establish mixed chimerism (> 5% cluster of differentiation [CD]3+ donor T-cell chimerism) in patients with nonmalignant inherited disorders.

II. Transplant related mortality at day 100.

III. Incidence and severity of graft-versus-host disease (GHVD).

IV. Immune reconstitution.

V. Infections during the first 200 days after HCT.


NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 1 hour on days -6 to -2; cyclophosphamide IV over 1 hour on days -6 and -5; and undergo total body irradiation on day -1.

TRANSPLANTATION: Patients undergo allogeneic bone marrow transplant on day 0.

POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on days 3 and 4, and mycophenolate mofetil orally (PO) every 8 hours on days 5-30 then twice daily (BID) to day 40, and then if there is no evidence of active GVHD and donor engraftment is > 95% (or by principal investigator [PI] approval) taper until approximately day 96, or faster at discretion of PI. Patients also receive tacrolimus IV continuously over 22-24 hours starting on day 5 post-transplant and continue on tacrolimus through day 100 followed by a taper to approximately day 180 if there is no evidence of GVHD and their graft is doing well. Patients may convert to oral tacrolimus given BID or three times daily (TID) when the patient is able to take medications orally and has a therapeutic drug level. In addition, patients will receive sirolimus PO beginning on day 5 through day 180 followed by a taper to approximately day 210 if there is no evidence of GVHD and their graft is doing well.

After completion of study treatment, patients are followed up at 6, 12, 18, and 24 months, and then annually for 5 years.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: HLA-Haploidentical Related Marrow Grafts for the Treatment of Primary Immunodeficiencies and Other Nonmalignant Disorders Using Conditioning With Low-Dose Cyclophosphamide, TBI and Fludarabine and Postgrafting Cyclophosphamide
Actual Study Start Date : May 24, 2006
Estimated Primary Completion Date : December 1, 2023
Estimated Study Completion Date : December 1, 2023

Arm Intervention/treatment
Experimental: Treatment (chemo, total-body irradiation, transplant)
See Detailed Description
Procedure: Allogeneic Bone Marrow Transplantation
Undergo allogeneic bone marrow transplantation
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: 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
  • 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 bone marrow transplantation
Other Names:
  • Non-myeloablative allogeneic transplant
  • Nonmyeloablative Stem Cell Transplantation
  • NST

Drug: Sirolimus
Given PO
Other Names:
  • AY 22989
  • RAPA
  • Rapamune
  • Rapamycin
  • SILA 9268A
  • WY-090217

Drug: Tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Fujimycin
  • Hecoria
  • Prograf
  • Protopic

Radiation: Total-Body Irradiation
Undergo total-body irradiation
Other Names:
  • Whole-Body Irradiation

Primary Outcome Measures :
  1. Graft rejection/failure rate [ Time Frame: Day 84 ]
  2. Transplant related mortality [ Time Frame: Day 100 ]
  3. Incidence of grade III/IV acute graft versus host disease (GVHD) preceding diagnosis of chronic GVHD [ Time Frame: By day 100 ]
    This will be deemed to occur if the lower level of a one-sided 80% confidence interval for either proportion exceeds 25% and will be evaluated after 5 patients have been followed. Adverse events will be assessed using an adapted version of the Common Toxicity Criteria.

Secondary Outcome Measures :
  1. Proportion of patients who achieve greater than 5% donor T-cell chimerism [ Time Frame: By day 84 ]

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Primary immunodeficiency disorder or other nonmalignant inherited disease (except Fanconi anemia) treatable by allogeneic HCT
  • Patients with pre-existing medical conditions or other factors that renders them at high risk for regimen related toxicity or ineligible for conventional myeloablative HCT and who do not have HLA-matched related or unrelated donors
  • Patients with a related donor who is identical for one HLA haplotype
  • Acquired aplastic anemia: severe aplastic anemia (SAA) is defined as follows:

    • Bone marrow cellularity < 25%, or marrow cellularity < 50% but with < 30% residual hematopoietic cells
    • Two out of three of the following (in peripheral blood): neutrophils < 0.5 x 10^9/L; platelets < 20 x 10^9/L; reticulocytes < 20 x 10^9/L
    • SAA diagnostic criteria may be applied to assessment at initial diagnosis or follow-up assessments
  • DONOR: Related donors who are identical for one HLA haplotype
  • DONOR: Bone marrow will be the only allowed stem cell source

Exclusion Criteria:

  • Fanconi anemia
  • Suitably HLA-matched related or unrelated donors
  • Patients with metabolic storage diseases who have severe central nervous system (CNS) involvement of disease, defined as intelligence quotient (IQ) score < 70
  • Cardiac ejection fraction < 30% (or, if unable to obtain ejection fraction, shortening fraction < 26%) on multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (echo), symptomatic coronary artery disease, or other cardiac failure requiring therapy; patients with a history of, or current cardiac disease should be evaluated with appropriate cardiac studies and/or cardiology consult; patients with a shortening fraction of < 26% must be seen by cardiology for approval
  • Poorly controlled hypertension despite anti-hypertensive medications
  • Patients with clinical or laboratory evidence of liver disease will need to be evaluated for the cause of the liver disease, its clinical severity in terms of liver function and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dl, or symptomatic biliary disease
  • Positive for human immunodeficiency virus (HIV)
  • Females who are pregnant (beta-human chorionic gonadotropin positive [beta-HCG+]) or breast-feeding
  • Fertile men or women who are unwilling to use contraceptives during HCT and up to 12 months post-treatment
  • Patients with fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month will not be eligible for this protocol (either regimen A or B)
  • DONOR: Donor-recipient pairs in which the HLA-mismatch is only in the host-versus-graft (HVG) direction; patients are homozygous and donor is heterozygous
  • 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)
  • DONOR: HIV-positive donors
  • DONOR: A positive anti-donor cytotoxic cross match is absolute donor exclusion
  • DONOR: < 6 months old and > 75 years old

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 identifier (NCT number): NCT00358657

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United States, Tennessee
The Children's Hospital at TriStar Centennial
Nashville, Tennessee, United States, 37203
Vanderbilt University/Ingram Cancer Center
Nashville, Tennessee, United States, 37232
United States, Washington
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Cancer Institute (NCI)
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Kanwaldeep Mallhi Fred Hutch/University of Washington Cancer Consortium
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Responsible Party: Fred Hutchinson Cancer Research Center Identifier: NCT00358657    
Other Study ID Numbers: 2032.00
NCI-2010-00192 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2032.00 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P01HL122173 ( U.S. NIH Grant/Contract )
P30CA015704 ( U.S. NIH Grant/Contract )
First Posted: August 1, 2006    Key Record Dates
Last Update Posted: January 31, 2020
Last Verified: January 2020
Additional relevant MeSH terms:
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Anemia, Aplastic
Immunologic Deficiency Syndromes
Immune System Diseases
Hematologic Diseases
Bone Marrow Diseases
Mycophenolic Acid
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
Calcineurin Inhibitors
Enzyme Inhibitors
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents