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

This study is currently recruiting participants.
Verified November 2013 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT00358657
First received: July 28, 2006
Last updated: November 18, 2013
Last verified: November 2013
  Purpose

This phase I/II trial studies the side effects of fludarabine phosphate, cyclophosphamide and total-body irradiation followed by donor bone marrow transplant, cyclophosphamide, mycophenolate mofetil, and tacrolimus in treating patients with immunodeficiency or noncancerous inherited disorders. Giving low doses of chemotherapy and total-body irradiation before a donor bone marrow transplant helps stop the growth of abnormal cells. It also helps stop the patient's immune system from rejecting 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. Giving cyclophosphamide, mycophenolate mofetil, and tacrolimus after transplant may stop this from happening.


Condition Intervention Phase
Nonneoplastic Condition
Drug: cyclophosphamide
Radiation: total-body irradiation
Drug: fludarabine phosphate
Drug: mycophenolate mofetil
Drug: tacrolimus
Procedure: allogeneic bone marrow transplantation
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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; Postgrafting Immunosuppression Will Consist of a Single Low Dose of Cyclophosphamide, MMF and Tacrolimus

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Safety as assessed by the probability of transplant-related mortality exceeding 25% or of grades III-IV acute GVHD exceeding 25% [ Time Frame: By day 100 ] [ Designated as safety issue: Yes ]
    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:
  • Proportion of patients who achieve greater than 5% donor T-cell chimerism [ Time Frame: By day 84 ] [ Designated as safety issue: No ]
    Although not definitive, for the endpoint of mixed chimerism given the small number of patients, we shall consider this study a success if the observed rate of successful establishment of mixed chimerism (> 5% donor T-cell chimerism) is 80% or greater (8/10). If the true rate is 90%, then the probability that 16 or more patients among 20 will develop mixed chimerism is approximately 93%. If the true rate is 70%, 60%, or 50% then this probability is 38%, 17%, or 5%, respectively.


Estimated Enrollment: 10
Study Start Date: May 2006
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (chemo, total-body irradiation, transplant)

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine 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 transplantation on day 0.

POST-TRANSPLANT IMMUNOSUPPRESSION: Patients receive cyclophosphamide IV over 1 hour on days 3 and 4, and mycophenolate mofetil PO every 8 hours on days 5-35. Patients also receive tacrolimus IV continuously over 22-24 hours or over 1-2 hours on days 5-180, followed by tacrolimus PO (when tolerated), with taper on day 84.

Drug: cyclophosphamide
Given IV
Other Names:
  • CPM
  • CTX
  • Cytoxan
  • Endoxan
  • Endoxana
Radiation: total-body irradiation
Undergo total-body irradiation
Other Name: TBI
Drug: fludarabine phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • Fludara
Drug: mycophenolate mofetil
Given PO
Other Names:
  • Cellcept
  • MMF
Drug: tacrolimus
Given IV or PO
Other Names:
  • FK 506
  • Prograf
Procedure: allogeneic bone marrow transplantation
Undergo allogeneic bone marrow transplantation
Other Names:
  • bone marrow therapy, allogeneic
  • bone marrow therapy, allogenic
  • transplantation, allogeneic bone marrow
  • transplantation, allogenic bone marrow
Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic bone marrow transplantation
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To 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.

SECONDARY OBJECTIVES:

I. To 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. To determine the transplant related mortality at day 100.

III. To determine the incidence and severity of graft-versus-host disease (GHVD).

IV. To assess immune reconstitution.

V. To evaluate the infections during the first 200 days after HCT.

OUTLINE:

NONMYELOABLATIVE CONDITIONING REGIMEN: Patients receive fludarabine 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 transplantation 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 5-35. Patients also receive tacrolimus IV continuously over 22-24 hours or over 1-2 hours on days 5-180, followed by tacrolimus PO (when tolerated), with taper on day 84.

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

  Eligibility

Ages Eligible for Study:   up to 54 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 (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 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 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
  • Seropositive for human immunodeficiency virus (HIV)
  • Females who are pregnant (beta- human chorionic gonadotropin [B-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
  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00358657

Locations
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Lauri M. Burroughs    206-667-2396      
Principal Investigator: Lauri M. Burroughs         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Lauri Burroughs 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: NCT00358657     History of Changes
Other Study ID Numbers: 2032.00, NCI-2010-00192, 2032, 6297, 2032.00, P30CA015704
Study First Received: July 28, 2006
Last Updated: November 18, 2013
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Immune System Diseases
Cyclophosphamide
Mycophenolate mofetil
Fludarabine monophosphate
Tacrolimus
Fludarabine
Mycophenolic Acid
Vidarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Enzyme Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on April 17, 2014