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HLA-Haploidentical Related Marrow Grafts for the Treatment of Primary Immunodeficiencies and Other Nonmalignant Disorders Using Conditioning With Low-Dose Cyclophosphamide, 200 cGy TBI and Fludarabine; Postgrafting Immunosuppression Will Consist of a Single Low Dose of Cyclophosphamide, MMF and Tacrolimus.


Phase 2
N/A
54 Years
Open (Enrolling)
Both
Nonneoplastic Condition

Thank you

Trial Information

HLA-Haploidentical Related Marrow Grafts for the Treatment of Primary Immunodeficiencies and Other Nonmalignant Disorders Using Conditioning With Low-Dose Cyclophosphamide, 200 cGy TBI and Fludarabine; Postgrafting Immunosuppression Will Consist of a Single Low Dose of Cyclophosphamide, MMF and Tacrolimus.


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 oral mycophenolate mofetil 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
oral tacrolimus (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.


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

- For any patient who has aplastic anemia with marrow failure involving two of the
three following criteria: Granulocytes < 500/uL; a corrected reticulocyte count of <
1%; platelet count of < 20,000/uL

- 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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety as assessed by the probability of transplant-related mortality exceeding 25% or of grades III-IV acute GVHD exceeding 25%

Outcome Description:

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.

Outcome Time Frame:

By day 100

Safety Issue:

Yes

Principal Investigator

Lauri Burroughs

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Federal Government

Study ID:

2032.00

NCT ID:

NCT00358657

Start Date:

May 2006

Completion Date:

Related Keywords:

  • Nonneoplastic Condition
  • Immunologic Deficiency Syndromes

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109