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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

Information source: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Aplastic Anemia; Non-Cancer Diagnosis

Intervention: Allogeneic Bone Marrow Transplantation (Procedure); Cyclophosphamide (Drug); Fludarabine Phosphate (Drug); Laboratory Biomarker Analysis (Other); Mycophenolate Mofetil (Drug); Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation (Procedure); Sirolimus (Drug); Tacrolimus (Drug); Total-Body Irradiation (Radiation)

Phase: Phase 2

Status: Recruiting

Sponsored by: Fred Hutchinson Cancer Research Center

Official(s) and/or principal investigator(s):
Lauri Burroughs, Principal Investigator, Affiliation: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

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.

Clinical Details

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

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

Primary outcome:

Graft rejection/failure rate

Incidence of grade III/IV acute GVHD preceding diagnosis of chronic GVHD

Transplant related mortality

Secondary outcome: Proportion of patients who achieve greater than 5% donor T-cell chimerism

Detailed description: PRIMARY OBJECTIVES: 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. SECONDARY OBJECTIVES: 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. OUTLINE: 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) until day 150 with taper until approximately day 180. Patients also receive tacrolimus IV continuously over 22-24 hours or orally starting on day 5 post-transplant and will 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. In addition, patients will receive sirolimus orally 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 thereafter for 5 years.

Eligibility

Minimum age: N/A. Maximum age: 54 Years. Gender(s): Both.

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

- 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 [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

Locations and Contacts

Vanderbilt University/Ingram Cancer Center, Nashville, Tennessee 37232, United States; Active, not recruiting

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium, Seattle, Washington 98109, United States; Recruiting
Lauri M. Burroughs, Phone: 206-667-2396, Email: lburroug@fhcrc.org
Lauri M. Burroughs, Principal Investigator

Additional Information

Starting date: May 2006
Last updated: August 5, 2015

Page last updated: August 20, 2015

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