- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00358657
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
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 Overview
Status
Intervention / Treatment
- Other: Laboratory Biomarker Analysis
- Drug: Cyclophosphamide
- Drug: Mycophenolate Mofetil
- Drug: Fludarabine Phosphate
- Drug: Tacrolimus
- Drug: Sirolimus
- Radiation: Total-Body Irradiation
- Procedure: Allogeneic Bone Marrow Transplantation
- Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Detailed Description
PRIMARY OBJECTIVE:
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) 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Tennessee
-
Nashville, Tennessee, United States, 37232
- Vanderbilt University/Ingram Cancer Center
-
Nashville, Tennessee, United States, 37203
- The Children's Hospital at TriStar Centennial
-
-
Washington
-
Seattle, Washington, United States, 98109
- Fred Hutch/University of Washington Cancer Consortium
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (chemo, total-body irradiation, transplant)
See Detailed Description
|
Correlative studies
Given IV
Other Names:
Given PO
Other Names:
Given IV
Other Names:
Given IV or PO
Other Names:
Given PO
Other Names:
Undergo total-body irradiation
Other Names:
Undergo allogeneic bone marrow transplantation
Other Names:
Undergo allogeneic bone marrow transplantation
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Graft Rejection
Time Frame: Day 84
|
Number of patients with graft rejection (CD3 donor chimerisms <5%).
|
Day 84
|
Graft Failure
Time Frame: Day 84
|
Number of patients with graft failure (grade IV thrombocytopenia and neutropenia after day 21 that lasts > 2 weeks andn is refractory to growth factor support).
|
Day 84
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Proportion of Patients Who Achieve Greater Than 5% Donor T-cell Chimerism
Time Frame: By day 84
|
Number of patients who achieve greater than 5% donor T-cell (CD3+) chimerisms
|
By day 84
|
Number of Patients With Transplant Related Mortality
Time Frame: Day 100 post transplant
|
The number of patients with transplant related mortality
|
Day 100 post transplant
|
Incidence of Grade I/II Acute Graft Versus Host Disease (GVHD)
Time Frame: Day 100 post transplant
|
Number of patients diagnosed with overall GI/G2 acute GVHD by Day 100
|
Day 100 post transplant
|
Incidence of Grade III/IV Acute Graft Versus Host Disease (GVHD)
Time Frame: Day 100 post transplant
|
Number of patients diagnosed with overall GIII/IV acute GVHD by Day 100
|
Day 100 post transplant
|
Incidence of Chronic GVHD
Time Frame: 1 year post transplant
|
Number of patients diagnosed with chronic GVHD by 1 year post transplant
|
1 year post transplant
|
Immune Reconstitution
Time Frame: 1 year post transplant
|
Number of patients with normal range CD3 @ 1 year post transplant
|
1 year post transplant
|
Number of Patients With Infections
Time Frame: Through day 200 after HCT
|
Number of patients with clinically significant infections requiring treatment within 200 days after HCT
|
Through day 200 after HCT
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Kanwaldeep Mallhi, Fred Hutch/University of Washington Cancer Consortium
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Immune System Diseases
- Bone Marrow Diseases
- Hematologic Diseases
- Anemia
- Bone Marrow Failure Disorders
- Disease
- Immunologic Deficiency Syndromes
- Primary Immunodeficiency Diseases
- Anemia, Aplastic
- Genetic Diseases, Inborn
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Enzyme Inhibitors
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Antitubercular Agents
- Antibiotics, Antitubercular
- Calcineurin Inhibitors
- Cyclophosphamide
- Fludarabine
- Fludarabine phosphate
- Tacrolimus
- Mycophenolic Acid
- Sirolimus
Other Study ID Numbers
- 2032.00 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)
- P30CA015704 (U.S. NIH Grant/Contract)
- NCI-2010-00192 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- 2032
- P01HL122173 (U.S. NIH Grant/Contract)
- RG9213024 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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