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

NCT ID: NCT00358657

Last Updated: 2021-01-26

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-05-24
• Study Completion Date: 2019-05-25

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.

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.

Conditions

Immunodeficiency Syndrome; Severe Aplastic Anemia; Genetic Disorder

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (chemo, total-body irradiation, transplant)

See Detailed Description

Group Type: EXPERIMENTAL

Allogeneic Bone Marrow Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic bone marrow transplantation

Cyclophosphamide

Intervention Type: DRUG

Given IV

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Mycophenolate Mofetil

Intervention Type: DRUG

Given PO

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo allogeneic bone marrow transplantation

Sirolimus

Intervention Type: DRUG

Given PO

Tacrolimus

Intervention Type: DRUG

Given IV or PO

Total-Body Irradiation

Intervention Type: RADIATION

Undergo total-body irradiation

Interventions

Allogeneic Bone Marrow Transplantation

Undergo allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

Cyclophosphamide

Given IV

Intervention Type: DRUG

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Mycophenolate Mofetil

Given PO

Intervention Type: DRUG

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Undergo allogeneic bone marrow transplantation

Intervention Type: PROCEDURE

Sirolimus

Given PO

Intervention Type: DRUG

Tacrolimus

Given IV or PO

Intervention Type: DRUG

Total-Body Irradiation

Undergo total-body irradiation

Intervention Type: RADIATION

Other Intervention Names

Allo BMT; Allogeneic BMT; (-)-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; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; Cellcept; MMF; Non-myeloablative allogeneic transplant; Nonmyeloablative Stem Cell Transplantation; NST; AY 22989; RAPA; Rapamune; Rapamycin; SILA 9268A; WY-090217; FK 506; Fujimycin; Hecoria; Prograf; Protopic; TOTAL BODY IRRADIATION; Whole-Body Irradiation

Eligibility 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 [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

• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Kanwaldeep K Mallhi

Assistant Professor, Clinical Research Division, Fred Hutch

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kanwaldeep Mallhi

Role: PRINCIPAL_INVESTIGATOR

Fred Hutch/University of Washington Cancer Consortium

Locations

The Children's Hospital at TriStar Centennial

Nashville, Tennessee, United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2010-00192

Identifier Type: REGISTRY

Identifier Source: secondary_id

2032

Identifier Type: -

Identifier Source: secondary_id

2032.00

Identifier Type: OTHER

Identifier Source: secondary_id

P01HL122173

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

RG9213024

Identifier Type: OTHER

Identifier Source: secondary_id

2032.00

Identifier Type: -

Identifier Source: org_study_id