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

NCT00358657 | Terminated Phase 2 Results DMC

• 6 other identifiers: 2032.00NCI-2010-001922032P01HL122173P30CA015704RG9213024
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 3

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.

Conditions

Immunodeficiency Syndrome; Severe Aplastic Anemia; Genetic Disorder

Outcome Measures

Primary Outcomes (2)

• Graft Rejection

  Number of patients with graft rejection (CD3 donor chimerisms \<5%).

  Day 84

• Graft Failure

  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 Outcomes (7)

• Proportion of Patients Who Achieve Greater Than 5% Donor T-cell Chimerism

  By day 84

• Number of Patients With Transplant Related Mortality

  Day 100 post transplant

• Incidence of Grade I/II Acute Graft Versus Host Disease (GVHD)

  Day 100 post transplant

• Incidence of Grade III/IV Acute Graft Versus Host Disease (GVHD)

  Day 100 post transplant

• Incidence of Chronic GVHD

  1 year post transplant

Study Arms (1)

Treatment (chemo, total-body irradiation, transplant)

EXPERIMENTAL

See Detailed Description

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

Interventions

Allogeneic Bone Marrow Transplantation PROCEDURE

Undergo allogeneic bone marrow transplantation

Also known as: Allo BMT, Allogeneic BMT

Treatment (chemo, total-body irradiation, transplant)

Cyclophosphamide DRUG

Given IV

Also known as: (-)-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

Treatment (chemo, total-body irradiation, transplant)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Treatment (chemo, total-body irradiation, transplant)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (chemo, total-body irradiation, transplant)

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

Treatment (chemo, total-body irradiation, transplant)

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo allogeneic bone marrow transplantation

Also known as: Non-myeloablative allogeneic transplant, Nonmyeloablative Stem Cell Transplantation, NST

Treatment (chemo, total-body irradiation, transplant)

Sirolimus DRUG

Given PO

Also known as: AY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217

Treatment (chemo, total-body irradiation, transplant)

Tacrolimus DRUG

Given IV or PO

Also known as: FK 506, Fujimycin, Hecoria, Prograf, Protopic

Treatment (chemo, total-body irradiation, transplant)

Total-Body Irradiation RADIATION

Undergo total-body irradiation

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

Treatment (chemo, total-body irradiation, transplant)

Eligibility Criteria

• Age: Up to 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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: \< 6 months old and \> 75 years old

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (3)

The Children's Hospital at TriStar Centennial

Nashville, Tennessee, 37203, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

MeSH Terms

Conditions

Immunologic Deficiency Syndromes; Anemia, Aplastic; Genetic Diseases, Inborn

Interventions

Cyclophosphamide; fludarabine phosphate; Mycophenolic Acid; Sirolimus; Tacrolimus; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Immune System Diseases; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Failure Disorders; Bone Marrow Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Macrolides; Lactones; Radiotherapy; Therapeutics; Investigative Techniques

Results Point of Contact

• Title: Dr. Kanwaldeep Mallhi
• Organization: Fred Hutchinson Cancer Research Center

kmallhi@fredhutch.org

206-667-2014

Study Officials

• Kanwaldeep Mallhi

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Clinical Research Division, Fred Hutch

Study Record Dates

• First Submitted: July 28, 2006
• First Posted: August 1, 2006
• Study Start: May 24, 2006
• Primary Completion: August 17, 2018
• Study Completion: May 25, 2019
• Last Updated: January 26, 2021
• Results First Posted: January 26, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)