Stem Cell Transplant for Inborn Errors of Metabolism

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00176904
First received: September 12, 2005
Last updated: November 6, 2012
Last verified: November 2012
  Purpose

The purpose of this study is to determine the safety and engraftment of donor hematopoietic cells using this conditioning regimen in patients undergoing a hematopoietic (blood forming) cell transplant for an inherited metabolic storage disease.


Condition Intervention Phase
Adrenoleukodystrophy
Metachromatic Leukodystrophy
Globoid Cell Leukodystrophy
Gaucher's Disease
Fucosidosis
Wolman Disease
Niemann-Pick Disease
Batten Disease
GM1 Gangliosidosis
Tay Sachs Disease
Sandhoff Disease
Procedure: Stem Cell Transplant
Drug: Busulfan, Cyclophosphamide, Antithymocyte Globulin
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Treatment of Lysosomal and Peroxisomal Inborn Errors of Metabolism by Bone Marrow Transplantation

Resource links provided by NLM:

Genetics Home Reference related topics: alpha-methylacyl-CoA racemase deficiency CASK-related intellectual disability Chanarin-Dorfman syndrome CHMP2B-related frontotemporal dementia cholesteryl ester storage disease congenital neuronal ceroid lipofuscinosis D-bifunctional protein deficiency frontotemporal dementia with parkinsonism-17 fucosidosis Gaucher disease GM1 gangliosidosis GRN-related frontotemporal dementia inclusion body myopathy with early-onset Paget disease and frontotemporal dementia infantile neuronal ceroid lipofuscinosis juvenile Batten disease Krabbe disease Kufs disease Langerhans cell histiocytosis late-infantile neuronal ceroid lipofuscinosis leukoencephalopathy with vanishing white matter MECP2 duplication syndrome megalencephalic leukoencephalopathy with subcortical cysts metachromatic leukodystrophy Niemann-Pick disease peroxisomal acyl-CoA oxidase deficiency PPM-X syndrome Renpenning syndrome Sandhoff disease Schindler disease succinic semialdehyde dehydrogenase deficiency Tay-Sachs disease Wolman disease X-linked adrenoleukodystrophy Zellweger spectrum
Genetic and Rare Diseases Information Center resources: Gaucher Disease Neuronal Ceroid Lipofuscinoses Batten Disease Frontotemporal Dementia Frontotemporal Dementia, Ubiquitin-positive Pick's Disease Primary Progressive Aphasia Semantic Dementia Tay-Sachs Disease Sandhoff Disease Spielmeyer-Vogt Disease Cholesteryl Ester Storage Disease Lysosomal Acid Lipase Deficiency Wolman Disease Niemann-Pick Disease Leukodystrophy Metachromatic Leukodystrophy Krabbe Leukodystrophy Adrenomyeloneuropathy Adrenoleukodystrophy X-linked Fucosidosis GM1 Gangliosidosis Beta-galactosidase-1 Deficiency Niemann-Pick Disease Type C1 Adult Neuronal Ceroid Lipofuscinosis Ceroid Storage Disease Sphingolipidosis Hypoadrenalism Hand-Schuller-Christian Disease Langerhans Cell Histiocytosis
U.S. FDA Resources

Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Overall Survival [ Time Frame: 100 Days, 1 Year and 3 Years ] [ Designated as safety issue: No ]
    Number of patients alive at designated timepoints after transplant.


Secondary Outcome Measures:
  • Overall Donor Engraftment [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    Number of patients with full donor chimerism (state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease) by Day 100 post-transplant of at least 90%.

  • Number of Patients With Grade II-IV Acute Graft-Versus-Host Disease [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening.

  • Number of Patients With Grade III-IV Acute Graft-Versus-Host Disease [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening.

  • Number of Patients With Chronic Graft-Versus-Host Disease [ Time Frame: 1 Year Post Transplant ] [ Designated as safety issue: Yes ]
    Number of patients who exhibited chronic graft-versus-host disease by 1 Year post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Chronic GVHD is an extension of this syndrome.


Enrollment: 135
Study Start Date: January 1995
Study Completion Date: June 2010
Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treated Patients
All patients treated with protocol regimen (chemotherapy and surgery).
Procedure: Stem Cell Transplant
The purpose of hematopoietic cell transplantation is to introduce hematopoietic cells from a normal donor that contains an enzyme able to get rid of the substances that have accumulated in the body of patients with storage diseases. Hematopoietic cells can come from bone marrow, peripheral blood (i.e., the blood circulating in our body's blood vessels) or umbilical cord blood (i.e., blood taken from the umbilical cord after a baby is born and umbilical cord is cut).
Other Name: Bone marrow transplant
Drug: Busulfan, Cyclophosphamide, Antithymocyte Globulin
Subjects will receive BUSULFAN intravenously (IV)- patients < or= 12 kg 1.1 mg/kd/dose IV every 6 hours for 16 doses; patients > 12kg 0.8 mg/kg/dose IV every 6 hours for 16 doses - via the Hickman line four times daily for 4 days, CYCLOPHOSPHAMIDE intravenously (50 mg/kg/day IV over 2 hours) via the Hickman line once a day for 4 days, and ANTI-THYMOCYTE GLOBULIN IV (15 mg/kg/day over 2 hours) via the Hickman line twice daily for three days before the transplant. These three drugs are being given to help the new marrow "take" and grow. METHYLPREDNISOLONE will be given as a pre-medication for the ATG.
Other Name: Busulfex, Cytoxan, ATG

Detailed Description:

Prior to transplantation, subjects will receive Busulfan intravenously (IV) via the Hickman line four times daily for 4 days, Cyclophosphamide intravenously via the Hickman line once a day for 4 days, and Anti-Thymocyte Globulin (ATG) intravenously (IV) via the Hickman line twice daily for three days before the transplant. These three drugs are being given to subjects to help the new marrow "take" and grow.

On the day of transplantation, the donor's hematopoietic cells will be transfused via central venous catheter.

After hematopoietic cell transplant, subjects will then receive two drugs, cyclosporin and either methylprednisolone or Mycophenolate Mofetil (MMF). Cyclosporin and methylprednisolone or MMF are given to help prevent the complication of graft-versus-host disease and to decrease the chance that the new donor cells will be rejected.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy, Gaucher's disease, Fucosidosis, Wolman disease, Niemann-Pick disease and Batten disease (CLN3) who have a human leukocyte antigen (HLA)-identical or haplotype mismatched (at 1-3 antigens) related marrow, or umbilical cord blood donor. One or two umbilical cord blood (UCB) units may be used.
  • Patients with GM1 gangliosidosis, Tay Sachs disease or Sandhoff disease who have a HLA-identical or 1 antigen mismatched related or unrelated donor, or suitably matched umbilical cord blood unit(s). One or two UCB units may be used.
  • Patients with adrenoleukodystrophy must have magnetic resonance imaging (MRI) findings, neurological and neuropsychometric function consistent with the diagnosis, and for boys with parietal-occipital dysmyelination a performance intelligence quotient (IQ) ≥80. In cases, when the performance IQ is not ≥80, the protocol committee may recommend transplant if the patient's clinical condition and neuropsychometric status are deemed to be acceptable based upon consideration of such factors as age at onset of cerebral disease, magnitude of change in performance IQ and neurologic deficits.
  • Patients with arylsulfatase A deficiency (Metachromatic Leukodystrophy) must have either the presymptomatic late infantile, juvenile or adult form of the disease and must have acceptable neurological and neuropsychometric function.
  • Patients with galactocerebrosidase deficiency (Globoid Cell Leukodystrophy) must have acceptable neurological and neuropsychometric function.
  • Patients with acid lipase deficiency (Wolman disease) must have a liver biopsy that documents no evidence of hepatic cirrhosis, and acceptable neurological and neuropsychometric function.
  • Patients with fucosidase deficiency (Fucosidosis) must have acceptable neurological and neuropsychometric function.
  • Patients with glucocerebrosidase deficiency (Gaucher's Disease) must have acceptable neurologic and neuropsychometric function.
  • Patients with Batten's disease (CLN3) must have acceptable Neurological and neuropsychometric function.
  • Absence of major organ dysfunction. Organ evaluation results as follows:
  • Cardiac: ejection fraction >30%
  • Renal: serum creatinine <2x normal or creatinine clearance 60 mL/min.
  • Hepatic: total bilirubin <2x normal and Aspartate aminotransferase (AST) <2x normal
  • Signed consent.

Exclusion Criteria:

  • Patients with symptomatic late infantile form of metachromatic leukodystrophy.
  • Patients with symptomatic infantile globoid leukodystrophy.
  • Note: Patients with Hurler syndrome, mucopolysaccharidosis (MPS) VI, or Mannosidosis disease are no longer eligible for this protocol, but can be transplanted under protocol MT 9907 (NCT00176917 - Hematopoietic Cell Transplantation for Hurler Syndrome, Maroteaux Lamy Syndrome (MPS VI), and Alpha Mannosidase Deficiency (Mannosidosis)).
  • Pregnancy
  • Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology
  • Patients or parents are psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance.
  • Patients ≥ 50 kg may be at risk for having cell doses below the goal of ≥ 10 x 10^6 CD34 cells/kg and therefore will not be eligible to receive unrelated peripheral blood stem cells (PBSCs)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00176904

Locations
United States, Minnesota
Masonic Cancer Center, University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Paul Orchard, MD Masonic Cancer Center, University of Minnesota
  More Information

No publications provided by Masonic Cancer Center, University of Minnesota

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00176904     History of Changes
Obsolete Identifiers: NCT00005894
Other Study ID Numbers: MT1995-01
Study First Received: September 12, 2005
Results First Received: May 17, 2011
Last Updated: November 6, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by Masonic Cancer Center, University of Minnesota:
Inborn errors
Storage disease
errors of metabolism
stem cell transplant

Additional relevant MeSH terms:
Tay-Sachs Disease
Gaucher Disease
Metabolism, Inborn Errors
Leukodystrophy, Metachromatic
Aphasia, Primary Progressive
Pick Disease of the Brain
Frontotemporal Dementia
Adrenoleukodystrophy
Niemann-Pick Diseases
Niemann-Pick Disease, Type A
Niemann-Pick Disease, Type C
Gangliosidoses
Wolman Disease
Neuronal Ceroid-Lipofuscinoses
Leukodystrophy, Globoid Cell
Sandhoff Disease
Fucosidosis
Gangliosidosis, GM1
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases

ClinicalTrials.gov processed this record on September 18, 2014