HSCT for High Risk Inherited Inborn Errors

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00383448
First received: September 29, 2006
Last updated: July 8, 2014
Last verified: July 2014
  Purpose

Hematopoietic stem cell transplantation has proven effective therapy for individuals with adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD, or Krabbe disease). This protocol also considers other inherited metabolic diseases such as, but not limited to, GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome or Sandhoff disease, I-cell disease (mucolipidosis II).

For patients with advanced or rapidly progressive disease, the morbidity and mortality with transplantation is unacceptably high. Unfortunately, there are no viable alternative therapeutic options for these patients; if transplantation is not performed the patients are sent home to die. Our group at Minnesota has developed a new protocol incorporating transplantation using a reduced intensity conditioning regimen designed to decrease toxicity associated with the transplant procedure. This regimen will make use of the drug clofarabine, which has lympholytic and immune suppressive properties without the neurologic toxicity observed in the related compound, fludarabine, commonly used for transplantation. In addition, several agents providing anti-oxidant and anti-inflammatory properties will be used to assist in the stabilization of the disease processes. This revised transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol, 2) the mortality associated with transplant by day 100, 3) patient outcomes, based on differential neurologic, neuropsychologic, imaging and biologic evaluations prior to transplantation and at designated points after transplantation (day 100, 6 months, 1, 2 and 5 years). Additional biologic studies will include pharmacokinetics of clofarabine and mycophenolate mofetil (MMF). In addition, for patients undergoing lumbar puncture studies, cerebrospinal fluid (CSF) will be requested for determinations of biologic parameters.


Condition Intervention Phase
Adrenoleukodystrophy
Metachromatic Leukodystrophy
Globoid Cell Leukodystrophy
Tay Sachs Disease
Sandhoffs Disease
Wolman Disease
I-Cell Disease
Sanfilippo Syndrome
GM1 Gangliosidosis
Drug: Clofarabine
Procedure: Total body Irradiation
Drug: Melphalan
Biological: Hematopoietic Stem Cell Transplantation
Drug: Alemtuzumab
Drug: mycophenylate mofetil
Device: Cyclosporine A
Drug: Hydroxyurea
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Treatment of High Risk, Inherited Lysosomal And Peroxisomal Disorders by Reduced Intensity Hematopoietic Stem Cell Transplantation

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Donor Cell Engraftment [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    The process of transplanted stem cells reproducing new cells.


Secondary Outcome Measures:
  • Transplant Related Mortality [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation.

  • Concentrations of mycophenylate mofetil (MMF) [ Time Frame: Day 3 ] [ Designated as safety issue: No ]
    MMF levels are to be sent on day +3 to the main laboratory for determinations of MMF kinetics.

  • Changes in Magnetic Resonance Imaging (MRI) [ Time Frame: Day 30, 60, 100 and 1 and 2 Years ] [ Designated as safety issue: No ]
  • Changes in Neuropsychometric Function [ Time Frame: 6 Months, 1 Year, 2 Years, 3 Years ] [ Designated as safety issue: No ]
  • Incidence of Acute Graft Versus Host Disease [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host.

  • Incidence of Chronic Graft Versus Host Disease [ Time Frame: 1 Year ] [ Designated as safety issue: Yes ]
    Chronic Graft-Versus-Host Disease is a severe long-term complication created by infusion of donor cells into a foreign host.


Estimated Enrollment: 30
Study Start Date: January 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treated Patients
Patients receiving chemotherapy (Hydroxyurea, Alemtuzumab, Clofarabine, Melphalan), Hematopoietic Stem Cell Transplantation and radiation therapy (Total body Irradiation) mycophenylate mofetil and cyclosporine A.
Drug: Clofarabine
days -7 through -3: 40 mg/m^2 intravenously over 2 hours
Other Name: Clolar
Procedure: Total body Irradiation
Administration of TBI: The dose of TBI will be 200 cGy given in a single fraction on day -1. The dose rate will be between 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
Other Name: TLI
Drug: Melphalan
day -2: 140 mg/m^2 intravenously over 30 minutes
Other Name: Alkeran
Biological: Hematopoietic Stem Cell Transplantation
receives infusion of stem cells on day 0
Drug: Alemtuzumab
0.3 mg/kg intravenously (IV) days -12 through -8
Other Name: Campath 1-H
Drug: mycophenylate mofetil
Day -3 through Day 30: 1 gram three times daily (total daily dose 3 grams/day) if the recipient is >50 kg, or 15 mg/kg three times daily if the recipient is ≤50 kg. The same dosage is used orally or intravenously. Consider dose modification if renal impairment (GFR<25 mL/minute corrected)
Other Name: MMF
Device: Cyclosporine A

Patients will receive CsA therapy beginning on day -3. Dosing of CsA will be 2.5 mg/kg/dose intravenously (IV); if the recipient body weight is <40 kg, dosing will be 3 times daily, and if > 40 kg twice daily. An attempt will be made to maintain a trough cyclosporine level of 250 mg/L to 350 mg/L. Once the patient can tolerate oral medications and has a normal gastrointestinal transit time, CsA will be converted to an oral form at a dose 2.5 x the current IV dose (maximum 12.5 mg/kg/day as initial oral dose).

CsA taper begins at day +100.

Other Name: CsA
Drug: Hydroxyurea
hydroxyurea (HU) beginning day -28 and continuing through alemtuzumab administration
Other Names:
  • Hydria
  • HU

Detailed Description:

Hematopoietic stem cell transplantation has proven effective therapy for individuals with adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD, or Krabbe disease). However, for patients with advanced or rapidly progressive disease, the morbidity and mortality with transplantation is unacceptably high. Unfortunately, there are no viable alternative therapeutic options for these patients; if transplantation is not performed the patients are sent home to die. Our group at Minnesota has developed a new protocol incorporating transplantation using a reduced intensity conditioning regimen designed to decrease toxicity associated with the transplant procedure. This regimen will make use of the drug clofarabine, which has lympholytic and immune suppressive properties without the neurologic toxicity observed in the related compound, fludarabine, commonly used for transplantation. In addition, several agents providing anti-oxidant and anti-inflammatory properties will be used to assist in the stabilization of the disease processes. This revised transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol, 2) the mortality associated with transplant by day 100, 3) patient outcomes, based on differential neurologic, neuropsychologic, imaging and biologic evaluations prior to transplantation and at designated points after transplantation (day 100, 6 months, 1, 2 and 5 years). Additional biologic studies will include pharmacokinetics of clofarabine and mycophenolate mofetil (MMF), develop experience in kinetics of N-acetylcysteine, and evaluate biologic markers of oxidative status during transplantation. In addition, for patients undergoing lumbar puncture studies, cerebrospinal fluid (CSF) will be requested for determinations of biologic parameters.

  Eligibility

Ages Eligible for Study:   up to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adrenoleukodystrophy: Patients from 0-55 years of age diagnosed with ALD as determined by very long chain fatty acid testing will be eligible for this protocol if they have evidence of cerebral or cerebellar disease based on MRI testing, AND they are determined high risk for any of the following reasons:

    1. Age >18 years
    2. MRI score >10
    3. Evidence of aggressive disease that in the judgment of the Inherited Metabolic and Storage Disease group is sufficiently concerning to consider transplantation with a reduced intensity regimen instead of a standard full preparative regimen.
  • Metachromatic Leukodystrophy: Patients from 0-55 years of age diagnosed with MLD as determined by determinations of arylsulfatase A testing will be eligible for this protocol IF they are determined high risk for any of the following reasons:

    1. Age >18 years
    2. Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
    3. Evidence of aggressive disease such as rapidly changing MRI determinations that in the judgment of the Inherited Metabolic and Storage Disease group is sufficiently concerning to consider transplantation with a reduced intensity regimen instead of a standard full preparative regimen.
  • Globoid Cell Leukodystrophy: Patients from 0-55 years of age diagnosed with GLD as determined by determinations of galactocerebrosidase testing will be eligible for this protocol IF they are determined high risk for any of the following reasons:

    1. Age >18 years
    2. Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
    3. Evidence of aggressive disease such as rapidly changing MRI determinations that in the judgment of the Inherited Metabolic and Storage Disease group is sufficiently concerning to consider transplantation with a reduced intensity regimen instead of a standard full preparative regimen.
  • Patients with GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome, Wolman disease or Sandhoff disease or other inherited metabolic diseases including but not limited to I-cell disease (mucolipidosis II) who are determined to be sufficiently advanced or high risk based on the following reasons:

    1. Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
    2. Evidence of an expected poor outcome based on genetic testing or a prior family history of aggressive disease.
    3. Other metabolic disorders, including but not limited to I-cell disease, that are deemed to be high-risk for a poor outcome with a standard transplant regimen due to anticipated toxicity based on experience gained at the University of Minnesota or other centers.

Exclusion criteria:

  • Major organ dysfunction.
  • Advanced Disease Exclusion: Following evaluation, if a consensus of the members of the Inherited Metabolic and Storage Disease Program is that a patient is too advanced to benefit in a measurable and meaningful way from transplant, this will be communicated to the family, and transplant will not be offered. Measures to assist in those determinations may include: neurologic/neurocognitive functions such as activities of daily living, motor function, vision, hearing, interaction with environment, toileting, swallowing, or other standardized measures
  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: NCT00383448

Contacts
Contact: Paul Orchard, M.D. 612-626-2961 orcha001@umn.edu

Locations
United States, Minnesota
Masonic Cancer Center, University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Paul Orchard, MD    612-626-2961    orcha001@umn.edu   
Sub-Investigator: Kendra Bjoraker, Ph.D.         
Sub-Investigator: Lawrence Charnas, MD         
Sub-Investigator: Katherine Dusenbery, MD         
Sub-Investigator: Margaret MacMillan, MD         
Sub-Investigator: Elsa Shapiro, MD         
Sub-Investigator: Marcie Tomblyn, MD         
Sub-Investigator: Jakub Tolar, MD, Ph.D.         
Sub-Investigator: John Wagner, MD         
Sub-Investigator: Brenda Weigel, MD         
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: NCT00383448     History of Changes
Other Study ID Numbers: MT2006-14, 0606M87246
Study First Received: September 29, 2006
Last Updated: July 8, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Masonic Cancer Center, University of Minnesota:
Adrenoleukodystrophy (ALD)
Stem cell transplantation
Inborn errors of metabolism
Metachromatic leukodystrophy (MLD)
Globoid cell leukodystrophy (GLD or Krabbe)
Tay Sachs
Sandhoff
Sanfilippo syndrome
Mucopolysaccharidosis III (MPS-III)
GM1 gangliosidosis
I-cell
mucolipidosis

Additional relevant MeSH terms:
Adrenoleukodystrophy
Syndrome
Leukodystrophy, Metachromatic
Gangliosidoses
Wolman Disease
Tay-Sachs Disease
Mucopolysaccharidosis III
Leukodystrophy, Globoid Cell
Sandhoff Disease
Gangliosidosis, GM1
Disease
Pathologic Processes
Hereditary Central Nervous System Demyelinating Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Sulfatidosis
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Leukoencephalopathies
Demyelinating Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders

ClinicalTrials.gov processed this record on September 29, 2014