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Treatment of High Risk, Inherited Lysosomal And Peroxisomal Disorders by Reduced Intensity Hematopoietic Stem Cell Transplantation


Phase 2
N/A
55 Years
Open (Enrolling)
Both
Adrenoleukodystrophy, Metachromatic Leukodystrophy, Globoid Cell Leukodystrophy, Tay Sachs Disease, Sandhoffs Disease, Wolman Disease, I-Cell Disease, Sanfilippo Syndrome, GM1 Gangliosidosis

Thank you

Trial Information

Treatment of High Risk, Inherited Lysosomal And Peroxisomal Disorders by Reduced Intensity Hematopoietic Stem Cell Transplantation


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.


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. Evidence of major organ impairment, including:

1. Cardiac: ejection fraction <25%

2. Renal: serum Cr >3 x normal or Cr clearance <20 mL/min.

3. Hepatic: total bilirubin >5 x normal, or ALT > 5 x normal

4. Pulmonary: requirement for respiratory support, as defined by continuous requirement
for oxygen supplementation Pregnancy HIV: Evidence of HIV infection or known HIV
positive serology Inability to Obtain Consent: Patients or parents are
psychologically incapable of undergoing BMT with associated strict isolation or
documented history of medical non-compliance.

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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Donor Cell Engraftment

Outcome Description:

The process of transplanted stem cells reproducing new cells.

Outcome Time Frame:

Day 42

Safety Issue:

No

Principal Investigator

Paul Orchard, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota

Authority:

United States: Institutional Review Board

Study ID:

MT2006-14

NCT ID:

NCT00383448

Start Date:

September 2006

Completion Date:

December 2013

Related Keywords:

  • Adrenoleukodystrophy
  • Metachromatic Leukodystrophy
  • Globoid Cell Leukodystrophy
  • Tay Sachs Disease
  • Sandhoffs Disease
  • Wolman Disease
  • I-Cell Disease
  • Sanfilippo Syndrome
  • GM1 Gangliosidosis
  • Stem cell transplantation
  • Inborn errors of metabolism
  • Adrenoleukodystrophy (ALD)
  • Metachromatic leukodystrophy (MLD)
  • Globoid cell leukodystrophy (GLD or Krabbe)
  • Tay Sachs
  • Sandhoff
  • Sanfilippo syndrome
  • Mucopolysaccharidosis III (MPS-III)
  • GM1 gangliosidosis
  • I-cell
  • mucolipidosis
  • Gangliosidoses
  • Mucolipidoses
  • Leukodystrophy, Globoid Cell
  • Leukodystrophy, Metachromatic
  • Mucopolysaccharidosis III
  • Sandhoff Disease
  • Tay-Sachs Disease
  • Wolman Disease
  • Cholesterol Ester Storage Disease
  • Gangliosidosis, GM1
  • Adrenoleukodystrophy
  • Peroxisomal Disorders

Name

Location

Masonic Cancer Center, University of MinnesotaMinneapolis, Minnesota  55455