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Treatment of High Risk, Inherited Lysosomal and Peroxisomal Disorders by Reduced-Intensity Hematopoietic Cell Transplantation and Low-Dose Total Body Irradiation With Marrow Boosting by Volumetric-Modulated Arc Therapy (VMAT)


N/A
N/A
55 Years
Open (Enrolling)
Both
Lysosomal Storage Disease, Peroxisomal Disorder

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Trial Information

Treatment of High Risk, Inherited Lysosomal and Peroxisomal Disorders by Reduced-Intensity Hematopoietic Cell Transplantation and Low-Dose Total Body Irradiation With Marrow Boosting by Volumetric-Modulated Arc Therapy (VMAT)


The conditioning regimen consists of alemtuzumab (Campath-1H), clofarabine, melphalan, and
VMAT-delivered low-dose TBI with boosted marrow irradiation. Additional graft-versus-host
disease prophylaxis consists of mycophenolate mofetil and cyclosporine.


Inclusion Criteria:



- Adrenoleukodystrophy (ALD): 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:

- Age >18 years

- Magnetic resonance imaging (MRI )radiographic severity (Loes) score >10

- 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 (MLD): Patients from 0-55 years of age diagnosed with
MLD as determined by arylsulfatase A activity. Testing will be eligible for this
protocol IF they are determined high risk for any of the following reasons:

- Age >18 years

- Symptomatic disease, as based on neurologic examination or evidence of
deterioration based on subsequent neuropsychologic evaluations.

- 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 (GLD): Patients from 0-55 years of age diagnosed with GLD
as determined by galactocerebrosidase activity will be eligible for this protocol IF
they are determined high risk for any of the following reasons:

- Age >18 years

- Symptomatic disease, as based on neurologic examination or evidence of
deterioration based on subsequent neuropsychologic evaluations.

- 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.

- Wolman's disease, GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome,
Sandhoff disease or other inherited metabolic diseases including but not limited to
I-cell disease (mucolipidosis II): Patients who are determined to be sufficiently
advanced or high risk based on the following reasons:

- Symptomatic disease, as based on neurologic examination or evidence of
deterioration based on subsequent neuropsychologic evaluations.

- Evidence of an expected poor outcome based on genetic testing or a prior family
history of aggressive disease.

- 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.

Donor Availability

- Patients considered for transplantation must have a sufficient graft as based on
current criteria of the University of Minnesota Blood and Marrow Transplantation
Program

- Transplantation using sufficiently matched related donors (such as matched
siblings) or unrelated donors will be considered. Both granulocyte-colony
stimulating factor (G-CSF) stimulated peripheral blood grafts and bone marrow
grafts will be considered, although bone marrow will be the priority.

- Cord blood grafts, both related and unrelated, are also eligible. As this
protocol will use a reduced intensity regimen, this protocol will use the
current recommendations of the University of Minnesota for choosing cord blood
grafts. If a single cord blood unit cell dose is insufficient, double cord
transplantation should be considered if sufficiently matched cord blood units
are available. The priority of choosing cord blood donors is based on the
current institutional recommendations.

- Exclusion of Metabolic Disorder Carrier Status from related donor and unrelated
cord blood grafts as appropriate for primary disease.

- Adequate Organ Function - Measured within 30 days of study enrollment and defined as:

- Cardiac: left ventricular ejection fraction ≥ 25%

- Renal: serum creatinine ≤ 3 x normal for age and/or glomerular filtration rate
(GFR) ≥ 20 mL/min

- Hepatic: total bilirubin and Alanine transaminase (ALT) ≤ 5 x upper limit of
normal (ULN)

- Pulmonary: does not require continuous oxygen supplementation

- Signed consent

Exclusion Criteria:

- Inability to receive total body irradiation (TBI) with marrow boosting per protocol
guidelines as determined by the Radiation Oncologist - any patient who has had prior
radiation therapy or TBI will be evaluated by the Radiation Oncologist for approval
for study participation.

- Pregnant - Menstruating females must have a negative serum pregnancy test within 14
days of treatment start.

- 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 neuro-radiographic imaging, neuropsychometric
testing, and general neurologic assessment.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Donor (Allogeneic) Hematopoietic Engraftment

Outcome Description:

Number of patients who achieve hematopoietic engraftment - assessment of nucleated peripheral blood cells for donor (allogeneic) chimerism following this reduced-intensity HCT.

Outcome Time Frame:

Day 100 Following Hematopoietic Cell Transplant (HCT)

Safety Issue:

No

Principal Investigator

Weston Miller, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota

Authority:

United States: Institutional Review Board

Study ID:

2011LS147

NCT ID:

NCT01626092

Start Date:

July 2012

Completion Date:

June 2020

Related Keywords:

  • Lysosomal Storage Disease
  • Peroxisomal Disorder
  • bone marrow transplantation
  • reduced intensity conditioning
  • Adrenoleukodystrophy
  • Metachromatic Leukodystrophy
  • Globoid Cell Leukodystrophy
  • Wolman's disease
  • GM1 gangliosidosis
  • Tay Sachs disease
  • Sanfilippo syndrome
  • Sandhoff disease
  • inherited metabolic
  • I-cell disease
  • mucolipidosis II
  • Lysosomal Storage Diseases
  • Metabolic Diseases
  • Peroxisomal Disorders

Name

Location

Masonic Cancer Center, University of MinnesotaMinneapolis, Minnesota  55455