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Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism

Primary Purpose

Hurler's Syndrome, Maroteaux-Lamy Syndrome, Sly Syndrome

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Stem Cell Transplantation
Cyclophosphamide
Campath-1H
Busulfan
Sponsored by
Masonic Cancer Center, University of Minnesota
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hurler's Syndrome focused on measuring Inborn errors of metabolism, Sphingolipidoses, Recessive Leukodystrophies- GLD, Krabbe disease, MLD, Peroxisomal Disorders, Wolman syndrome, Niemann-Pick B patients, Niemann-Pick C subtype 2

Eligibility Criteria

undefined - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Mucopolysaccharidosis (MPS) Disorders:

    • MPS IH (Hurler syndrome)
    • MPS-VI (Maroteaux-Lamy syndrome)
    • MPS VII (Sly syndrome).

  • Glycoprotein metabolic disorders:

    • Alpha mannosidosis
    • Fucosidosis
    • Aspartylglucosaminuria
  • Sphingolipidoses and Recessive Leukodystrophies: Presymptomatic patients with globoid cell leukodystrophy (GLD, also known as Krabbe disease) and metachromatic leukodystrophy (MLD) will be eligible for treatment on this protocol. White matter disease by magnetic resonance imaging (MRI) alone is not an exclusion if the patient is asymptomatic.
  • Peroxisomal Disorders: Presymptomatic patients with inherited peroxisomal disorders associated with of very long chain fatty acids (VLCFA) elevation, identified by family history or laboratory testing (including neonatal screening), are eligible for this protocol. White matter disease by MRI alone is not an exclusion if the patient is asymptomatic.

  • Other Inherited Diseases of Metabolism:

    • Wolman syndrome (acid lipase deficiency)
    • Niemann-Pick B patients (sphingomyelin deficiency)
    • Niemann-Pick C subtype 2
  • 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: Priority will be as follows, although in circumstances in which timing is of the essence, cord blood grafts may be chosen over an unrelated graft, despite the priority listed above.
  • Multidisciplinary Evaluation: Patients will be eligible for transplantation only after they are seen and evaluated by members of the Inherited Metabolic and Storage Disease Program (IMSD) team, and the team has offered transplantation to the patient/family.

Exclusion Criteria:

  • Symptomatic patients with peroxisomal or lysosomal disorders are excluded but may be considered for other treatment protocols.

  • Major organ dysfunction. Evidence of major organ impairment, including:

    • Cardiac: left ventricular ejection fraction <40%
    • Renal: serum creatinine >2.5 x normal for age
    • Hepatic: total bilirubin >3 x normal, or Alanine transaminase (ALT) > 3 x normal
    • Pulmonary: requirement for continuous oxygen supplementation
  • Pregnancy
  • Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology
  • Patients >21 years of age.

Sites / Locations

  • University of Minnesota, Fairview

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Intent-to-Treat

Arm Description

All patients treated with study regimen.

Outcomes

Primary Outcome Measures

Number of Patients Achieving Engraftment
Rate of successful engraftment - patients who achieved and sustained donor engraftment; donor chimerism by day 100 of at least 90% after undergoing hematopoietic stem cell transplantation.

Secondary Outcome Measures

Overall Survival
Number of patients alive at timepoints.

Full Information

First Posted
April 25, 2008
Last Updated
December 3, 2017
Sponsor
Masonic Cancer Center, University of Minnesota
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1. Study Identification

Unique Protocol Identification Number
NCT00668564
Brief Title
Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
Official Title
Treatment of Lysosomal and Peroxisomal Inborn Errors of Metabolism by Hematopoietic Cell Transplantation
Study Type
Interventional

2. Study Status

Record Verification Date
December 2017
Overall Recruitment Status
Terminated
Why Stopped
Replaced by another study
Study Start Date
March 2008 (undefined)
Primary Completion Date
February 2010 (Actual)
Study Completion Date
February 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Masonic Cancer Center, University of Minnesota

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary objective of this clinical trial is to evaluate the ability to achieve and sustain donor engraftment in patients with lysosomal and peroxisomal inborn errors of metabolism undergoing hematopoietic stem cell transplantation (HCT).
Detailed Description
This has been an ongoing area of interest by our group at the Univ. of Minnesota, but this is a new protocol to take the place of several older protocols. While survival has been very good on the prior protocols over the past decade, incomplete engraftment has remained somewhat problematic. Therefore, we have modified the preparative regimen somewhat to increase engraftment by replacing anti-thymocyte globulin (ATG) with Campath-1H, a drug that is more immune suppressive. In addition, we have modified the supportive care regimen. Based on this, we will monitor levels of an anti-oxidant therapy (N-acetylcysteine) and biomarkers of inflammation and oxidative stress for the families that consent to these research studies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hurler's Syndrome, Maroteaux-Lamy Syndrome, Sly Syndrome, Alpha Mannosidosis, Fucosidosis, Aspartylglucosaminuria, Sphingolipidoses, Krabbe Disease, Wolman's Disease, Niemann-Pick Disease Type B, Niemann-Pick Disease, Type C
Keywords
Inborn errors of metabolism, Sphingolipidoses, Recessive Leukodystrophies- GLD, Krabbe disease, MLD, Peroxisomal Disorders, Wolman syndrome, Niemann-Pick B patients, Niemann-Pick C subtype 2

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Intent-to-Treat
Arm Type
Experimental
Arm Description
All patients treated with study regimen.
Intervention Type
Procedure
Intervention Name(s)
Stem Cell Transplantation
Other Intervention Name(s)
Bone Marrow Transplant, cord blood transplant
Intervention Description
The purpose of hematopoietic stem cell transplantation is to introduce blood producing cells from a normal donor. These cells can either provide what is missing in the body to the other cells, or can change the body's immune response to the substances that have accumulated in the body. These normal hematopoietic stem 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). The new donor cells repopulate the blood and bone marrow system and enter the organs of the body, including the brain. Wherever these cells go, they will produce the needed enzyme.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Days before Transplant Drug Frequency 4 Cyclophosphamide Once, given over 2 hours 3 Cyclophosphamide Once, given over 2 hours 2 Cyclophosphamide Once, given over 2 hours 1 Cyclophosphamide Once, given over 2 hours
Intervention Type
Drug
Intervention Name(s)
Campath-1H
Other Intervention Name(s)
Alemtuzamab
Intervention Description
Days before Transplant Drug Frequency 12 Campath-1H Once, given over 2 hours 11 Campath-1H Once, given over 2 hours 10 Campath-1H Once, given over 2 hours
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
Busulfex
Intervention Description
Days before Transplant Drug Frequency 9 Busulfan Four times per day 8 Busulfan Four times per day 7 Busulfan Four times per day 6 Busulfan Four times per day
Primary Outcome Measure Information:
Title
Number of Patients Achieving Engraftment
Description
Rate of successful engraftment - patients who achieved and sustained donor engraftment; donor chimerism by day 100 of at least 90% after undergoing hematopoietic stem cell transplantation.
Time Frame
Day 100
Secondary Outcome Measure Information:
Title
Overall Survival
Description
Number of patients alive at timepoints.
Time Frame
Day 100, 1 Year, 3 Years

10. Eligibility

Sex
All
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Mucopolysaccharidosis (MPS) Disorders: MPS IH (Hurler syndrome) MPS-VI (Maroteaux-Lamy syndrome) MPS VII (Sly syndrome). Glycoprotein metabolic disorders: Alpha mannosidosis Fucosidosis Aspartylglucosaminuria Sphingolipidoses and Recessive Leukodystrophies: Presymptomatic patients with globoid cell leukodystrophy (GLD, also known as Krabbe disease) and metachromatic leukodystrophy (MLD) will be eligible for treatment on this protocol. White matter disease by magnetic resonance imaging (MRI) alone is not an exclusion if the patient is asymptomatic. Peroxisomal Disorders: Presymptomatic patients with inherited peroxisomal disorders associated with of very long chain fatty acids (VLCFA) elevation, identified by family history or laboratory testing (including neonatal screening), are eligible for this protocol. White matter disease by MRI alone is not an exclusion if the patient is asymptomatic. Other Inherited Diseases of Metabolism: Wolman syndrome (acid lipase deficiency) Niemann-Pick B patients (sphingomyelin deficiency) Niemann-Pick C subtype 2 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: Priority will be as follows, although in circumstances in which timing is of the essence, cord blood grafts may be chosen over an unrelated graft, despite the priority listed above. Multidisciplinary Evaluation: Patients will be eligible for transplantation only after they are seen and evaluated by members of the Inherited Metabolic and Storage Disease Program (IMSD) team, and the team has offered transplantation to the patient/family. Exclusion Criteria: Symptomatic patients with peroxisomal or lysosomal disorders are excluded but may be considered for other treatment protocols. Major organ dysfunction. Evidence of major organ impairment, including: Cardiac: left ventricular ejection fraction <40% Renal: serum creatinine >2.5 x normal for age Hepatic: total bilirubin >3 x normal, or Alanine transaminase (ALT) > 3 x normal Pulmonary: requirement for continuous oxygen supplementation Pregnancy Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology Patients >21 years of age.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Orchard, MD
Organizational Affiliation
University of Minnesota Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Minnesota, Fairview
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
21586746
Citation
Miller WP, Rothman SM, Nascene D, Kivisto T, DeFor TE, Ziegler RS, Eisengart J, Leiser K, Raymond G, Lund TC, Tolar J, Orchard PJ. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011 Aug 18;118(7):1971-8. doi: 10.1182/blood-2011-01-329235. Epub 2011 May 17.
Results Reference
derived

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Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism

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