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

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00668564
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arm: 1
• Duration (Months): 23.1
• Patients Per Site Per Month: 0.8

Study Details

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).

Condition or Disease	Intervention/Treatment	Phase
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	Procedure: Stem Cell Transplantation; Drug: Cyclophosphamide; Drug: Campath-1H; Drug: Busulfan	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Lysosomal and Peroxisomal Inborn Errors of Metabolism by Hematopoietic Cell Transplantation
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: Feb 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Intent-to-Treat All patients treated with study regimen.

Procedure: Stem Cell Transplantation; 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.; Other Names: Bone Marrow Transplant, cord blood transplant ; Drug: Cyclophosphamide; 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; Other Names: Cytoxan ; Drug: Campath-1H; 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; Other Names: Alemtuzamab ; Drug: Busulfan; 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; Other Names: Busulfex

Outcome Measures

Primary Outcome Measures

1. Number of Patients Achieving Engraftment [Day 100]

   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

1. Overall Survival [Day 100, 1 Year, 3 Years]

   Number of patients alive at timepoints.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota, Fairview	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota

Investigators

• Principal Investigator: Paul Orchard, MD, University of Minnesota Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00668564
• Other Study ID Numbers: MT2008-02; 0801M25202
• First Posted: Apr 29, 2008
• Last Update Posted: Dec 28, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: Inborn errors of metabolism; Sphingolipidoses; Recessive Leukodystrophies- GLD, Krabbe disease, MLD; Peroxisomal Disorders; Wolman syndrome; Niemann-Pick B patients; Niemann-Pick C subtype 2
• Additional relevant MeSH terms: Pick Disease of the Brain; Aphasia, Primary Progressive; Frontotemporal Dementia; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Leukodystrophy, Globoid Cell; Sphingolipidoses; Fucosidosis; Niemann-Pick Disease, Type B; Metabolism, Inborn Errors; Mannosidase Deficiency Diseases; alpha-Mannosidosis; Mucopolysaccharidosis I; Wolman Disease; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Aspartylglucosaminuria; Syndrome; Cyclophosphamide; Busulfan; Alemtuzumab

Study Results

Participant Flow

Arm/Group Title	Intent-to-Treat
Arm/Group Description	All patients treated with study regimen; Bone Marrow Transplant - cord blood transplant; Cyclophosphamide (50 mg/kg intravenous [IV] days 1-4 prior to transplant); Busulfan (if < or = 12 kg: 1.1 mg/kg or if > 12 kg: 0.8 mg/kg IV every 6 hours on days 6-9 before transplant) and Campath-1H (once per day 0.3 mg/kg IV on days 10-12 before transplant.
Period Title: Overall Study
STARTED	18
COMPLETED	18
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Intent-to-Treat
Arm/Group Description	All patients treated with study regimen; Bone Marrow Transplant - cord blood transplant; Cyclophosphamide (50 mg/kg intravenous [IV] days 1-4 prior to transplant); Busulfan (if < or = 12 kg: 1.1 mg/kg or if > 12 kg: 0.8 mg/kg IV every 6 hours on days 6-9 before transplant) and Campath-1H (once per day 0.3 mg/kg IV on days 10-12 before transplant.
Overall Participants	18
Age (Count of Participants)
<=18 years	18 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.7 (4.3)
Sex: Female, Male (Count of Participants)
Female	7 38.9%
Male	11 61.1%
Region of Enrollment (participants) [Number]
United States	18 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intent-to-Treat
Arm/Group Description	All patients treated with study regimen; Bone Marrow Transplant - cord blood transplant; Cyclophosphamide (50 mg/kg intravenous [IV] days 1-4 prior to transplant); Busulfan (if < or = 12 kg: 1.1 mg/kg or if > 12 kg: 0.8 mg/kg IV every 6 hours on days 6-9 before transplant) and Campath-1H (once per day 0.3 mg/kg IV on days 10-12 before transplant.
Measure Participants	18
Number [Participants]	14 77.8%

2. Secondary Outcome

Title	Overall Survival
Description	Number of patients alive at timepoints.
Time Frame	Day 100, 1 Year, 3 Years

Outcome Measure Data

Analysis Population Description

Year 3 survival endpoint was not done due to study being terminated prematurely.

Arm/Group Title	Intent-to-Treat
Arm/Group Description	All patients treated with study regimen; Bone Marrow Transplant - cord blood transplant; Cyclophosphamide (50 mg/kg intravenous [IV] days 1-4 prior to transplant); Busulfan (if < or = 12 kg: 1.1 mg/kg or if > 12 kg: 0.8 mg/kg IV every 6 hours on days 6-9 before transplant) and Campath-1H (once per day 0.3 mg/kg IV on days 10-12 before transplant.
Measure Participants	18
Day 100	14 77.8%
1 Year	12 66.7%

Adverse Events

Time Frame	Day 1 through Day 100 post-transplant.
Adverse Event Reporting Description	Only Serious Adverse Events were collected for this study.
Arm/Group Title	Intent-to-Treat
Arm/Group Description	All patients treated with study regimen; Bone Marrow Transplant - cord blood transplant; Cyclophosphamide (50 mg/kg intravenous [IV] days 1-4 prior to transplant); Busulfan (if < or = 12 kg: 1.1 mg/kg or if > 12 kg: 0.8 mg/kg IV every 6 hours on days 6-9 before transplant) and Campath-1H (once per day 0.3 mg/kg IV on days 10-12 before transplant.
All Cause Mortality
	Intent-to-Treat
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Intent-to-Treat
	Affected / at Risk (%)	# Events
Total	8/18 (44.4%)
Blood and lymphatic system disorders
Graft failure	2/18 (11.1%)	2
General disorders
Death	6/18 (33.3%)	6
Auto recovery	2/18 (11.1%)	2
Other (Not Including Serious) Adverse Events
	Intent-to-Treat
	Affected / at Risk (%)	# Events
Total	0/18 (0%)

Limitations/Caveats

Other secondary objectives outlined in study protocol were not analyzed; number of patients were too few to be relevant.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.