Stem Cell Transplant for Inborn Errors of Metabolism

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT00176904
• Collaborator: (none)
• Enrollment: 135
• Location: 1
• Arm: 1
• Duration (Months): 185
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and engraftment of donor hematopoietic cells using this conditioning regimen in patients undergoing a hematopoietic (blood forming) cell transplant for an inherited metabolic storage disease.

Condition or Disease	Intervention/Treatment	Phase
Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease	Procedure: Stem Cell Transplant; Drug: Busulfan, Cyclophosphamide, Antithymocyte Globulin	Phase 2/Phase 3

Detailed Description

Prior to transplantation, subjects will receive Busulfan intravenously (IV) via the Hickman line four times daily for 4 days, Cyclophosphamide intravenously via the Hickman line once a day for 4 days, and Anti-Thymocyte Globulin (ATG) intravenously (IV) via the Hickman line twice daily for three days before the transplant. These three drugs are being given to subjects to help the new marrow "take" and grow.

On the day of transplantation, the donor's hematopoietic cells will be transfused via central venous catheter.

After hematopoietic cell transplant, subjects will then receive two drugs, cyclosporin and either methylprednisolone or Mycophenolate Mofetil (MMF). Cyclosporin and methylprednisolone or MMF are given to help prevent the complication of graft-versus-host disease and to decrease the chance that the new donor cells will be rejected.

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Lysosomal and Peroxisomal Inborn Errors of Metabolism by Bone Marrow Transplantation
• Study Start Date: Jan 1, 1995
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jun 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treated Patients All patients treated with protocol regimen (chemotherapy and surgery).

Procedure: Stem Cell Transplant; The purpose of hematopoietic cell transplantation is to introduce hematopoietic cells from a normal donor that contains an enzyme able to get rid of the substances that have accumulated in the body of patients with storage diseases. Hematopoietic 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).; Other Names: Bone marrow transplant ; Drug: Busulfan, Cyclophosphamide, Antithymocyte Globulin; Subjects will receive BUSULFAN intravenously (IV)- patients < or= 12 kg 1.1 mg/kd/dose IV every 6 hours for 16 doses; patients > 12kg 0.8 mg/kg/dose IV every 6 hours for 16 doses - via the Hickman line four times daily for 4 days, CYCLOPHOSPHAMIDE intravenously (50 mg/kg/day IV over 2 hours) via the Hickman line once a day for 4 days, and ANTI-THYMOCYTE GLOBULIN IV (15 mg/kg/day over 2 hours) via the Hickman line twice daily for three days before the transplant. These three drugs are being given to help the new marrow "take" and grow. METHYLPREDNISOLONE will be given as a pre-medication for the ATG.; Other Names: Busulfex, Cytoxan, ATG

Outcome Measures

Primary Outcome Measures

1. Overall Survival [100 Days, 1 Year and 3 Years]

   Number of patients alive at designated timepoints after transplant.

Secondary Outcome Measures

1. Overall Donor Engraftment [Day 100]

   Number of patients with full donor chimerism (state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease) by Day 100 post-transplant of at least 90%.

2. Number of Patients With Grade II-IV Acute Graft-Versus-Host Disease [Day 100]

   Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening.

3. Number of Patients With Grade III-IV Acute Graft-Versus-Host Disease [Day 100]

   Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening.

4. Number of Patients With Chronic Graft-Versus-Host Disease [1 Year Post Transplant]

   Number of patients who exhibited chronic graft-versus-host disease by 1 Year post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Chronic GVHD is an extension of this syndrome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with adrenoleukodystrophy, metachromatic leukodystrophy, globoid cell leukodystrophy, Gaucher's disease, Fucosidosis, Wolman disease, Niemann-Pick disease and Batten disease (CLN3) who have a human leukocyte antigen (HLA)-identical or haplotype mismatched (at 1-3 antigens) related marrow, or umbilical cord blood donor. One or two umbilical cord blood (UCB) units may be used.

• Patients with GM1 gangliosidosis, Tay Sachs disease or Sandhoff disease who have a HLA-identical or 1 antigen mismatched related or unrelated donor, or suitably matched umbilical cord blood unit(s). One or two UCB units may be used.

• Patients with adrenoleukodystrophy must have magnetic resonance imaging (MRI) findings, neurological and neuropsychometric function consistent with the diagnosis, and for boys with parietal-occipital dysmyelination a performance intelligence quotient (IQ) ≥80. In cases, when the performance IQ is not ≥80, the protocol committee may recommend transplant if the patient's clinical condition and neuropsychometric status are deemed to be acceptable based upon consideration of such factors as age at onset of cerebral disease, magnitude of change in performance IQ and neurologic deficits.

• Patients with arylsulfatase A deficiency (Metachromatic Leukodystrophy) must have either the presymptomatic late infantile, juvenile or adult form of the disease and must have acceptable neurological and neuropsychometric function.

• Patients with galactocerebrosidase deficiency (Globoid Cell Leukodystrophy) must have acceptable neurological and neuropsychometric function.

• Patients with acid lipase deficiency (Wolman disease) must have a liver biopsy that documents no evidence of hepatic cirrhosis, and acceptable neurological and neuropsychometric function.

• Patients with fucosidase deficiency (Fucosidosis) must have acceptable neurological and neuropsychometric function.

• Patients with glucocerebrosidase deficiency (Gaucher's Disease) must have acceptable neurologic and neuropsychometric function.

• Patients with Batten's disease (CLN3) must have acceptable Neurological and neuropsychometric function.

• Absence of major organ dysfunction. Organ evaluation results as follows:

• Cardiac: ejection fraction >30%

• Renal: serum creatinine <2x normal or creatinine clearance 60 mL/min.

• Hepatic: total bilirubin <2x normal and Aspartate aminotransferase (AST) <2x normal

• Signed consent.

Exclusion Criteria:

• Patients with symptomatic late infantile form of metachromatic leukodystrophy.

• Patients with symptomatic infantile globoid leukodystrophy.

• Note: Patients with Hurler syndrome, mucopolysaccharidosis (MPS) VI, or Mannosidosis disease are no longer eligible for this protocol, but can be transplanted under protocol MT 9907 (NCT00176917 - Hematopoietic Cell Transplantation for Hurler Syndrome, Maroteaux Lamy Syndrome (MPS VI), and Alpha Mannosidase Deficiency (Mannosidosis)).

• Pregnancy

• Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology

• Patients or parents are psychologically incapable of undergoing bone marrow transplant (BMT) with associated strict isolation or documented history of medical non-compliance.

• Patients ≥ 50 kg may be at risk for having cell doses below the goal of ≥ 10 x 10^6 CD34 cells/kg and therefore will not be eligible to receive unrelated peripheral blood stem cells (PBSCs)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00176904
• Other Study ID Numbers: MT1995-01; NCT00005894
• First Posted: Sep 15, 2005
• Last Update Posted: Dec 28, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: Inborn errors; Storage disease; errors of metabolism; stem cell transplant
• Additional relevant MeSH terms: Gaucher Disease; Adrenoleukodystrophy; Pick Disease of the Brain; Gangliosidoses; Leukodystrophy, Metachromatic; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Neuronal Ceroid-Lipofuscinoses; Tay-Sachs Disease; Gangliosidosis, GM1; Sandhoff Disease; Leukodystrophy, Globoid Cell; Fucosidosis; Metabolism, Inborn Errors; Wolman Disease; Cyclophosphamide; Busulfan; Antilymphocyte Serum

Study Results

Participant Flow

Arm/Group Title	Patients Treated With Stem Cell Transplant
Arm/Group Description	All patients treated with protocol regimen (chemotherapy and stem cell transplant).
Period Title: Overall Study
STARTED	135
COMPLETED	135
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Patients Treated With Stem Cell Transplant
Arm/Group Description	All patients treated with protocol regimen (chemotherapy and stem cell transplant).
Overall Participants	135
Age (Count of Participants)
<=18 years	117 86.7%
Between 18 and 65 years	18 13.3%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.7 (8.9)
Sex: Female, Male (Count of Participants)
Female	44 32.6%
Male	91 67.4%
Region of Enrollment (participants) [Number]
United States	135 100%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Number of patients alive at designated timepoints after transplant.
Time Frame	100 Days, 1 Year and 3 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated With Stem Cell Transplant
Arm/Group Description	All patients treated with protocol regimen (chemotherapy and stem cell transplant).
Measure Participants	135
Day 100	120 88.9%
1 Year	92 68.1%
3 Years	81 60%

2. Secondary Outcome

Title	Overall Donor Engraftment
Description	Number of patients with full donor chimerism (state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease) by Day 100 post-transplant of at least 90%.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

1 Patient not included due to early death (before day 40).

Arm/Group Title	Patients Treated With Stem Cell Transplant
Arm/Group Description	All patients treated with protocol regimen (chemotherapy and stem cell transplant).
Measure Participants	134
Number [Participants]	123 91.1%

3. Secondary Outcome

Title	Number of Patients With Grade II-IV Acute Graft-Versus-Host Disease
Description	Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated With Stem Cell Transplant
Arm/Group Description	All patients treated with protocol regimen (chemotherapy and stem cell transplant).
Measure Participants	135
Number [Participants]	34 25.2%

4. Secondary Outcome

Title	Number of Patients With Grade III-IV Acute Graft-Versus-Host Disease
Description	Number of patients who exhibited acute graft-versus-host disease by Day 100 post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Grade I=mild, Grade II=moderate, Grade III=severe, Grade IV=life threatening.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated With Stem Cell Transplant
Arm/Group Description	All patients treated with protocol regimen (chemotherapy and stem cell transplant).
Measure Participants	135
Number [Participants]	13 9.6%

5. Secondary Outcome

Title	Number of Patients With Chronic Graft-Versus-Host Disease
Description	Number of patients who exhibited chronic graft-versus-host disease by 1 Year post transplant. Graft-versus-host disease (GVHD) is a complication that can occur after a stem cell or bone marrow transplant in which the newly transplanted material attacks the transplant recipient's body. Chronic GVHD is an extension of this syndrome.
Time Frame	1 Year Post Transplant

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated With Stem Cell Transplant
Arm/Group Description	All patients treated with protocol regimen (chemotherapy and stem cell transplant).
Measure Participants	135
Number [Participants]	13 9.6%

Adverse Events

Time Frame	Serious adverse experiences were collected during the first 100 days after transplant then 6 months and annually for 3 years.
Adverse Event Reporting Description	Selected serious adverse experiences (graft failure/autologous recovery, severe acute GVHD (grades III and IV) and death were collected during the first 100 days after transplant then 6 months and annually for 3 years. After day 100, only death or an unexpected adverse event will be reported. Adverse events were not collected in this study.
Arm/Group Title	Patients Treated With Stem Cell Transplant
Arm/Group Description	All patients treated with protocol regimen (chemotherapy and stem cell transplant).
All Cause Mortality
	Patients Treated With Stem Cell Transplant
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Patients Treated With Stem Cell Transplant
	Affected / at Risk (%)	# Events
Total	62/135 (45.9%)
Blood and lymphatic system disorders
Primary graft failure	2/135 (1.5%)	2
General disorders
Auto recovery	9/135 (6.7%)	9
Death	54/135 (40%)	54
Other (Not Including Serious) Adverse Events
	Patients Treated With Stem Cell Transplant
	Affected / at Risk (%)	# Events
Total	0/135 (0%)

Limitations/Caveats

Change in Neuropsychometric function data is not available. Data would have been noted as descriptive and patient specific, as well as disease specific; not table format. No formal analysis was intended.

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.