Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders

• ClinicalTrials.gov Identifier: NCT01043640
• Recruitment Status: Completed
• First Posted: January 7, 2010
• Results First Posted: May 12, 2017
• Last Update Posted: February 5, 2018
• Sponsor: Masonic Cancer Center, University of Minnesota
• Information provided by (Responsible Party): Masonic Cancer Center, University of Minnesota

Study Description

Brief Summary:

Rationale: Chemotherapy administration before a donor stem cell transplant is necessary to stop the patient's immune system from rejecting the donor's stem cells. When healthy stem cells from a donor are infused into the patient, the donor white blood cells can provide the missing enzyme that causes the metabolic disease. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving a monoclonal antibody, alemtuzumab, before transplant and cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening. This may be an effective treatment for inherited metabolic disorders.

Purpose: The design of this study is to achieve donor cell engraftment in patients with standard-risk inherited metabolic diseases with limited peri-transplant morbidity and mortality. This will be achieved through the administration of the chemotherapy regimen described. The intention is to follow transplanted patient for years after transplant monitoring them for complications of their disease and assisting families with a multifaceted interdisciplinary approach.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis; Hurler Syndrome; Hunter Syndrome; Maroteaux-Lamy Syndrome; Sly Syndrome; Alpha Mannosidosis; Fucosidosis; Aspartylglucosaminuria; Adrenoleukodystrophy (ALD); Krabbe Disease; Metachromatic Leukodystrophy (MLD); Sphingolipidoses; Peroxisomal Disorders	Drug: Campath-1H; Drug: Cyclophosphamide; Drug: Busulfan; Procedure: Allogeneic stem cell transplantation; Drug: Cyclosporine A; Drug: Mycophenolate Mofetil	Phase 2

Detailed Description:

Primary Objective:

• To estimate the proportion of patients with donor derived engraftment at day 100 post transplant as defined by 80% or greater donor cells in the CD3 (T cell) fraction

Secondary Objectives:

• To determine the incidence and severity of graft-versus-host disease (GVHD) by day 100
• To determine the incidence of peri-transplant mortality (death by day 100)
• To monitor donor cell chimerism at various time points following allogeneic transplantation with this transplant regimen as determined at day 28, 42, 100, 6 months and yearly for 5 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Allogeneic Hematopoietic Stem Cell Transplantation for Standard Risk Inherited Metabolic Disorders
• Study Start Date: December 2009
• Actual Primary Completion Date: June 2015
• Actual Study Completion Date: June 2017

Arms and Interventions

Arm

Intervention/treatment

Experimental: Transplant Patients; Includes patients who received allogeneic stem cell transplantation following treatment plan of Campath-1H, cyclophosphamide, cyclosporine A, mycophenolate mofetil, and busulfan.

Drug: Campath-1H; Administered Days -21, -20 and -19, 0.3 mg/kg subcutaneously (SQ) or intravenously (IV); Other Name: Alemtuzumab; Drug: Cyclophosphamide; Administered days -10 through -6, 50 mg/kg/day intravenous (IV) over 2 hours - with Mesna continuous infusion or 5 times daily.; Other Name: Cytoxan(R); Drug: Busulfan; Administered every 6 hours: If < or = 12 kg then 1.1 mg/kg/dose intravenous (IV). If > 12 kg then 0.8 mg/kg/dose IV; Other Name: Busulfex(R); Procedure: Allogeneic stem cell transplantation; Administered > 24 hours after last dose of busulfan.; Other Name: stem cell transplant; Drug: Cyclosporine A; 2.5 mg/kg/dose intravenous (IV_ beginning on day -3. Frequency of daily dosing will be based on the recipient's body weight: If body weight is ≤ 40 kg dosing will be 3 times daily; If body weight is > 40 kg dosing will be 2 times daily An attempt will be made to maintain a trough cyclosporine level of 250 mg/L to 350 mg/L. Once the patient can tolerate oral medications and has a normal gastrointestinal transit time, CsA will be converted to an oral form at a dose 2 times the current IV dose (maximum 12.5 mg/kg/day as initial oral dose).; Other Name: CsA; Drug: Mycophenolate Mofetil; 15 mg/kg/dose (max dose of 1gram) IV three times a day beginning on Day -3 at a dose based on body weight: The same dosage is used orally or intravenously. Stop MMF at day +42 or 7 days after engraftment achieved (ANC>500 x 10^6 neutrophils/L x 3 days and chimerism >90%), whichever is later.; Other Name: MMF

Outcome Measures

Primary Outcome Measures :

1. Number of Patients With Donor Derived Engraftment [ Time Frame: Day 100 Post Transplant ]
   Donor derived engraftment is defined as 80 percent or greater donor cells in the recipient's bone marrow and blood cells.

Secondary Outcome Measures :

1. Number of Patients With Grade 0 Graft-Versus-Host Disease (GVHD) [ Time Frame: Day 100 Post Transplant ]

   GVHD grading is performed using modified Glucksberg criteria and is as follows:

   grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4

2. Number of Patients With Grade 1 Graft-Versus-Host Disease (GVHD) [ Time Frame: Day 100 Post Transplant ]

   GVHD grading is performed using modified Glucksberg criteria and is as follows:

   grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4

3. Number of Patients With Grade 2 Graft-Versus-Host Disease (GVHD) [ Time Frame: Day 100 Post Transplant ]

   GVHD grading is performed using modified Glucksberg criteria and is as follows:

   grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4

4. Number of Patients With Grade 3 Graft-Versus-Host Disease (GVHD) [ Time Frame: Day 100 Post Transplant ]

   GVHD grading is performed using modified Glucksberg criteria and is as follows:

   grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4

5. Number of Patients With Grade 4 Graft-Versus-Host Disease (GVHD) [ Time Frame: Day 100 Post Transplant ]

   GVHD grading is performed using modified Glucksberg criteria and is as follows:

   grade 0: absence of any skin, liver and/or gastrointestinal (GI) involvement grade 1: skin stage 1 or 2 only grade 2: skin stage 3 or liver stage 1 or lower GI stage 1 or upper GI involvement grade 3: skin stage 0 - 3 plus liver stage 2-4 or lower GI stage 2-3 grade 4: skin stage 4 or lower GI stage 4

6. Number of Patients Who Died Peri-Transplant [ Time Frame: By Day 100 Post Transplant ]
   Peri-transplant is defined as within 100 days of transplant.
7. Donor Cell Chimerism Following Transplant [ Time Frame: Day 28 ]
   Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.
8. Donor Cell Chimerism Following Transplant [ Time Frame: Day 42 ]
   Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.
9. Donor Cell Chimerism Following Transplant [ Time Frame: Day 100 ]
   Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.
10. Donor Cell Chimerism Following Transplant [ Time Frame: 6 months ]
    Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.
11. Donor Cell Chimerism Following Transplant [ Time Frame: One year ]
    Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.

Eligibility Criteria

• Ages Eligible for Study: up to 21 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Must have diagnosis of one of the following: mucopolysaccharidosis disorder, glycoprotein metabolic disorder, sphingolipidoses or inherited leukodystrophy, peroxisomal disorder or other inherited diseases of metabolism
• Must have an acceptable graft source as defined by University of Minnesota criteria
• Adequate organ function

Exclusion Criteria:

• Pregnant - menstruating females must have a negative serum pregnancy test within 14 days of treatment start
• Evidence of human immunodeficiency virus (HIV) infection or known HIV positive serology

Contacts and Locations

Locations

United States, Minnesota

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

More Information

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT01043640
• Other Study ID Numbers: 2009LS088; MT2009-19 ( Other Identifier: Blood and Marrow Transplantation Program )
• First Posted: January 7, 2010
• Results First Posted: May 12, 2017
• Last Update Posted: February 5, 2018
• Last Verified: September 2017

Keywords provided by Masonic Cancer Center, University of Minnesota:

inherited metabolic disorders

Additional relevant MeSH terms:

Adrenoleukodystrophy; Mucopolysaccharidosis II; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Sphingolipidoses; Fucosidosis; Mucopolysaccharidoses; Mannosidase Deficiency Diseases; alpha-Mannosidosis; Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Peroxisomal Disorders; Mucopolysaccharidosis VII; Aspartylglucosaminuria; Metabolic Diseases; Disease; Syndrome; Pathologic Processes; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases