Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders

Allogeneic Hematopoietic Stem Cell Transplantation for Standard Risk Inherited Metabolic Disorders

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.

Study Overview

• Status: Completed
• Conditions: Mucopolysaccharidosis; Hurler Syndrome; Sphingolipidoses; Peroxisomal Disorders; Krabbe Disease; Adrenoleukodystrophy (ALD); Hunter Syndrome; Sly Syndrome; Fucosidosis; Aspartylglucosaminuria; Alpha Mannosidosis; Metachromatic Leukodystrophy (MLD); Maroteaux-Lamy Syndrome
• Intervention / Treatment: Drug: Campath-1H; Drug: Cyclophosphamide; Drug: Busulfan; Procedure: Allogeneic stem cell transplantation; Drug: Cyclosporine A; Drug: Mycophenolate Mofetil

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 Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: Busulfex(R); Procedure: Allogeneic stem cell transplantation; Administered > 24 hours after last dose of busulfan.; Other Names: 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 Names: 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 Names: MMF

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Grade 0 Graft-Versus-Host Disease (GVHD)	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	Day 100 Post Transplant
Number of Patients With Grade 1 Graft-Versus-Host Disease (GVHD)	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	Day 100 Post Transplant
Number of Patients With Grade 2 Graft-Versus-Host Disease (GVHD)	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	Day 100 Post Transplant
Number of Patients With Grade 3 Graft-Versus-Host Disease (GVHD)	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	Day 100 Post Transplant
Number of Patients With Grade 4 Graft-Versus-Host Disease (GVHD)	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	Day 100 Post Transplant
Number of Patients Who Died Peri-Transplant	Peri-transplant is defined as within 100 days of transplant.	By Day 100 Post Transplant
Donor Cell Chimerism Following Transplant	Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.	Day 28
Donor Cell Chimerism Following Transplant	Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.	Day 42
Donor Cell Chimerism Following Transplant	Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.	Day 100
Donor Cell Chimerism Following Transplant	Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.	6 months
Donor Cell Chimerism Following Transplant	Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin.	One year

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (ACTUAL): June 1, 2015
• Study Completion (ACTUAL): June 1, 2017

Study Registration Dates

• First Submitted: January 5, 2010
• First Submitted That Met QC Criteria: January 6, 2010
• First Posted (ESTIMATE): January 7, 2010

Study Record Updates

• Last Update Posted (ACTUAL): February 5, 2018
• Last Update Submitted That Met QC Criteria: January 9, 2018
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: inherited metabolic disorders
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Leukoencephalopathies; Adrenal Gland Diseases; Hereditary Central Nervous System Demyelinating Diseases; Adrenal Insufficiency; Sulfatidosis; Syndrome; Disease; Mucopolysaccharidosis II; Mucopolysaccharidoses; Mucopolysaccharidosis I; Metabolic Diseases; Peroxisomal Disorders; Adrenoleukodystrophy; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Sphingolipidoses; Mannosidase Deficiency Diseases; alpha-Mannosidosis; Fucosidosis; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Aspartylglucosaminuria; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Mycophenolic Acid; Busulfan; Cyclosporine; Cyclosporins; Alemtuzumab
• Other Study ID Numbers: 2009LS088; MT2009-19 (OTHER: Blood and Marrow Transplantation Program)