Adrenoleukodystrophy (ALD), Alpha Mannosidosis, Aspartylglucosaminuria, Fucosidosis, Hunter Syndrome, Hurler Syndrome, Krabbe Disease, Maroteaux-Lamy Syndrome, Metachromatic Leukodystrophy (MLD), Mucopolysaccharidosis, Peroxisomal Disorders, Sly Syndrome, Sphingolipidoses
Conditions
Keywords
inherited metabolic disorders
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.
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.
Interventions
DRUGCampath-1H
Administered Days -21, -20 and -19, 0.3 mg/kg subcutaneously (SQ) or intravenously (IV)
DRUGCyclophosphamide
Administered days -10 through -6, 50 mg/kg/day intravenous (IV) over 2 hours - with Mesna continuous infusion or 5 times daily.
DRUGBusulfan
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
PROCEDUREAllogeneic stem cell transplantation
Administered \> 24 hours after last dose of busulfan.
DRUGCyclosporine 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).
DRUGMycophenolate 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.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Donor Derived Engraftment | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Grade 1 Graft-Versus-Host Disease (GVHD) | 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 |
| Number of Patients With Grade 2 Graft-Versus-Host Disease (GVHD) | 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 |
| Number of Patients With Grade 3 Graft-Versus-Host Disease (GVHD) | 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 |
| Number of Patients With Grade 0 Graft-Versus-Host Disease (GVHD) | 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 |
| Number of Patients Who Died Peri-Transplant | By Day 100 Post Transplant | Peri-transplant is defined as within 100 days of transplant. |
| Donor Cell Chimerism Following Transplant | Day 28 | Donor cell chimerism is defined as the percentage of bone marrow and blood cells in the recipient that are of donor origin. |
| Number of Patients With Grade 4 Graft-Versus-Host Disease (GVHD) | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Transplant Patients Includes patients who received allogeneic stem cell transplantation following treatment plan of Campath-1H, cyclophosphamide, cyclosporine A, mycophenolate mofetil, and busulfan.
Campath-1H: Days -21, -20 and -19, 0.3 mg/kg SQ or IV Cyclophosphamide: Days -10 through -6, 50 mg/kg/day IV with Mesna Busulfan: Days -5 through Day -2, 1.1 mg/kg/dose IV if ≤ 12 kg; 0.8 mg/kg/dose IV if \> 12 kg Allogeneic stem cell transplantation: \> 24 hours after last dose of busulfan Cyclosporine A: 2.5 mg/kg/dose IV beginning on day -3. Dosing will be 3 times daily if body weight is ≤ 40 kg and 2 times daily if body weight is \> 40 kg
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:
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. | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | Transplant Patients |
|---|---|
| Age, Categorical <=18 years | 46 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 40 / 46 |
| serious Total, serious adverse events | 8 / 46 |
Outcome results
Primary
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.
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant Patients | Number of Patients With Donor Derived Engraftment | 42 Participants |
Secondary
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.
Time frame: One year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transplant Patients | Donor Cell Chimerism Following Transplant | 99 percentage of donor cells | Standard Deviation 4 |
Secondary
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.
Time frame: Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transplant Patients | Donor Cell Chimerism Following Transplant | 95 percentage of donor cells | Standard Deviation 9 |
Secondary
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.
Time frame: Day 42
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transplant Patients | Donor Cell Chimerism Following Transplant | 93 percentage of donor cells | Standard Deviation 15 |
Secondary
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.
Time frame: Day 100
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transplant Patients | Donor Cell Chimerism Following Transplant | 90 percentage of donor cells | Standard Deviation 26 |
Secondary
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.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Transplant Patients | Donor Cell Chimerism Following Transplant | 94 percentage of donor cells | Standard Deviation 22 |
Secondary
Number of Patients Who Died Peri-Transplant
Peri-transplant is defined as within 100 days of transplant.
Time frame: By Day 100 Post Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant Patients | Number of Patients Who Died Peri-Transplant | 2 Participants |
Secondary
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
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant Patients | Number of Patients With Grade 0 Graft-Versus-Host Disease (GVHD) | 32 Participants |
Secondary
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
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant Patients | Number of Patients With Grade 1 Graft-Versus-Host Disease (GVHD) | 2 Participants |
Secondary
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
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant Patients | Number of Patients With Grade 2 Graft-Versus-Host Disease (GVHD) | 5 Participants |
Secondary
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
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant Patients | Number of Patients With Grade 3 Graft-Versus-Host Disease (GVHD) | 2 Participants |
Secondary
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
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Transplant Patients | Number of Patients With Grade 4 Graft-Versus-Host Disease (GVHD) | 5 Participants |