A Phase 2 interventional study of Clofarabine and Total body Irradiation in Adrenoleukodystrophy, Metachromatic Leukodystrophy and Globoid Cell Leukodystrophy, sponsored by Masonic Cancer Center, University of Minnesota. Completed at 1 site in United States. Open to participants aged Up to 70 Years. Per ClinicalTrials.gov, last updated 2019-07-11.
Sponsored by Masonic Cancer Center, University of Minnesota · Phase 2, Interventional, and Treatment
Hematopoietic stem cell transplantation has proven effective therapy for individuals with adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD, or Krabbe disease). This protocol also considers other inherited metabolic diseases such as, but not limited to, GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome or Sandhoff disease, I-cell disease (mucolipidosis II).
For patients with advanced or rapidly progressive disease, the morbidity and mortality with transplantation is unacceptably high. Unfortunately, there are no viable alternative therapeutic options for these patients; if transplantation is not performed the patients are sent home to die. Our group at Minnesota has developed a new protocol incorporating transplantation using a reduced intensity conditioning regimen designed to decrease toxicity associated with the transplant procedure. This regimen will make use of the drug clofarabine, which has lympholytic and immune suppressive properties without the neurologic toxicity observed in the related compound, fludarabine, commonly used for transplantation. In addition, several agents providing anti-oxidant and anti-inflammatory properties will be used to assist in the stabilization of the disease processes. This revised transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol, 2) the mortality associated with transplant by day 100, 3) patient outcomes, based on differential neurologic, neuropsychologic, imaging and biologic evaluations prior to transplantation and at designated points after transplantation (day 100, 6 months, 1, 2 and 5 years). Additional biologic studies will include pharmacokinetics of clofarabine and mycophenolate mofetil (MMF). In addition, for patients undergoing lumbar puncture studies, cerebrospinal fluid (CSF) will be requested for determinations of biologic parameters.
Hematopoietic stem cell transplantation has proven effective therapy for individuals with adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD) or globoid cell leukodystrophy (GLD, or Krabbe disease). However, for patients with advanced or rapidly progressive disease, the morbidity and mortality with transplantation is unacceptably high. Unfortunately, there are no viable alternative therapeutic options for these patients; if transplantation is not performed the patients are sent home to die. Our group at Minnesota has developed a new protocol incorporating transplantation using a reduced intensity conditioning regimen designed to decrease toxicity associated with the transplant procedure. This regimen will make use of the drug clofarabine, which has lympholytic and immune suppressive properties without the neurologic toxicity observed in the related compound, fludarabine, commonly used for transplantation. In addition, several agents providing anti-oxidant and anti-inflammatory properties will be used to assist in the stabilization of the disease processes. This revised transplant protocol will test the following: 1) the ability to achieve engraftment with the reduced intensity protocol, 2) the mortality associated with transplant by day 100, 3) patient outcomes, based on differential neurologic, neuropsychologic, imaging and biologic evaluations prior to transplantation and at designated points after transplantation (day 100, 6 months, 1, 2 and 5 years). Additional biologic studies will include pharmacokinetics of clofarabine and mycophenolate mofetil (MMF), develop experience in kinetics of N-acetylcysteine, and evaluate biologic markers of oxidative status during transplantation. In addition, for patients undergoing lumbar puncture studies, cerebrospinal fluid (CSF) will be requested for determinations of biologic parameters.
68 studies on the registry are indexed under Adrenoleukodystrophy; 19 are open to participants now.
This study's enrollment of 38 is above the median of 31 across 40 interventional studies indexed under Adrenoleukodystrophy.
Browse Adrenoleukodystrophy studies →Masonic Cancer Center, University of Minnesota is the lead sponsor of 286 studies on the registry; 35 are open to participants now.
Of its 39 completed or terminated interventional studies of FDA-regulated products, 28 (72%) have results posted.
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Adrenoleukodystrophy: Patients from 0-55 years of age diagnosed with ALD as determined by very long chain fatty acid testing will be eligible for this protocol if they have evidence of cerebral or cerebellar disease based on MRI testing, AND they are determined high risk for any of the following reasons:
Metachromatic Leukodystrophy: Patients from 0-55 years of age diagnosed with MLD as determined by determinations of arylsulfatase A testing will be eligible for this protocol IF they are determined high risk for any of the following reasons:
Globoid Cell Leukodystrophy: Patients from 0-55 years of age diagnosed with GLD as determined by determinations of galactocerebrosidase testing will be eligible for this protocol IF they are determined high risk for any of the following reasons:
Patients with GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome, Wolman disease or Sandhoff disease or other inherited metabolic diseases including but not limited to I-cell disease (mucolipidosis II) who are determined to be sufficiently advanced or high risk based on the following reasons:
Exclusion criteria:
Patients receiving chemotherapy (Hydroxyurea, Alemtuzumab, Clofarabine, Melphalan), Hematopoietic Stem Cell Transplantation and radiation therapy (Total body Irradiation) mycophenylate mofetil and cyclosporine A.
Drug: Clofarabine · Procedure: Total body Irradiation · Drug: Melphalan · Biological: Hematopoietic Stem Cell Transplantation · Drug: Alemtuzumab · Drug: mycophenylate mofetil · Device: Cyclosporine A · Drug: Hydroxyurea
days -7 through -3: 40 mg/m\^2 intravenously over 2 hours
Also known as: Clolar
Administration of TBI: The dose of TBI will be 200 cGy given in a single fraction on day -1. The dose rate will be between 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
Also known as: TLI
day -2: 140 mg/m\^2 intravenously over 30 minutes
Also known as: Alkeran
receives infusion of stem cells on day 0
0.3 mg/kg intravenously (IV) days -12 through -8
Also known as: Campath 1-H
Day -3 through Day 30: 1 gram three times daily (total daily dose 3 grams/day) if the recipient is \>50 kg, or 15 mg/kg three times daily if the recipient is ≤50 kg. The same dosage is used orally or intravenously. Consider dose modification if renal impairment (GFR\<25 mL/minute corrected)
Also known as: MMF
Patients will receive CsA therapy beginning on day -3. Dosing of CsA will be 2.5 mg/kg/dose intravenously (IV); if the recipient body weight is \<40 kg, dosing will be 3 times daily, and if \> 40 kg twice 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 2.5 x the current IV dose (maximum 12.5 mg/kg/day as initial oral dose). CsA taper begins at day +100.
Also known as: CsA
hydroxyurea (HU) beginning day -28 and continuing through alemtuzumab administration
Also known as: Hydria, HU
Number of Patients With Donor Cell Engraftment
Donor Cell Engraftment is defined as the process of transplanted stem cells reproducing new cells.
Time frame: Day 100
Number of Patients Whose Death Was Related to the Transplant
In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation.
Time frame: Day 100
Concentrations of Mycophenylate Mofetil (MMF)
MMF levels are to be sent on day +3 to the main laboratory for determinations of MMF kinetics. Data was not collected on this outcome measure and is not available for reporting.
Time frame: Day 3
Number of Patients With Acute Graft Versus Host Disease (GVHD)
Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host. Acute GVHD can occur once the donor's cells have engrafted in the transplant recipient. The symptoms typically appear within weeks after transplant.
Time frame: Day 100
Number of Patients With Chronic Graft Versus Host Disease (GVHD)
Graft-Versus-Host Disease is a severe complication created by infusion of donor cells into a foreign host. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant.
Time frame: 1 year
| Milestone | Treated Patients |
|---|---|
| Started | 38 |
| Completed | 38 |
| Not completed | 0 |
Donor Cell Engraftment is defined as the process of transplanted stem cells reproducing new cells.
| Participants | Treated Patients |
|---|---|
| Number of Patients With Donor Cell Engraftment | 26 |
In the field of transplantation, toxicity is high and all deaths without previous relapse or progression are usually considered as related to transplantation.
| Participants | Treated Patients |
|---|---|
| Number of Patients Whose Death Was Related to the Transplant | 2 |
MMF levels are to be sent on day +3 to the main laboratory for determinations of MMF kinetics. Data was not collected on this outcome measure and is not available for reporting.
No measurements were reported for this outcome.
Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host. Acute GVHD can occur once the donor's cells have engrafted in the transplant recipient. The symptoms typically appear within weeks after transplant.
| Participants | Treated Patients |
|---|---|
| Number of Patients With Acute Graft Versus Host Disease (GVHD) | 3 |
Graft-Versus-Host Disease is a severe complication created by infusion of donor cells into a foreign host. Chronic GVHD can appear at any time after allogeneic transplant or several years after transplant.
| Participants | Treated Patients |
|---|---|
| Number of Patients With Chronic Graft Versus Host Disease (GVHD) | 2 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Treated Patients | — | 10/38 (26.3%) | 33/38 (86.8%) |
| Event | Treated Patients |
|---|---|
| Disease ProgressionGeneral disorders | 4/38 |
| Graft FailureGeneral disorders | 4/38 |
| Death Due to Disease ProgressionGeneral disorders | 2/38 |
| Infection with Grade 3 or 4 NeutrophilsInfections and infestations | 1/38 |
| Event | Treated Patients |
|---|---|
| PneumoniaInfections and infestations | 14/38 |
| Bacterial Infection, BloodInfections and infestations | 12/38 |
| Bacterial Infection, FecesInfections and infestations | 10/38 |
| Requires Intubation, NOSRespiratory, thoracic and mediastinal disorders | 9/38 |
| SeizuresNervous system disorders | 8/38 |
| Viral Infection, BloodInfections and infestations | 7/38 |
| Pericardial EffusionCardiac disorders | 7/38 |
| Viral Infection, RespiratoryInfections and infestations | 6/38 |
| HypertensionVascular disorders | 6/38 |
| Bacterial Infection, UrineInfections and infestations | 5/38 |
| Age, Categorical(Participants) | Treated Patients |
|---|---|
| <=18 years | 32 |
| Between 18 and 65 years | 6 |
| >=65 years | 0 |
| Sex: Female, Male(Participants) | Treated Patients |
|---|---|
| Female | 8 |
| Male | 30 |
The record gives a start of Sep 2006, a primary completion of Sep 2014 and a completion of Sep 2014. It does not say whether these dates are actual or estimated.
Results were first posted in Jul 2019, 4 years 10 months after primary completion.
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