HSCT for High Risk Inherited Inborn Errors

Related Clinical Trial
Study of Disease Progression in Adults With Inherited Forms of Spastic Paraplegia Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy and Metachromatic Leukodystrophy SMART-ALD – A New Lifestyle Intervention to Improve Quality of Life in Women With X-linked Adrenoleukodystrophy (X-ALD) Quality of Life in Women With X-linked Adrenoleukodystrophy A Clinical Study in Male Pediatric Patients With Cerebral X-linked Adrenoleukodystrophy (Cald) to Assess the Effects of MIN-102 Treatment on Disease Progression Prior to Human Stem Cell Transplant (HSCT) Plasma Exchange With Albumin in AMN Patients Stem Cell Transplant for Inborn Errors of Metabolism Human Placental-Derived Stem Cell Transplantation Precision Exercise in Children With Malignant Hemopathies Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders Safety, Pharmacokinetics and Pharmacodynamics of NV1205 in Pediatric Male Subjects With Adrenoleukodystrophy Effect of Pioglitazone Administered to Patients With Adrenomyeloneuropathy MD1003-AMN MD1003 in Adrenomyeloneuropathy A Clinical Study to Evaluate the Efficacy and Safety of MIN-102 (IMP) in Male AMN Patients. Observational Study to Evaluate Allogeneic HSCT Outcomes for Cerebral Adrenoleukodystrophy (CALD) A Clinical Trial for AMN: Validation of Biomarkers of Oxidative Stress, Efficacy and Safety of a Mixture of Antioxidants Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy Clinical Study and Gene Mutation Analysis of Adrenoleukodystrophy in Taiwanese Children Early Diagnosis Of Childhood Cerebral ALD Randomized Study of Beta Interferon and Thalidomide in Patients With Adrenoleukodystrophy Multi-center Clinical Study on the Diagnosis and Treatment Management of Rare Neurological Disease in Children HSCT for High Risk Inherited Inborn Errors Longitudinal Natural History Study of Patients With Peroxisome Biogenesis Disorders (PBD) UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells Study of Pulmonary Complications in Pediatric Patients With Storage Disorders Undergoing Allogeneic Hematopoietic Stem Cell Transplantation Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation (HaploHCT) Following Reduced Intensity Conditioning (RIC) for Selected High Risk Non-Malignant Diseases The Effect of Bezafibrate on the Level of Very Long Chain Fatty Acids (VLCFA) in X-linked Adrenoleukodystrophy (X-ALD) A Phase III Trial of Lorenzo’s Oil in Adrenomyeloneuropathy Lentiviral Gene Therapy for X-ALD MT2014-14 IT-MSC for Advanced Cerebral Adrenoleukodystrophy (cALD) Safety and Pharmacodynamic Study of Sobetirome in X-Linked Adrenoleukodystrophy (X-ALD) Newborn Screening for Adrenoleukodystrophy A Study to Prospectively Assess Disease Progression in Male Children With X-ALD Long-term Follow-up of Subjects With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product Exercise Study of Function and Pathology for Women With X-linked Adrenoleukodystrophy Expanded Access for Lorenzo’s Oil (GTO/GTE) in Adrenoleukodystrophy Minnesota Adrenoleukodystrophy Registry Study (MARS) and Biobank A Pilot Study of Vitamin D in Boys With X-linked Adrenoleukodystrophy Effect of Glycerol Trierucate on Clinical Course of Adrenoleukodystrophy

Brief Title

HSCT for High Risk Inherited Inborn Errors

Official Title

Treatment of High Risk, Inherited Lysosomal And Peroxisomal Disorders by Reduced Intensity Hematopoietic Stem Cell Transplantation

Brief Summary

      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.
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Patients With Donor Cell Engraftment

Secondary Outcome

 Number of Patients Whose Death Was Related to the Transplant

Condition

Adrenoleukodystrophy

Intervention

Clofarabine

Study Arms / Comparison Groups

 Treated Patients
Description:  Patients receiving chemotherapy (Hydroxyurea, Alemtuzumab, Clofarabine, Melphalan), Hematopoietic Stem Cell Transplantation and radiation therapy (Total body Irradiation) mycophenylate mofetil and cyclosporine A.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

38

Start Date

September 2006

Completion Date

September 2014

Primary Completion Date

September 2014

Eligibility Criteria

        Inclusion Criteria:

          -  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:

               1. Age >18 years

               2. MRI score >10

               3. Evidence of aggressive disease that in the judgment of the Inherited Metabolic
                  and Storage Disease group is sufficiently concerning to consider transplantation
                  with a reduced intensity regimen instead of a standard full preparative regimen.

          -  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:

               1. Age >18 years

               2. Symptomatic disease, as based on neurologic examination, or evidence of
                  deterioration based on subsequent neuropsychologic evaluations.

               3. Evidence of aggressive disease such as rapidly changing MRI determinations that
                  in the judgment of the Inherited Metabolic and Storage Disease group is
                  sufficiently concerning to consider transplantation with a reduced intensity
                  regimen instead of a standard full preparative regimen.

          -  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:

               1. Age >18 years

               2. Symptomatic disease, as based on neurologic examination, or evidence of
                  deterioration based on subsequent neuropsychologic evaluations.

               3. Evidence of aggressive disease such as rapidly changing MRI determinations that
                  in the judgment of the Inherited Metabolic and Storage Disease group is
                  sufficiently concerning to consider transplantation with a reduced intensity
                  regimen instead of a standard full preparative regimen.

          -  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:

               1. Symptomatic disease, as based on neurologic examination, or evidence of
                  deterioration based on subsequent neuropsychologic evaluations.

               2. Evidence of an expected poor outcome based on genetic testing or a prior family
                  history of aggressive disease.

               3. Other metabolic disorders, including but not limited to I-cell disease, that are
                  deemed to be high-risk for a poor outcome with a standard transplant regimen due
                  to anticipated toxicity based on experience gained at the University of Minnesota
                  or other centers.

        Exclusion criteria:

          -  Major organ dysfunction.

          -  Advanced Disease Exclusion: Following evaluation, if a consensus of the members of the
             Inherited Metabolic and Storage Disease Program is that a patient is too advanced to
             benefit in a measurable and meaningful way from transplant, this will be communicated
             to the family, and transplant will not be offered. Measures to assist in those
             determinations may include: neurologic/neurocognitive functions such as activities of
             daily living, motor function, vision, hearing, interaction with environment,
             toileting, swallowing, or other standardized measures
      

Gender

All

Ages

N/A - 70 Years

Accepts Healthy Volunteers

No

Contacts

Paul Orchard, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00383448

Organization ID

MT2006-14

Secondary IDs

0606M87246

Responsible Party

Sponsor

Study Sponsor

Masonic Cancer Center, University of Minnesota


Study Sponsor

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


Verification Date

July 2019