HSCT for High Risk Inherited Inborn Errors

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 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

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