HSCT for High Risk Inherited Inborn Errors

NCT00383448 | Completed Phase 2 Results

• 2 other identifiers: MT2006-140606M87246
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

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.

Conditions

Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Tay Sachs Disease; Sandhoffs Disease; Wolman Disease; I-Cell Disease; Sanfilippo Syndrome; GM1 Gangliosidosis

Keywords

Stem cell transplantation; Inborn errors of metabolism; Adrenoleukodystrophy (ALD); Metachromatic leukodystrophy (MLD); Globoid cell leukodystrophy (GLD or Krabbe); Tay Sachs; Sandhoff; Sanfilippo syndrome; Mucopolysaccharidosis III (MPS-III); GM1 gangliosidosis; I-cell; mucolipidosis

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Donor Cell Engraftment

  Donor Cell Engraftment is defined as the process of transplanted stem cells reproducing new cells.

  Day 100

Secondary Outcomes (4)

• Number of Patients Whose Death Was Related to the Transplant

  Day 100

• Concentrations of Mycophenylate Mofetil (MMF)

  Day 3

• Number of Patients With Acute Graft Versus Host Disease (GVHD)

  Day 100

• Number of Patients With Chronic Graft Versus Host Disease (GVHD)

  1 year

Study Arms (1)

Treated Patients

EXPERIMENTAL

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

Interventions

Clofarabine DRUG

days -7 through -3: 40 mg/m\^2 intravenously over 2 hours

Also known as: Clolar

Treated Patients

Total body Irradiation PROCEDURE

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

Treated Patients

Melphalan DRUG

day -2: 140 mg/m\^2 intravenously over 30 minutes

Also known as: Alkeran

Treated Patients

Hematopoietic Stem Cell Transplantation BIOLOGICAL

receives infusion of stem cells on day 0

Treated Patients

Alemtuzumab DRUG

0.3 mg/kg intravenously (IV) days -12 through -8

Also known as: Campath 1-H

Treated Patients

mycophenylate mofetil DRUG

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

Treated Patients

Cyclosporine A DEVICE

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

Treated Patients

Hydroxyurea DRUG

hydroxyurea (HU) beginning day -28 and continuing through alemtuzumab administration

Also known as: Hydria, HU

Treated Patients

Eligibility Criteria

• Age: Up to 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Age \>18 years
• MRI score \>10
• 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:
• Age \>18 years
• Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
• 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:
• Age \>18 years
• Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
• 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:
• Symptomatic disease, as based on neurologic examination, or evidence of deterioration based on subsequent neuropsychologic evaluations.
• Evidence of an expected poor outcome based on genetic testing or a prior family history of aggressive disease.

You may not qualify if:

• Major organ dysfunction.

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead

Study Sites (1)

Masonic Cancer Center, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (1)

• Miller WP, Rothman SM, Nascene D, Kivisto T, DeFor TE, Ziegler RS, Eisengart J, Leiser K, Raymond G, Lund TC, Tolar J, Orchard PJ. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy: the largest single-institution cohort report. Blood. 2011 Aug 18;118(7):1971-8. doi: 10.1182/blood-2011-01-329235. Epub 2011 May 17.

  PMID: 21586746 DERIVED

MeSH Terms

Conditions

Adrenoleukodystrophy; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Tay-Sachs Disease; Sandhoff Disease; Wolman Disease; Mucolipidoses; Mucopolysaccharidosis III; Gangliosidosis, GM1; Metabolism, Inborn Errors

Interventions

Clofarabine; Whole-Body Irradiation; Melphalan; Hematopoietic Stem Cell Transplantation; Alemtuzumab; Hydroxyurea

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Demyelinating Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System; Peroxisomal Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases; Sulfatidosis; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Gangliosidoses, GM2; Gangliosidoses; Cholesterol Ester Storage Disease; Infant, Newborn, Diseases; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Carbohydrate Metabolism, Inborn Errors; Mucopolysaccharidoses; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides; Radiotherapy; Therapeutics; Investigative Techniques; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phenylalanine; Amino Acids, Aromatic; Amino Acids, Cyclic; Amino Acids; Amino Acids, Peptides, and Proteins; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Urea; Amides

Limitations and Caveats

Because the diseases being treated on this study are rare, our intent was to only report these outcomes in context with other protocols. The data was collected, but is not interpretable without combining the data with additional studies.

Results Point of Contact

• Title: Dr. Paul Orchard
• Organization: Masonic Cancer Center, University of Minnesota

orcha001@umn.edu

612-626-2313

Study Officials

• Paul Orchard, MD

  Masonic Cancer Center, University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2006
• First Posted: October 3, 2006
• Study Start: September 1, 2006
• Primary Completion: September 1, 2014
• Study Completion: September 1, 2014
• Last Updated: July 11, 2019
• Results First Posted: July 11, 2019

Record last verified: 2019-07

Locations

US (1)