Reduced-Intensity Hematopoietic Stem Cell Transplant for High Risk Lysosomal and Peroxisomal Disorders

NCT01626092 | Completed Results DMC

• 2 other identifiers: 2011LS147MT2011-24
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

This study is designed to test the ability to achieve donor hematopoietic engraftment while maintaining low rates of transplant-related mortality (TRM) in patients with high-risk lysosomal and peroxisomal disorders using a novel conditioning regimen for hematopoietic cell transplantation (HCT). After a reduced-intensity conditioning regimen using volumetric-modulated arc therapy (VMAT)-delivered low-dose total body irradiation (TBI) with highly conformal marrow boosting, patients will be transplanted using either a related or unrelated allograft. The cell source may be marrow, peripheral blood or cord blood based on donor availability.

Conditions

Lysosomal Storage Disease; Peroxisomal Disorder

Keywords

bone marrow transplantation; reduced intensity conditioning; Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Wolman's disease; GM1 gangliosidosis; Tay Sachs disease; Sanfilippo syndrome; Sandhoff disease; inherited metabolic; I-cell disease; mucolipidosis II

Outcome Measures

Primary Outcomes (1)

• Donor (Allogeneic) Hematopoietic Engraftment

  Number of patients who achieve hematopoietic engraftment - assessment of nucleated peripheral blood cells for donor (allogeneic) chimerism following this reduced-intensity HCT.

  Day 100 Following Hematopoietic Cell Transplant (HCT)

Secondary Outcomes (2)

• Transplant-Related Mortality

  Day 100 following HCT

• Neurologic Outcomes

  Changes from Baseline, Days 30, 60, 100, Year 1, Year 2, Year 3 Following HCT

Study Arms (1)

Intent-To-Treat Patients

EXPERIMENTAL

Patients with high-risk lysosomal and peroxisomal disorders treated with preparative regimen (Campath-1H 0.3 mg/kg intravenous (IV) on days -12 through -8, clofarabine 40 mg/m\^2 IV on days -9 through -5, melphalan 140 mg/m\^2 IV on day -4 and Total Body Irradiation with Marrow Boosting \[ first dose of 200 cGy single dose; 5 doses of 160cGy for marrow boosting - 1000cGy cumulative exposure\] by Volumetric-Modulated Arc Therapy \[VMAT\] on days -3 through -1). Hematopoietic stem cell transplantation will be infused on Day 0. Post-transplant immunosuppression to follow: Mycophenolate mofetil (MMF) begin day -3 and continue to day +30 or 7 days after engraftment, whichever is later; Cyclosporine A (CsA) begin day -3 and then taper at day +100 if related donor, day +180 for unrelated donor.

Drug: Campath-1H; Drug: Clofarabine; Drug: Melphalan; Radiation: Total Body Irradiation with Marrow Boosting; Biological: Hematopoietic stem cell transplantation; Drug: Cyclosporine A; Drug: Mycophenolate mofetil

Interventions

Campath-1H DRUG

A daily dose of 0.3 mg/kg IV over 2 hours will be administered on days - 12, -11, -10, -9, and -8.

Also known as: alemtuzumab-1H

Intent-To-Treat Patients

Clofarabine DRUG

A daily dose of 40 mg/m2 will be administered IV over 2 hours on days -9, -8, -7, -6, and -5.

Also known as: Clolar

Intent-To-Treat Patients

Melphalan DRUG

A single dose of 140 mg/m2 will be given IV on day -4 over 15 minutes.

Also known as: Alkeran

Intent-To-Treat Patients

Total Body Irradiation with Marrow Boosting RADIATION

1. Dose to total body 200 cGy in single dose 2. Dose to bone marrow of the following bones 800 cGy in 5 divided daily fractions (160 cGy x 5 doses ). Treated with up to 3 abutting VMAT photon arcs from top of head to maximum inferior border.

Also known as: Volumetric-Modulated Arc Therapy (VMAT)

Intent-To-Treat Patients

Hematopoietic stem cell transplantation BIOLOGICAL

Patients will be transplanted using either a related or unrelated allograft. The cell source may be marrow, peripheral blood or cord blood based on donor availability.

Intent-To-Treat Patients

Cyclosporine A DRUG

Patients will receive CsA therapy beginning on day -3. Dosing of CsA will be 2.5 mg/kg/dose 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 200 mg/L to 400 mg/L.

Also known as: CsA

Intent-To-Treat Patients

Mycophenolate mofetil DRUG

Patients will receive mycophenolate mofetil (MMF) therapy beginning on day -3. Dosing of MMF will be 1 gram three times daily (total daily dose 3 grams/day) if the recipient is \>50 kg, or 15 mg/kg/dose three times daily if the recipient is ≤50 kg. The same dosage is used orally or intravenously.

Also known as: MMF

Intent-To-Treat Patients

Eligibility Criteria

• Age: Up to 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Adrenoleukodystrophy (ALD): 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,
• Metachromatic Leukodystrophy (MLD): Patients from 0-55 years of age diagnosed with MLD as determined by arylsulfatase A activity.
• Globoid Cell Leukodystrophy (GLD): Patients from 0-55 years of age diagnosed with GLD as determined by galactocerebrosidase activity will be eligible for this protocol
• Wolman's disease, GM1 gangliosidosis, Tay Sachs disease, Sanfilippo syndrome, Sandhoff disease or other inherited metabolic diseases including but not limited to I-cell disease (mucolipidosis II): Patients 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.
• 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.
• Donor Availability
• Transplantation using sufficiently matched related donors (such as matched siblings) or unrelated donors will be considered. Both granulocyte-colony stimulating factor (G-CSF) stimulated peripheral blood grafts and bone marrow grafts will be considered, although bone marrow will be the priority.
• Cord blood grafts, both related and unrelated, are also eligible. As this protocol will use a reduced intensity regimen, this protocol will use the current recommendations of the University of Minnesota for choosing cord blood grafts. If a single cord blood unit cell dose is insufficient, double cord transplantation should be considered if sufficiently matched cord blood units are available. The priority of choosing cord blood donors is based on the current institutional recommendations.
• Adequate Organ Function - Measured within 30 days of study enrollment
• Signed consent

You may not qualify if:

• Inability to receive total body irradiation (TBI) with marrow boosting per protocol guidelines as determined by the Radiation Oncologist
• Pregnant - Menstruating females must have a negative serum pregnancy test within 14 days of treatment start.

Sponsors & Collaborators

• Masonic Cancer Center, University of Minnesota: lead

Study Sites (1)

Masonic Cancer Center, University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

MeSH Terms

Conditions

Lysosomal Storage Diseases; Peroxisomal Disorders; Adrenoleukodystrophy; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Wolman Disease; Gangliosidosis, GM1; Tay-Sachs Disease; Mucopolysaccharidosis III; Sandhoff Disease; Mucolipidoses

Interventions

Alemtuzumab; Clofarabine; Melphalan; Whole-Body Irradiation; Radiotherapy, Intensity-Modulated; Hematopoietic Stem Cell Transplantation; Cyclosporine; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; 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; Heredodegenerative Disorders, Nervous System; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases; Sulfatidosis; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders; Cholesterol Ester Storage Disease; Infant, Newborn, Diseases; Gangliosidoses; Gangliosidoses, GM2; Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Weston P Miller, MD
• Organization: Masonic Cancer Center, University of Minnesota

mill4991@umn.edu

612-626-2778

Study Officials

• Weston Miller, MD

  Masonic Cancer Center, University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2012
• First Posted: June 22, 2012
• Study Start: July 11, 2012
• Primary Completion: November 1, 2013
• Study Completion: November 1, 2013
• Last Updated: December 5, 2017
• Results First Posted: October 11, 2016

Record last verified: 2017-12

Locations

US (1)