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MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2016 by Masonic Cancer Center, University of Minnesota
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT02171104
First received: June 20, 2014
Last updated: August 15, 2016
Last verified: August 2016
  Purpose
This study aims to test the effectiveness and safety of a novel conditioning regimen in attaining donor blood stem cell engraftment in persons with certain inherited metabolic disorders, severe osteopetrosis and males with Rett syndrome who undergo blood stem cell transplantation.

Condition Intervention Phase
Mucopolysaccharidosis I
Mucopolysaccharidosis II
Mucopolysaccharidosis VI
Mucopolysaccharidosis VII
Hurler Syndrome
Hunter Syndrome
Maroteaux Lamy Syndrome
Sly Syndrome
Glycoprotein Metabolic Disorders
Alpha Mannosidosis
Fucosidosis
Aspartylglucosaminuria
Adrenoleukodystrophy
Peroxisomal Disorders
Osteopetrosis
Sphingolipidosis
Gangliosidosis
Globoid Cell Leukodystrophy
Metachromatic Leukodystrophy
Niemann Pick B
Niemann Pick C Subtype 2
I-cell Disease
Procedure: blood stem cell transplant
Drug: Rabbit Anti-Thymocyte Globulin (ATG)
Drug: Fludarabine
Drug: Busulfan
Drug: Cyclophosphamide
Drug: Cyclosporine A (CSA)
Drug: Methylprednisolone
Drug: Mycophenolate Mofetil (MMF)
Drug: Granulocyte-Colony Stimulating Factor (G-CSF)
Drug: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)
Drug: N-acetylcysteine
Drug: Celecoxib
Drug: Vitamin E
Drug: Alpha Lipoic Acid
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: MT2013-31: Allogeneic Hematopoietic Cell Transplantation for Inherited Metabolic Disorders and Severe Osteopetrosis Following Conditioning With Busulfan (Therapeutic Drug Monitoring), Fludarabine +/- ATG

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • percentage of subjects who achieve high-level donor hematopoietic engraftment (defined as neutrophil recovery by Day +42 post-transplant and ≥ 80% donor cells on the myeloid fraction of peripheral blood at Day +100 post-transplant) [ Time Frame: neutrophil recovery by Day +42 post-transplant and ≥ 80% donor cells on the myeloid fraction of peripheral blood at Day +100 post-transplant ]

Secondary Outcome Measures:
  • percentage of subjects who develop graft-versus-host disease [ Time Frame: by Day +100 post-transplant ]
  • number of subjects who die from transplant complications [ Time Frame: Day +100 days post-transplant ]
  • incidence of regimen-related toxicity (such as infection, acute renal failure, respiratory failure, cardiac failure, and veno-occlusive disease) [ Time Frame: Day +100 post-transplant ]
  • incidence of radiographic, physiologic, neuro-psychologic, and/or biochemical changes [ Time Frame: at 6 months, 1 year and yearly for a total of 5 years ]

Estimated Enrollment: 100
Study Start Date: July 2014
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: September 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Allo HCT following Conditioning w/Busulfan, Fludarabine +/-ATG
See intervention descriptions.
Procedure: blood stem cell transplant

Patients with various Inherited Metabolic Disorders and males with Rett syndrome:

PBSC: ≥ 10 x 106 CD34+ cells (max. 20 x 106)/kg recipient body weight

Related and Unrelated Bone Marrow: ≥ 2.5 x 108 nucleated cells (target ≥ 5 x 108)/kg recipient body weight

UCB: unit(s) selected in accordance with the protocol and with the University of Minnesota Umbilical Cord Blood Graft Selection Algorithm

Patients with Osteopetrosis:

PBSC: ≥ 15 x 106 CD34+ cells (max. 20 x 106)/kg recipient body weight

Related and Unrelated Bone Marrow: ≥ 2.5 x 108 nucleated cells (target ≥ 6 x 108)/kg recipient body weight

UCB: unit(s) selected in accordance with the protocol and with the University of Minnesota Umbilical Cord Blood Graft Selection Algorithm

Drug: Rabbit Anti-Thymocyte Globulin (ATG)

2.5 mg/kg IV once daily for 4 consecutive days (total = 10 mg/kg IV)

Graft Source:

UCB: Days -8, -7, -6, -5

HLA-matched sibling donor: no ATG will be used

Other graft: Days -5, -4, -3, -2

Drug: Fludarabine
All Patients: 40 mg/m2 IV once daily, days -5, -4, -3 and -2 (total preparative regimen exposure = 160 mg/m2)
Drug: Busulfan

Patients with IMD and males with Rett syndrome: Once daily IV, days -5, -4, -3 and -2 (total preparative regimen drug exposure, AUCcum targeted to 21,000 - 22,000 µM•min∙L-1)

Osteopetrosis Recipients of Bone Marrow or Peripheral Blood Stem Cell Grafts (Including Haplo): Once daily IV, days -3 and -2 (total preparative regimen drug exposure, AUCcum, targeted to 10,000 - 11,000 µM•min∙L-1)

Osteopetrosis Recipients of Umbilical Cord Blood: Once daily IV, days -5, -4, -3 and -2 (total preparative regimen drug exposure, AUCcum, targeted to 21,000 - 22,000 µM•min∙L-1)

Drug: Cyclophosphamide
Osteopetrosis patients receiving haploidentical graft: 50 mg/kg IV once daily, days +3 and +4 (total exposure = 100 mg/kg IV) utilizing hyperhydration and MESNA
Drug: Cyclosporine A (CSA)

Osteopetrosis patients receiving haploidentical graft: Begin Day +5

All other patients, all graft sources: Begin Day -2

Drug: Methylprednisolone
All UCB Recipients, All Diagnoses: Day 0 through Day +42
Drug: Mycophenolate Mofetil (MMF)

Osteopetrosis patient receiving haploidentical graft: Begin Day +5 through Day +30

All other diagnoses receiving any graft other than UCB: Begin Day -2 through Day +30

Dosing: 15 mg/kg (maximum 1 gram), three times daily

Drug: Granulocyte-Colony Stimulating Factor (G-CSF)

Patients with IMD and males with Rett syndrome:

UCB Recipients Only: 5 mcg/kg IV once daily. Begin day +1 and continue through ANC > 2,500 /μL x 2 consecutive days

Drug: Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)

Patients with Osteopetrosis:

Recipients of Haploidentical Grafts: 250 mcg/m2 IV once daily. Begin day +5. Continue GM-CSF through ANC > 2,500 /μL x 2 consecutive days

Recipients of any graft other than a Haploidentical Graft: 250 mcg/m2 IV once daily. Begin day +1. Continue GM-CSF through ANC > 2,500 /μL x 2 consecutive days

Drug: N-acetylcysteine

Cerebral Adrenoleukodystrophy (c-ALD) Patients Only (as part of a mandatory randomized 4 arm sub-study of anti-oxidant and anti-inflammatory supportive care):

Standard-Risk, Regimen A: Beginning after the preparative regimen (day +1), 70 mg/kg/dose IV, every 6 hours (while inpatient) and 3 times daily (once outpatient), through day +28

Standard-Risk, Regimen B: Beginning after the preparative regimen (day +1), 70 mg/kg/dose IV, every 6 hours (while inpatient) and 3 times daily (once outpatient), through day +56

High-Risk, Regimen C: Beginning just prior to the preparative regimen (day -8 or -5, depending upon the graft source), 70 mg/kg/dose IV, every 6 hours (while inpatient) and 3 times daily (once outpatient), through day +100

High-Risk, Regimen D: Beginning just prior to the preparative regimen (day -8 or -5, depending upon the graft source), 70 mg/kg/dose IV, every 6 hours (while inpatient) and 3 times daily (once outpatient), through day +100

Drug: Celecoxib

Cerebral Adrenoleukodystrophy (c-ALD) Patients Only (as part of a mandatory randomized 4 arm sub-study of anti-oxidant and anti-inflammatory supportive care):

High-Risk, Regimen C and D: Beginning at the start of the preparative regimen (day -8 or - 5, depending upon the graft source) and continuing through day +100 Patients >25 kg: 100 mg PO twice daily Patients ≥ 10 kg and ≤ 25 kg: 50 mg PO twice daily

Drug: Vitamin E

Cerebral Adrenoleukodystrophy (c-ALD) Patients Only (as part of a mandatory randomized 4 arm sub-study of anti-oxidant and anti-inflammatory supportive care):

High-Risk, Regimen D: 300 mg PO daily, beginning at the start of the preparative regimen (day -8 or -5, depending upon the graft source) and continuing through day +100

Drug: Alpha Lipoic Acid

Cerebral Adrenoleukodystrophy (c-ALD) Patients Only (as part of a mandatory randomized 4 arm sub-study of anti-oxidant and anti-inflammatory supportive care):

High-Risk, Regimen D: 200 mg PO twice daily, beginning at the start of the preparative regimen (day -8 or -5, depending upon the graft source) and continuing through day +100


Detailed Description:
This single-institution, phase II study is designed to test the ability to achieve donor hematopoietic engraftment while maintaining low rates of transplant-related mortality (TRM) using a busulfan- and fludarabine-based conditioning regimen with busulfan therapeutic drug monitoring (TDM) for patients with certain inherited metabolic disorders (IMD), severe osteopetrosis and males with Rett syndrome. Additionally, this study will explore the efficacy of various anti-oxidant and anti-inflammatory regimens in patients undergoing HCT for cerebral adrenoleukodystrophy.
  Eligibility

Ages Eligible for Study:   up to 55 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 0 through 55 years of age
  • Adequate graft available
  • Adequate organ function

Exclusion Criteria:

  • Any patient who in the judgment of the University of Minnesota Inherited Metabolic and Storage Disease Group has disease that is not likely to benefit from allogeneic HSCT, based on its nature, severity or state of progression
  • Prior myeloablative chemotherapy exposure within 4 months of the start of conditioning on this protocol
  • Uncontrolled bacterial, fungal or viral infections including HIV
  • Pregnancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02171104

Contacts
Contact: Weston Miller, M.D. 612-626-2778 mill4991@umn.edu
Contact: Patty Kleinke 612-273-0857 pkleink1@fairview.org

Locations
United States, Minnesota
University of Minnesota Medical Center, Fairview Recruiting
Minneapolis, Minnesota, United States, 55455
Sub-Investigator: Troy Lund, M.D.         
Sub-Investigator: David Nascene, M.D.         
Sub-Investigator: Paul Orchard, M.D.         
Sub-Investigator: Gerald Raymond, M.D.         
Sub-Investigator: Jakub Tolar, M.D.         
Sub-Investigator: John Wagner, M.D.         
Sub-Investigator: Shernan G Holtan, M.D.         
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Weston Miller, M.D. Masonic Cancer Center, University of Minnesota
  More Information

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT02171104     History of Changes
Other Study ID Numbers: 2013LS104 
Study First Received: June 20, 2014
Last Updated: August 15, 2016

Keywords provided by Masonic Cancer Center, University of Minnesota:
Hurler syndrome
Hunter syndrome
Maroteaux Lamy syndrome
Sly syndrome
Sanfilippo syndrome
allogeneic hematopoietic cell transplantation
bone marrow transplantation
Mucopolysaccharidosis I
Mucopolysaccharidosis II
Mucopolysaccharidosis VI
Mucopolysaccharidosis VII
Glycoprotein Metabolic Disorders
Alpha Mannosidosis
Fucosidosis
Aspartylglucosaminuria
Adrenoleukodystrophy
Peroxisomal Disorders
Osteopetrosis
Sphingolipidosis
Gangliosidosis
Globoid Cell Leukodystrophy
Metachromatic Leukodystrophy
Niemann Pick B
Niemann Pick C subtype 2
I-cell disease
Mucolipidosis
Wolmans disease
Sandhoff disease
Inherited Metabolic

Additional relevant MeSH terms:
Syndrome
Disease
Mucopolysaccharidoses
Mucopolysaccharidosis II
Adrenoleukodystrophy
Leukodystrophy, Metachromatic
Mucopolysaccharidosis I
Gangliosidoses
Metabolic Diseases
Aspartylglucosaminuria
Mucopolysaccharidosis VII
Mucolipidoses
Fucosidosis
Peroxisomal Disorders
Sphingolipidoses
Mucopolysaccharidosis VI
Leukodystrophy, Globoid Cell
Osteopetrosis
Mannosidase Deficiency Diseases
alpha-Mannosidosis
Pathologic Processes
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations

ClinicalTrials.gov processed this record on February 20, 2017