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

Purpose

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 busulfan- and fludarabine-based conditioning regimens with busulfan therapeutic drug monitoring (TDM) for patients with various inherited metabolic disorders (IMD) and severe osteopetrosis (OP).

Condition	Intervention	Phase
Mucopolysaccharidosis Disorders Hurler Syndrome Hunter Syndrome Maroteaux Lamy Syndrome Sly Syndrome Alpha-Mannosidosis Fucosidosis Aspartylglucosaminuria Glycoprotein Metabolic Disorders Sphingolipidoses Recessive Leukodystrophies Globoid Cell Leukodystrophy Metachromatic Leukodystrophy Niemann-Pick B Niemann-Pick C Subtype 2 Sphingomyelin Deficiency Peroxisomal Disorders Adrenoleukodystrophy With Cerebral Involvement Zellweger Syndrome Neonatal Adrenoleukodystrophy Infantile Refsum Disease Acyl-CoA Oxidase Deficiency D-Bifunctional Enzyme Deficiency Multifunctional Enzyme Deficiency Alpha-methylacyl-CoA Racmase Deficiency Mitochondrial Neurogastrointestingal Encephalopathy Severe Osteopetrosis Hereditary Leukoencephalopathy With Axonal Spheroids (HDLS; CSF1R Mutation) Inherited Metabolic Disorders	Biological: Stem Cell Transplantation Drug: IMD Preparative Regimen Drug: Osteopetrosis Only Preparative Regimen Drug: Osteopetrosis Haploidentical Only Preparative Regimen Drug: cALD SR-A (Standard-Risk, Regimen A) Drug: cALD SR-B (Standard-Risk, Regimen B) Drug: cALD HR-D (High-Risk, Regimen C) Drug: cALD HR-D (High-Risk, Regimen D)	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Intervention Model: Single Group Assignment Masking: No masking 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:

Genetics Home Reference related topics: D-bifunctional protein deficiency RNAse T2-deficient leukoencephalopathy Refsum disease alpha-mannosidosis alpha-methylacyl-CoA racemase deficiency aspartylglucosaminuria fucosidosis leukoencephalopathy with vanishing white matter megalencephalic leukoencephalopathy with subcortical cysts osteopetrosis peroxisomal acyl-CoA oxidase deficiency

MedlinePlus related topics: Metabolic Disorders

Genetic and Rare Diseases Information Center resources: Mucopolysaccharidosis X-linked Adrenoleukodystrophy Adrenomyeloneuropathy Mucopolysaccharidosis Type VI Peroxisomal Biogenesis Disorders Mucopolysaccharidosis Type II Hurler Syndrome Leukodystrophy Alpha-mannosidosis Krabbe Disease Osteopetrosis Metachromatic Leukodystrophy Refsum Disease Mucopolysaccharidosis Type VII Mitochondrial Neurogastrointestinal Encephalopathy Syndrome Sphingolipidosis Fucosidosis Zellweger Syndrome Refsum Disease, Infantile Form Aspartylglycosaminuria D-bifunctional Protein Deficiency Neonatal Adrenoleukodystrophy Pseudoneonatal Adrenoleukodystrophy Mucopolysaccharidosis Type I Turner Syndrome Gonadal Dysgenesis Intestinal Pseudo-obstruction Encephalomyopathy Hypoadrenalism Mucopolysaccharidosis Type IV Charcot-Marie-Tooth Disease Hereditary Neuropathy With Liability to Pressure Palsy Roussy Levy Syndrome

U.S. FDA Resources

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

Primary Outcome Measures:

Percent of subjects who achieve high-level donor hematopoietic engraftment [ Time Frame: Day +42 post-transplant ]
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
Percent of subjects who achieve high-level donor hematopoietic engraftment [ Time Frame: Day +100 post-transplant ]
Defined as ≥ 80% donor cells on the myeloid fraction of peripheral blood at Day +100 post-transplant

Secondary Outcome Measures:

Graft-versus-host disease [ Time Frame: Day +100 post-transplant ]
Incidence and severity of GvHD
Transplant-related mortality [ Time Frame: Day +100 post-transplant ]
Incidence of TRM
Regimen-related toxicity [ Time Frame: Day +100 post-transplant ]
Defined as infection, acute renal failure, respiratory failure, cardiac failure, and veno-occlusive disease
Post-HSCT changes in disease [ Time Frame: 1 year ]
Incidence of radiographic, physiologic, neuro-psychologic, and/or biochemical aspects of the disease as assessed on a disease-specific basis
Post-HSCT changes in disease [ Time Frame: 2 years ]
Incidence of radiographic, physiologic, neuro-psychologic, and/or biochemical aspects of the disease as assessed on a disease-specific basis


Estimated Enrollment:	100
Actual Study Start Date:	July 10, 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: IMD - Except Haplo-identical Inherited Metabolic Disease (IMD) - Except Haplo-Identical See intervention descriptions.	Biological: Stem Cell Transplantation Infusion given on Day 0 Drug: IMD Preparative Regimen Anti-thymocyte Globulin (ATG) Fludarabine Busulfan
Experimental: OP - Except Haplo-Identical Severe Osteoperosis (OP) - Except Haplo-Identical See intervention descriptions.	Biological: Stem Cell Transplantation Infusion given on Day 0 Drug: Osteopetrosis Only Preparative Regimen Anti-thymocyte Globulin (ATG) Fludarabine Busulfan Thiotepa
Experimental: OP and IMD -Haplo-Identical Only Severe Osteopetrosis (OP) and Inhterited Metabolic Disorders (IMD) -Haplo-Identical Only See intervention descriptions.	Biological: Stem Cell Transplantation Infusion given on Day 0 Drug: Osteopetrosis Haploidentical Only Preparative Regimen Rituximab Alemtuzumab Busulfan Fludarabine
Experimental: cALD SR-A (Standard-Risk, Regimen A) See intervention descriptions.	Biological: Stem Cell Transplantation Infusion given on Day 0 Drug: IMD Preparative Regimen Anti-thymocyte Globulin (ATG) Fludarabine Busulfan Drug: cALD SR-A (Standard-Risk, Regimen A) N-acetylcysteine start day +1 through day +28
Experimental: cALD SR-B (Standard-Risk, Regimen B) See intervention descriptions.	Biological: Stem Cell Transplantation Infusion given on Day 0 Drug: IMD Preparative Regimen Anti-thymocyte Globulin (ATG) Fludarabine Busulfan Drug: cALD SR-B (Standard-Risk, Regimen B) N-acetylcysteine start day +1through day +56
Experimental: cALD HR-C (High-Risk, Regimen C) See intervention descriptions.	Biological: Stem Cell Transplantation Infusion given on Day 0 Drug: IMD Preparative Regimen Anti-thymocyte Globulin (ATG) Fludarabine Busulfan Drug: cALD HR-D (High-Risk, Regimen C) N-acetylcysteine and celecoxib start day of admission (prior to conditioning regimen) and continue through day +100
Experimental: cALD HR-D (High-Risk, Regimen D) See intervention descriptions.	Biological: Stem Cell Transplantation Infusion given on Day 0 Drug: IMD Preparative Regimen Anti-thymocyte Globulin (ATG) Fludarabine Busulfan Drug: cALD HR-D (High-Risk, Regimen D) N-acetylcysteine, celecoxib, vitamin E and alpha lipoic acid start day of admission (prior to conditioning regimen) and continue through day +100

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
Eligible Diseases:
- Mucopolysaccharidosis Disorders:
  - MPS IH (Hurler syndrome)
  - MPS II (Hunter syndrome) if the patient has no or minimal evidence of symptomatic neurologic disease but is expected to have a neurologic phenotype
  - MPS VI (Maroteaux-Lamy syndrome)
  - MPS VII (Sly syndrome)
- Glycoprotein Metabolic Disorders:
  - Alpha mannosidosis
  - Fucosidosis
  - Aspartylglucosaminuria
- Sphingolipidoses and Recessive Leukodystrophies:
  - Globoid cell leukodystrophy
  - Metachromatic leukodystrophy
  - Niemann-Pick B patients (sphingomyelin deficiency)
  - Niemann-Pick C subtype 2
- Peroxisomal Disorders:
  - Adrenoleukodystrophy with cerebral involvement
  - Zellweger syndrome
  - Neonatal Adrenoleukodystrophy
  - Infantile Refsum disease
  - Acyl-CoA-Oxidase Deficiency
  - D-Bifunctional enzyme deficiency
  - Multifunctional enzyme deficiency
  - Alpha-methylacyl-CoA Racmase Deficiency (AMACRD)
  - Mitochondrial Neurogastrointestingal Encephalopathy (MNGIE)
- Severe Osteopetrosis (OP)
- Hereditary Leukoencephalopathy with axonal spheroids (HDLS; CSF1R mutation)
- Other Inherited Metabolic Disorders (IMD): Patients will also be considered who have other lifethreatening, rare lysosomal, peroxisomal or other similar inherited disorders characterized by white matter disease or other neurologic manifestations for which there is rationale that transplantation would be of benefit, such as certain patients with Wolman's disease, GM1 gangliosidosis, I-cell disease, Tay-Sachs disease, Sandhoff disease or others.
- Voluntary written consent

Exclusion Criteria:

Pregnancy - menstruating females must have a negative serum or urine pregnancy test within 14 days of study treatment start
Prior myeloablative chemotherapy exposure within 4 months of the start of conditioning on this protocol (patients excluded for this reason may be eligible for other institutional protocols)
Uncontrolled bacterial, fungal or viral infections including HIV (including active infection with Aspergillus or other mold within 30 days)

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: Kim Nelson	612-273-2925	knelso62@fairview.org

Locations


United States, Minnesota
Masonic Cancer Center, University of Minnesota	Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Kim Nelson 612-273-2925 knelso62@fairview.org

Sponsors and Collaborators

Masonic Cancer Center, University of Minnesota

Investigators


Principal Investigator:	Weston Miller, MD	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:	June 15, 2017


Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No
Product Manufactured in and Exported from the U.S.:		No

Keywords provided by Masonic Cancer Center, University of Minnesota:


allogeneic hematopoietic cell transplantation bone marrow transplantation IMD AMACRD	MNGIE HDLS OP ALD

Additional relevant MeSH terms:


Fucosidosis Disease Syndrome Brain Diseases Mucopolysaccharidoses Metabolic Diseases Mucopolysaccharidosis II Adrenoleukodystrophy Leukodystrophy, Metachromatic Leukoencephalopathies Osteopetrosis Mannosidase Deficiency Diseases alpha-Mannosidosis Mucopolysaccharidosis I Leukodystrophy, Globoid Cell	Sphingolipidoses Mucopolysaccharidosis VI Peroxisomal Disorders Mucopolysaccharidosis VII Zellweger Syndrome Refsum Disease, Infantile Refsum Disease Aspartylglucosaminuria Hearing Loss, Sensorineural Gonadal Dysgenesis, 46,XX Intestinal Pseudo-Obstruction Mitochondrial Encephalomyopathies Pathologic Processes Central Nervous System Diseases Nervous System Diseases

ClinicalTrials.gov processed this record on July 13, 2017