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

MT2013-31: Allogeneic Hematopoietic Cell Transplantation for Inherited Metabolic Disorders and Severe Osteopetrosis Following Conditioning With Busulfan (Therapeutic Drug Monitoring), Fludarabine +/- ATG

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).

Study Overview

• Status: Recruiting
• Conditions: Hurler Syndrome; Sphingolipidoses; Peroxisomal Disorders; Metachromatic Leukodystrophy; Alpha-Mannosidosis; Hunter Syndrome; Mucopolysaccharidosis Disorders; Maroteaux Lamy Syndrome; Sly Syndrome; Fucosidosis; Aspartylglucosaminuria; Glycoprotein Metabolic Disorders; Recessive Leukodystrophies; Globoid Cell Leukodystrophy; Niemann-Pick B; Niemann-Pick C Subtype 2; Sphingomyelin Deficiency; 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
• Intervention / Treatment: 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)

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Troy Lund, M.D.Ph.D.; Phone Number: 612-625-4185; Email: lundx072@umn.edu
• Study Contact Backup: Name: Lisa Burke; Phone Number: 612-273-8482; Email: lburke3@Fairview.org

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • Masonic Cancer Center, University of Minnesota
      • Contact: Lisa Burke; Phone Number: 612-273-8482; Email: lburke3@Fairview.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 55 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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 life-threatening, 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Paul Orchard, M.D., Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2014
• Primary Completion (Estimated): July 14, 2025
• Study Completion (Estimated): July 14, 2028

Study Registration Dates

• First Submitted: June 20, 2014
• First Submitted That Met QC Criteria: June 20, 2014
• First Posted (Estimated): June 23, 2014

Study Record Updates

• Last Update Posted (Estimated): November 3, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: allogeneic hematopoietic cell transplantation; bone marrow transplantation; MNGIE; IMD; AMACRD; HDLS; OP; ALD
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Demyelinating Diseases; Kidney Diseases; Urologic Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Endocrine System Diseases; Disease; Congenital Abnormalities; Liver Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Musculoskeletal Diseases; Connective Tissue Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Bone Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Nervous System Malformations; Abnormalities, Multiple; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Bone Diseases, Developmental; Adrenal Gland Diseases; Osteochondrodysplasias; Polyneuropathies; Hereditary Central Nervous System Demyelinating Diseases; Adrenal Insufficiency; Sulfatidosis; Osteosclerosis; Hereditary Sensory and Motor Neuropathy; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Syndrome; Mucopolysaccharidosis II; Mucopolysaccharidoses; Mucopolysaccharidosis I; Brain Diseases; Metabolic Diseases; Peroxisomal Disorders; Leukoencephalopathies; Adrenoleukodystrophy; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Sphingolipidoses; Mannosidase Deficiency Diseases; alpha-Mannosidosis; Osteopetrosis; Refsum Disease; Zellweger Syndrome; Fucosidosis; Refsum Disease, Infantile; Mucopolysaccharidosis VI; Mucopolysaccharidosis VII; Aspartylglucosaminuria
• Other Study ID Numbers: 2013LS104

Drug and device information, study documents

• 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