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

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Recruiting

CT.gov ID

NCT02171104

Collaborator

(none)

100

Enrollment

Location

Arms

100.7

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	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 Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

None (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

Actual Study Start Date :

Jul 10, 2014

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

Percent of subjects who achieve high-level donor hematopoietic engraftment [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 [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 [Day +100 post-transplant]
Incidence and severity of GvHD
Transplant-related mortality [Day +100 post-transplant]
Incidence of TRM
Regimen-related toxicity [Day +100 post-transplant]
Defined as infection, acute renal failure, respiratory failure, cardiac failure, and veno-occlusive disease
Post-HSCT changes in disease [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 [2 years]
Incidence of radiographic, physiologic, neuro-psychologic, and/or biochemical aspects of the disease as assessed on a disease-specific basis

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)