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

Study Overview
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Brief Summary
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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).

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

Conditions
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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

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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allogeneic hematopoietic cell transplantation, bone marrow transplantation, IMD, AMACRD, MNGIE, HDLS, OP, ALD