Biochemical Correction of Severe EB by Allo HSCT and Off-the-shelf MSCs

Study Overview
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Brief Summary
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This is an open-label, single institution, phase II study in patients with epidermolysis bullosa (EB). The underlying hypothesis is that the infusion of bone marrow or umbilical cord blood from a healthy unaffected donor will correct the collagen, laminin, integrin, or plakin deficiency and reduce the skin fragility characteristic of severe forms of EB. A secondary hypothesis is that mesenchymal stem cells from a healthy donor will enhance the safety and efficacy of the allogeneic hematopoietic stem cell transplant as well as serve as a source of renewable cells for the treatment of focal areas of residual blistering.

Detailed Description
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The primary objective of this study is to estimate the event-free survival rate by 1 year post-transplant with an event defined as a death or failure to have a demonstrable increase in collagen, laminin, integrin, keratin or plakin deposition by 1 year post-transplant or other biochemical, structural or physical measure of improvement. The secondary objectives of this study are to i) determine the incidence of transplant-related mortality (TRM) at 180 days; ii) describe the pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin or plakin) and related structural and physical changes; iii) describe health quality of life at day 365 and 730 as compared to pretreatment results; iv) describe the pattern and durability of HSC and third party MSC engraftment in the skin; v) determine the probability of survival at 1 year. Patients with severe epidermolysis bullosa will be screened to meet the eligibility requirements, related or unrelated donor marrow or UCB will be infused, and subjects will be followed for a minimum of 5 years after stem cell transplant. A target accrual of 75 subjects over 5 years will be recruited to the study.

Official Title
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MT2009-09: Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Stem Cell Transplantation and Off-the-shelf Mesenchymal Stem Cells

Conditions
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Epidermolysis Bullosa

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Anti-thymocyte globulin
* Drug: Cyclosporine A
* Drug: Mycophenolate mofetil
* Procedure: Mesenchymal stem cell transplantation
* Radiation: Total body irradiation
* Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of severe form of epidermolysis bullosa (EB) characterized by collagen, laminin, integrin, keratin or plakin deficiency. Assessment criteria for severe EB: Documented collagen, laminin, integrin, keratin or plakin deficiency (by immunofluorescence staining with protein specific antibodies or Western blotting and by mutation analysis) Adequate Organ Function Criteria Renal: glomerular filtration rate within normal range for age Hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (AST/ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal Pulmonary: adequate pulmonary function in the opinion of the enrolling investigator Cardiac: left ventricular ejection fraction ≥ 45%, normal electrocardiogram (EKG) or approved by Cardiology for transplant. Available Healthy HSC Donor (order of preference) Related Donor (marrow or UCB) HLA-A, B, C, DRB1 genotypic identical (sibling) donor HLA-A, B, C, DRB1 phenotypic identical donor 7/8 HLA matched donor at HLA-A, B, C, DRB1 Unrelated Donor Marrow HLA-A, B, C, DRB1 phenotypic identical donor 7/8 HLA matched donor at HLA-A, B, C, DRB1 UCB HLA-A, B (antigen level) and DRB1 (allele level) matched donor 5/6 HLA matched donor at HLA-A, B, DRB1 4/6 HLA matched donor at HLA-A, B, DRB1 Voluntary written consent Absence of Exclusion Criteria: Active systemic infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days). History of human immunodeficiency virus (HIV) infection Evidence of squamous cell carcinoma Donor has EB Pregnancy females of child-bearing age must have a documented negative pregnancy test and agree to use contraception as a condition for enrollment.

Ages Eligible for Study
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Maximum Age: 25 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transplant in Epidermolysis Bullosa<br> | Drug: Cyclophosphamide<br>* Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.<br>* Other names: Cytoxan;Drug: Fludarabine<br>* 40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.<br>* Other names: Fludara;Drug: Anti-thymocyte globulin<br>* 30 mg/kg on Days -4, -3 and -2.<br>* Other names: ATG;Drug: Cyclosporine A<br>* Days -3 to 100+ to maintain a level of >200 ng/ml; initial dose 2.5 mg/kg over 2 hours every 8-12 hours for children.<br>* Other names: CSA;Drug: Mycophenolate mofetil<br>* 15 mg/kg intravenous twice per day on days -3 through 30.<br>* Other names: CellCept(R);Procedure: Mesenchymal stem cell transplantation<br>* infused via intravenous drip on Day 0<br>* Other names: MSCT;Radiation: Total body irradiation<br>* 300 cGY on Day -1 administered in a single fraction at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.<br>Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation<br>* Bone marrow or UCB products will be infused as soon as the product arrives and within 30 minutes. The product is infused via IV drip.<br>* Other names: UCBSCT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival rate | Event-free survival rate, with an event defined as death or failure to have a demonstrable increase in collagen, laminin, intergrin, keratin or plakin deposition. | 1 year and 2 Years Post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transplant-related mortality (TRM) | Incidence of transplant-related mortality (TRM) | 180 Days Post Transplant | 
| Pattern of biochemical improvement | Describe pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin, or plakin) and related structural and physical changes | Through 1 Year Post-Transplant | 
| Measure patients Quality of Life using a questionnaire | Health quality of life questionnaire or iscorEB as compared to pretreatment results | Pretreatment, Day 100, 6 months, 1 and 2 years | 
| Durability of HSC and third party MSC engraftment in the skin | Incidence of HSC and third party MSC engraftment in the skin | 100 Days | 
| Probability of Survival | Number of surviving patients one year after engraftment | 1 Year | 
| Number of participants experiencing Acute GVHD | Incidence of acute GCHD | 100 Days |