Allogeneic Stem Cell Transplantation (ALLOSCT) in Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Study Overview
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Brief Summary
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Reduced Intensity Conditioning (RIC) and Allogeneic Stem Cell Transplantation (AlloSCT) from family-related donors and unrelated cord blood (UCB) donors will be safe and well tolerated in selected patients with RDEB. To determine the event-free survival (EFS) and overall survival (OS) following RIC consisting of busulfan/fludarabine/alemtuzumab (BFA) and AlloSCT in selected patients with RDEB.

Detailed Description
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Epidermolysis bullosa (EB), is a diverse group of genodermatoses, which is considered a rare and orphan disease and affects approximately 1 in 20,000 people in the United States for a cumulative total of close to 20,000[1-4]. There are three major subtypes of inherited EB, including EB simplex (EBS), junctional EB (JEB), and dystrophic EB[1-4]. RDEB is among the most severe and represents approximately 10% of all forms of EB[1-4]. A rough estimate would then project that there are several thousand patients with RDEB in the U.S. at the current time. Up to 30 different clinical phenotypes and mutations in at least 10 structural genes in different sub-types of EB have been reported[4-8]. In addition to heritable subtypes of EB, there is an acquired autoimmune form in which the patients develop auto-antibodies directed against similar proteins of the inherited dystrophic forms of EB, including EB acquisita (EBA). We have previously reported our experience with RIC with BFA [48] in pediatric AlloSCT recipients (mean age 9.5 yrs [1.4-21], 11/4 M/F, 10 non-malignant, 5 malignant disease, [6 sibling, 5 UCB, 5 matched unrelated donor]); median time to ANC ≥ 500/mm3 and platelet count ≥20K/mm3 was 22 and 30 days, respectively. Probability of day +180 and 365 donor chimerism was 90% (Figure 7), and OS was 95% (Figure 8). This conditioning regimen therefore results in a high degree of donor chimerism and survival with minimal regimen related mortality.

Official Title
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A Pilot Study of Reduced Intensity Conditioning (RIC) and Allogeneic Stem Cell Transplantation (ALLOSCT) In Children With Recessive Dystrophic Epidermolysis Bullosa (RDEB)

Conditions
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Epidermolysis Bullosa

Intervention / Treatment
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* Drug: Palifermin
* Drug: Fludarabine
* Drug: Busulfan
* Drug: Lorazepam
* Drug: Alemtuzumab
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recessive Dystrophic Epidermolysis Bullosa (RDEB) Diagnosis of RDEB using molecular diagnosis and sequencing of mutations Skin biopsy to determine status of type VII collagen Age ≤21 years Patient must have adequate organ function as below: Adequate renal function defined as: Serum creatinine less than or equal to 1.5 x normal, or Creatinine clearance or radioisotope glomerular filtration rate (GFR) =40 ml/min/m2 or > 60 ml/min/1.73 m2 or an equivalent GFR as determined by the institutional normal range Adequate liver function defined as: Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase (AST)) or serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase (ALT))< 5.0 x normal Adequate cardiac function defined as: Shortening fraction of ≥28% by echocardiogram, or Ejection fraction of ≥48% by radionuclide angiogram or echocardiogram Adequate pulmonary function defined as: Uncorrected diffusing capacity of the lungs for carbon monoxide (DLCO) ≥35% by pulmonary function test For children who are uncooperative, no evidence of dyspnea at rest Exclusion Criteria: Karnofsky/Lansky Performance Score <50% Pregnant or nursing Uncontrolled bacterial, viral or mold infection History or presence of skin squamous cell carcinoma

Ages Eligible for Study
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Maximum Age: 21 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: RIC Group<br>Reduced Intensity Transplant Conditioning (RIC): Palifermin (Kepivance®) 60 mcg/kg/day for 6 days Fludarabine 30 mg/m2 IV x 1 for 6 days Busulfan 4 mg/kg/day IV divided BID for 4 days Lorazepam 0.02-0.05 mg/kg for 5 days Alemtuzumab 20 mg/m2 IV for 5 days Tacrolimus 0.03mg/kg/24 hours as continuous infusion for 4 days | Drug: Palifermin<br>* 60 mcg/kg/day for 6 days<br>* Other names: Kepivance;Drug: Fludarabine<br>* 30 mg/m2 IV x 1 for 6 days<br>* Other names: Fludara;Drug: Busulfan<br>* 4 mg/kg/day IV divided BID for 4 days<br>* Other names: Myleran;Drug: Lorazepam<br>* 0.02-0.05 mg/kg for 5 days<br>* Other names: Ativan;Drug: Alemtuzumab<br>* 20 mg/m2 IV for 5 days<br>* Other names: Lemtrada;Drug: Tacrolimus<br>* 0.03mg/kg/24 hours as continuous infusion for 4 days<br>* Other names: Hecoria;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) |  | Up to 2 years | 
| Overall Survival (OS) |  | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of whole blood (CD45), T-cell (CD3), and NK cell (CD56) chimerism following RIC and AlloSCT in selected patients with RDEB |  | Up to Day +730 | 
| Percentage of donor skin dermal chimerism following RIC and AlloSCT in selected patients with RDEB. |  | Up to Day +730 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Allogeneic Stem Cell Transplant, AlloSCT, RDEB, recessive dystrophic epidermolysis bullosa