Allogeneic Hematopoietic Stem Cell Transplant For Epidermolysis Bullosa

Study Overview
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Brief Summary
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RATIONALE: In animal models, stem cells have been shown to home to the skin and repair the biochemical and structural abnormalities associated with recessive dystrophic epidermolysis bullosa (RDEB) (collagen 7 deficiency). PURPOSE: To determine the safety and effectiveness of stem cell infusion in the treatment of RDEB.

Detailed Description
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OBJECTIVES: Primary Estimate the incidence of detectable donor-derived collagen type VII at day 100 in patients with epidermolysis bullosa by donor. Secondary Determine the incidence of transplant-related mortality at day 180 Determine the incidence of blood chimerism at days 21, 100, 180, 365, and 730 Determine the incidence of neutrophil recovery at day 42 and platelet recovery at day 180 Determine the incidence of acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV at day 100 Determine the incidence of chronic GVHD at 1 year Determine the probability of survival at 1 and 2 years Determine the incidence of donor derived cells in the skin Determine resistance to blister formation OUTLINE: This is an open-label, pilot study. Conditioning regimen: Busulfan intravenously (IV) over 2 hours every 6 hours on days -9 to -4, fludarabine phosphate IV over 1 hour on days -5 to -3, and high-dose cyclophosphamide IV over 1 hour on days -5 to -2. Stem cell transplantation on day 0. After completion of study treatment, patients are followed periodically for at least 5 years. PROJECTED ACCRUAL: 30 patients

Official Title
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Allogeneic Hematopoietic Cell Transplantation to Correct the Biochemical Defect and Create Tolerance to Donor Tissue in Subjects With Epidermolysis Bullosa

Conditions
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Epidermolysis Bullosa

Intervention / Treatment
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* Drug: busulfan
* Drug: cyclophosphamide
* Drug: fludarabine phosphate
* Procedure: hematopoietic bone marrow transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Diagnosis of epidermolysis bullosa (EB) Documented collagen type VII deficiency by: Antigenic mapping (LH7.2 antibody) Ultrastructure analysis of anchoring fibrils DNA mutation analysis Performance status: >50% Lansky; >50% Karnofsky Adequate organ function Renal: glomerular filtration rate > 60ml/min/1.73m2 patients aged ≤ 10 years Hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (AST/ALT), Alkaline phosphatase (ALP) < 5 x upper limit of normal 4.2.3 Pulmonary: oxygen saturation >92% 4.2.4 Cardiac: left ventricular ejection fraction > 45%. Healthy related hematopoietic stem cell donor available and meeting 1 of the following criteria: HLA-A, B, DRB1-identical sibling bone marrow and/or umbilical cord blood donor (first priority) HLA-A, B, DRB1-matched or partially matched related donor (second priority) Donor may be a carrier but must be unaffected by EB 8/8 HLA A, B, C, DRB1 allele level matched unrelated marrow donor (third priority) 7/8 HLA-A, B, C, DRB1 allele level matched unrelated marrow donor or 4/6 HLA-A, B (antigen level), DRB1 (allele level) matched unrelated cord blood donor (fourth priority) Exclusion criteria: Active infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days) Squamous cell carcinoma of the skin History of human immunodeficiency virus (HIV) infection Prior transplantation with donor skin

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: Epidermolysis Bullosa (EB) Patients<br>Epidermolysis bullosa patients treated per study regimen with chemotherapy and stem cell transplant. | Drug: busulfan<br>* Day -9 through Day -6: 1.1 mg/kg if < 12 kg IV every 6 hours; 0.8 mg/kg if > 12 kg.<br>* Other names: Bulsulfex;Drug: cyclophosphamide<br>* Day -5 through Day -2: 50 mg/kg IV over 120 min.<br>* Other names: Cytoxan;Drug: fludarabine phosphate<br>* Day -5 through Day -3: 25 mg/m2 IV over 60 min.<br>* Other names: Fludara;Procedure: hematopoietic bone marrow transplantation<br>* allogeneic bone marrow, peripheral stem cell or umbilical cord blood transplantation<br>* Other names: Bone marrow transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Detectable Collagen Type VII | Number of patients with epidermolysis bullosa who had collagen type VII. Type VII collagen defects cause recessive dystrophic epidermolysis bullosa (RDEB), a blistering skin disorder often accompanied by epidermal cancers. | Day 100 Post Transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With >70% Donor Chimerism | Number of patients with donor chimerism - percentage of donor cells in the patient via the peripheral blood or bone marrow. | Days 21, 100, 180, 365 and 730 Post Transplant | 
| Number of Patients With Transplant-Related Mortality | Number of patients who died due to complications of the transplant (includes all deaths without previous relapse or progression). | Day 180 Post Transplant | 
| Number of Patients With Platelet Engraftment | Number of patients with a platelet count >5 x 10^10 cells/liter for 3 consecutive measurements. | Day 180 Post Transplant | 
| Number of Patients With Acute Graft-Versus-Host Disease (GVHD) | Number of patients with GVHD. Acute Graft-Versus-Host Disease is a severe short-term complication created by infusion of donor cells into a foreign host. | Day 100 Post Transplant | 
| Number of Patients With Chronic Graft-Versus-Host Disease (cGVHD) | Number of patients with cGVHD; a severe long-term complication created by infusion of donor cells into a foreign host. | Day 365 Post Transplant | 
| Overall Survival | Survival is defined as the number of patients that were alive post transplant. | 1 year and 2 years Post Transplant | 
| Number of Patients With Donor Derived Cells in Skin | Number of patients who had donor skin chimerism - donor cells in the patient's epidermis (a state in bone marrow transplantation in which bone marrow and host cells exist compatibly without signs of graft-versus-host rejection disease). | Day 90 Post Transplant | 
| Number of Patients With Resistance to Blister Formation | Resistance to Blister Formation demonstrated by response to negative pressure. | Month 1 through Month 24 Inclusive | 
| Number of Patients With Neutrophil Engraftment | Number of patients with an absolute neutrophil count >5 x 10^8 cells/liter for 3 consecutive days. | Day 42 Post Transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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epidermolysis bullosa, dystrophic epidermolysis bullosa