Epidermolysis Bullosa
Conditions
Keywords
epidermolysis bullosa, dystrophic epidermolysis bullosa
Brief summary
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
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
Interventions
DRUGbusulfan
Day -9 through Day -6: 1.1 mg/kg if \< 12 kg IV every 6 hours; 0.8 mg/kg if \> 12 kg.
DRUGcyclophosphamide
Day -5 through Day -2: 50 mg/kg IV over 120 min.
DRUGfludarabine phosphate
Day -5 through Day -3: 25 mg/m2 IV over 60 min.
PROCEDUREhematopoietic bone marrow transplantation
allogeneic bone marrow, peripheral stem cell or umbilical cord blood transplantation
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 25 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Detectable Collagen Type VII | Day 100 Post Transplant | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Transplant-Related Mortality | Day 180 Post Transplant | Number of patients who died due to complications of the transplant (includes all deaths without previous relapse or progression). |
| Number of Patients With Platelet Engraftment | Day 180 Post Transplant | Number of patients with a platelet count \>5 x 10\^10 cells/liter for 3 consecutive measurements. |
| Number of Patients With Acute Graft-Versus-Host Disease (GVHD) | Day 100 Post Transplant | 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. |
| Number of Patients With Chronic Graft-Versus-Host Disease (cGVHD) | Day 365 Post Transplant | Number of patients with cGVHD; a severe long-term complication created by infusion of donor cells into a foreign host. |
| Number of Patients With >70% Donor Chimerism | Days 21, 100, 180, 365 and 730 Post Transplant | Number of patients with donor chimerism - percentage of donor cells in the patient via the peripheral blood or bone marrow. |
| Number of Patients With Donor Derived Cells in Skin | Day 90 Post Transplant | 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). |
| Number of Patients With Resistance to Blister Formation | Month 1 through Month 24 Inclusive | Resistance to Blister Formation demonstrated by response to negative pressure. |
| Number of Patients With Neutrophil Engraftment | Day 42 Post Transplant | Number of patients with an absolute neutrophil count \>5 x 10\^8 cells/liter for 3 consecutive days. |
| Overall Survival | 1 year and 2 years Post Transplant | Survival is defined as the number of patients that were alive post transplant. |
Countries
United States
Participant flow
Pre-assignment details
All subjects were registered with the BMT Biostatistical Support Group at the University of Minnesota.
Participants by arm
| Arm | Count |
|---|---|
| Epidermolysis Bullosa (EB) Patients Epidermolysis bullosa patients enrolled for treatment with chemotherapy (Busulfan 0.8 or 1.1 mg/kg Days 6-9 before transplant; Fludarabine 25 mg/m\^2 Days 3-5 before transplant; Cyclophosphamide 50 mg/kg Days 2-5 before transplant) and stem cell infusion (Day 0) followed by donor epidermal transplant . | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not receive transplant | 1 |
Baseline characteristics
| Characteristic | Epidermolysis Bullosa (EB) Patients |
|---|---|
| Age, Categorical <=18 years | 7 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 6.0 years STANDARD_DEVIATION 4.5 |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 7 |
| serious Total, serious adverse events | 6 / 7 |
Outcome results
Primary
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.
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Patients | Number of Patients With Detectable Collagen Type VII | 5 participants |
Secondary
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.
Time frame: Days 21, 100, 180, 365 and 730 Post Transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Evaluable Patients | Number of Patients With >70% Donor Chimerism | Day 21 | 6 participants |
| Evaluable Patients | Number of Patients With >70% Donor Chimerism | Day 100 | 5 participants |
| Evaluable Patients | Number of Patients With >70% Donor Chimerism | Day 180 | 5 participants |
| Evaluable Patients | Number of Patients With >70% Donor Chimerism | Day 365 | 5 participants |
| Evaluable Patients | Number of Patients With >70% Donor Chimerism | Day 730 | 5 participants |
Secondary
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.
Time frame: Day 100 Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Patients | Number of Patients With Acute Graft-Versus-Host Disease (GVHD) | 1 participants |
Secondary
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.
Time frame: Day 365 Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Patients | Number of Patients With Chronic Graft-Versus-Host Disease (cGVHD) | 0 participants |
Secondary
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).
Time frame: Day 90 Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Patients | Number of Patients With Donor Derived Cells in Skin | 6 participants |
Secondary
Number of Patients With Neutrophil Engraftment
Number of patients with an absolute neutrophil count \>5 x 10\^8 cells/liter for 3 consecutive days.
Time frame: Day 42 Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Patients | Number of Patients With Neutrophil Engraftment | 6 participants |
Secondary
Number of Patients With Platelet Engraftment
Number of patients with a platelet count \>5 x 10\^10 cells/liter for 3 consecutive measurements.
Time frame: Day 180 Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Patients | Number of Patients With Platelet Engraftment | 5 participants |
Secondary
Number of Patients With Resistance to Blister Formation
Resistance to Blister Formation demonstrated by response to negative pressure.
Time frame: Month 1 through Month 24 Inclusive
Population: Added blister formation testing later in study; only 2 patients had pre-transplant test.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Patients | Number of Patients With Resistance to Blister Formation | 2 participants |
Secondary
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).
Time frame: Day 180 Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Evaluable Patients | Number of Patients With Transplant-Related Mortality | 0 participants |
Secondary
Overall Survival
Survival is defined as the number of patients that were alive post transplant.
Time frame: 1 year and 2 years Post Transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Evaluable Patients | Overall Survival | 1 Year Post Transplant | 5 participants |
| Evaluable Patients | Overall Survival | 2 Years Post Transplant | 5 participants |