Biochemical Correction of Severe EB by Allo HSCT and "Off-the-shelf" MSCs
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Transplant in Epidermolysis Bullosa
|
Drug: Cyclophosphamide
Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.
Other Names:
Drug: Fludarabine
40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.
Other Names:
Drug: Anti-thymocyte globulin
30 mg/kg on Days -4, -3 and -2.
Other Names:
Drug: Cyclosporine A
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.
Other Names:
Drug: Mycophenolate mofetil
15 mg/kg intravenous twice per day on days -3 through 30.
Other Names:
Procedure: Mesenchymal stem cell transplantation
infused via intravenous drip on Day 0
Other Names:
Radiation: Total body irradiation
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.
Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Event-free survival rate [1 year and 2 Years Post-transplant]
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.
Secondary Outcome Measures
- Transplant-related mortality (TRM) [180 Days Post Transplant]
Incidence of transplant-related mortality (TRM)
- Pattern of biochemical improvement [Through 1 Year Post-Transplant]
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
- Measure patients Quality of Life using a questionnaire [Pretreatment, Day 100, 6 months, 1 and 2 years]
Health quality of life questionnaire or iscorEB as compared to pretreatment results
- Durability of HSC and third party MSC engraftment in the skin [100 Days]
Incidence of HSC and third party MSC engraftment in the skin
- Probability of Survival [1 Year]
Number of surviving patients one year after engraftment
- Number of participants experiencing Acute GVHD [100 Days]
Incidence of acute GCHD
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Minnesota Masonic Cancer Center and Medical Center | Minneapolis | Minnesota | United States | 55455 |
Sponsors and Collaborators
- Masonic Cancer Center, University of Minnesota
Investigators
- Principal Investigator: Jakub Tolar, MD, PhD, Masonic Cancer Center, University of Minnesota
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MT2009-09
- 0911M74035