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

Epidermolysis Bullosa Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01033552
• Other study ID #: MT2009-09
• Secondary ID: 0911M74035
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: January 2010
• Est. completion date: August 12, 2021

Study information

• Verified date: March 2024
• Source: Masonic Cancer Center, University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: August 12, 2021
• Est. primary completion date: August 12, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 25 Years

Eligibility

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.

Related Conditions & MeSH terms

• Epidermolysis Bullosa

Intervention

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.
• Fludarabine
40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.
• Anti-thymocyte globulin
30 mg/kg on Days -4, -3 and -2.
• Myeloablative Busulfan
Targeting AUC 1000 umol/min

Procedure:
• Mesenchymal stem cell transplantation
infused via intravenous drip on Day 0

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.

Locations

Country	Name	City	State
United States	University of Minnesota Masonic Cancer Center and Medical Center	Minneapolis	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Event-free Survival	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. Assessed at follow up appointments through questionnaire and patient samples.	1 year and 2 Years Post-transplant
Secondary	Percentage of Participants Transplant-related Mortality (TRM)	Incidence of transplant-related mortality (TRM)	180 Days Post Transplant
Secondary	Average Biochemical Improvement	Pattern of biochemical improvement measured by cumulative increase in protein expression and related structural and physical changes	1 Year Post-Transplant
Secondary	Measure Patients Quality of Life Using a Questionnaire	Health quality of life questionnaire as compared to pretreatment results. Scores can range from 0 to 100. The QOLS scores are summed so that a higher score indicates higher quality of life.	Pretreatment and 1 year
Secondary	Durability of HSC Donor Engraftment in the Skin	Incidence of HSC donor engraftment in the skin	100 Days
Secondary	Probability of Survival	Surviving patients one year after engraftment	1 Year
Secondary	Percentage of Participants Who Experienced Acute GVHD	Incidence of acute GCHD	100 Days