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

Phase 1

Completed

• Conditions: Epidermolysis Bullosa
• Interventions: Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Myeloablative Busulfan; Drug: Anti-thymocyte globulin; Procedure: Mesenchymal stem cell transplantation; Procedure: Bone marrow or umbilical cord blood (UCG) stem cell transplantation; Radiation: Total body irradiation

• Registration Number: NCT01033552
• Lead Sponsor: Masonic Cancer Center, University of Minnesota

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.

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 Timeline

• Study First Submitted: 2009-12-14
• Study First Submitted QC: 2009-12-14
• Study First Posted: 2009-12-16
• Study Start: 2010-01
• Primary Completion: 2021-08-12
• Study Completion: 2021-08-12
• Results First Submitted: 2023-12-05
• Status Verified: 2024-03
• Results First Submitted QC: 2024-03-06
• Last Update Submitted: 2024-03-06
• Results First Posted: 2024-04-03
• Last Update Posted: 2024-04-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 32

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
RDEB Mac	Bone marrow or umbilical cord blood (UCG) stem cell transplantation	Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
JEB MAC	Cyclophosphamide	Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
RDEB RIC	Mesenchymal stem cell transplantation	Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
RDEB RIC	Bone marrow or umbilical cord blood (UCG) stem cell transplantation	Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
JEB RIC	Mesenchymal stem cell transplantation	Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
JEB RIC	Bone marrow or umbilical cord blood (UCG) stem cell transplantation	Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
RDEB Mac	Myeloablative Busulfan	Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
RDEB Mac	Mesenchymal stem cell transplantation	Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
RDEB RIC	Total body irradiation	Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
JEB MAC	Mesenchymal stem cell transplantation	Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
JEB MAC	Bone marrow or umbilical cord blood (UCG) stem cell transplantation	Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
JEB RIC	Anti-thymocyte globulin	Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
RDEB RIC	Anti-thymocyte globulin	Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
JEB RIC	Total body irradiation	Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
JEB MAC	Myeloablative Busulfan	Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
RDEB Mac	Cyclophosphamide	Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
RDEB Mac	Fludarabine	Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
RDEB RIC	Cyclophosphamide	Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
RDEB RIC	Fludarabine	Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
JEB MAC	Fludarabine	Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
JEB RIC	Cyclophosphamide	Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
JEB RIC	Fludarabine	Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Event-free Survival	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. Assessed at follow up appointments through questionnaire and patient samples.

Secondary Outcome Measures

Name	Time	Method
Average Biochemical Improvement	1 Year Post-Transplant	Pattern of biochemical improvement measured by cumulative increase in protein expression and related structural and physical changes
Measure Patients Quality of Life Using a Questionnaire	Pretreatment and 1 year	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.
Probability of Survival	1 Year	Surviving patients one year after engraftment
Percentage of Participants Transplant-related Mortality (TRM)	180 Days Post Transplant	Incidence of transplant-related mortality (TRM)
Percentage of Participants Who Experienced Acute GVHD	100 Days	Incidence of acute GCHD
Durability of HSC Donor Engraftment in the Skin	100 Days	Incidence of HSC donor engraftment in the skin

Trial Locations

Locations (1)

University of Minnesota Masonic Cancer Center and Medical Center; 🇺🇸 Minneapolis, Minnesota, United States