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

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

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Masonic Cancer Center and Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RDEB Mac; 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	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: Cytoxan; Drug: Fludarabine; 40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.; Other Names: Fludara; Procedure: Mesenchymal stem cell transplantation; infused via intravenous drip on Day 0; Other Names: MSCT; 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: UCBSCT; Drug: Myeloablative Busulfan; Targeting AUC 1000 umol/min
Experimental: RDEB RIC; 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)	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: Cytoxan; Drug: Fludarabine; 40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.; Other Names: Fludara; Drug: Anti-thymocyte globulin; 30 mg/kg on Days -4, -3 and -2.; Other Names: ATG; Procedure: Mesenchymal stem cell transplantation; infused via intravenous drip on Day 0; Other Names: MSCT; 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: UCBSCT
Experimental: JEB MAC; Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg	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: Cytoxan; Drug: Fludarabine; 40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.; Other Names: Fludara; Procedure: Mesenchymal stem cell transplantation; infused via intravenous drip on Day 0; Other Names: MSCT; 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: UCBSCT; Drug: Myeloablative Busulfan; Targeting AUC 1000 umol/min
Experimental: JEB RIC; 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)	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: Cytoxan; Drug: Fludarabine; 40 mg/m^2/day intravenously on Days -6, -5, -4, -3 and -2.; Other Names: Fludara; Drug: Anti-thymocyte globulin; 30 mg/kg on Days -4, -3 and -2.; Other Names: ATG; Procedure: Mesenchymal stem cell transplantation; infused via intravenous drip on Day 0; Other Names: MSCT; 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: UCBSCT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

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

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Investigators: Principal Investigator: Jakub Tolar, MD, PhD, Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2010
• Primary Completion (Actual): August 12, 2021
• Study Completion (Actual): August 12, 2021

Study Registration Dates

• First Submitted: December 14, 2009
• First Submitted That Met QC Criteria: December 14, 2009
• First Posted (Estimated): December 16, 2009

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Skin Diseases, Genetic; Skin Diseases, Vesiculobullous; Skin Abnormalities; Epidermolysis Bullosa; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Busulfan; Antilymphocyte Serum
• Other Study ID Numbers: MT2009-09; 0911M74035 (Other Identifier: IRB, University of Minnesota)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes