MT2009-09: Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Stem Cell Transplantation and "Off-the-shelf" Mesenchymal Stem Cells
Phase: PHASE1
Conditions: Epidermolysis Bullosa
Sponsor: Masonic Cancer Center, University of Minnesota

 
 
UNIVERSITY OF MINNESOTA BLOOD & MARROW TRANSPLANTATION PROGRAM 
 
 
 
MT2009-09 
 
BIOCHEMICAL CORRECTION OF SEVERE EPIDERMOLYSIS BULLOSA BY 
ALLOGENEIC STEM CELL TRANSPLANTATION 
 
 
 
 
 
Version Date:  November 21, 2016 
 
 
 
 
 
 
Study Committee 
 
University of Minnesota Medical School 
 
 
Jakub Tolar, M.D., Ph.D., Sponsor/Investigator 
 
John E. Wagner, M.D. 
Bruce Blazar, M.D. 
Maria Hordinsky, M.D. 
Mark Osborn, Ph.D. 
Todd Defor, M.S. 
David H. McKenna, M.D. 
Kathryn Dusenbery, M.D. 
 
 
 
 
 
FDA IND#14166 
 
 
This document contains confidential information that is the property of the University of Minnesota Blood 
and Marrow Transplant Program. 
Do not copy, disclose, or circulate without written authorization of the Principal Investigator or from the 
University of Minnesota Medical Center-Fairview Blood and Marrow Transplant Services Medical 
Directors.

MT 2009-09:  Stem Cell Transplant for EB 
 
 
 
 
 
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Amendment History 
Version 
Date 
Amendment 
Number 
Modification(s) 
Consent 
Modification 
09/01/09 
Original 
 
NA 
10/22/09 
Revision 1 
• Addition of IND Number 
• Deletion of references to intra-lesion mesenchymal 
stem cells throughout document 
• Subsection 4.5.6 pregnancy exclusion and 
requirement for birth control 
• Subsection 4.6.2 additional details on required 
assessment criteria 
• Subsection 6.5 reference to institutional SOPs for 
supportive care guidelines  
• Section 7.0 details on standard procedures for skin 
biopsies and GI endoscopy and mucosal biopsies 
• Section 9.0 reference to following FDA regulations for 
adverse event reporting and donor eligibility 
requirements 
Yes (delete 
directed MSC 
donor consent); 
otherwise no 
changes 
 
03/18/10 
Revision 2 
• Add opportunity for patients with a sibling donor and 
complete chimerism at > 6 months post transplant to 
receive up to two MSC infusions at least one month 
apart.  Section 4.7-4.12 details eligibility criteria for 
sibling donor MSC’s;  Insert Section 6.5 detail of 
sibling MSC administration; Section 8.2 update with 
adverse event monitoring pre and 4 hours post MSC 
infusion; Insert new section 10.6 regarding statistical 
analysis of sibling MSC’s;   
• Section 6.1 – Busulfan -  replace phenytoin with 
Keppra as seizure prophylactic;  
• Update adverse event reporting (section 8), data and 
safety monitoring (section 9), and conduct of the study 
(section 11) with current U of MN language.  
• Clarifications, administrative, and formatting changes 
in treatment plan and study parameters.  Delete 
eligibility checklist and add targeted toxicity form to the 
appendices. 
Yes, update all 
consents, new 
patient/parent 
consent for sibling 
donor MSC 
infusions 
05/21/10 
Revision 3 
Section 5.2 Staggering of Enrollment – After discussion 
with the FDA – patients with the JEB Herlitz variant of EB 
will be exempt from the enrollment delay (requiring at 
least 4 weeks between patients for the first 5 enrolled in 
each stratum); section 4.2.4 add normal EKG or 
approved by Cardiology for transplant; section 4.5.1 
clarify “systemic” infection; Section 8 – update the 
definition of UPIRTSO; Section 9.1 DSMB added 
reference to section 5.2.   
No 
09/18/10 
Revision 4 
Section 4.3 Deleted references to use of HLA 
mismatched adult volunteer donors.  Section 6.3.2 
Deleted reference to T cell depletion of unrelated donor 
marrow. 
No, consents do 
not specifically 
address use of T 
cell depletion or 
HLA matching of 
donor 

MT 2009-09:  Stem Cell Transplant for EB 
 
 
 
 
 
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Version 
Date 
Amendment 
Number 
Modification(s) 
Consent 
Modification 
 
04/21/11 
Revision 5 
Treatment schema (page 7) changed to reflect modified 
conditioning regimen, replacing the busulfan, 
cyclophosphamide and fludarabine myeloablative 
conditioning with a non –myeloablative regimen 
consisting of cyclophosphamide, fludarabine, low dose 
total body irradiation and antithymocyte globulin.  
Addition of Subsections 2.3.4 and 2.3.5 reviewing results 
of this trial to date and rationale/results with the proposed 
conditioning regimen.  Section 6 and 6.1 modified to 
reflect the new treatment plan using cyclophosphamide, 
fludarabine, low dose TBI and ATGAM.  Section 12 
includes a change in the references to the literature, 
updated citation 42 updates the prior citation reflecting 
the Minnesota experience of the initial clinical trial and 
new citations 47 and 48 support the use of the new 
conditioning regimen.  Appendix 5 changes reflect a 
more detailed plan for collection of autologous PBSC and 
addition of a monitoring plan for EBV reactivation.  
Section 8 – update to current IND safety reporting 
requirements 
Yes, update patient 
transplant specific  
consents to reflect 
change in 
conditioning 
regimen 
10/07/2011 
Revision 6 
At request of FDA, update to clarify unlicensed cord 
blood units may be used as a cell source (sections 4.3, 
8.1, and 9.3), minor administrative changes/updates 
No 
02/14/2012 
Revision 7 
Remove staggering of enrollment – permission received 
effective 02/08/2012 from the FDA to proceed without the 
1 month between patient enrollments; clarify QOL 
completion is not required for children < 2 years of age; 
restore sibling cell dose to section 4.3 that was deleted 2 
versions ago in error;  
Yes 
03/26/2012 
Revision 8 
Section 8 clarify adverse event monitoring and 
documentation will end at day +100 except for in 
association with the late MSC infusion; 
Correct section numbering sections 5 and 6 
No 
09/24/2012 
Revision 9 
Section 4.3 – clarification of match criteria and order of 
donor preference  
Section 8.3 – update MCC SAE coordinator contact info 
No 
02/20/2014 
Revision 10 
Section 2.3 – clinical experience with non myeloablative 
transplant and noted increased incidence of partial 
engraftment, providing the rationale for higher dose TBI.   
Section 6 – shows TBI 300 cGy.   
Section 7.2 – added zinc, selenium, vitamin D3 levels at 
specific time points 
Appendix 11 – add iscorEB  
Yes 
12/03/2015 
Revision 11 
Title page – designate Jakub Tolar as principal 
investigator and IND sponsor; 
page header and section 10.7 – remove references to Dr. 
Wagner 
No – previously 
updated 
11/21/2016 
Revision 12 
Synopsis, section 4 – updated eligibility criteria 
Section 7.1, 7.2 updated clinical assessments 
Synopsis, section 7.2 – subject follow up will end after 2 
years 
Yes 

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Table of Contents 
Protocol Synopsis ......................................................................................................... 5 
Subject Screening and Enrollment Schema ............................................................... 6 
1 
HYPOTHESIS AND OBJECTIVES ......................................................................... 8 
2 
BACKGROUND ...................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................... 24 
4 
ELIGIBILITY CRITERIA ........................................................................................ 24 
5 
SUBJECT  REGISTRATION ................................................................................ 25 
6 
TREATMENT PLAN ............................................................................................. 27 
7 
STUDY PARAMETERS ........................................................................................ 34 
8 
ADVERSE EVENT DOCUMENTATION AND REPORTING ................................ 41 
9 
DATA AND SAFETY MONITORING .................................................................... 45 
10 
STATISTICAL CONSIDERATIONS ..................................................................... 46 
11 
CONDUCT OF THE STUDY ................................................................................. 49 
12 
REFERENCES ...................................................................................................... 49 
Appendix 1 – Performance Status Scales ................................................................. 52 
Appendix 2 – External Advisory Board (EAP) .......................................................... 53 
Appendix 3 – Process Flow ........................................................................................ 54 
Appendix 4 - Data and Safety Monitoring Board ...................................................... 55 
Appendix 5 – Supportive Care Guidelines ................................................................ 56 
Appendix 6 – Measurement of Skin Fragility ............................................................ 58 
Appendix 7 – Quality of Life Questionnaire .............................................................. 58 
Appendix 8 – Diagnosis and Treatment of Acute GVHD .......................................... 61 
Appendix 9 – Classification of Chronic GVHD ......................................................... 62 
Appendix 10 – Targeted Toxicity Form ..................................................................... 63 
Appendix 11 - iscorEB (Instrument for Scoring Clinical Outcomes for Research of 
Epidermolysis Bullosa) – insert iscorEB survey of 2015-20 ................................... 66 
 
 
 
 
 
Sponsor/Investigator Contact Information: 
Jakub Tolar, M.D., Ph.D.  
Hematology/Oncology and Transplantation 
Department of Pediatrics 
460 Cancer Research Building 
425 East River Road 
Minneapolis, MN  55455 
612 626-2912 (phone) 
612 624-3913 (fax) 
tolar001@umn.edu (email) 
 
 

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Protocol Synopsis 
 
BIOCHEMICAL CORRECTION OF SEVERE EPIDERMOLYSIS BULLOSA BY 
ALLOGENEIC STEM CELL TRANSPLANTATION  
 
 
Study design: 
 
Open label, single institution, phase II study 
 
Primary objective: 
To estimate the event-free survival rate by 1 year post-
transplant with an event defined as death or failure to have a 
demonstrable increase in collagen, laminin, intergrin, keratin 
or plakin deposition by 1 year post-transplant or other 
biochemical, structural or physical measure of improvement. 
 
Secondary Objectives: 
Determine the incidence of transplant-related mortality at 
180 days; describe the pattern of biochemical improvement 
as measured by increase in protein expression (collagen, 
laminin, integrin, keratin or plakin); describe health quality of 
life at day 365 and 730 as compared to pretreatment results; 
evaluate the pattern and durability of hematopoietic stem cell 
(HSC) and third party mesenchymal stem cell (MSC) 
engraftment in the skin; determine the probability of survival 
at 1 year. 
 
Eligible disease: 
 
Severe forms of inherited blistering skin diseases, referred to 
as epidermolysis bullosa (EB).  
 
Eligibility criteria:  
 
Subjects must be 0-25 years of age and have adequate 
organ function, , an available healthy HLA matched or 
partially HLA matched related or unrelated HSC donor and 
MSC graft. 
 
Exclusion Criteria:     
 
Evidence of HIV infection or known HIV positive serology; 
current active serious infection; diagnosis of squamous cell 
carcinoma; donor with EB; pregnancy or breast feeding.  
 
Accrual Objective: 
 
75 subjects over 5 years. 
 
Study duration: 
Subjects will be followed for a minimum of 2 years after stem 
cell transplant. 
 
 

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Subject Screening and Enrollment Schema 
Subject with severe EB 
that meets all eligibility 
requirements
HSC donor identified        
-related donor (marrow or UCB)
-unrelated donor (marrow or UCB) 
per section 4.3
HSC / MSC infused
Post infusional evaluations        
-Toxicity profile 
-Efficacy endpoints
DSMB review
-First 5 patients (done)                       
-First 5 in cohort (for each donor type)                                         
-Annually
Not eligible
Not eligible
Not evaluable
No
No
No
Yes
Yes
 

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Mycophenolate - 3 to + 30
G-CSF until ANC >2500/uL
CSA - 3 to + 100
Fludarabine    
-2
-8
-7
-5
-9
100
sTBI
-3
-4
-6
-1
Cyclophosphamide
0
Banked MSCs
Allogeneic HSCs
30
60
Skin biopsies   
Photographs            
Blister test           
Chimerism (blood/skin)
Systemic Treatment Plan
Cyclophosphamide 50 mg/kg IV on day -6                                            
Fludarabine 40 mg/m2 IV on days -6, -5, -4, -3, -2                              
Antithymocyteglobulin (ATG) 30 mg/kg IV on days -4, -3, -2       
Total body irradiation 300 cGy on day -1
 
 
After 6 months from transplant, patients with a sibling donor and complete chimerism may be eligible to receive up to 
two MSC infusions at least one month apart from the sibling donor.   
 

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1 
HYPOTHESIS AND OBJECTIVES 
The underlying hypothesis is that the infusion of bone marrow (BM) or umbilical cord 
blood (UCB) from a healthy unaffected donor will correct the collagen, laminin, integrin, 
keratin or plakin deficiency and reduce the skin fragility characteristic of severe forms of 
epidermolysis bullosa (EB).  A secondary hypothesis are that fludarabine-based 
reduced intensity preparative regimen will be well tolerated and sufficient for donor 
engraftment, and that mesenchymal stem cells (MSC) from a healthy donor will 
enhance the safety and effectiveness of the allogeneic hematopoietic stem cell (HSC) 
transplant as well as serve as a source of renewable cells for the treatment of focal 
areas of residual blistering. 
   
1.1 Primary Objective 
To estimate the event-free survival rate by 1 year post-transplant with an 
event defined as 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. 
 
1.2 
Secondary Objectives 
1.2.1 Determine the incidence of transplant-related mortality (TRM) at 
180 days. 
1.2.2 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. 
1.2.3 Describe health quality of life at day 365 and 730 as compared to 
pretreatment results. 
1.2.4 Describe the pattern and durability of HSC and third party MSC 
engraftment in the skin. 
1.2.5 Determine the probability of survival at 1 year. 
 
 
 
2 
BACKGROUND 
2.1 
Dystrophic Epidermolysis Bullosa (DEB) 
2.1.1 Clinical Manifestation and Natural History of DEB   
Dystrophic EB (DEB) is a group of heritable mechanobullous skin 
diseases characterized by skin fragility, blister formation, and scarring.  
The BMZ is characterized by a paucity or diminutive size of AF (Figure 1)1-
3.  The most severe form of DEB is generalized recessive DEB, 
characterized by mutilating scarring, blisters (up to 70-80% of the body 
surface), joint contractures, strictures of the esophagus, corneal erosions, 
renal disease and aggressive squamous cell carcinoma (SCC). 
 

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The high incidence and aggressive nature of the SCC is the number one 
cause of mortality among DEB patients. It is unknown what causes the 
fast growing, multiple appearance and early metastasizing of the SCC in 
DEB patients, but the risk of developing the carcinoma increases with age. 
SCC can appear as early as 13 years of age and by age of 40 years, one 
in every two patients will suffer and die from SCC. At 60 years, the 
cumulative risk of SCC is 76.5%, a much higher cumulative risk than the 
average person in USA (4-14%). The prognosis of a DEB patient with 
SCC is poor with death in most before age 304, 5. 
 
Recently a study conducted with the National EB Registry showed that 
renal failure was a significant cause of mortality among DEB patients.  
Patients with severe form of DEB have a 12.3% incidence of renal failure 
by age 35 years, making renal failure the second most common cause of 
mortality among adult patients surpassed only by SCC mortality 
incidence5. 
 
Patients with severe DEB are also affected by profound physical 
disabilities with social and psychological implications.  Daily activities 
(toileting, feeding, bathing, walking, etc.) are major challenges for these 
patients with many requiring complete assistance. For example one study 
demonstrated that only 24% of children with DEB can walk without 
assistance 6. The quality of life of children with DEB worsens with age. 
One third of the parents of a DEB patient based their marriage relationship 
exclusively to the day to day care and logistic of the affected child.  In 
addition, the majority of divorced families with DEB children blame the 
family disintegration on the disease7.    
 
 
 
 
 
2.1.2 Recessive Dystrophic EB (RDEB)  
As shown in Figure 1, RDEB is due to a deficiency of collagen type VII 
(Col7).  Col7 is synthesized and secreted by both human keratinocytes 
Anchoring
Anchoring
Fibrils
Fibrils
From Uitto and Pullkinen. Arch Dermatol. 2001;137:1458-1461 (3). 
Lamina Densa 
Anchoring 
Fibrils 
Figure 1 

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and fibroblasts.  It is secreted within the basement membrane zone (BMZ) 
lying between the epidermis and dermis of skin6.  Col7 is the major 
component of  BMZ attachment structures known as anchoring fibrils 
(AFs), which provide epidermal-dermal adherence1, 2, 3.  Genetic defects in 
the Col7 gene, designated COL7A1 result in RDEB8, 9, 10. 
 
DEB can be inherited in an autosomal dominant or autosomal recessive 
pattern. The most severe form of recessive disease (referred to as RDEB-
severe generalized) is associated with extensive scarring and blistering. 
The skin blistering is usually present at birth and scarring starts within the 
first few months of life. The blisters and scarring are present at birth or 
become visible the first days after birth. The blisters in the neonate can 
cover the whole body, including oral and esophageal mucosa11. The 
blistering and scarring continues throughout life, resulting in disfigurement 
of both hands and feet, hallmarks of the disease. Other complications 
develop over time that contribute to the clinical profile including growth 
retardation, anemia, osteoporosis, renal dysfunction, lung and cardiac 
problems6, 12-14.  
 
Ultrastructural and genetic evidence identified the cause of the clinical 
symptoms profile through life. Is known that mutations in the COL7A1 
gene result in abnormal morphology, low numbers or absence of the AFs2, 
3 which in turn result in cleavage or detachment of the sublamina densa to 
the underlying dermis with subsequent extreme skin fragility2, 3. 
 
2.1.3 Junctional EB (JEB)  
As shown in Figure 1, J JEB is due to a deficiency of laminin 332 (LAM5) 
caused by autosomal recessive mutations in the LAMA3, LAMB3, or 
LAMC2 genes (encoding the 3, 3 and 2 polypeptides of laminin 332, 
respectively),. Alternatively, some forms of JEB result from mutations in 
collagen type XVII (Col17) encoded by the gene COL17A1.  In all forms of 
JEB, there is splitting within the lamina lucida of the basal keratinocytes. In 
the Herlitz subtype, the hemidesmosomes are reduced in number and are 
hypoplastic and anchoring filaments may also be reduced or absent.  In 
the non-Herlitz type, hemidesmosomes may be reduced or hypoplastic., IF 
staining reveals abnormal or absence of laminin 332 (LAM5) or collagen 
XVII depending on the underlying gene pathology in individual cases 15. 
 
All forms of JEB are inherited in an autosomal recessive manner. The 
most severe form is the Herlitz type which manifests at birth with severe 
blistering with little or no trauma and granulation tissue involving the 
trachea.  Congenital malformations of the urinary tract may also occur.  
Blistering and scarring continues throughout life, resulting in early death in 
many affected children.  In contrast, the non-Herlitz type may be less 
severe although it can be severe and often life-threatening in neonates. 
 

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Some forms of JEB can also be caused by mutations in the ITGA6 and 
ITGB4 genes encoding the hemidesmosome-associated protein 64 
integrin. In some affected individuals the severity and prognosis can 
resemble Herlitz JEB. In addition, there typically extracutaneous 
abnormalities, specifically pyloric atresia, which can be a life-threatening 
complication, the non-Herlitz type may be less severe and may not show 
up during the neonatal period16. 
 
2.1.4 Other Severe Forms of EB  
The classification of EB has recently been expanded to include intra-
epithlial junctional blistering diseases, notably involving structural 
components of desmosome cell-cell junctions. Recent mouse data have 
demonstrated that BMT has the potential to restore genetically defective 
desmosomal proteins, with recovery of epidermal integrity in desmoglein 
3-null mice17. From a human disease perspective, pathogenic mutations 
have been reported in 9 different desmosomal proteins, several of which 
can involve severe skin fragility (e.g. desmoplakin and plakophilin 1). Of 
particular interest, mutations in desmoplakin can also be associated with 
extracutaneous abnormalities such as cardiomyopathy which may start in 
childhood or in young adult life. Thus, if BMT is able to correct an inherited 
disorder od desmoplakin, there is the potential to carry our therapeutic 
BMT in the clinical window between onset of skin fragility (at birth) and the 
later development of life-threatening cardiomyopathy. Although less 
common than RDEB and JEB, inherited disorders of desmosomes and 
keratins represent a subtype of EB that, in some cases, may also warrant 
consideration for BMT. 
 
2.2 
Treatment of Severe EB 
 
2.2.1 Supportive Care  
Care for patients with severe EB is entirely supportive with the aim of 
maximizing mucosal and skin integrity, reducing infection and minimizing 
pain and scar formation18.  The mainstays of supportive care applicable to 
most children and adults with severe EB are: 
▪ Protection of the skin and skin care with bandages to prevent shearing 
of the skin with friction and minimal trauma as well as infection 
prevention 
▪ Treatment of growth failure by maximizing nutrition that may require 
gastrostomy tube or nasogastric feeding 
▪ Esophageal dilatation to  treat esophageal strictures secondary to 
repeated trauma and gastroesophageal reflux 
▪ Treatment of gastroesophageal reflux with H2 blockers or proton pump 
inhibitors 
▪ Prevention and treatment of chronic constipation 
▪ Treatment of severe iron deficiency anemia secondary to chronic blood 
loss from mucosal and cutaneous blisters 

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▪ Surgical correction of scarring, contractures and syndactyly from 
repeated blistering  
▪ Correction of severe dental problems, corneal and conjunctival 
adhesions and osteoporosis prevention/treatment. 
 
2.2.2 Skin Grafting in EB  
A subpopulation of patients with particularly severe areas of involvement 
requires skin grafting.  Numerous reports suggest transient benefit of 
allogeneic skin grafts or artificial skin equivalents to treat the cutaneous 
manifestations of EB.  Results have been limited by the allogeneic 
immune response and rejection as well as local infections.  
 
The main allogeneic skin graft used to treat RDEB patients is Graftskin 
(Apligraf, Organogenesis Inc., Canton, MA) approved by FDA in 1998 to 
treat venous ulcers on the lower extremities and in 1999 to treat diabetic 
foot ulcers. Apligraft is a bilayer skin construct derived from human 
neonatal foreskin keratinocytes and dermal fibroblast cultures in a 
collagen matrix19. Apligraft provides the proper environment, growth 
factors, and components to stimulate healing and reconstitution of antigen 
expression in cases of DEB skin treatments in newborns20 and children 
with severe DEB21. In the latter study 79% of the wounds healed as early 
as 7 days up to 18 weeks of follow up. In a recent Graftskin replacement 
therapy, the healing in five children with severe EBD was noted to have 
decreased itching and pain at the Graftskin treatment sites. However milia 
formation and erythema occurred for up to one year at sites prone to 
mechanical friction like the elbows, knees and ankles22.  In general the 
quality of life improved but what is not clear is the long-term survival of the 
graft and health outcome of treatments.  
 
In an attempt to enhance skin graft survival, combined use of allogeneic 
skin and BM transplantation has been performed23.  A 4-month-old child 
with Herlitz type JEB was treated with BM transplant followed by 
transplant of skin grafts from the same donor. In this case, peripheral 
blood stem cells obtained from the child’s haploidentical father 
(mismatched at 3 HLA antigens) were infused after conditioning with 
cyclophosphamide (CY) 120 mg/kg, melphalan 140 mg/m2 and anti-
thymocyte globulin (ATG) 60 mg/kg.  Four weeks after BM transplant, 
rapid progression of skin blistering occurred, resulting in loss of 2/3 of the 
total epidermis.  While GVHD was not proven, excess sensitivity to 
melphalan as well as the natural course of Herlitz type-JEB likely resulted 
in the intensified loss of the epidermal surface.  Skin transplant was 
performed using split thickness skin grafts (2 mm) from the thigh of the 
father.  Grafts were placed on the dorsal trunk and gluteal region of the 
child.  The remaining wounds were covered with glycerolized allogeneic 
skin to reduce fluid and protein losses.  One week and 2 weeks 
afterwards, temporary grafts were replaced with donor skin grafts.  All skin 

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grafts healed completely with excellent biomechanical and cosmetic 
results.  Presence of skin derived from the donor was verified 17 and 67 
days after skin grafting, supporting the use of this strategy for permanent 
large scale skin exchange in the setting of allogeneic BM transplantation.  
While 
engraftment 
was 
successful, 
presence 
of 
Pseudomonas 
colonization prior to transplantation, excessive chemosensitivity to 
melphalan and/or delayed immune recovery after HLA mismatched BM 
transplantation contributed to the development of systemic opportunistic 
infection and death. 
 
2.2.3 New Therapeutic Interventions   
New strategies for severe EB have focused on gene-, protein-, and cell-
based therapies.  However, to date, clinical trials in patients with RDEB 
have principally been limited to skin grafting with autologous skin grafts, 
autologous cultured keratinocytes, allogeneic keratinocytes, and skin bio-
equivalents.  None of these approaches have resulted in any long term 
success.   
 
Allogeneic Fibroblasts.  More recently, Wong et al2 used intradermal 
injections of allogeneic fibroblasts in patients with RDEB. In 5 patients, an 
increase in Col7 was documented at the DEJ at 2 weeks and at 3 months 
following injection with increased numbers of AF, although none had 
normal morphology. While no adverse effects were reported, there was a 
beneficial effect albeit not permanent or systemic.  The investigators 
hypothesized that the major effect of allogeneic fibroblasts is to increase 
the recipients' own COL7A1 mRNA levels leading to greater deposition of 
mutant Col7 resulting in the formation of additional rudimentary AF and 
partial functional improvement.  Nonetheless these results provide the 
‘proof of principle’ that allogeneic fibroblasts can have a positive effect and 
may be useful in particular for treating local areas that are repeatedly 
traumatized. 
 
Mesenchymal Stem/Stromal Cells (MSC).  Clinical investigation with 
MSC is expanding exponentially.  MSC are a well-characterized 
population of adult stem cells found in the BM, capable of forming fat cells, 
cartilage, bone, tendon and ligaments, muscles cells, nerve cells and skin 
cells. MSC have been studied in great detail and have been used in 
hundreds of patients worldwide administered both systemically and 
locally24-30. Importantly data suggest that MSC can repair damaged skin 
even in humans30. 
MSCs can be obtained in quantities appropriate for clinical applications, 
making them good candidates for use in tissue repair. Techniques for 
isolation and amplification of MSCs in culture have been established and 
the cells can be maintained and propagated in culture for long periods of 
time, without losing their capacity to form all the above cell types.  

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Furthermore, MSC can be frozen and when thawed they function normally, 
thus allowing for future "off-the-shelf" therapy approaches.  At a dose of 1-
5 x 106/kg (the MSC dose range used in most reported series) toxicities 
have rarely been reported28. 
BM-MSC are the most advanced population of MSC with regard to clinical 
development.  Osiris (Columbia, MD) has launched multiple clinical trials 
using MSC for enhancing engraftment and prevention and treatment of 
acute GVHD after allogeneic HSC transplantation.  In addition, Osiris has 
trials in the treatment of myocardial diseases and type I diabetes among 
others27.  The safety profile is established with few reports of toxicity.  
While theoretical, there have been no reports of ectopic tissue formation31-
33.  Notably, there has been one report of malignant transformation (MSC 
derived sarcoma) observed in one animal model 34. 
2.3 
Rationale for Evaluating BMT for Severe EB 
It has long been known that BM derived cells play a critical role in wound 
healing.  As wounds enroll many mature inflammatory cells which 
orchestrate the healing process, many less well characterized BM derived 
cells also migrate to wounds. Recent reports have illustrated that BM 
contains stem and progenitor cells capable of differentiating into non 
hematopoietic tissues, including skin35.  Wounding is likely one 
mechanism by which BM-derived cells are recruited to organs.  Data 
suggest that BM-derived cells promote wound healing particularly in 
settings where resident skin stem cells are deficient or defective. 
 
In addition, allogeneic HSCT is an established approach for the correction 
of various metabolic diseases, such as mucopolysaccharidoses (ie, 
Hurler, Maroteaux–Lamy, and Sly syndromes), leukodystrophies (ie, 
childhood and adolescent cerebral X-adrenoleukodystrophy, globoid cell 
leukodystrophy 
and 
metachromatic 
leukodystrophy), 
fucosidosis, 
mannosidosis, Gaucher disease, Niemann–Pick type B, and malignant 
infantile osteopetrosis36.  The mechanism of action is through the transfer 
of lysosomal and perioxisomal  proteins from BM-derived cells into other 
cells missing the critical protein.  Together, these observations led to the 
possibility that allogeneic HSCT might correct the dermatological 
manifestations of DEB and serve as a treatment of other diseases due to 
defects of secreted matrix proteins. 
 
2.3.1 Preclinical Studies-“Proof of Concept” 
Animal Model of EB.  With the information on the molecular culprit of 
DEB, the next logical step was to develop a DEB animal model in which 
the experimental hypothesis about pathological mechanisms and possible 
therapeutic approaches can be tested.  
 

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The animal was generated by replacing exons 46-69 with antibiotic 
resistant genes. This led to a truncated messenger with eventual lack of a 
functional Col7 protein in the mice. Heterozygous results in normal mice, 
null mice results in mice with extensive cutaneous blistering. The null 
knockout mice show all the hallmark of the disease. Extensive blistering, 
fusion of fingers and toes, sublamina densa detachment from underlaying 
dermis, absence of AF and lack of immunostaining of the Col7 at the 
membrane basement37. 
 
In general, the evidence points out that the Col7A1 knockout mice show 
many of the clinical, genetic and ultrastructural features  
 
of the DEB. This animal system allows testing of different therapeutic 
approaches towards  
the cure of the clinical symptoms. A suitable candidate approach is cell 
replacement therapy using allogeneic hematopoietic cell replacement.  
 
Adoptive Transfer of Col7 after Allogeneic HSCT.    As  the   DEB    
mutant newborns develop blisters and do not survive after two weeks of 
life,   we   have   been able to identify the mutant pups readily.   Further, 
rapid lethality provides a robust readout for the cellular interventions. As 
BM has previously been shown to seed various organs, including skin, we 
reasoned that a Col7 producing cell may be present in BM 
compartment.  To prove this in vivo, we tested multiple BM candidate 
populations for cellular therapy of DEB in the animal model.  Populations 
tested were: total BM epidermal stem cells, multipotent progenitor cells, 
MSC, lineage positive and lineage negative BM cell fractions, and 
transitional epithelial cells.  All cell populations tested failed to provide 
phenotypic correction, even when used at varying time points after birth, 
varying 
dosing 
regimens 
and 
varying 
routes 
of 
administration 
(intravenously or intrahepatically). 
Recently identified SLAM positive populations in the BM have been shown 
to have a significant pluripotentiality38-40.  Therefore, we tested 
CD150+/CD48- BM cell populations at multiple dose levels and infused the 
cells either in utero (into preterm pups) or early postnatally into 
unconditioned DEB mutant mice.  CD150+/CD48- BM cells at a dose 8 
million cells per mouse administered intravenously on day 3 or 4 after birth 
resulted in survival in 3 of 13 animals tested.  One animal was sacrificed 
on day 55 of life and two were sacrificed on day 70 of life.  Tissues from 
each animal were evaluated extensively.  First, all 3 mice were confirmed 
to be mutants, not only by phenotype of the blisters postnatally, but also 
by genotype, using PCR typing. The weights of these animals were lower 
than that of their normal litter mates and they were weaned two weeks 
later than usual.  The blisters on the paws of these animals healed with 
contractures, but there was no re-blistering noted.  Chimerism (presence 
7 at DEJ 

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of donor cells) was confirmed in 
the peripheral blood (mean: 3%) 
and BM (mean: 12%).  Tissue 
analyses 
showed 
that 
the 
adoptive transfer of donor SLAM 
CD150 selected BM resulted in 
production of VII collagen mRNA, 
as 
assessed 
by 
reverse 
transcriptase PCR.  BM cells 
explanted from the 3 surviving 
recipients showed Col7 producing 
cells (Figure 2).  Remarkably, we 
were able to show AFs, structures in the skin that require Col7 protein, on 
electron 
microscopy, 
showing 
conclusively that adoptive transfer 
of wild-type BM cells resulted in, at 
least partial, functional correction 
of collagen synthesizing defect 
(Figure 3). Collectively, these data 
demonstrate the proof of principle 
of BM transfer for correction of 
DEB defect in the murine model41 . 
2.3.2 “First in Human” Clinical 
Trial   
Allogeneic BM transplantation is a 
standard treatment option for an 
increasing number of malignant 
and 
non-malignant 
disorders, 
including 
metabolic 
disorders 
where missing proteins/enzymes that can be replaced by BM-
derived cells from healthy related or unrelated donors36. To reconstitute 
hematopoiesis 
after 
an 
intensive 
myeloablative 
therapy, 
the 
transplantation of pluripotential HSC, such as from BM or UCB, is 
required. 
       
Between October 2007 and August 28, 2009, 7 children aged 9 months to 
14 years were enrolled in a clinical trial to receive BM and/or UCB after 
high dose chemotherapy (Table 1). All had more than 50% body surface 
area (BSA) covered with blisters and erosions before transplantation.  
They were conditioned with busulfan (BU, 12.8-16 mg/kg), fludarabine 
(FLU, 75 mg/m2) and CY (200 mg/kg) followed by the infusion of sibling 
donor BM (n=5) or unrelated donor UCB (n=1) on day 0.  Patient 2 who 
presented with significant renal impairment (glomerular filtration rate 26 
mL/min/1.73 m2) secondary to perinatal cardiac arrest necessitated a 50% 
FLU dose reduction.   
Figure 3 

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Six 
of 
seven 
patients 
completed 
the 
treatment 
plan; 
patient 2 died of 
cardiomyopathy 
on day 0 prior to 
BM 
infusion.  
Three of the 6 
evaluable 
patients 
demonstrated 
moderate clinical 
improvement 
(defined as less than 25% of BSA affected) and the remaining three 
patients had marked clinical improvement (defined as less than 10% of 
BSA affected (Figure 4). 
 
D
C
Pre-
transplant
Day 
+60
Patient 3
Patient 4
200 nm
Figure 5
 
Remarkably, results of immunofluorescence (IF) for Col7 and electron 
microscopic (EM) studies for AFs qualitative and quantitative assessments 
demonstrated increased quantity of Col7 by IF and gradual increase in 
numbers and maturity of AFs by EM (Figure 5).  Unexpectedly (on the 
basis of finding in the animal model), a significant proportion of skin cells 
were of donor origin. 
+100
Pre-
+67
Patient  5
Pre-
+100
+100
Pre-
+100
Patient  4
Patient  3
Pre-
Patient 1
Patient 3
Figure 4

 
 
Table 1. Patient Characteristics 
Pt 
 Pre Treatment Clinical 
Status 
 and Col7 mutation 
Donor 
(cell dose: NC x 
108/kg) 
Transplant Related 
Toxicities 
C7 
Assessment  
Anchoring 
Fibril 
Assessment 
Clinical Outcome 
and Change in 
Dressing Use 
Skin Chimerism 
by Molecular 
Analysis 
Survival 
Days (as of 
08/01/09) 
1 
15 month old male; 
Mitten deformity; esophageal 
stricture; FTT, c.3472delC 
(p.Pro1158fsX3) 
IVS51+1G>A  
HLA 8/8 male 
Sibling BM 
(3.04) and UCB (0.66) 
Hyper-bilirubinemia 
 
Increased by 
IF and 
Western 
 
↑ 
Rudimentary  
AFs 
Moderate reduction in 
blistering 
 
 
11.4% 
 
 
Alive  
d1,292 
2 
9 month old female; renal 
failure; neonatal cardiac 
arrest; gastrostomy 
c.3840delC (p.Thr1280fsX45) 
c.8780G>A (p.Arg2927His) 
HLA 8/8 male           
Sibling BM 
(N/D) 
Cardiomyopathy 
                                                                              
Not evaluable; patient died before BM infusion 
3 
5.9 year old male; mitten 
deformity; gastrostomy, 
pulmonary artery stenosis, 
flexion contractures; FTT 
c.3472delC (p.Pro1158fsX3) 
IVS51+1G>A 
HLA 5/6 female         
URD UCB 
(0.55); 
 
HLA 5/6 female         
URD UCB 
(0.56) 
Graft rejection after 
first transplant; 
infection and ARDS 
after second 
transplant 
Increased by 
IF            
and Western 
↑ 
Rudimentary 
AFs 
Moderate reduction in 
blistering 
0-46.8% 
             
Died 
d183 
4 
6.3 year old male; 
esophageal stricture; peri-
rectal fissures 
IVS85-2delAG                
IVS92+5G>A 
HLA 8/8 female         
Sibling BM 
(3.76) 
Transient 
Hemodialysis; 
Mechanical 
Ventilation 
No change 
by IF○ 
but increased 
by Western 
↑ 
Rudimentary 
AFs;          
Normal AFs 
observed 
Marked reduction in 
blistering; Marked 
reduction in dressings  
0-27.4% 
             
Alive 
d880 
5 
6.2 year old female; mitten 
deformity; flexion 
contractures; esophageal 
stricture; FTT, anemia 
c.6176A>G (p.Glu2059Gly) 
IVS5+1G>A 
HLA 8/8 male           
Sibling BM 
(3.07) 
Transient 
Hemodialysis 
              
Increased by 
IF and 
Western 
              
↑ 
Rudimentary 
AFs 
Marked reduction in 
blistering; Marked 
reduction in dressings; 
resolution of anemia 
                  
22.1-93% 
             
Alive 
d761  
6 
6.9 year old female; mitten 
deformity; flexion 
contractures; esophageal 
stricture; FTT, anemia 
c.4919delG 
(p.Gly1640FSX70); 
c.8254 8255delAG 
(p.Arq2751fsX20) 
HLA 8/8  
Female 
Sibling BM 
(5.04) 
Hyperbilirubinemia 
Absent C7 
Absent AF 
Moderate reduction in 
blistering 
 
9-33% 
 
Alive  
d689 
7 
14.5 year old female; mitten 
→deformity; esophageal 
stricture; FTT, c.6781C →T 
(p.Arg2261X); 
IVS110-1G→C 
HLA 8/8 male Sibling 
BM (3.04) and UCB 
(0.66) 
Hyperbilirubinemia  
 
Increased by 
IF and 
Western 
 
↑ 
Rudimentary 
AFs 
Marked reduction in 
blistering; Marked 
reduction in dressings; 
 
18-51% 
 
     Alive 
     d623 
FTT=failure to thrive; BM=bone marrow; UCB=umbilical cord blood; URD=unrelated donor; IF=immunofluorescence staining for C7; AF=anchoring fibrils 
†HLA typing of the patient and donor was performed at allele level for HLA-A, B, C and DRB1 in marrow recipients; however, in unrelated UCB recipients, HLA typing was performed at antigen level for 
HLA-A and B and allele level for DRB1.   
‡Patient 3 received a second transplant 47 days after the first transplant in response to immune graft rejection.  Prior to the transplantation of a second HLA 5/6 (DRB1 antigen mismatched) UCB unit, 
conditioning consisted of rituximab 375 mg/m2 IV as a single dose (day -5) and anti-thymocyte globulin 15 mg/kg/day IV on three days (days –4 to –2, total dose 45 mg/kg). ARDS=acute respiratory 
distress syndrome  

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DEJ
Patient 3
Patient 5
XY
XY
Figure 6
DEJ
Patient 3
Patient 5
XY
XY
Figure 6
As shown (Table 1),  chimerism in the skin ranged between 0-93% varying 
between the location of the skin biopsy and time after transplant42. Two 
patients (3 and 5) received sex mismatched BM grafts.  Fluorescent in-situ 
hybridization for XX and XY was performed demonstrated perivascular 
clustering of donor cells in the dermis.  While the identity of these cells 
remains to be determined, these results suggest that the application of 
stem cells from marrow or UCB may not represent homologous use. 
 
2.3.3 Induction of Tolerance after Allogeneic HSCT   
Tolerance is routinely achieved after allogeneic HSCT when donor derived 
immune cells specifically fail to recognize and react to host MHC while 
maintaining a normal alloreactive response to third party MHC and other 
pathogeneic antigens.  Once tolerance is achieved, the patient is able to 
come off all immunosuppressive therapy without development of graft 
rejection or GVHD.  In animal models, tolerance is proven when third party 
skin explants are rejected and donor skin explants are accepted life long43. 
 
It has previously been shown that MSC are potent immune modulators.  
The mechanism by which they inhibit various inflammatory reactions 
include production of immune suppressive cytokines, such as IL-10, 
induction of tryptophan depletion, and providing signal 1 in absence of 
costimulation.  The immunosuppressive effects of MSCs have been 
generally ascribed to the inhibitory effect on T cells, but recently it was 
been shown that MSCs also have inhibitory effects on other immune cells, 
including dendritic cells44-46.  In vivo, infusion of MSCs prolong skin 
allograft survival and may decrease GVHD in animal models28, 32.  Clinical 
data also demonstrate that MSC can enhance engraftment and prevent 
GVHD24 26, 32, 33.  Together with the potential direct effect of MSC on repair 
of skin in RDEB, these data provide a rationale for infusing MSC as a 
strategy for reducing the immunological risks associated with allogeneic 
HSCT. 
 
 

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2.3.4 Transplantation of HSC and MSC for Severe EB: Preliminary 
Results 
Thus far, 9 children (7 with RDEB and 2 JEB-Herlitz variant) have been 
treated on this protocol using BU, CY, FLU followed by the infusion of HLA 
matched or partially matched HSC (4 with a sibling donor, 2 with an 
unrelated marrow donor and 3 with an unrelated cord blood donor).  As of 
March 31, 2011 7 of 9 are alive 20 to 406 days after transplantation with 
one child with JEB dying 44 days from infections despite engraftment and 
one with RDEB dying 101 days after HSCT from multi-organ toxicity.  
Marrow recovery occurred in all patients with one child with RDEB having 
autologous recovery.  Of the six remaining patients, three had increased 
levels of the missing protein, two had no change thus far and one has not 
had the first scheduled evaluation.  In all patients with hematopoietic 
engraftment, chimerism (6-33%) was also present in the skin with 6-33% 
of skin cells derived from the HSC donor.  Notably, one patient had 
chimerism in the skin from the MSC donor (4%) at day 100.  Three 
patients with increased protein had improved wound healing, and 
resistance to blister formation.  In the one evaluable patient with JEB, 
blistering markedly decreased. 
 
2.3.5 Rationale for Reduced Intensity Conditioning 
 
The two trials at the University of Minnesota together suggest that the 
infusion of allogeneic BM can ameliorate the biochemical, structural and 
clinical manifestations of RDEB and JEB.  While allogeneic BMT can be a 
disease-modifying intervention with clinical benefit for severe EB, the 
conditioning regimen is associated with considerable toxicity and risk of 
opportunistic infection.  Toxcities in the two prior tirals have included: 
hepatic veno-occlusive disease (n=3), acute renal failure (n=6) requiring 
hemodialysis (transiently in most), severe cutaneous toxicity (n=1), 
respiratory failure (n=8) requiring ventilatory support.  Therefore, we 
propose to evaluate a reduced intensity conditioning regimen, consisting 
of CY 50 mg/kg, Flu 200 mg/m2, TBI 200 cGy and ATG 90 mg/kg; a 
regimen used at the University of Minnesota since 2000 in older patients 
with malignant disease or those with pre-existing comorbidities excluding 
them from a full myeloablative therapy47.  
 
2.3.5.1 
Clinical 
Experience 
with 
CY50/FLU200/TBI200+/-
ATGAM90 
In 
2000, 
the 
reduced 
intensity 
conditioning 
regimen 
of 
CY50/FLU200/TBI200 was developed as a strategy for reducing 
the risk of regimen related toxicity and consequent TRM specifically 
for patients >45 years of age or younger patients with preexisting 
co-morbidities or active opportunistic infections, undergoing UCB 
transplantation.  Due to the finding that absence of recent prior 
chemotherapy (i.e., within 3 months of transplant) was associated 

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with an increased risk of graft failure, such patients subsequently 
had ATGAM added to their preparative therapy which successfully 
increased the probability of engraftment.  The following summarizes 
the outcomes in the first 110 adults aged 17-69 years (median 51 
years) treated for malignant diseases. 
 
Engraftment 
Compared to historical controls in whom there was no recent 
chemotherapy, addition of ATGAM improved engraftment (83% 
versus 64%) in an interim analysis performed in 2007.   
 
In a more recent analysis using this treatment plan where ATGAM 
is added only for those without recent chemotherapy, engraftment 
is good whether the graft is composed of a one (90% [95% CI: 80-
97%]), n=43, median=16 days) or two UCB units (94% [95% CI: 91-
96%]), n=277, median=14 days). Multivariate analysis reveals low 
UCB graft cell dose (and not absence of recent chemotherapy) as 
the only risk factor for graft failure, suggesting that the addition of 
ATGAM has reduced the risk.     
 
GVHD 
The cumulative incidences of grades II-IV and grades III and IV 
acute GVHD at day 100 were 59% (95% CI, 49%-69%) and 22% 
(95% CI, 14%-30%), respectively.  
 
Twenty one patients had grade III and 3 had grade IV GVHD. In 
multivariate analysis, patients who received double-unit UCB grafts 
and those not receiving ATGAM had a higher relative risk of GVHD. 
The cumulative incidence of chronic GVHD was 23% (95% CI, 
15%-31%) at 1 year with no factor identified as predictive of chronic 
GVHD. 
 
EBV Reactivation 
Among 95 patients who received an NMA preparative regimen, the 
incidence of EBV viremia or PTLD was 7% (95% CI, 2%-14%).  
However, there was a significantly higher risk among patients who 
received ATG (21% vs 2%, p=.01). Among 30 patients who 
received ATG, 5 developed EBV PTLD and 1 developed EBV 
viremia.  Patients who received an NMA preparative regimen with 
ATG were more likely to be older, male, weigh more, and be a 
recipient of 2 UCB units. 
 
Rituximab was administered in 9 of 15 patients who developed 
EBV-related complications, with 5 responding and all 5 alive and 
EBV disease free beyond 1 year. Among the 4 patients who failed 

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rituximab, 3 received the drug alone and 1 received the drug in 
combination with vincristine.48 
 
2.3.6 Impact of Reduced Intensity Conditioning in Patients with EB 
 
Due to the toxicity profile with a myeloablative regimen, a new conditioning 
regimen was developed that was non-myeloablative.  It has been better 
tolerated with less renal and hepatic complications.   
 
2.3.6.1 
Clinical 
Experience 
with 
the 
Nonmyeloablative 
Regimen In Patients With Severe EB 
 
Engraftment 
Thus far 12 patients were treated on with the non-myeloablative 
regimen.  Engraftment was good.    By donor type:3 of 4 with a 
sibling marrow donor engrafted (one graft failure); 6 of 6 with a 
matched unrelated marrow donor engrafted (no graft failure) and 1 
of 2 with a mismatched unrelated UCB donor engrafted (one graft 
failure).  However, one patient (RDEB6) had primary engraftment 
but experienced a late graft failure after a viral like illness and 
underwent second transplant successfully. 
 
Importantly, while engraftment was documented in all, 3 patients 
(RDEB9, RDEB12 and RDEB15) required donor lymphocyte 
infusions to enhance the proportion of donor cells.  Two of the three 
responded; the other died from infectious complications prior 
complete evaluation.   
 
GVHD 
GVHD was uncommon occurring in one patient thus far.  Whether 
this is related to the immunosuppressive properties of the MSC 
infusion, differences in GVHD targets in the mucosa and skin of 
children with EB or some other factor, is as yet not known.   
 
EBV Reactivation 
Among 12 patients who received the non-myeloablative regimen, 
no patient demonstrated EBV reactivation or PTLD. 
 
2.3.7 Rationale for TBI 300 cGy 
 
Delaney et al 49 recently reported on the efficacy of TBI 300 cGy in 
reducing the risk of graft failure in patients considered to be high risk for 
graft failure. In a study where all patients received an identical treatment 
except for TBI dose, ie fludarabine and cyclophosphamide as part of the 
conditioning and CsA and MMF for GVHD prophylaxis (exactly as in 

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patients with EB), TBI 300 cGy resulted in high engraftment rates with no 
increase in toxicity.   
Specifically, in this study, 48 patients median age 59 years (range 25 - 73) 
and comorbidity index = 3 (range 0 - 8) with high risk hematologic 
malignancies received TBI 200 cGy if there was no risk factor for graft 
failure and TBI 300 cGy if the patient was considered high risk for graft 
failure.  High risk for graft failure was defined as receiving < 2 cycles of 
multiagent chemotherapy or no multiagent chemotherapy within the 3 
months prior to UCB transplant.  Forty-seven of 48 patients received 2 
UCB units (one patient received a single UCB) with a median cell dose of 
4.05 x 107 nucleated cells per kg and a post-thaw median CD34+cells/kg 
of 1.75 x 105. UCB grafts (98%) were 1-2 HLA antigen mismatched with 
the recipient. Twenty-six patients were assigned to Arm 1 (low risk for 
graft failure) and 22 patients were assigned to Arm 2 (high risk for graft 
failure).  
All evaluable patients engrafted (n = 46). Patients on Arm 1 achieved 
neutrophil recovery (ANC > 500 x 3 days) at a median of 12 days (range 6 
- 38) versus 23 days (range 7-46) in patients on Arm 2 (p = 0.01). Day +28 
chimerism values were evaluable for 23 patients on Arm 1 and 20 patients 
on Arm 2. Median chimerism in the CD3+ compartment was 100% (57 - 
100) and 100% (0-100) on Arm 1 and Arm 2 respectively (p = 0.58). 
Median chimerism in the CD33+ compartment was 98% (15-100) and 
100% (44-100) on Arm 1 and Arm 2 respectively (p =0.26). Median 
chimerism in the bone marrow was 98% (15-100) and 100% (4-100) on 
Arm 1 and Arm 2 respectively (p = 0.84). This was maintained at Day +80. 
Acute graft versus host disease (GVHD) grades II - IV was seen in 84% (n 
= 21) and 68% (n = 15) of patients on Arm 1 and 2 respectively with 5% 
and 12% grade III-IV GVHD in the respective arms. Chronic GVHD was 
seen in 40% of patients on Arm 1 (8 mild, 2 moderate) and 23% on Arm 2 
(3 mild, 1 moderate, 1 severe). Overall survival at 1 year in Arm 1 was 
43% (95% CI: 22-62%) and Arm 2 was 46% (95% CI: 20-69%).  
2.4 
The goal of this study was to assess engraftment rates by neutrophil 
recovery and Day +28 chimerism in patients at low versus high risk of graft 
rejection. Although time to neutrophil recovery was significantly faster in 
patients with low risk of graft failure treated with TBI 200 cGy, patients at 
high risk of graft failure treated with TBI 300 cGy achieved a similar 
incidence of completer chimerism at Day +28 as those at low risk. 
Summary 
We believe that engraftment after TBI 200 cGy, while good, is still not 
optimal in patients with EB.  On the basis of the recent report by Delaney 
et al, we plan to make modest increase in the TBI dose from 200 cGy to 
300 cGy in an attempt to enhance the proportion of patients with complete 
chimerism without the need for ATG or donor lymphocyte infusions.  While 

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engraftment will be slowest in recipients of UCB, the majority of patients 
will receive sibling or unrelated marrow in whom the rate of hematopoietic 
recovery will likely be faster.   
 
 
 
3 
STUDY DESIGN 
This is an open label, single institution, phase II study.   
 
The primary objective is to estimate the event-free survival rate by 1 year post-transplant 
with an event defined as death or failure to have a demonstrable increase in collagen, 
laminin, intergrin,  keratin or plakin deposition or other biochemical, structural or physical 
measure of improvement. 
 
 
4 
ELIGIBILITY CRITERIA 
4.1 
Age and Disease Criteria 
4.1.1 Patients aged 0-25 years 
4.1.2 Diagnosis of severe form of EB characterized by collagen, laminin, 
integrin, keratin or plakin deficiency.  Assessment criteria for severe 
EB: 
a. Documented collagen, laminin, integrin, keratin or plakin 
deficiency (by immunofluorescence staining with protein specific 
antibodies or Western blotting and by mutation analysis)  
 
4.2 
Adequate Organ Function Criteria 
4.2.1 Renal: glomerular filtration rate within normal range for age  
4.2.2 Hepatic: bilirubin, AST/ALT, ALP < 5 x upper limit of normal 
4.2.3 Pulmonary: adequate pulmonary function in the opinion of the 
enrolling investigator 
4.2.4 Cardiac: left ventricular ejection fraction ≥ 45%, normal EKG or 
approved by Cardiology for transplant. 
 
4.3 
Available Healthy HSC Donor (order of preference) 
4.3.1 Related Donor (marrow or UCB) 
4.3.1.1 HLA-A, B, C, DRB1 genotypic identical (sibling) donor  
4.3.1.2 HLA-A, B, C, DRB1 phenotypic identical donor 
4.3.1.3 7/8 HLA matched donor at HLA-A, B, C, DRB1 
 
4.3.2 Unrelated Donor 
4.3.2.1 Marrow 
4.3.2.1.1 HLA-A, B, C, DRB1 phenotypic identical donor 
4.3.2.1.2 7/8 HLA matched donor at HLA-A, B, C, DRB1 

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4.3.2.2 UCB 
4.3.2.2.1 HLA-A, B (antigen level) and DRB1 (allele level) 
matched donor 
4.3.2.2.2 5/6 HLA matched donor at HLA-A, B, DRB1 
4.3.2.2.3 4/6 HLA matched donor at HLA-A, B, DRB1 
 
Considerations when using UCB as a cell source  
The use of a FDA-licensed unit is preferred; however an unlicensed UCB unit 
that meets the required cell dose and HLA matching criteria (as defined in 
section 4.3) may be used if an ‘equivalent’, licensed UCB unit is not available.  
UCB units will be selected using the current University of Minnesota UCB Graft 
Selection Algorithm. 
 
4.4 
Available ‘off-the-shelf’ MSC  
MSC product with a dose of 2 x 106/kg. 
 
4.5 
Absence of Exclusion Criteria 
4.5.1 Active systemic infection at time of transplantation (including active 
infection with Aspergillus or other mold within 30 days).  
4.5.2 History of HIV infection 
4.5.3 Evidence of squamous cell carcinoma 
4.5.4 Donor has EB 
4.5.5 Pregnancy Females of child-bearing age must have a documented 
negative pregnancy test and agree to use contraception as a 
condition for enrollment. 
 
 
 
4.6 
Consent 
Voluntary written consent  
 
Refer to appendix 2 regarding review of patient disease status by members of an 
external advisory panel at the time of study work-up and appendix 3 for the work-
up process flow. 
 
 
5 SUBJECT  REGISTRATION 
5.1 
Registration Procedure 
Parental or subject informed consent must be signed prior to the performance of 
any study related procedures or assessments. 
 
To be eligible for registration to this study, the patient must meet each criteria 
listed on the eligibility checklist found in ONCORE based on the eligibility 
assessment documented in the patient’s medical record.   
 

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Upon completion of the screening evaluation, eligibility confirmation and 
obtaining informed consent, a designated study site staff person will enroll the 
patient into ONCORE and contact the BMT Biostatistical Support Group at the 
University of Minnesota by fax to register the subject.   
 
5.2 
Staggering of Enrollment 
On February 8, 2012 permission was received from the FDA to remove the 
staggering of enrollment effective immediately.  The 4 week waiting period 
between patients within each stratum is no longer required.   
 
5.3 
Updating ONCORE for Sibling Donor MSC’s Infusions 
ONCORE will be updated to reflect the 6 month post-transplant infusion of sibling 
donor MSCs to release the associated electronic case report forms. 
 
5.4 
Subject Withdrawal Prior to Treatment Start 
If a patient is registered to the study, and is later found not able to begin the 
planned study treatment, the patient will be removed from study.  The BMT 
Registrar will be notified of the patient’s non-treatment status and ONCORE will 
be updated.  Study data will be collected until the time the patient is off study.  
The reason for removal from study will be clearly indicated on the case report 
forms.  The registration number cannot be reassigned. 

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6 TREATMENT PLAN 
 
Day 
Drug 
Dose 
-6 
Cyclophosphamide 
Fludarabine 
50mg/kg IV over 120 min 
40mg/ m2 IV over 60 min 
-5 
Fludarabine  
 
40 mg/ m2 IV over 60 min 
 
-4 
Fludarabine  
ATG 
40 mg/ m2 IV over 60 min 
30 mg/kg IV over 6-8 hours 
-3 
Fludarabine  
ATG 
40 mg/ m2 IV over 60 min 
30 mg/kg IV over 6-8 hours 
-2 
Fludarabine 
ATG 
40 mg/ m2 IV over 60 min 
30 mg/kg IV over 6-8 hours  
-1 
TBI 300cGy 
 
 0 
HSC/MSC infusion 
 
 
6.1 
Conditioning Regimen 
 
Cyclophosphamide  
CY 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg (days –6).  
CY will be administered with a high volume fluid flush starting >4 hours 
prior to CY and MESNA (MT[S]1996-02) on day -6 with CY according to 
institutional practices. 
 
Fludarabine  
Fludarabine 40 mg/m2/day IV over 1 hour x 5 days, total dose 200 mg/m2 
(days –6 to –2).  Flu will be administered IV over one hour at a constant 
rate. Flu dose will be modified based if there is renal dysfunction 
according to institutional practices. 
 
Anti-thymocyte Globulin (ATG) 
ATGAM 30 mg/kg IV over 6-8 hours x 3 days, total dose 90 mg/kg (days -
4 to -2).  ATGAM premedication will include diphenhydramine and 
methylprednisolone 1 mg/kg (or equivalent steroid) IV 30 minutes prior to 
the start of ATGAM and it may be repeated during the infusion for 
treatment of hives or pruritis.   
 
Radiation Therapy (total body irradiation, (TBI)) 
The TBI dose will be 300 cGy 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.  The TBI will be delivered with right and left lateral 

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fields, with the patient supine on a specially designed couch.  TBI will be 
delivered with a linear accelerator using 6, 18, or 24 MV X-rays.  Based on 
measurements of transverse thicknesses, aluminum compensators may 
be used to ensure that the dose homogeneity across the field is within 
10% of the prescribed dose.  Usually head/neck, leg and lung 
compensators are used (although based on calculated midmediastinal 
doses, lung compensators are often not needed).  A beam “spoiler” will be 
used to ensure a full skin dose.  Half value layer lung and kidney blocks 
will not be utilized.  Testicular boosts are not needed.    
 
6.2 
Immunosuppressive Therapies 
Patients will not be eligible for any GVHD prophylaxis studies. 
All patients will receive GVHD prophylaxis with 2 drugs as follows: 
 
Cyclosporine (CSA) 
Patients will receive cyclosporine (CSA) therapy beginning on day -3 
maintaining a level of > 200 ng/mL.  For children < 40 kg the initial dose 
will be 2.5 mg/kg IV over 2 hours every 8 hours.  For children > 40 kg, the 
dosing is 2.5 mg/kg/dose IV q 12 hours. 
 
Dose adjustments will be made on the basis of toxicity and CSA levels 
with a targeted trough level of 200-400 mg/L (Supportive Care, Appendix 
5).  Once the patient can tolerate oral medications, CSA will be converted 
to an oral form suggested at 5 mg/kg PO twice daily. CSA dosing will be 
monitored and altered as clinically appropriate by Pharm D or physician.  
 
Patients with an HLA matched sibling donor will receive CSA until day 
+100.  If no GVHD, the dose will be tapered 10% per week beginning on 
day 101, to discontinue 10 weeks later.  Patients with an alternative (non 
HLA matched sibling) donor will receive CSA until day +180.  If no GVHD, 
the dose will be tapered 10% per week beginning on day 181, to 
discontinue 10 weeks later.  
 
Mycophenolate Mofetil (MMF) 
All patients will begin mycophenolate mofetil (MMF) on day -3.  Patients 
<45 kilograms will receive MMF at the dose of 15 mg/kg/dose every 8 
hours (max dose 1 gm/dose) (PO or IV).  IV route will be used between 
days –3 and +5, then, if tolerated, may change to PO between days +6 
and +30. Patients >45 kg will receive MMF 1.5gm IV/po every 12 hours.  
Levels will be modified if clinically indicated. 
 
Stop MMF at day +30 or 7 days after engraftment or 7 days after control of 
acute GVHD, whichever is later. (Definition of engraftment is 1st day of 3 
consecutive days of absolute neutrophil count [ANC] > 0.5 x 109 /L).  
 

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6.3 
Processing and Infusion of HSC 
6.3.1 HLA identical related donor BM 
• No T cell depletion 
• Infuse fresh, unirradiated with filtration of bone fragments 
• May be supplemented with cryopreserved UCB if available as 
source of HSC to supplement marrow if available 
• 30 mL of BM will be removed for potential future manufacture of 
MSC should residual focal areas of blistering be identified. 
 
6.3.2 HLA 8/8 allele matched unrelated donor BM 
• No T cell depletion 
• Infuse fresh, unirradiated with filtration of bone fragments 
• 30 mL removed for potential future manufacture of MSC 
 
6.3.3 HLA matched or mismatched related or unrelated UCB 
• Thaw, wash and infuse without further manipulation 
 
6.3.4 HSC infusions (regardless of ABO match) will be infused with: 
• Twice maintenance fluids initiated 12 hours prior to scheduled 
transplant and maintained for 24 hours. 
• Premedication with acetaminophen, diphenhydramine, anti-
emetic (if cryopreserved product is infused). 
• The product is infused via IV drip directly into the central line 
without a needle or pump. 
• UCB products will be infused as soon as the product arrives on 
the PCU and within 30 minutes.   
• After the product bag empties (regardless of HSC source or 
prior processing), the bag and IV tubing will be flushed with 
sterile normal saline.  Saline may be either injected directly into 
the bag or a 50 cc saline IV bag may be attached to the product 
bag. 
 
6.4 
Processing and Infusion of MSC 
6.4.1 MSC Donors 
To be eligible as a MSC donor, the donor must have tested negative for 
HIV-I, HIV-II, HTLV-I/II, hepatitis B and C, CMV, syphilis, CJD and 
tuberculosis, and free of active infection at the time of BM harvest, in good 
health.  For unmatched, ‘off-the-shelf’ MSC, 25-35 mL BM will be 
harvested from an unrelated donor using local anesthesia only.   
 
Because of the potential future need for additional MSC therapy to focal 
areas of persistent disease after transplant, 25-35 mL BM will be obtained 
at the time of marrow harvest for HSC collection.  BM from the HSC donor 
will be cryopreserved and stored until the time it is needed.  

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6.4.2 MSC Manufacture and Storage  
BM MNC’s are cultured under standardized conditions.  After expansion 
culture, cells are removed for testing with the remainder cryopreserved in 
aliquots for future use.  MSC’s will be banked prior to use and will not be 
released to patient until results of all quality control assays (sterility, 
epitope analysis and differentiation potential) satisfy lot release criteria (as 
defined in the IND).  Details on the manufacturing procedure, including lot 
release testing and specifications can be found in the Chemistry, 
Manufacturing and Controls (CMC) section of the Investigational New 
Drug (IND) application.  Only MSC lots meeting lot release will be 
available for clinical use. 
 
All patients who are enrolled onto this trial are eligible to receive “off-the-
shelf” MSC. 
 
6.4.3 Administration of Unmatched “Off-the-Shelf” MSC (dose of 2 x 
106/kg) 
1. Infuse 4 hours after BM or UCB infusion.   
2. Premedication with acetaminophen, diphenhydramine, anti-emetic; if 
infused as scheduled additional hydration is not required beyond that 
described for HSC infusion in section 6.4.1. 
3. MSC product will be infused within 30 minutes of arrival on the PCU. 
4. The product is infused via IV drip directly into the central line without a 
needle or pump at 4-6 mL/minute. 
5. While adverse events are rare based on substantial past experiences 
with MSC, infusional toxicity will be evaluated by continuous monitoring 
of the subject’s vital signs and O2 saturation by pulse oximetry during 
the MSC administration and for two hours afterward.  Infusional toxicity 
will be based on a decrease in oxygen saturation during the infusion 
period.  If there are signs of respiratory distress (oxygen saturation 
below 90% off oxygen or shortness of breath), the infusion will be 
discontinued.  Such event will count toward the study stopping rules 
(refer to section 10.4.1). 
6. After the product bag empties (regardless of HSC source or prior 
processing), the bag and IV tubing will be flushed with sterile normal 
saline.  Saline may be either injected directly into the bag or a 50 cc 
saline IV bag may be attached to the product bag. 
7. Post infusion assessments will be done per section 8.2 
 
6.5 
Supportive Care 
Supportive care is not specific to patients with EB but to transplant patients in 
general.  For this study, patients will receive Neupogen (G-CSF) 5 mcg/kg/day IV 
based on the actual body weight IV beginning on day +1 after HSC infusion 
regardless of HSC source.  Neupogen will be administered daily until the ANC 
exceeds 2.5 x 109/L for three consecutive days and then discontinued.  If the 

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ANC decreases to <1.0 x 109/L, G-CSF will be reinstituted.  Supportive care 
guidelines, including the management of graft failure and EBV reactivation with 
or without post-transplant lymphoproliferative disease (PTLD) are detailed in 
institutional SOPs and summarized in Appendix  5. 
 
However, in the event that focal blistering persists, patients may be eligible to 
receive HSC donor derived MSC infusions in an attempt to reduce further 
blistering.  Eligibility and treatment plan are shown below: 
 
6.5.1  Eligibility for ‘Directed-Donor’ MSC Infusions   
6.5.1.1 .Patient >6 months from HSC transplant with complete 
chimerism (i.e., > 95% donor cells) in the blood and 
marrow 
6.5.1.2 
Persistent mucocutaneous blistering 
6.5.1.3 
Adequate organ function (as in 4.2) 
6.5.1.4 
Available donor specific MSC containing a dose of 2 x 
106/kg 
6.5.1.5 
Absence of exclusion criteria (as in 4.5) 
6.5.1.6 
Voluntary written consent  (separate consent) 
 
6.5.2 Treatment Plan 
Infusions will be given in the outpatient clinic.  
 
6.5.2.1 
Premedication with acetaminophen, diphenhydramine, 
anti-emetic; additional hydration is not required. 
6.5.2.2 
MSC product will be infused within 30 minutes of product 
arrival in clinic. 
6.5.2.3 
The product is infused via IV drip directly into the central 
line without a needle or pump at 4-6 mL/minute. 
6.5.2.4 
While adverse events are rare based on substantial past 
experiences with MSC, infusional toxicity will be 
evaluated by continuous monitoring of the subject’s vital 
signs and O2 saturation by pulse oximetry during the 
MSC administration and for two hours afterward.  
Infusional toxicity will be based on a decrease in oxygen 
saturation during the infusion period.  If there are signs of 
respiratory distress (oxygen saturation below 90% off 
oxygen or shortness of breath), the infusion will be 
discontinued.  Such event will count toward the study 
stopping rules (refer to section 10.4.1). 
6.5.2.5 
After the product bag empties, the bag and IV tubing will 
be flushed with sterile normal saline.  Saline may be 
either injected directly into the bag or a 50 cc saline IV 
bag may be attached to the product. 
6.5.2.6 
Post infusion assessments will be done per section 8.2  
 

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6.6 
Treatment Related Toxicities 
6.6.1 Potential Toxicities Associated With Preparative Therapies 
 
Cyclophosphamide 
Common 
Occurs in 21-100 people out of 
100 
Less Frequent 
Occurs in 5-20 people 
out of every 100 
Uncommon 
Occurs in <5 people out of every 100 
hypotension 
nausea and vomiting 
diarrhea 
hemorrhagic cystitis 
leukopenia 
amenorrhea 
 
syndrome of inappropriate ADH  
hemorrhagic myocardopathy 
Stevens-Johnson syndrome 
toxic epidermal necrolysis 
azoospermia 
oligozoospermia 
interstitial pneumonia 
 
Fludarabine 
Common 
Occurs in 21-100 people 
out of 100 
Less Frequent 
Occurs in 5-20 people 
out of every 100 
Uncommon 
Occurs in <5 people out of every 100 
severe suppression of blood 
counts 
diarrhea  
anorexia 
mucositis 
nausea/vomiting 
stomatitis 
osteoporosis 
dysuria 
chills 
fever 
GI bleeding 
peripheral edema 
neurotoxicity 
agitation and confusion 
blurred vision 
peripheral neuropathy 
hearing loss  
headache 
cerebellar syndrome 
blindness 
coma  
weakness 
depression 
insomnia 
hemorrhagic cystitis (except in FA) 
abnormal renal function test 
autoimmune hemolytic anemia 
deep venous thrombosis 
aneurysms 
pruritic skin rash 
abnormal liver function/liver failure 
constipation 
transient ischemic attack 
dysphagia 
myalgia 
arthralgia 
renal failure 
 
 
 

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ATGAM 
Common 
Occurs in 21-100 people 
out of 100 
Less Frequent 
Occurs in 5-20 people 
out of every 100 
Uncommon 
Occurs in <5 people out of every 100 
malaise 
hives/rash 
fever/chills 
decreased white blood cells 
joint aches and 
pains 
infection 
low blood pressure 
seizure 
difficulty breathing 
 
TBI 300 cGy 
Common 
Occurs in 21-100 people 
out of 100 
Less Frequent 
Occurs in 5-20 people 
out of every 100 
Uncommon 
Occurs in <5 people out of every 100 
nausea 
decreased white blood cells 
mucositis 
diarrhea 
vomiting 
 
dysphagia 
parotiditis 
 
Other effects associated with TBI but unknown at this low dose include cataracts, 
increased risk of secondary neoplasms, sterility/infertility, endocrinopathies, 
interstitial pneumonitis. 
 
6.6.2 Potential Toxicities Associated With Immunosuppressive 
Therapies 
Cyclosporine (CSA)  
 
 
Mycophenolate Mofetil (MMF) 
nephrotoxcity 
seizures 
hypertension 
hirsutism 
increased risk of relapse 
thrombotic thrombocytopenic purpura 
electrolyte imbalances 
paresthesias/neuropathy 
gingival hyperplasia 
increased risk of opportunistic infection 
pancytopenia 
headache 
insomnia 
electrolyte imbalances 
leg cramps/bone pain 
hypertension 
dizziness 
hyperglycemia 
rash 
nausea/diarrhea 
 
6.6.3 Potential Toxicities Associated With Neupogen (G-CSF) 
bone pain 
headaches 
body aches 
fatigue  
nausea/vomiting 
insomnia 
dyspnea 
rash 
edema 
 
6.6.4 Potential Toxicities Associated With MSC Infusions 
allergic reaction to fbs (rare) 
shortness of breath (rare) 
ectopic tissue formation (theoretical) 
malignancy (one reported case) 
opportunistic infection (rare) 

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7 
STUDY PARAMETERS 
7.1 
Assessments and Procedures 
7.1.1 Patient Clinical Assessments and Procedures (Clinical Costs)  
 
Screen 
Day 0 to 30 
Day 31 to 100 
Follow-up 
Daily 
Weekly 
Day +28 
(+/- 3 days) 
Weekly 
Day 
+60 
(+/- 7 
days) 
Day 
+100 
(+/- 7 
days) 
6 months, 
1 and 2 
years 
(+/- 30 days) 
Patient’s General Assessments 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
X 
 
 
X 
Physical exam 
X 
X 
 
 
X 
 
 
X 
Quality of Life 
Questionnaire or iscorEB3 
X 
 
 
 
 
 
X 
X 
Performance status 
X 
 
 
X 
 
 
X 
X 
Height/Weight 
X 
 
 
 
 
 
X 
X 
GVHD evaluation 
 
 
X 
 
X 
 
 
X 
Adverse event notation 
 
X 
 
 
X 
 
 
X 
Patient’s Laboratory Assessments2 
CBC, diff  
X 
X 
 
 
X 
 
 
X 
Platelet 
X 
X 
 
 
X 
 
 
X 
PT/PTT 
X 
 
 
 
 
 
X 
 
Comprehensive Metabolic 
Panel 
X 
 
X 
 
X 
 
 
X 
Basic Metabolic Panel 
 
X4 
 
 
 
 
 
 
Iron studies  
X 
 
 
 
 
 
X 
X 
Zinc, Selenium, Vitamin D3 
X 
 
 
 
 
 
 
6 month, 1 
year only 
Viral serology  
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
GFR 
X 
 
 
 
 
 
 
 
Blood DNA to Molecular 
Diagnostics 
Lab 
for 
Chimerism Assessment 
X 
 
 
X 
 
X 
X 
X 
Skin DNA to Molecular 
Diagnostics Lab for 
Chimerism Assessment 
 
 
 
 
 
 
X 
X 
Immune Panel and Ig 
levels 
X 
 
 
X 
 
X 
X 
X 
Patient’s Procedures 
EKG 
X 
 
 
 
 
 
 
 
ECHO  
X 
 
 
 
 
 
 
 
Chest Xray or CT 
X 
 
 
 
 
 
 
 
Oxygen saturation 
X 
 
 
 
 
 
 
 
Renal Function 
X 
 
 
 
 
 
 
 
Ophthalmology consult1 
 
 
 
 
 
 
X 
X 
Skin biopsy and 
GIendoscopy and biopsy* 
X 
 
 
 
 
 
X 
X 
*Skin and gastrointestinal evaluations will be performed at scheduled intervals in order to 
document severity of disease pre-transplant and response to therapy after transplant. GI 
mucosal biopsy material will only be obtained if there is a need for clinical care. Additional skin 
biopsies maybe completed as clinically indicated. Standard procedures for these evaluations 
are briefly described below: 
Skin Biopsy  
▪ 
Alcohol swab is applied to the skin. 
▪ 
Lidocaine with epinephrine [1-3 mL] is injected SQ for anesthesia.  

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▪ 
3-4 mm punch biopsies are performed around skin erosions.  
▪ 
Each of them is closed with a 4-0 Prolene suture; alternatively 5 mm x 5mm gelfoam “plugs” 
are used for hemostasis. 
▪ 
Dressings are applied in a manner usual for each patient.  
Gastrointestinal Endoscopy and Mucosal Biopsy 
• 
Antibiotics are given before procedure. 
• 
General anesthesia is introduced. 
• 
Endoscopic evaluation of stomach and esophagus is performed up to the superior 
esophageal sphincter via a previously placed gastric tube; alternatively oral route may be 
used.  
• 
1-2 mm mucosal biopsies are collected from esophagus and stomach (if clinically required). 
• 
Dilatation of esophageal strictures is done using a balloon technique (if indicated). 
1 If clinically indicated 
2 If lab draw outside of window due to blood volume limitations, this will not be considered a deviation from protocol 
3 If patient began protocol prior to incorporation of iscorEB, quality of life survey will continue to be collected; if patient began protocol after iscorEB 
added to protocol, this will be collected in place of the quality of life survey (iscorEB is considered standard of care, quality of life questionnaire is 
research; iscorEB will be given to patient/parent any time a skin biopsy is done as standard of care as well) 
4 If patient undergoes a comprehensive metabolic panel, do not also draw basic metabolic panel 
 
7.1.2 Patient Research Assessments (Research Costs)  
 
Screen 
Day +28 
(+/- 3 days) 
Day +60 
(+/- 7 days) 
Day +100 
(+/- 7 days) 
6 months, 1 
and 2 years 
(+/- 30 days) 
Research 
related 
bloods 
for 
Tolar Lab: 
≥40kg patient weight: draw One 5 
mL red top tube (serum) and One 
5mL purple top tube (plasma/PBL) 
<40kg patient weight: draw One 0.2 
mL/10kg red top tube (serum) and 
One 0.2 mL/10kg purple top tube 
(plasma/PBL) 
X 
X 
X 
X 
X 
Skin biopsy specimens 
-protein expression 
-structural assessment  
  -blister roofs  
X 
 
 
X 
X 
Skin fragility testing (Appendix 6) 
X 
 
 
X 
X 
Photographs of skin 
X 
 
 
X 
X 
Quality of Life Questionnaire (not 
required for children < 2 years)       
(Appendix 7, 11) or iscorEB3 
X 
 
 
X 
X (1 and 2 
years) 
3 If patient began protocol prior to incorporation of iscorEB, quality of life survey will continue to be collected; if patient began protocol after iscorEB 
added to protocol, this will be collected in place of the quality of life survey (iscorEB is considered standard of care, quality of life questionnaire is 
research) 
 
 
7.1.3 HSC Donor Clinical Assessments and Procedures (Clinical 
Costs)  
 
Screen 
Day 0 
Donor’s General Assessments 
Informed consent 
X 
 
Medical history 
X 
 
Physical exam 
X 
 
Donor’s Laboratory Assessments 
CBC, diff  
X 
 
Platelet 
X 
 

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PT/PTT 
X 
 
Serum chemistries 
X 
 
Mutation analysis 
X 
 
Viral serology  
X 
 
Urinalysis 
X 
 
Blood DNA to Molecular 
Diagnostics Lab for future 
chimerism Assessment 
X 
 
Donor’s Procedures 
BM Harvest 
 
X 
EKG 
X 
 
Chest X-ray 
X 
 
Skin biopsy 
 
X 
7.1.4 HSC Donor Research Assessments (Research Costs)  
Donor’s Procedures 
 
after consent 
Skin fragility test (including parents) 
(Appendix 6) 
X 
 
Research related bloods for Tolar Lab: 
≥40kg patient weight: draw One 5 mL red 
top tube (serum) and One 5mL purple top 
tube (plasma/PBL) 
<40kg patient weight: draw One 0.2 
mL/10kg red top tube (serum) and One 0.2 
mL/10kg purple top tube (plasma/PBL) 
X 
Skin biopsy specimens 
-protein expression 
-structural assessment  
  -blister roofs  
X 
 
 
7.1.5 MSC Donor Clinical Assessments (Research Costs)  
 
Screen 
After Consent  
Donor’s General Assessments 
Informed consent 
X 
 
Medical history 
X 
 
Physical exam 
X 
 
Donor’s Laboratory Assessments 
CBC, diff  
X 
 
Platelet 
X 
 
PT/PTT 
X 
 
Viral serology  
X 
 
MSC DNA to Molecular 
Diagnostics Lab for future 
chimerism Assessment 
 
X (after MSC 
manufacture) 
Donor’s Procedures 
BM Aspirate 
 
X 
 
7.2 
Patient Pre-Study Screening Procedure 
• Medical history of allergies, previous chemotherapy, prior radiotherapy 
and response to treatment 
• Performance status (Appendix 1) 
• Physical examination 
• Complete blood count with leukocyte differential 

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• Comprehensive Metabolic Panel 
• PTT, CH50, C3 and C4 
• Ferritin, TIBC, serum iron zinc, selenium, vitamin D3 
• Assessment of immune function (complete phenotype panel; 
immunoglobulin levels), ANA 
• Viral tests (HSV, CMV, EBV, HIV, HBsAg, HBcAb, HC, HTLV1/2) 
• Electrocardiogram and echocardiography with measurement of the left 
ventricular ejection fraction (LVEF) 
• Oxygen saturation 
• Chest CT without contrast to exclude occult infection prior to transplant 
for patients  
• GFR 
• Blood 
o DNA 
for 
chimerism 
assessments 
(Molecular 
Diagnostic 
Laboratory) 
o Research related bloods for Tolar Lab: 
≥40kg patient weight: draw One 5 mL red top tube (serum) and 
One 5mL purple top tube (plasma/PBL) 
<40kg patient weight: draw One 0.2 mL/10kg red top tube 
(serum) and One 0.2 mL/10kg purple top tube (plasma/PBL) 
• Skin evaluations 
o DNA for chimerism assessment 
o Photography (skin) 
o IF or Western to assess protein expression (collagen, laminin, 
integrin, keratin or plakin) 
o EM to assess structural changes 
o Skin fragility testing (time to blister formation) to assess physical 
changes (Appendix 6) 
• GI mucosa evaluations 
o Photography (oral mucosa) 
o Endoscopy via G tube 
• Quality of Life questionnaire (Appendix 7- not required for children < 2 
years of age, Appendix 11) or iscorEB 
 
7.3 
Patient Evaluations: During Therapy to Day 28 
• Medical history interval history daily (while hospitalized) 
• Assessment of MSC infusional adverse events (during infusion and for 
4 hours thereafter) 
• Performance status at day 28 
• Physical examination daily (while hospitalized) 
• Complete blood count (with leukocyte differential when count is 
>500/uL) daily (while hospitalized) 
• BMP daily, CMP weekly while hospitalized 
• Blood submitted to Molecular Diagnostic Laboratory for chimerism 
studies on day 28 +/- 3 days 

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• Blood on day 28 +/- 3 days 
o DNA 
for 
chimerism 
assessments 
(Molecular 
Diagnostic 
Laboratory). 
o Research related bloods for Tolar Lab: 
≥40kg patient weight: draw One 5 mL red top tube (serum) and 
One 5mL purple top tube (plasma/PBL) 
<40kg patient weight: draw One 0.2 mL/10kg red top tube 
(serum) and One 0.2 mL/10kg purple top tube (plasma/PBL 
• GI mucosa evaluations on day 28 +/- 3 days (if clinically indicated) 
• Photography (oral mucosa) (if clinically indicated) 
• Endoscopy via G tube (if clinically indicated) 
• Assessment of acute GVHD weekly  in hospital (Appendix 8) 
 
7.4 Subject Evaluations: Day 31 to day 100 
• Medical interval history weekly 
• Performance status at day 100 +/- 7 days 
• Physical examination weekly 
• Complete blood count with leukocyte differential weekly 
• CMP weekly 
• PTT, CH50, C3 and C4day 100 +/- 7 days 
• Ferritin, TIBC, and serum Fe day 100 +/- 7 days 
• Assessment of immune function (complete phenotype panel; 
immunoglobulin levels) on day 60 +/- 3 days and day 100 +/- 7 days  
• Blood on day 60 +/- 3 days and day 100 +/- 7 days 
o DNA 
for 
chimerism 
assessments 
(Molecular 
Diagnostic 
Laboratory) 
o Research related bloods for Tolar Lab: 
≥40kg patient weight: draw One 5 mL red top tube (serum) and 
One 5mL purple top tube (plasma/PBL) 
<40kg patient weight: draw One 0.2 mL/10kg red top tube 
(serum) and One 0.2 mL/10kg purple top tube (plasma/PBL 
• Skin evaluations on day 100 +/- 7 days 
o DNA for chimerism assessment 
o Photography (skin) 
o IF or Western to assess protein expression (collagen, laminin, 
integrin, keratin or plakin) 
o EM to assess structural changes 
o Skin fragility testing (time to blister formation) to assess physical 
changes (Appendix 6) 
• GI mucosa evaluations on day100 +/- 7 days (if clinically indicated) 
o Photography (oral mucosa) 
o Endoscopy via G tube 
• Ophthalmology consult day 100 +/- 7 days (if clinically indicated) 

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• Quality of Life questionnaire or iscorEB on day 100 +/- 7 days 
(appendix 7- quality of life questionnaire not required for children < 
2 years of age, appendix 11) 
• Assessment of acute GVHD on day 60 +/- 3 days and day 100 +/- 7 
days 
 
7.5 
Subject Evaluations: 6 Months, 1 Year and 2 year 
• Medical interval history  
• Performance status  
• Physical examination  
• Complete blood count with leukocyte differential  
• CMP 
• Zinc, Selenium and Vitamin D3 on day +180 and 1 year 
• Assessment of immune function (complete phenotype panel; 
immunoglobulin levels), ANA 
• Ferritin, TIBC, serum iron  
• Viral tests (CMV, EBV, HBsAg, HBcAb, HC) 
• Blood  
o DNA for chimerism assessments (Molecular Diagnostic Laboratory) 
o Research related bloods for Tolar Lab: 
≥40kg patient weight: draw One 5 mL red top tube (serum) and 
One 5mL purple top tube (plasma/PBL) 
<40kg patient weight: draw One 0.2 mL/10kg red top tube (serum) 
and One 0.2 mL/10kg purple top tube (plasma/PBL) 
• Skin evaluations  
o DNA for chimerism assessment 
o Photography (skin) 
o IF or Western to assess protein expression (collagen, laminin, 
integrin, keratin or plakin) 
o EM to assess structural changes 
o Skin fragility testing (time to blister formation) to assess physical 
changes (Appendix 6) 
• GI mucosa evaluations (if clinically indicated) 
o Photography (oral mucosa) 
o Endoscopy via G tube 
• Ophthalmology consult (if clinically indicated) 
• Quality of Life questionnaire (appendix 7- not required for children <2 
years of age, appendix 11) or iscorEB 
• Assessment of acute GVHD and chronic GVHD (Appendix 8 and 9) 
 
7.6 
Skin Evaluations 
Prior to transplant, on days 100, and at 6 months, 1 and 2 years after transplant, 
the following skin evaluations will be performed in an attempt to objectively 
demonstrate change in skin structure and function over time. 
 

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7.6.1 Assessment of Chimerism (also day +28 and +60) 
Skin biopsies will be sent to the Molecular Diagnostics Laboratory and the 
proportion of cells derived from the HSC and MSC donors will be 
determined.  Standard methods will be used to distinguish DNA 
polymorphisms unique to the two stem cell donors and host.  In cases 
where there is a sex mismatched HSC or MSC donor, a histological 
section will be further evaluated for the presence of XX and XY by 
fluorescent in situ hybridization. 
 
7.6.2 Biochemical Assessment 
Protein expression (collagen, laminin, integrin, keratin or plakin) will be 
assessed using standard IF and Western blot assays on biopsy sections 
or cell preparations. 
 
7.6.3 Structural Assessments 
Skin architecture will be determined using standard transmission electron 
microscopy. 
 
7.6.4 Physical Assessments 
• Assessment of Skin Fragility.  Using negative pressure, time to 
blister formation before and after transplant will be determined.  
As shown in Appendix 6, the device permits an objective 
assessment of blister formation resistance. 
• Photographs.  Total body photographs will be obtained to 
assess changes in degree of blistering and surface area 
involved.  In addition photographs of mouth, stomach and 
esophagus will be obtained at the time of endoscopy via the G 
tube if possible. 
 
7.7 
Hematopoietic Engraftment Evaluation 
Chimerism studies will be performed on the blood on days 28, 60, and 100, and 
at 6 months, 1 and 2 years.  In cases of slow engraftment, a BM aspirate and 
biopsy will be performed at any time.   
 
7.8 
GVHD Evaluation 
Patients will be staged weekly between days 0 and 100 after transplantation 
using standard criteria (acute GVHD, Appendix 8).  Patients will be assigned an 
overall acute GVHD score based on extent of skin rash, volume of diarrhea and 
maximum bilirubin level.  Patients will be rescored at 6 months, and at 1 and 2 
years with additional scores as events occur once discharged to home.  Chronic 
GVHD is graded using standard criteria (Appendix 9). 
 
7.9 
Sample Storage 
Residual skin biopsy and blood specimens will be cryopreseved for future 
molecular analyses.  Skin biopsy samples and blood samples will be stored at 

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the University of Minnesota (Laboratory of Jakub Tolar).  Samples will be stored 
indefinitely.  Samples will only be used for additional analyses to verify correction 
of the EB and engraftment of donor cells, presence of antibody to fetal calf 
serum, MSC HLA antigens, new protein (collagen, laminin, integrin, plakin), and 
further studies of skin architecture. 
 
 
8 
ADVERSE EVENT DOCUMENTATION AND REPORTING 
 
Toxicity and adverse events will be classified according to NCI's Common Terminology 
Criteria for Adverse Events V 4.0 (CTCAE).  A copy of the CTCAE can be downloaded 
from the CTEP home page. 
  (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40) 
 
Note:  throughout this section the generic term “drug” refers to the study treatment. 
 
8.1 
Definitions 
The following definitions are based on the Code of Federal Regulations Title 21 
Part 312.32 (21CFR312.32(a)). 
  
 
Adverse Event:  Any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  
 
Suspected Adverse Reaction:  Any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  
 
Life-Threatening Adverse Event Or Life-Threatening Suspected Adverse 
Reaction: An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the investigator or sponsor, its occurrence 
places the patient or subject at immediate risk of death. 
   
Serious Adverse Event Or Serious Suspected Adverse Reaction:  An 
adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or sponsor, it results in any of the following 
outcomes:  
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 

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medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
 
If either the IND sponsor or the investigator believes the event is life-threatening 
or serious, the event must be evaluated by the sponsor for expedited reporting 
(21CRF 312.32(a)).  
 
Unexpected adverse event or unexpected suspected adverse reaction: An 
adverse event or suspected adverse reaction is considered “unexpected” if it is 
not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended.  Thus, 
adverse events that occur as part of the disease process or underlying medical 
conditions are considered unexpected; however, they will not be reportable per 
section 8.3. 
 
 
Unanticipated (unexpected) problems/events as defined by the University Of 
Minnesota IRB are those that are not already described as potential risks in the 
consent form, not listed in the Investigator’s Brochure or not part of an underlying 
disease. 
 
Note:  The major discord between the FDA and IRB definitions is whether or not 
the underlying disease is included when considering expectedness. 
 
 
FOR UNLICENSED UCB UNITS ONLY:  Selected expected adverse 
reactions determined to be caused by or probably caused by the UCB unit 
based on objective evidence will be reported in an expedited manner to the FDA 
under University of Minnesota IND BB-14797 (C. Brunstein, MD, PhD – 
sponsor/investigator). Included are the following: 
• The unit is mislabeled or failure to pass local lot release 
• Serious infusion reaction within first 24 hours after infusion 
• Recipient bacteremia with clinical signs and symptoms related to a 
contaminated UCB within 24 hours after infusion 
 
UPIRTSO: Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] 
require the IRB to ensure that researchers promptly report “any unanticipated 
problems involving risk to subjects or others” (UPIRTSOs).  The University of 
Minnesota IRB defines a UPIRTSO as any problem or event which in the opinion 
of the local researcher was unanticipated, reflects new or increased risk to the 
subjects and at least possibly related to the research procedures.  
 
In addition, the IRB has defined the following problems/events as reportable 
within 5 working days using the UPRITSO form found on the IRB website: 

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• 
Any accidental or unintentional change to the IRB-approved protocol that 
increases risk or has the potential to recur  
• 
Any deviation from the protocol taken without prior IRB review to eliminate 
apparent immediate hazard to a research subject  
• 
Any publication in the literature, safety monitoring report (including Data and 
Safety Monitoring Reports), interim result or other finding that indicates an 
unexpected change to the risk/benefit ratio of the research  
• 
Any breach in confidentiality that may involve risk to the subject or others  
• 
Any complaint of a subject that cannot be resolved by the research staff  
• 
Any other possibly related event which in the opinion of the investigator 
constitutes an unanticipated risk  
 
Expedited (Rapid) Reporting: Certain events may require rapid notification to 
entities providing patient safety oversight (e.g. IRB, FDA) as detailed in section 
8.3.  For the IRB this is 5 working days.  For studies under an IND, it is 7 or 15 
calendar days. 
 
8.2 
Adverse Event Documentation 
Due to the intentional clearing of the marrow with chemotherapy as preparation 
for the HSCT and MSC infusion, it is expected that all patients will experience 
severe depression of their blood counts and other related toxicities as detailed in 
section 6.6.  Therefore, adverse event collection for the purposes of this study 
will focus on targeted adverse events and unexpected adverse events at 
specific time points in relation to the MSC infusion.  A list of targeted adverse 
events is found in appendix 10. 
 
The targeted toxicity form (appendix 10) will be completed at the following time 
points: 
Day 0:  pre HSCT 
Day 0: pre MSC infusion 
Day 0: 4 hours post MSC infusion 
 
The pre-MSC infusion assessment will record the worse grade of the targeted 
toxicity observed in the previous 24 hours.     
 
The 4 hour post infusion assessment will record the worse grade of any targeted 
toxicity since the MSC infusion, in addition to any unexpected toxicity observed.  
After 4 hours, targeted adverse event data collection will not be done however; 
standard of care post-transplant adverse event assessments will continue per 
7.1.1.  From these assessments through day 100,  events deemed unexpected, 
regardless of grade, and/or meet the definition of serious will be recorded on the 
study’s case report forms.   
 
Patients also will be closely monitored for excessive toxicity as measured by 
inability to complete the MSC infusion, graft failure and treatment related 
mortality by day 100.  While these events may not necessarily constitute an 

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adverse event; such events count toward early study stopping rules as detailed in 
section 10.4.  
 
For patients receiving donor MSC infusions > 6 months from HSCT the targeted 
toxicity form will be completed at the following time points: 
• pre MSC infusion 
• 4 hours post MSC infusion 
 
Since these patients will be more than 100 days from transplant, event 
documentation will end with the 4 hour post MSC infusion assessment, unless an 
event meets the definition of requiring expedited reporting per section 8.3.  
Transplant related outcomes will continue to be collected as routine by the BMT 
Database. 
 
8.3 
Required Reporting: IRB, FDA, and MCC SAE Coordinator 
Monitoring and documenting of adverse events will end at day 100; however 
after this time point the investigator is obligated, upon knowledge of, to report 
any adverse event requiring expedited reporting as defined in section 8.1.  An 
exception to this is the short time frame around the MSC infusion given more 
than 6 months after transplant.  
Agency 
Criteria for reporting 
Timeframe 
Form to Use 
Submission address/ fax 
numbers 
Copy AE to: 
U of MN 
IRB 
UPIRTSO: any event 
which is unanticipated, 
involved new or increased 
risk to subjects, and was 
at least possibly related to 
study procedures 
5 Working Days 
 
UMCC SAE and 
IRB Report form 
University Of Minnesota IRB 
MMC 820 
Masonic Cancer 
Center SAE 
Coordinator 
mcc-
saes@umn.edu 
Other Problems or 
Events  – refer to the IRB 
website for complete 
details 
 
IRB Report 
Form 
 
FDA 
Unexpected and fatal or 
life threatening suspected 
adverse reaction 
 
7 Calendar-Day  
FDA prefers 
MedWatch 
3500a Form but 
alternative 
formats are 
acceptable (e.g. 
summary letter) 
Submit to as an 
amendment to IND 
1) Serious and 
unexpected suspected 
adverse reaction or 
2)  increased occurrence 
of serious suspected 
adverse reactions over 
that listed in the protocol 
or investigator 
brochure or 
3) findings from other 
sources (other studies, 
animal or in vitro testing) 
15 Calendar-
Day 
All other events per CRF 
312.33   
At time of IND 
annual report 
Summary 
format 
Submit as part of the IND 
annual report 
Not applicable 

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In each IND safety report, the sponsor must identify all IND safety reports 
previously submitted to the FDA concerning a similar suspected adverse reaction 
and must analyze the significance of the suspected adverse reaction in light of 
the previous, similar reports or other relevant information. 
 
The SAE Coordinator will provide the Masonic Cancer Center’s Data and Safety 
Monitoring Council (DSMC) with the SAE in an appropriate format depending on 
the individual SAE (as reported or in a summary format). 
 
 
 
9 
DATA AND SAFETY MONITORING  
9.1 
External Data and Safety Monitoring Board  
The DSMB is composed of the three External Advisory Panel members 
(appendix 2) who are considered experts in EB, in addition to an expert in 
pediatric blood and marrow transplantation.  The Board members will review the 
clinical and histopathological data at the following specified time points:  
• weeks after first 5 subjects have been treated 
• weeks after first 5 subjects have been treated within a specific stratum (ie., 
sibling donor, unrelated marrow donor, unrelated UCB donor) 
• Annually (all strata) 
 
The Board will be asked to assess the safety and efficacy endpoints.  The DSMB 
will make a recommendation at each time point regarding the appropriateness of 
study continuation and whether enrollment should be staggered as defined in 
section 5.2 for the first 5 patients in each stratum. 
 
The DSMB reports will be submitted to the IRB and FDA along with the 
scheduled annual reports to the various University and external agencies. 
 
9.2 
Data and Safety Monitoring Plan 
The study’s Data and Safety Monitoring Plan will be in compliance with the 
University of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan 
(DSMP), 
which 
can 
be 
accessed 
at 
http://www.cancer.umn.edu/for-
researchers/investigator-resources/cancer-protocol-review-commitee. 
 
For the purposes of data and safety monitoring, this study is classified as high 
risk (performed under an IND).  Therefore the following requirements will be 
fulfilled: 
 
Note:  Events due to the disease under treatment or an underlying medical condition will not require expedited 
reporting to the FDA for the purposes of this study 
MCC SAE 
Coordinator 
  Early study stopping rule 
event 
upon reporting 
Early study 
stopping rule  
SAE Coordinator 
mcc-saes@umn.edu 
Not  applicable 

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▪ The PI will complete and submit a quarterly Trial Progress Report to the 
Masonic Cancer Center Data and Safety Monitoring Council (DSMC) with the 
understanding the Cancer Protocol Review Committee (CPRC) may require 
more frequent reporting. 
▪ The PI will comply with at least twice yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
▪ The PI will oversee the submission of all reportable adverse events per the 
definition of reportable in section 8.3 to the Masonic Cancer Center’s SAE 
Coordinator and the University of Minnesota IRB.   
 
In addition, at the time of the continuing review with the University of Minnesota 
IRB, a copy of the report with any attachments will be submitted to the Cancer 
Protocol Review Committee (CPRC). 
 
9.3 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the sponsor-investigator will 
submit a progress report annually.  The report will be submitted within 60 days of 
the anniversary date that the IND went into effect.  
 
Additional reporting on unlicensed UCB units will be done under University of 
Minnesota IND BB-14797 (C. Brunstein, MD, PhD - sponsor/investigator).  
 
 
 
10 
STATISTICAL CONSIDERATIONS 
10.1 Statistical Endpoints 
The underlying hypothesis is that the infusion of BM or UCB from a healthy 
unaffected donor will correct the underlying collagen, laminin, integrin, keratin or 
plakin deficiency and reduce the skin fragility characteristic of severe EB.  In 
addition, it is hypothesized that MSCs from a healthy donor will enhance the 
safety and effectiveness of the transplant procedure as demonstrated by 
engraftment in the skin on day 28 after MSC administration. 
 
10.1.1 Primary Endpoint 
To estimate the event-free survival rate by 1 year post-transplant with an 
event defined as death or failure to have a demonstrable increase in 
collagen, laminin, intergrin, keratin or plakin deposition by 1 year post-
transplant or other biochemical, structural or physical measure of 
improvement. 
10.1.2 Secondary Endpoints 
• Incidence of transplant-related mortality (TRM) at 180 days. 
• Incidence of biochemical improvement as measured by increased 
collagen, laminin, intergrin, keratin or plakin deposition. 

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• Describe health quality of life at day 365 and 730 as compared to 
pretreatment results. 
• Incidence of HSC and third party MSC donor engraftment in the skin at 
day 100 
• Incidence of acute GVHD at 100 days 
• Probability of survival at 1 year 
 
10.2 Statistical Analysis  
Kaplan-Meier curves will be used to estimate event-free survival and survival. 
Cumulative incidence will be used to estimate the probability of biochemical 
improvement, engraftment of HSC and third party MSC donor cells in the skin 
and acute GVHD, treating non-event deaths as a competing risk. Ninety-five 
percent confidence intervals will be calculated for all estimates. Descriptive 
statistics will be applied to the quality of life assessments to determine whether 
there has been any positive or negative change compared to the pretransplant 
assessment.  Endpoints will be estimated separately for the three different donor 
types.   
  
10.3 Sample-Size Justification 
A minimum sample size of 25 patients per group (n=75 total) is sufficient to 
maintain an overall type I error of 5% while providing 80% statistical power. The 
sample size calculation is based on the Simon method using an optimum two-
stage (44). The two-stage design uses a two-step enrollment procedure with 
early stopping for low observed success as defined by the primary endpoint. 
Using 50% event-free survival as unacceptably low and 75% as a rate worthy of 
further study, the first stage of enrollment will include 11 patients with an early 
stop if 6 or fewer patients fail to have event-free survival by 1 year. If 7 or more 
respond and are alive at 1 year after transplant, we would enroll an additional 16 
patients. Significant clinical activity would require at least 17 patients with event-
free survival by 1 year with an event defined as death or failure to have a 
demonstrable increase in collagen, laminin, intergrin, keratin or plakin deposition or 
other biochemical, structural or physical measure of improvement.  Enrollment 
will continue during the potential 1 year waiting period after the 11th patient has 
been enrolled if no stopping rules have been met.  
 
Initially, we expect to enroll 5-15 patients per year but with current demand 
among these patients, we expect this rate to increase significantly.   
 
10.4 Toxicity Monitoring and Stopping Rules 
Monitoring guidelines will be set up for MSC infusional toxicity, graft failure by 
day 42 and TRM by day 100.  Monitoring guidelines will be applied separately to 
each stratum (donor type).      
 

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10.4.1 MSC Infusional Toxicity and Late Effects 
While adverse events are rare based on substantial past experiences with 
MSC, infusional toxicity will be evaluated by continuous monitoring of the 
subject’s vital signs and O2 saturation by pulse oximetry during the MSC 
administration and for two hours afterward.  Infusional toxicity will be 
based on a decrease in oxygen saturation during the infusion period.  If 
there are signs of respiratory distress (oxygen saturation below 90% off 
oxygen or shortness of breath), the infusion will be discontinued.  If 3 
patients cannot obtain the complete MSC infusion, the study will be 
stopped. 
 
10.4.2 Graft Failure 
Given a hypothesized graft failure (defined as failing to achieve an ANC 
>500/uL of donor origin by day 42) rate of 10%, a maximum tolerated rate 
of 25% and a maximum sample size of 10 patients, the trial will be 
stopped if: 4/8, 5/14, 6/20 or 7 patients fail to engraft. This has a type I 
error rate of 5% and a power of 80%.   
 
10.4.3 Treatment Related Morbidity by Day 100 
Given a hypothesized treatment related mortality rate of 10%, a maximum 
tolerated rate of 25% and a sample size of 10 patients, the trial will be 
stopped if: 4/8, 5/14, 6/20 or 7 patients die by day 100 post-transplant. 
This has a type I error rate of 5% and a power of 80%.   
 
10.5 Directed MSC Donor Subset Analysis  
Response to directed MSCs will be descriptive.  Toxicities will be assessed as 
with ‘off the shelf’ MSCs. 
 
10.6 Gender and Ethnicities Statement 
This study is open to both males and females and to all racial/ethnic groups. The 
patient enrollment pattern is expected to be similar to that of other hematological 
malignancy studies. It is not anticipated that the outcome will be affected by 
either race or gender.  The study will not have separate accrual targets for 
different subgroups. 
 
10.7 Data Collection 
Routine peri- and post-transplant data will be collected by the principal 
investigator, biostatistics and clinical management team and stored in the Blood 
and Marrow Transplant database in Oracle 8i.  
 
 
 

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11 
CONDUCT OF THE STUDY 
11.1 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki.  The IRB will review all appropriate study documentation 
in order to safeguard the rights, safety and well-being of the patients.  The study 
will only be conducted at sites where IRB approval has been obtained.  The 
protocol, informed consent, written information given to the patients, safety 
updates, progress reports, and any revisions to these documents will be provided 
to the IRB by the Investigator.   
11.2 Auditing and Monitoring 
The investigator will permit study-related monitoring, audits, IRB, government 
regulatory bodies, and University of Minnesota compliance and quality assurance 
groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will 
ensure the capability for inspections of applicable study-related facilities. 
 
11.3 Record Retention 
Essential clinical documents will be maintained to demonstrate the validity of the 
study and the integrity of the data collected.  Master files should be established 
at the beginning of the study, maintained for the duration of the study.  The 
investigator will retain study records, including source data, copies of case report 
form, and all study correspondence in a secured facility until at least 6 years after 
the IRB/IND study file closure. In addition, the Masonic Cancer Center Clinical 
Trials Office will keep a master log of all patients participating in the study with 
sufficient information to allow retrieval of the medical records. 
 
Please contact the Masonic Cancer Center Clinical Trials Office prior to 
destroying of any study related records. 
 
 
12 
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34. 
Tolar J, Nauta AJ, Osborn MJ, et al. Sarcoma derived from cultured mesenchymal stem cells. 
Stem Cells 2007;25:371-9. 
35. 
Borue X, Lee S, Grove J, et al. Bone marrow-derived cells contribute to epithelial engraftment 
during wound healing. Am J Pathol 2004;165:1767-72. 
36. 
Orchard PJ, Blazar BR, Wagner J, Charnas L, Krivit W, Tolar J. Hematopoietic cell therapy for 
metabolic disease. J Pediatr 2007;151:340-6. 
37. 
Heinonen S, Mannikko M, Klement JF, Whitaker-Menezes D, Murphy GF, Uitto J. Targeted 
inactivation of the type VII collagen gene (Col7a1) in mice results in severe blistering phenotype: 
a model for recessive dystrophic epidermolysis bullosa. J Cell Sci 1999;112 ( Pt 21):3641-8. 
38. 
Kim I, He S, Yilmaz OH, Kiel MJ, Morrison SJ. Enhanced purification of fetal liver hematopoietic 
stem cells using SLAM family receptors. Blood 2006;108:737-44. 
39. 
Yilmaz OH, Kiel MJ, Morrison SJ. SLAM family markers are conserved among hematopoietic 
stem cells from old and reconstituted mice and markedly increase their purity. Blood 
2006;107:924-30. 
40. 
Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ. SLAM family receptors distinguish 
hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 
2005;121:1109-21. 
41. 
Tolar J, Ishida-Yamamoto A, Riddle M, et al. Amelioration of epidermolysis bullosa by transfer of 
wild-type bone marrow cells. Blood 2009;113:1167-74. 
42. 
Wagner JE, Ishida-Yamamoto A, McGrath JA, Hordinsky M, Keane D, Christiano AM, Blazar BR, 
Tolar J.  Bone marrow transplantation for recessive dystrophic epidermolysis bullosa.  New Engl J 
Med 2010; 363:629-39 
43. 
Sykes M. Mechanisms of tolerance. Hematopoietic Cell Transplantation, Edited by Blume KG, 
Forman SJ, Appelbaum FR  Blackwell Publishing, Oxford 2004;3rd Edition:300-23. 
44. 
Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell 
responses. Blood 2005;105:1815-22. 
45. 
Zhang W, Ge W, Li C, et al. Effects of mesenchymal stem cells on differentiation, maturation, and 
function of human monocyte-derived dendritic cells. Stem Cells Dev 2004;13:263-71. 
46. 
Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE. Mesenchymal stem cells inhibit 
generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 
2006;177:2080-7 
47. 
Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR, McGlave PB, and 
Wagner JE. Umbilical cord blood transplantation after non-myeloablative conditioning: impact on 
transplant outcomes in 110 adults with hematological disease.  Blood 2007; 110:3064-70. 
48. 
Brunstein CG, Weisdorf DJ, DeFor T, Barker JN, Tolar J, van Burik JA, Wagner JE.  Marked 
increased risk of epstein-barr virus-related complications with the additional of anti-thymocyte 
globulin to a non-myeloablative conditioning prior to umbilical cord blood transplantation. Blood 
2006; 108: 2874-80. 
49. 
Salit RB, Milano F, Gutman JA, Maris MB, Chauncey T, Peterson F, Delaney C.  Umbilical cord 
blood transplant patients at high risk of graft rejection achieve early full donor chimerism when 
300 cGy is used in the reduced intensity conditioning regimen.  Blood 2013; 122: 697A. 
  
 
 

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Appendix 1 – Performance Status Scales 
 
Lansky Play Scale 
Percentage 
 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of, and less time spent in, play activities 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play; able to participate in all 
quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
Unresponsive 
0 
Dead 
 
Karnofsky Scale 
Percentage 
 
100 
Normal, no complaints, no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled, hospitalization indicated.  Death not imminent 
20 
Very sick, hospitalization necessary, active supportive treatment necessary 
10 
Moribund, fatal processes, progressing rapidly 
0 
Dead 
 
 

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Appendix 2 – External Advisory Board (EAP) 
 
The EAP is composed of three members who are considered expert in EB.  The panel 
members will review the clinical and histopathological data for each prospective patient 
and assess the severity of the EB.  Patients considered to have severe EB, based on 
biochemical and clinical data as well as self- or parental-assessment of quality of life, 
will be offered therapy. 
 
In addition, panel members will review the clinical and histopathological data for all 
patients annually at the time of the annual IRB review.  Patient demographics and 
identifiers will be removed. 
 
Panel Members: 
John A. McGrath (john.mcgrath@kcl.ac.uk) advisory panel chair 
Alain Hovnanian (alain.hovnanian@inserm.fr) 
Katsuto Tamai (tamai@gts.med.osaka-u.ac.jp) 
 
Severity Assessment 
EAP members will assess the severity of the patient’s disease on the basis of 
• Initial history and physical at the transplant center 
• Photographs of the affected skin and mucosa 
• Examination of the biochemical and structural assessments and/or mutation 
analysis 
• Quality of life survey 
 
In order to be eligible for the proposed treatment, the patient must be considered to 
have a severe form of EB.  The EAP will receive patient data without identifiers via a 
password protected secure website. 
 

 
 
Appendix 3 – Process Flow 
EB REFERRAL 
 
                        Information 
 
• 
Medical record (surgeries, list of 
medications, transfusions, problem list, 
      allergies) 
• 
Photographs documenting severity 
• 
Mutation analysis (if available) 
• 
GT present or absent 
• 
Skin biopsy report with: 
            Immunoflourescence documenting  
            collagen, lamin, integrin, keratin or 
            plakin 
             
 
 
     NEW TRANSPLANT CONSULTATION 
 
 
 
 
       Parent Only 
 
 
 
 Parents and  
                           (consult only)       
   Child (consult & treatment planning) 
 
 
Schedule  
Donor Search 
 
 
 
 
 
 
Biopsies 
Skin fragility testing 
Photographs 
Sibling  
 
Unrelated 
 
 
 
 
 
QOL Questionnaire 
G-tube placement (if not present) 
Consultations 
Anesthesia 
Gastroenterology 
Other  
 
 
 
 
 
 
 
 
 
 
 
 
               
 
 
PRE TRANSPLANT EVALUATION 
 
 
      
 
 
 
 
 
Schedule  
Biopsies 
Photographs 
Central line placement 
Consultations 
Infectious Disease (r/o cellulitis; colonization) 
Dermatology (r/o malignancy) 
  
ADMISSION 
 
if not done previously at the 
New Transplant Consultation 
External Advisory Panel 
Assessment 
 

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Appendix 4 - Data and Safety Monitoring Board 
 
The DSMB is composed of the three EAP members who are considered expert in EB in addition to an 
expert in pediatric blood and marrow transplantation.  The Board members will review the clinical and 
histopathological data at specified time points defined in the protocol.  The Board will be asked to 
assess the safety and efficacy endpoints.  The DSMB will make a recommendation at each time point 
regarding the appropriateness of study continuation and whether enrollment should be staggered as 
defined in the protocol for the first 5 patients in each stratum. 
 
Board Members: 
 
• Colleen Delaney, M.D., Blood and Marrow Transplant Program, Fred Hutchinson Cancer 
Research Center, Seattle, Washington—DSMB Chair 
• John A. McGrath (john.mcgrath@kcl.ac.uk ) 
• Alain Hovnanian (alain.hovnanian@inserm.fr) 
• Katsuto Tamai (tamai@gts.med.osaka-u.ac.jp)  
 
Assessments: 
 
Safety Assessments 
DSMB members will assess 
• MSC infusional toxicities 
• All SAEs and unexpected AEs 
 
Efficacy Assessments 
DSMB members will assess 
• Hematopoietic engraftment 
• Evidence of biochemical, structural and clinical correction 
• Chimerism in the skin (from the marrow and MSC donors) 
 
The DSMB will receive patient data via a password protected secure website. 
 
DSMB Reporting Requirements: 
• 4 weeks after first 5 subjects have been treated 
• 4 weeks after first 5 subjects have been treated within a specific stratum 
(ie., sibling donor, unrelated marrow donor, unrelated UCB donor) 
▪ Annually (all strata) 
 

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Appendix 5 – Supportive Care Guidelines 
 
1. 
Anemia 
Transfusions of packed red blood cells are indicated for symptomatic management of anemia.  An 
attempt will be made to maintain the hematocrit >24% and hemoglobin >8 g/dl.  Irradiated (1500-3000 
cCy) blood products will be used.  If CMV negative patient, CMV negative blood products or leukocyte 
poor blood products will be administered.   
 
2. 
Thrombocytopenia 
Prophylactic platelet transfusions should be given to maintain the platelet count >10,000 ml or above 
the level at which signs of bleeding are known to occur, whichever is greater.  When available, 
autologous stored platelets may be used.  All aspirin-containing drugs are to be avoided.  The 
patients should receive no IM nor SQ injections.  Irradiated (1500-3000 cCy) blood products will be 
used.  If CMV negative patient, CMV negative blood products or leukocyte poor blood products will be 
administered. 
 
3. 
Fever 
Aggressive diagnostic and therapeutic management of fever in the neutropenic patient is mandatory.  
At the onset of fever, the patient will be thoroughly examined and cultured, after which empiric broad-
spectrum antibiotics will be initiated. Anti-mold antibiotics should be considered for patients failing to 
respond to antibiotics.  Granulocyte transfusions may be given at the investigator's discretion.  
Irradiation (1500-3000 cCy) of blood products is required. 
 
4. 
Nutrition 
All patients will be candidates for total parenteral nutrition 
 
5. 
CSA dose modifications 
To minimize the risk of CSA toxicity, the serum creatinine/BUN will be determined daily for the first 30 
days after transplantation.  Subsequently, the frequency will be determined by the patient's clinical 
status.  Trough CSA levels will be determined twice weekly for all inpatients with levels obtained on 
the basis of the patients clinical status thereafter.  CSA dose adjustment on the basis of toxicity or low 
trough level.  The goal is to achieve a CSA trough level of at least 200-400 mg/L without significant 
renal toxicity.   
 
Adjustment of CSA should be based on CSA levels in conjunction with clinical observations of the 
biological effects of the drug, i.e., renal and neurologic toxicity, and the physician's assessment of the 
patient's need for immunosuppression.  As a guideline, if the serum creatinine exceeds 2x baseline or 
is >2.0 mg/dL, then the CSA dose should be decreased by 50%; if the serum creatinine exceeds 3x 
baseline or the patient requires hemodialysis, then the CSA dose should be held.  As a guideline, if 
the patient becomes disoriented or develops visual disturbance, paresis, aphasia or seizure, the CSA 
dose should be held during the evaluation of the neurological disturbance.  CSA should be 
reinstituted as soon as possible. 
 
6. 
G-CSF 
All patients will receive G-CSF 5 ug/kg/day IV based on the actual body weight IV beginning on day 
+1 after HSC infusion.  G-CSF will be administered daily until the ANC exceeds 2.5 x 109/L for three 
consecutive days and then discontinued.  If the ANC decreases to <1.0 x 109/L, G-CSF will be 
reinstituted. 

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7. 
Monitoring and Treatment of EBV-Reactivation and PTLD 
EBV-reactivation and PTLD are relatively rare complications after allogeneic HSCT, unless the graft 
is T cell depleted.  However, we have previously observed an increased incidence specifically in adult 
recipients of unrelated UCB who receive ATGAM in combination with CY50/FLU200/TBI20048.  In 
response to this observation, we monitor patients for EBV reactivation with planned early intervention 
using Rituximab, anti-CD20 antibody, to eradicate the infected B cell population.  While the incidence 
of this complication has been lower than in this initial report48, Rituximab is a generally accepted 
treatment strategy when rising titers of EBV are detected or PTLD has been diagnosed. 
 
 Monitoring.  EBV PCR is assessed every 2 weeks between days 30 and 180 after transplant.  
If PCR is positive (> 1000 copies of EBV DNA per milliliter of whole blood) the patient will be 
evaluated for adenopathy by physicial examination and CT scans of the chest, abdomen and 
pelvis.   
 
Treatment. If the diagnosis is EBV reactivation only with PTLD, the patient will receive 
Rituximab with frequent monitoring thereafter according to institutional practice.  If there is a 
adenopathy, the patient will receive Rituximab with or without chemotherapy depending upon 
the extent of disease, results of the lymph node biopsy, and other active problems related to 
the transplant. 

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Appendix 6 – Measurement of Skin Fragility 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Magnified view of 
the cup on the arm 
and the blister 
Magnified view of 
the cup on the arm 
and the blister 
To assess skin fragility after transplant, gentle negative pressure is applied to the skin.  
In normal individuals, blister formation takes up to 1 hour. Notably, individuals with one 
mutation in Col7A1 will form a blister after approximately 30 minutes in comparison to 
1-3 minutes in patients with RDEB who have mutations in both alleles.  It is 
hypothesized that biochemical correction of severe EB will result in increasing 
resistance to the negative pressure and a prolongation in time before blister formation 
occurs. 

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Appendix 7 – Quality of Life Questionnaire 
Please answer these questions about how EB affects your life. Please choose an option from the right hand column that 
most closely matches your situation. Completion not required for children ≤ 2 years of age 
 
1) Does your EB affect your ability to move 
around at home? 
• Not at all 
• A little 
• A lot 
• Severely 
2) Does your EB affect your ability to bath or 
shower? 
• No, No impact 
• Yes, I sometimes need assistance  
• Yes, need assistance most of the time 
• Yes, I need assistance every time I 
bath/shower 
3) Does your EB cause you physical pain? 
• No pain 
• Occasional pain  
• Frequent pain 
• Constant pain 
4) How does your EB affect your ability to 
write?  
• It does not interfere with writing 
• I find it difficult to grip the pen  
• I find it easier to type than write  
• I cannot write due to my EB 
5) Does your EB affect your ability to eat? 
• No, I eat normally 
• A little  
• A lot  
• I rely on my gastrostomy tube for nutrition 
6) Does your EB affect your ability to go 
shopping? 
• No, not at all 
• A little 
• A lot 
• I need assistance all the time. 
7) How does EB affect your involvement in 
sports? 
• No impact. 
• I need to be cautious in sports 
• I need to avoid some sports 
• I need to avoid all sports 
8) How frustrated do you feel about your EB? 
• No frustration 
• A little 
• A lot 
• So frustrated that I am angry most of the 
time  

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How long did it take you to complete this questionnaire? …………….. Minutes 
9) Does your EB affect your ability to move 
around outside of your home? 
• Not at all 
• A little 
• A lot 
• Severely 
10) How does your EB affect your relationships 
with family members? 
• No impact at all 
• A small impact 
• A large impact  
• A very large impact 
11) How embarrassed do people make you feel 
about your EB? 
 
• No embarrassment 
• A little 
• A lot 
• Extremely 
12) Have you needed to, or do you need to 
modify your home (installing ramps etc) due to 
your EB? 
• No, not at all  
• A few  
• A lot 
• Extensive 
13) Does your EB affect your relationships with 
friends? 
• No, Not at all 
• A little 
• A lot 
• It severely restricts my social interaction 
14) How worried or anxious do you feel 
because of your EB? 
• Not anxious at all 
• A little 
• A lot 
• Extremely  
15) How are you or your family affected 
financially by your EB? 
• No financial impact 
• Slightly Affected 
• Greatly Affected  
• Severely Affected  
16) How depressed do you feel because of 
your EB? 
• Not depressed at all 
• A little 
• A lot 
• Constantly very depressed 
17) How uncomfortable are you made to feel by 
others (eg- teasing or staring) because of your 
EB? 
• Not at all 
• A little 
• A lot 
• So much that I don ‘t go out socially 

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Appendix 8 – Diagnosis and Treatment of Acute GVHD 
 
Patients will be considered evaluable acute GVHD if they demonstrate donor cell engraftment and 
survive to day 28.  Organ involvement will be staged using the criteria outlined in the table below.  
Biopsy of each organ site at diagnosis or major change in disease activity will be performed unless 
clinical circumstances make it impossible. 
 
Consensus Clinical Stage and Grade of Acute GVHD (Przepiorka et al, 1995) 
Stage 
Skin 
Liver 
Lower 
Gastrointestinal 
Tract 
Upper 
Gastrointestinal 
Tract 
1 
Maculopapular 
rash <25% of 
body surface 
Bilirubin 2.0 – 3.0 
mg/dl 
Diarrhea 500 – 1000 
mL/day or 280 – 555 
mL/m2 
No protracted 
nausea and 
vomiting 
2 
Maculopapular 
rash 25-50% 
body surface 
Bilirubin 3.1 – 6.0 
mg/dl 
Diarrhea 1000 – 
1500 mL/day or 556 
– 833 mL/m2 
Persistent nausea, 
vomiting or 
anorexia 
3 
Generalized 
erythroderma 
Bilirubin 6.1 – 
15.0 mg/dl 
Diarrhea >1500 
mL/day or    >833 
mL/m2 
 
4 
Generalized 
erythroderma with 
bullous formation 
and 
desquamation 
Bilirubin > 15 
mg/dl 
Severe abdominal 
pain, with or without 
ileus, or stool with 
frank blood or 
melena 
 
 
Grading for Treatment Criteria: 
 
Mild GVHD   
Skin stage I-II only (Equivalent to Seattle Grade I). 
 
Moderate GVHD 
Skin stage I-III and/or liver I-IV and/or Gastrointestinal tract (GI) I-III and/or Upper 
GI (UGI).  (Equivalent to Seattle Grade II, III). 
 
Severe GVHD 
Any stage IV along with severe clinical illness. 
 
Patients progressing during initial therapy or not improving sufficiently after 2 courses of therapy are 
to be treated as severe GVHD. 
 
Acute GVHD treatment may be by institutional guidelines. The recommended treatment for patients 
demonstrating moderate or severe GVHD (Grade II-IV) is methylprednisolone at 48 mg/m2/day or 
prednisone 60 mg/m2/day followed by a taper which starts a day 8 of acute GVHD therapy.  If there is 
no response in 7 days or there is progression of the disease, ATG 15 mg/kg every 12 hours for 5 
days will be added.   

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Appendix 9 – Classification of Chronic GVHD 
 
Limited CGVHD 
Localized skin involvement (<50% body surface area) and/or 
Limited hepatic involvement (abnormal LFTS; bilirubin < 3 mg/dl) 
 
Extensive CGVHD  
The presence of one or more of the following criteria may be used for the diagnosis of extensive 
CGVHD: 
• Generalized skin involvement ( 50% body surface area)  
• Liver histology consistent with involvement by CGVHD with bilirubin  3 mg/dl 
• Positive Schirmer’s test (< 5 mm wetting) 
• Histologically-proven involvement by CGVHD of oral mucosa or salivary glands 
• Lung dysfunction with bronchiolitis obliterans with no evidence of viral causation on histology. 
• Gastrointestinal involvement: malabsorption and/or weight loss due to anorexia without 
explanation other than CGVHD 

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Appendix 10 – Targeted Toxicity Form 
Refer to next page 

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MT2009-09 - Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Stem Cell 
Transplantation  
Targeted Toxicity Form  
Patient Initials:   
       
 
 
 
Study Day 
 
Date of assessment: 
-
-
      
 
  Month        Day               Year 
  baseline assessment   
  4 hours post MSC infusion 
 
Toxicity 
Grade 
0 
1 
2 
3 
4 
 
 
Allergy reaction / 
hypersensitivity 
(including drug fever) 
 
  
 
0   
None 
 
1   
Transient rash, drug fever 
<38° C (<100.4° F) 
 
2   
Urticaria, drug fever 
38° C (100.4° F) and/or 
asymptomatic 
bronchospasm 
 
3   
Systematic bronchospasm 
requiring parenteral 
medication(s), with or without 
urticaria; allergy-related 
edema/angioedema 
 
4   
Anaphylaxis 
 
 
Sinus bradycardia 
 
  
 
0   
None 
 
1   
Asymptomatic , not requiring 
treatment 
 
2   
Symptomatic, but not 
requiring treatment 
 
3   
Symptomatic and requiring 
treatment 
 
4   
Life-threatening (e.g.) 
arrhythmia associated 
with CHF,hypotension, 
syncope, shock) 
 
 
Bleeding- Hemorrhage 
 
0   
None 
 
1   
 Mild without a transfusion 
 
2   
 
 
3   
 Requiring transfusion 
 
4   
  Catastrophic  
bleeding requiring 
major non- elective 
intervention 
 
 
Sinus tachycardia 
 
  
 
0   
None 
 
1   
Asymptomatic, not requiring 
treatment 
 
2   
Symptomatic, but not 
requiring treatment 
 
3   
Symptomatic and requiring 
treatment of underlying cause 
 
4   
 
 
 
Hypertension 
 
  
 
 
0   
None 
 
1   
asymptomatic, transcient 
increase by >20 mmHg 
(diastolic) or to >150/100* if 
previously WNL; not requiring 
treatment 
 
2   
Recurrent or persistent 
symptomatic increase 
by >20 mmHg (diastolic) 
or to >150/100* if 
previously WNL; not 
requiring treatment 
 
3   
Requiring therapy or more 
intensive therapy than 
previously 
 
4   
Hypertensive crisis 
 
 
Hypotension 
 
  
 
0   
None 
 
1   
Changes, but not requiring 
therapy (including transient 
orthostatic hypotension) 
 
2   
Requiring brief fluid 
replacement or other 
therapy; no physiologic 
consequences 
 
3   
Requiring therapy and 
sustained medical attention, 
but resolves without 
persisting physiologic 
consequences 
 
4   
Shock (associated with 
academia and 
impairing vital organ 
function due to tissue 
hypoperfusion) 
 
 
 
Fever 
  
 
0   
None 
 
1   
38.0 – 39.0 °C 
(100.4 – 102.2 °F) 
 
2   
39.1 – 40.0 °C 
(102.3 – 104.0 °F) 
 
3   
>40.0 °C (>104.0 °F) 
for <24 hrs 
 
4   
>40.0 °C (>104.0 °F) 
for >24 hrs 
 
 
 
Note: The temperature measurements listed above are oral or tympanic. 
 
 
Rigors, chills  
 
0   
None 
 
1   
Mild, requiring 
symptomatic treatment 
(e.g., blanket) or non-
narcotic medication 
 
2   
Severe and/or prolonged, 
requiring narcotic 
medication 
 
3   
Not responsive to narcotic 
medication 
 
 
 
Rash 
 
  
 
0   
None 
 
1   
Erythema 
<25% of surface 
 
2   
Erythema 25% to 50% of 
skin surface 
 
3   
Erythema >50% of surface 
requires intervention 
 
4   
Blistering skin 

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Patient Initials:   
       
 
 
 
Study Day 
 
Date of assessment: 
-
-
      
 
  Month        Day               Year 
  baseline assessment   
  4 hours post MSC infusion 
 
page 2 
 
Toxicity 
Grade 
 
 
 
 
0 
1 
2 
3 
4 
 
Dyspnea 
(shortness of breath) 
 
 
0   
None 
 
n/a 
 
2   
Dyspnea on exertion 
 
3   
Dyspnea at normal level or 
activity 
 
4   
Dyspnea at rest 
 
Hypoxia 
 
 
0   
Normal 
 
n/a 
 
2   
Decreased oxygen 
saturation with exercise    
 
 
3   
Decreased oxygen  
saturation at rest, requiring 
supplemental oxygen 
 
4   
Decreased oxygen 
saturation, requiring 
pressure support 
(CPAP) or assisted 
ventilation 
 
Neurologic:  
 
Specify:__________ 
  
 
0   
Norne 
  
    1   
 
      Mild 
 
2   
 
  Moderate          
 
  3   
  
   Severe 
 
4   
 
Life-threatening; 
disabling 
 
Other:  
 
Specify:__________ 
 
Expected or unexpected  
 
 
0   
Norne 
  
    1   
 
      Mild 
 
2   
 
  Moderate          
 
  3   
  
   Severe 
 
4   
 
Life-threatening; 
disabling 
 
 
Comments: 
 
 
 
 
 
All are treatment 
related except the 
following: 
 
 
 
 
 
 
 
Completed by: 
 
-- 
 Month        Day               Year 
 
Physician 
signature: 
 
 
 
 
 

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 iscorEB PATIENT SUBSCORE (max 120) 
The following questions attempt to assess how much of your (your child’s) life is affected by 
having epidermolysis bullosa (EB). All responses range from 0 to 8; where 0 means no impact 
(for example if the question is about pain, 0 =no pain) to a maximum of 8 (for example if the 
question is about pain, 8 = the worst possible pain).  
There are 15 questions grouped in 7 separate categories (domains). Please provide an answer 
to each question by circling the number that corresponds to the best descriptor of your (your 
child’s) status in the past 4 weeks. 
ID: 
Age (years): 
      Male              Female 
Date (mm/dd/yy):  /  / 
F. PAIN DOMAIN 
F1. Please rate how much OVERALL PAIN you (your child) typically had in the last 4 
weeks by circling one of the options below. 
 
 
 
  None                 Mild              Moderate          Severe       Worst possible 
 
     0                       2                       4                      6                       8 
SCORES 
F1= 
F2. Please rate how much SKIN PAIN you (your child) typically had in the last 4 
weeks by circling one of the options below. 
 
 
 
  None                 Mild              Moderate          Severe       Worst possible 
 
     0                       2                       4                      6                       8 
 
 
F2= 
F3. Please rate how much MOUTH PAIN you (your child) typically had in the last 4 
weeks by circling one of the options below. 
 
 
 
  None                 Mild              Moderate          Severe       Worst possible 
 
     0                       2                       4                      6                       8 
 
F3= 

MT 2009-09:  Stem Cell Transplant for EB 
 
 
 
 
 
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Page 68 of 70 
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F4. Please rate how much EYE PAIN you (your child) typically had in the last 4 
weeks by circling one of the options below. 
 
 
 
  None                 Mild              Moderate          Severe       Worst possible 
 
     0                       2                       4                      6                       8 
 
F4= 
F5. Please rate how much BONE/JOINT PAIN you (your child) typically had in the 
last 4 weeks by circling one of the options below. 
 
 
 
  None                 Mild              Moderate          Severe       Worst possible 
 
     0                       2                       4                      6                       8 
 
F5= 
G. ITCHING DOMAIN 
G. Please rate how much ITCH you (your child) typically had in the last 4 weeks by 
circling one of the options below. 
  None                 Mild              Moderate          Severe        Worst possible 
 
     0                       2                       4                      6                       8 
 
G= 
H. ESSENTIAL FUNCTIONS DOMAIN 
H1. Please rate how much DIFFICULTY WITH EATING/DRINKING you (your child) 
typically had in the last 4 weeks by circling one of the options below. 
None                 Mild              Moderate          Severe        Unable to drink 
 
     0                       2                       4                      6                       8 
 
H1= 
H2. Please rate how much DIFFICULTY HAVING A REGULAR BOWEL MOVEMENT 
(BM) you (your child) typically had in the last 4 weeks by circling one of the options 
below. 
None                 Mild              Moderate          Severe     Unable to have a BM 
 
     0                       2                       4                      6                       8 
 
H2= 
H3. Please rate how much URINATING/VOIDING you (your child) typically 
experienced in the last 4 weeks by circling one of the options below. 
None                 Mild              Moderate          Severe       Unable to urinate 
 
     0                       2                       4                      6                       8 
 
H3= 

MT 2009-09:  Stem Cell Transplant for EB 
 
 
 
 
 
November 21, 2016 
Page 69 of 70 
proprietary document 
 
 
I. SLEEPING DOMAIN 
I. Please rate how much SLEEP DISTURBANCE (difficulty falling or staying 
asleep) you (your child) typically had in the last 4 weeks by circling one of the 
options below. 
None                 Mild              Moderate          Severe       Unable to sleep 
 
     0                       2                       4                      6                       8 
 
I= 
J. DAILY ACTIVITIES DOMAIN 
J1. Please rate how much DIFFICULTY MOVING AROUND you (your child) typically 
experienced in the last 4 weeks by circling one of the options below. 
None                 Mild              Moderate          Severe       Unable to move 
 
     0                       2                       4                      6                       8 
 
 
J1= 
J2. Please rate how much DIFFICULTY USING HANDS you (your child) typically 
experienced in the last 4 weeks by circling one of the options below. 
None                 Mild              Moderate          Severe     Unable to use hands 
 
     0                       2                       4                      6                       8 
 
J2= 
K. MOOD DOMAIN 
K. Please rate how you/your child typically FELT in the last 4 weeks by circling one 
of the options below. 
Happy        Mostly happy      Somewhat unhappy   Unhappy    Very Unhappy  
 
     0                       2                          4                             6                       8 
 
K= 
L. IMPACT DOMAIN 
L1. Please rate how much IMPACT ON LEISURELY ACTIVITIES (play, relaxation, 
etc) your (your child’s) disease typically had on your activities in the last 4 weeks 
by circling one of the options below. 
None                 Mild              Moderate          Severe             Unable to do  
                                                                                                  anything            
     0                       2                       4                      6                       8 
 
L1= 
L2. Please rate how much IMPACT ON WORK/SCHOOL/LEARNING your (your 
child’s) disease typically had on your activities in the last 4 weeks by circling one 
of the options below. 
None                 Mild              Moderate          Severe             Unable to go to  
                                                                                            work/school/learn 
     0                       2                       4                      6                       8 
 
L2= 
 
PATIENT SUBSCORE (sum of all domains)               max 120 
 
 

MT 2009-09:  Stem Cell Transplant for EB 
 
 
 
 
 
November 21, 2016 
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proprietary document 
 
Filled by patient                 Parent/Caregiver  
 
Clinician Subtotal Score 
 
Patient Subtotal Score 
 
TOTAL iscorEB