Epidermolysis Bullosa
Conditions
Brief summary
This is an open-label, single institution, phase II study in patients with epidermolysis bullosa (EB). The underlying hypothesis is that the infusion of bone marrow or umbilical cord blood from a healthy unaffected donor will correct the collagen, laminin, integrin, or plakin deficiency and reduce the skin fragility characteristic of severe forms of EB. A secondary hypothesis is that mesenchymal stem cells from a healthy donor will enhance the safety and efficacy of the allogeneic hematopoietic stem cell transplant as well as serve as a source of renewable cells for the treatment of focal areas of residual blistering.
Detailed description
The primary objective of this study is to estimate the event-free survival rate by 1 year post-transplant with an event defined as a death or failure to have a demonstrable increase in collagen, laminin, integrin, keratin or plakin deposition by 1 year post-transplant or other biochemical, structural or physical measure of improvement. The secondary objectives of this study are to i) determine the incidence of transplant-related mortality (TRM) at 180 days; ii) describe the pattern of biochemical improvement as measured by an increase in protein expression (collagen, laminin, integrin, keratin or plakin) and related structural and physical changes; iii) describe health quality of life at day 365 and 730 as compared to pretreatment results; iv) describe the pattern and durability of HSC and third party MSC engraftment in the skin; v) determine the probability of survival at 1 year. Patients with severe epidermolysis bullosa will be screened to meet the eligibility requirements, related or unrelated donor marrow or UCB will be infused, and subjects will be followed for a minimum of 5 years after stem cell transplant. A target accrual of 75 subjects over 5 years will be recruited to the study.
Interventions
DRUGCyclophosphamide
Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.
DRUGFludarabine
40 mg/m\^2/day intravenously on Days -6, -5, -4, -3 and -2.
DRUGAnti-thymocyte globulin
30 mg/kg on Days -4, -3 and -2.
DRUGMyeloablative Busulfan
Targeting AUC 1000 umol/min
infused via intravenous drip on Day 0
RADIATIONTotal body irradiation
300 cGY on Day -1 administered in a single fraction at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
PROCEDUREBone marrow or umbilical cord blood (UCG) stem cell transplantation
Bone marrow or UCB products will be infused as soon as the product arrives and within 30 minutes. The product is infused via IV drip.
Sponsors
Masonic Cancer Center, University of Minnesota
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 25 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of severe form of epidermolysis bullosa (EB) characterized by collagen, laminin, integrin, keratin or plakin deficiency. Assessment criteria for severe EB: * Documented collagen, laminin, integrin, keratin or plakin deficiency (by immunofluorescence staining with protein specific antibodies or Western blotting and by mutation analysis) * Adequate Organ Function Criteria * Renal: glomerular filtration rate within normal range for age * Hepatic: bilirubin, aspartate aminotransferase/alanine aminotransferase (AST/ALT), Alkaline phosphatase (ALP) \< 5 x upper limit of normal * Pulmonary: adequate pulmonary function in the opinion of the enrolling investigator * Cardiac: left ventricular ejection fraction ≥ 45%, normal electrocardiogram (EKG) or approved by Cardiology for transplant. * Available Healthy HSC Donor (order of preference) * Related Donor (marrow or UCB) * HLA-A, B, C, DRB1 genotypic identical (sibling) donor * HLA-A, B, C, DRB1 phenotypic identical donor * 7/8 HLA matched donor at HLA-A, B, C, DRB1 * Unrelated Donor * Marrow * HLA-A, B, C, DRB1 phenotypic identical donor * 7/8 HLA matched donor at HLA-A, B, C, DRB1 * UCB * HLA-A, B (antigen level) and DRB1 (allele level) matched donor * 5/6 HLA matched donor at HLA-A, B, DRB1 * 4/6 HLA matched donor at HLA-A, B, DRB1 * Voluntary written consent Absence of
Exclusion criteria
* Active systemic infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days). * History of human immunodeficiency virus (HIV) infection * Evidence of squamous cell carcinoma * Donor has EB * Pregnancy females of child-bearing age must have a documented negative pregnancy test and agree to use contraception as a condition for enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Event-free Survival | 1 year and 2 Years Post-transplant | Event-free survival rate, with an event defined as death or failure to have a demonstrable increase in collagen, laminin, intergrin, keratin or plakin deposition. Assessed at follow up appointments through questionnaire and patient samples. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Biochemical Improvement | 1 Year Post-Transplant | Pattern of biochemical improvement measured by cumulative increase in protein expression and related structural and physical changes |
| Measure Patients Quality of Life Using a Questionnaire | Pretreatment and 1 year | Health quality of life questionnaire as compared to pretreatment results. Scores can range from 0 to 100. The QOLS scores are summed so that a higher score indicates higher quality of life. |
| Percentage of Participants Transplant-related Mortality (TRM) | 180 Days Post Transplant | Incidence of transplant-related mortality (TRM) |
| Probability of Survival | 1 Year | Surviving patients one year after engraftment |
| Percentage of Participants Who Experienced Acute GVHD | 100 Days | Incidence of acute GCHD |
| Durability of HSC Donor Engraftment in the Skin | 100 Days | Incidence of HSC donor engraftment in the skin |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| RDEB Mac Recessive Dystrophic EB (RDEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
Cyclophosphamide: Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.
Fludarabine: 40 mg/m\^2/day intravenously on Days -6, -5, -4, -3 and -2.
Myeloablative Busulfan: Targeting AUC 1000 umol/min
Mesenchymal stem cell transplantation: infused via intravenous drip on Day 0
Bone marrow or umbilical cord blood (UCG) stem cell transplantation: Bone marrow or UCB products will be infused as soon as the product arrives and within 30 minutes. The product is infused via IV drip. | 7 |
| RDEB RIC Recessive Dystrophic EB (RDEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
Cyclophosphamide: Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.
Fludarabine: 40 mg/m\^2/day intravenously on Days -6, -5, -4, -3 and -2.
Anti-thymocyte globulin: 30 mg/kg on Days -4, -3 and -2.
Mesenchymal stem cell transplantation: infused via intravenous drip on Day 0
Total body irradiation: 300 cGY on Day -1 administered in a single fraction at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
Bone marrow or umbilical cord blood (UCG) stem cell transplantation: Bone marrow or UCB products will be infused as soon as the product arrives and within 30 minutes. The product is infused via IV drip. | 16 |
| JEB MAC Junctional EB (JEB) - Myeloablative conditioning (MAC) Participants receive Myeloablative Busulfan (targeting AUC 1000 umol/min), Fludarabine 75 mg/m2, and Cyclophosphamide 200 mg/kg
Cyclophosphamide: Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.
Fludarabine: 40 mg/m\^2/day intravenously on Days -6, -5, -4, -3 and -2.
Myeloablative Busulfan: Targeting AUC 1000 umol/min
Mesenchymal stem cell transplantation: infused via intravenous drip on Day 0
Bone marrow or umbilical cord blood (UCG) stem cell transplantation: Bone marrow or UCB products will be infused as soon as the product arrives and within 30 minutes. The product is infused via IV drip. | 2 |
| JEB RIC Junctional EB (JEB) - Reduced Intensity Condition Participants received Fludarabine 500 mg/m2, Cyclosphosphamide 50 mg/kg, equine Anti-thymocyte globulin 90 mg/kg, and low dose total body irradiation (either 200 or 300 cGy)
Cyclophosphamide: Cyclophosphamide 50 mg/kg/day IV over 2 hours x 1 day, total dose 50 mg/kg will be administered on Day -6.
Fludarabine: 40 mg/m\^2/day intravenously on Days -6, -5, -4, -3 and -2.
Anti-thymocyte globulin: 30 mg/kg on Days -4, -3 and -2.
Mesenchymal stem cell transplantation: infused via intravenous drip on Day 0
Total body irradiation: 300 cGY on Day -1 administered in a single fraction at a dose rate of 10-19 cGy/minute prescribed to the midplane of the patient at the level of the umbilicus.
Bone marrow or umbilical cord blood (UCG) stem cell transplantation: Bone marrow or UCB products will be infused as soon as the product arrives and within 30 minutes. The product is infused via IV drip. | 7 |
| Total | 32 |
Baseline characteristics
| Characteristic | RDEB Mac | RDEB RIC | JEB MAC | JEB RIC | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 15 Participants | 2 Participants | 7 Participants | 31 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 15 Participants | 2 Participants | 5 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 2 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 14 Participants | 0 Participants | 0 Participants | 21 Participants |
| Region of Enrollment United States | 7 participants | 16 participants | 2 participants | 7 participants | 32 participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 1 Participants | 3 Participants | 15 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 1 Participants | 4 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 7 | 3 / 16 | 1 / 2 | 6 / 7 |
| other Total, other adverse events | 7 / 7 | 16 / 16 | 2 / 2 | 7 / 7 |
| serious Total, serious adverse events | 7 / 7 | 16 / 16 | 2 / 2 | 7 / 7 |
Outcome results
Primary
Percentage of Participants With Event-free Survival
Event-free survival rate, with an event defined as death or failure to have a demonstrable increase in collagen, laminin, intergrin, keratin or plakin deposition. Assessed at follow up appointments through questionnaire and patient samples.
Time frame: 1 year and 2 Years Post-transplant
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RDEB Mac | Percentage of Participants With Event-free Survival | 1 year | 67 Percentage of participants |
| RDEB Mac | Percentage of Participants With Event-free Survival | 2 year | 44 Percentage of participants |
| RDEB RIC | Percentage of Participants With Event-free Survival | 2 year | 80 Percentage of participants |
| RDEB RIC | Percentage of Participants With Event-free Survival | 1 year | 80 Percentage of participants |
| JEB MAC | Percentage of Participants With Event-free Survival | 1 year | 50 Percentage of participants |
| JEB MAC | Percentage of Participants With Event-free Survival | 2 year | 50 Percentage of participants |
| JEB RIC | Percentage of Participants With Event-free Survival | 1 year | 29 Percentage of participants |
| JEB RIC | Percentage of Participants With Event-free Survival | 2 year | 14 Percentage of participants |
Secondary
Average Biochemical Improvement
Pattern of biochemical improvement measured by cumulative increase in protein expression and related structural and physical changes
Time frame: 1 Year Post-Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RDEB Mac | Average Biochemical Improvement | 29 Percentage of participants |
| RDEB RIC | Average Biochemical Improvement | 31 Percentage of participants |
| JEB MAC | Average Biochemical Improvement | 0 Percentage of participants |
| JEB RIC | Average Biochemical Improvement | 0 Percentage of participants |
Secondary
Durability of HSC Donor Engraftment in the Skin
Incidence of HSC donor engraftment in the skin
Time frame: 100 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RDEB Mac | Durability of HSC Donor Engraftment in the Skin | 11 Percentage of Incidence |
| RDEB RIC | Durability of HSC Donor Engraftment in the Skin | 7 Percentage of Incidence |
| JEB MAC | Durability of HSC Donor Engraftment in the Skin | 0 Percentage of Incidence |
| JEB RIC | Durability of HSC Donor Engraftment in the Skin | 9 Percentage of Incidence |
Secondary
Measure Patients Quality of Life Using a Questionnaire
Health quality of life questionnaire as compared to pretreatment results. Scores can range from 0 to 100. The QOLS scores are summed so that a higher score indicates higher quality of life.
Time frame: Pretreatment and 1 year
Population: Participants unnable to complete quality of life questionnaires at various time points.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RDEB Mac | Measure Patients Quality of Life Using a Questionnaire | Pretreatment | 43 Scores on a scale |
| RDEB Mac | Measure Patients Quality of Life Using a Questionnaire | 1 year | 37 Scores on a scale |
| RDEB RIC | Measure Patients Quality of Life Using a Questionnaire | Pretreatment | 17 Scores on a scale |
| RDEB RIC | Measure Patients Quality of Life Using a Questionnaire | 1 year | 68 Scores on a scale |
| JEB RIC | Measure Patients Quality of Life Using a Questionnaire | Pretreatment | 1 Scores on a scale |
Secondary
Percentage of Participants Transplant-related Mortality (TRM)
Incidence of transplant-related mortality (TRM)
Time frame: 180 Days Post Transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RDEB Mac | Percentage of Participants Transplant-related Mortality (TRM) | 43 Percentage of participants |
| RDEB RIC | Percentage of Participants Transplant-related Mortality (TRM) | 19 Percentage of participants |
| JEB MAC | Percentage of Participants Transplant-related Mortality (TRM) | 50 Percentage of participants |
| JEB RIC | Percentage of Participants Transplant-related Mortality (TRM) | 86 Percentage of participants |
Secondary
Percentage of Participants Who Experienced Acute GVHD
Incidence of acute GCHD
Time frame: 100 Days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RDEB Mac | Percentage of Participants Who Experienced Acute GVHD | 14 Percentage of participants |
| RDEB RIC | Percentage of Participants Who Experienced Acute GVHD | 19 Percentage of participants |
| JEB MAC | Percentage of Participants Who Experienced Acute GVHD | 0 Percentage of participants |
| JEB RIC | Percentage of Participants Who Experienced Acute GVHD | 29 Percentage of participants |
Secondary
Probability of Survival
Surviving patients one year after engraftment
Time frame: 1 Year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RDEB Mac | Probability of Survival | 71 Percentage of participants |
| RDEB RIC | Probability of Survival | 81 Percentage of participants |
| JEB MAC | Probability of Survival | 50 Percentage of participants |
| JEB RIC | Probability of Survival | 29 Percentage of participants |