Epidermolysis Bullosa
Conditions
Brief summary
This is a single-institution, phase II study to determine the event-free survival at 1 year post allogeneic transplant and serial mesenchymal stem cell (MSC) infusions from a related donor (HLA identical, mismatched or haploidentical) or matched unrelated donor for the biochemical correction of severe epidermolysis bullosa (EB).
Interventions
DRUGThymoglobulin
0.5 mg/kg IV over 6 hours on day -9 and 2 mg/kg IV over 4 hours on day -8 and day -7 with premeds and solumedrol through day -2
DRUGCyclophosphamide
14.5 mg/kg IV over 1 hour day -6 and -5 50 mg/kg IV over 2 hours with mesna 40 mg/kg IV day +2 and +3
DRUGFludarabine
30 mg/m2 IV over 60 minutes days -6 through day -2
RADIATIONTotal Body Irradiation
See arm description for dosing.
PROCEDUREBone marrow infusion
Bone marrow infusion on Day 0
DRUGTacrolimus
Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors). When used in non-MSD recipients, tapered over 6-8 weeks starting at day +100.
DRUGMycophenolate Mofetil
15 mg/kg IV q8h (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams. Day +5 through day 35
BIOLOGICALDonor mesenchymal stem cell infusions
Day 60, 100 and 180 (collected during donor BM harvest for graft)
DRUGBusulfan
busulfan IV over 3 hours on days -3 and -2 for HLA-mismatched BM recipients only (Arms F and G)
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 EB characterized by collagen, laminin, integrin, keratin or plakin deficiency (by immunofluorescence staining with protein specific antibodies or Western blotting and by mutation analysis). * Adequate organ function within 4 weeks of study registration defined as: * Renal: glomerular filtration rate within normal range for age * Hepatic: Hepatic: bilirubin, AST/ALT, 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 EKG or approved by Cardiology for transplant * Sexually active participants must agree to use adequate birth control for the during the study period (from before the start of the preparative chemotherapy through 1 year post-transplant) * Available donor per section 5: targeted MFI \< 1,000 (MFI exceeding 1000 must be approved by the PI and treatment team.) * Voluntary written consent - adult or parent (with information sheet for minors, if applicable) prior to any research related procedures or treatment
Exclusion criteria
* beta 3 laminin JEB mutants * Active untreated systemic infection at time of transplantation (including active infection with Aspergillus or other mold within 30 days) * History of HIV infection * Evidence of squamous cell carcinoma * Pregnant or breast feeding. Females of child-bearing potential must have a negative pregnancy test prior to study registration as the agents administered in this study are Pregnancy Category C and D.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | 1 year post-transplant | An event defined as death or a 50% increase in a patient's IScoreEB from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Transplant-related Mortality | 180 days post-transplant | Cumulative incidence will be used to estimate the probability of relapse treating non-relapse death as a competing risk and transplant-related mortality conversely treating relapse as a competing risk. |
| Average Change in Quality of Life | 1 year post-transplant | Measured by the Lansky or Karnofsky score (10-100). Higher scores indicate a better outcome. Midpoint of change in scores used to indicate median. |
| Change of a Patient's iscorEB | 1 year post-transplant | iscorEB surveys are a validated, standard of care tool used to assess disease status in patients with Epidermolysis Bullosa. Measure changes in quality of life (QOL) through pain, itching, and general QOL IScorEB questionnaire. Scores can range from 16 to 112. The QOLS scores are summed so that a higher score indicates higher quality of life. |
| Myeloid Chimerism | Day 28, 60, 100, 180, and year 1 and 2 post-transplant | Median hematopoietic cells that are of donor origin per participant. |
| Average Change of a Patient's iscorEB | 2 year post-transplant | iscorEB surveys are a validated, standard of care tool used to assess disease status in patients with Epidermolysis Bullosa. Measure percent of changes in quality of life (QOL) through pain, itching, and general QOL IScorEB questionnaire. Scores can range from 16 to 112. The QOLS scores are summed so that a higher score indicates higher quality of life. |
| Lymphoid Chimerism | Day 28, 60, 100, 180, and year 1 and 2 post-transplant | Median hematopoietic cells that are of donor origin per participant. |
Countries
United States
Participant flow
Pre-assignment details
The JEB subject (n=1) was enrolled on Arm B, receiving the same therapy as the RDEB subjects, but pulled out and reported separately due to the very different baseline disease course.
Participants by arm
| Arm | Count |
|---|---|
| RDEB: HCT Plus MSC B Recessive dominant epidermolysis bullosa (RDEB) patients treated per study regimen on a post-transplant cyclophosphamide allogeneic hematopoietic cell transplant (HCT) platform conditioned with reduced intensity chemotherapy and low dose total body irradiation (300 cGy), followed post-HCT by serial infusions of donor-derived mesenchymal stromal cells (MSC). | 7 |
| RDEB: HCT Plus MSC E Recessive dominant epidermolysis bullosa (RDEB) patients treated per study regimen on a post-transplant cyclophosphamide allogeneic hematopoietic cell transplant (HCT) platform conditioned with reduced intensity chemotherapy and low dose total body irradiation (400 cGy), followed post-HCT by serial infusions of donor-derived mesenchymal stromal cells (MSC). | 9 |
| JEB: HCT Plus MSC Arm B Junctional epidermolysis bullosa (JEB) patient treated per study regimen on a post-transplant cyclophosphamide allogeneic hematopoietic cell transplant (HCT) platform conditioned with reduced intensity chemotherapy and low dose total body irradiation (300 cGy), followed post-HCT by serial infusions of donor-derived mesenchymal stromal cells (MSC). | 1 |
| Total | 17 |
Baseline characteristics
| Characteristic | RDEB: HCT Plus MSC B | RDEB: HCT Plus MSC E | JEB: HCT Plus MSC Arm B | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 8 Participants | 1 Participants | 16 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 1 Participants | 1 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 8 Participants | 0 Participants | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 9 Participants | 0 Participants | 15 Participants |
| Region of Enrollment United States | 7 participants | 9 participants | 1 participants | 17 participants |
| Sex: Female, Male Female | 3 Participants | 5 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 1 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 1 / 9 | 1 / 1 |
| other Total, other adverse events | 2 / 7 | 1 / 9 | 1 / 1 |
| serious Total, serious adverse events | 2 / 7 | 1 / 9 | 0 / 1 |
Outcome results
Primary
Event-free Survival
An event defined as death or a 50% increase in a patient's IScoreEB from baseline
Time frame: 1 year post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RDEB: HCT Plus MSC Arm B | Event-free Survival | 4 Count of Participants |
| RDEB: HCT Plus MSC Arm E | Event-free Survival | 2 Count of Participants |
| JEB: HCT Plus MSC Arm B | Event-free Survival | 1 Count of Participants |
Secondary
Average Change in Quality of Life
Measured by the Lansky or Karnofsky score (10-100). The Karnofsky Performance Scale is an assessment tool intended to gauge a patient's functional status and ability to carry out activities of daily living. Higher scores indicate a better outcome. Midpoint of change in scores used to indicate median.
Time frame: 2 years post-transplant
Population: Participant in JEB: HCT plus MSC Arm B deceased at 2 year post-transplant timepoint.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RDEB: HCT Plus MSC Arm B | Average Change in Quality of Life | 10 Change in score |
| RDEB: HCT Plus MSC Arm E | Average Change in Quality of Life | 0 Change in score |
Secondary
Average Change in Quality of Life
Measured by the Lansky or Karnofsky score (10-100). Higher scores indicate a better outcome. Midpoint of change in scores used to indicate median.
Time frame: 1 year post-transplant
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RDEB: HCT Plus MSC Arm B | Average Change in Quality of Life | 10 Change in score |
| RDEB: HCT Plus MSC Arm E | Average Change in Quality of Life | 0 Change in score |
| JEB: HCT Plus MSC Arm B | Average Change in Quality of Life | -30 Change in score |
Secondary
Average Change of a Patient's iscorEB
iscorEB surveys are a validated, standard of care tool used to assess disease status in patients with Epidermolysis Bullosa. Measure percent of changes in quality of life (QOL) through pain, itching, and general QOL IScorEB questionnaire. Scores can range from 16 to 112. The QOLS scores are summed so that a higher score indicates higher quality of life.
Time frame: 2 year post-transplant
Population: Participant in JEB: HCT plus MSC Arm B deceased at 2 year post-transplant timepoint.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RDEB: HCT Plus MSC Arm B | Average Change of a Patient's iscorEB | 9 units on a scale |
| RDEB: HCT Plus MSC Arm E | Average Change of a Patient's iscorEB | -2 units on a scale |
Secondary
Change of a Patient's iscorEB
iscorEB surveys are a validated, standard of care tool used to assess disease status in patients with Epidermolysis Bullosa. Measure changes in quality of life (QOL) through pain, itching, and general QOL IScorEB questionnaire. Scores can range from 16 to 112. The QOLS scores are summed so that a higher score indicates higher quality of life.
Time frame: 1 year post-transplant
| Arm | Measure | Value (MEAN) |
|---|---|---|
| RDEB: HCT Plus MSC Arm B | Change of a Patient's iscorEB | -10 units on a scale |
| RDEB: HCT Plus MSC Arm E | Change of a Patient's iscorEB | -24 units on a scale |
| JEB: HCT Plus MSC Arm B | Change of a Patient's iscorEB | 110 units on a scale |
Secondary
Lymphoid Chimerism
Median hematopoietic cells that are of donor origin per participant.
Time frame: Day 28, 60, 100, 180, and year 1 and 2 post-transplant
Population: Participants in RDEB: HCT plus MSC arm unable to be analyzed due to missed visits.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RDEB: HCT Plus MSC Arm B | Lymphoid Chimerism | Day 100 | 88 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Lymphoid Chimerism | Day 60 | 99 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Lymphoid Chimerism | 1 year | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Lymphoid Chimerism | Day 180 | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Lymphoid Chimerism | Day 28 | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Lymphoid Chimerism | 2 years | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Lymphoid Chimerism | 2 years | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Lymphoid Chimerism | Day 28 | 60 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Lymphoid Chimerism | Day 60 | 78 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Lymphoid Chimerism | Day 100 | 94 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Lymphoid Chimerism | Day 180 | 98.5 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Lymphoid Chimerism | 1 year | 100 Percentage of donor derived cells |
| JEB: HCT Plus MSC Arm B | Lymphoid Chimerism | Day 100 | NA Percentage of donor derived cells |
| JEB: HCT Plus MSC Arm B | Lymphoid Chimerism | Day 28 | NA Percentage of donor derived cells |
| JEB: HCT Plus MSC Arm B | Lymphoid Chimerism | Day 60 | NA Percentage of donor derived cells |
| JEB: HCT Plus MSC Arm B | Lymphoid Chimerism | Day 180 | NA Percentage of donor derived cells |
Secondary
Myeloid Chimerism
Median hematopoietic cells that are of donor origin per participant.
Time frame: Day 28, 60, 100, 180, and year 1 and 2 post-transplant
Population: Participants in RDEB: HCT plus MSC arm unable to be analyzed due to missed visits.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| RDEB: HCT Plus MSC Arm B | Myeloid Chimerism | Day 60 | 32 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Myeloid Chimerism | 2 years | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Myeloid Chimerism | Day 28 | 76 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Myeloid Chimerism | Day 100 | 46 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Myeloid Chimerism | Day 180 | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm B | Myeloid Chimerism | 1 year | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Myeloid Chimerism | Day 180 | 97.5 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Myeloid Chimerism | 1 year | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Myeloid Chimerism | Day 100 | 96 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Myeloid Chimerism | 2 years | 100 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Myeloid Chimerism | Day 60 | 96 Percentage of donor derived cells |
| RDEB: HCT Plus MSC Arm E | Myeloid Chimerism | Day 28 | 95 Percentage of donor derived cells |
| JEB: HCT Plus MSC Arm B | Myeloid Chimerism | Day 100 | 0 Percentage of donor derived cells |
| JEB: HCT Plus MSC Arm B | Myeloid Chimerism | Day 60 | 0 Percentage of donor derived cells |
| JEB: HCT Plus MSC Arm B | Myeloid Chimerism | Day 28 | 23 Percentage of donor derived cells |
| JEB: HCT Plus MSC Arm B | Myeloid Chimerism | Day 180 | 0 Percentage of donor derived cells |
Secondary
Transplant-related Mortality
Cumulative incidence will be used to estimate the probability of relapse treating non-relapse death as a competing risk and transplant-related mortality conversely treating relapse as a competing risk.
Time frame: 180 days post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RDEB: HCT Plus MSC Arm B | Transplant-related Mortality | 0 Participants |
| RDEB: HCT Plus MSC Arm E | Transplant-related Mortality | 0 Participants |
| JEB: HCT Plus MSC Arm B | Transplant-related Mortality | 0 Participants |