MT2015-20: Biochemical Correction of Severe EB by Allo HSCT and Serial Donor MSCs

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Recruiting

CT.gov ID

NCT02582775

Collaborator

(none)

Enrollment

Location

Arms

105

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Epidermolysis Bullosa	Drug: Thymoglobulin Drug: Cyclophosphamide Drug: Fludarabine Radiation: Total Body Irradiation Procedure: Bone marrow infusion Drug: Tacrolimus Drug: Mycophenolate Mofetil Biological: Donor mesenchymal stem cell infusions Drug: Busulfan	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

84 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

MT2015-20: Biochemical Correction of Severe Epidermolysis Bullosa by Allogeneic Cell Transplantation and Serial Donor Mesenchymal Cell Infusions

Actual Study Start Date :

Mar 1, 2016

Anticipated Primary Completion Date :

Dec 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CLOSED TO ACCRUAL Arm A: HCT with 300 cGy of TBI Epidermolysis bullosa patients treated per study regimen with chemotherapy and stem cell transplant without mesenchymal stem cell infusions.	Drug: Thymoglobulin 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 Other Names: ATG anti-thymocyte globulin Drug: Cyclophosphamide 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 Other Names: Cytoxan Drug: Fludarabine 30 mg/m2 IV over 60 minutes days -6 through day -2 Other Names: fludarabine phosphate Fludara Radiation: Total Body Irradiation See arm description for dosing. Other Names: TBI Procedure: Bone marrow infusion Bone marrow infusion on Day 0 Other Names: HCT Drug: Tacrolimus Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors) Other Names: Prograf Drug: Mycophenolate 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 Other Names: MMF
Experimental: CLOSED TO ACCRUAL Arm B: HCT plus MSC, 300 cGy of TBI Epidermolysis bullosa patients treated per study regimen with chemotherapy and hematopoietic stem cell transplant with mesenchymal stem cell infusions using 300 cGY of TBI.	Drug: Thymoglobulin 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 Other Names: ATG anti-thymocyte globulin Drug: Cyclophosphamide 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 Other Names: Cytoxan Drug: Fludarabine 30 mg/m2 IV over 60 minutes days -6 through day -2 Other Names: fludarabine phosphate Fludara Radiation: Total Body Irradiation See arm description for dosing. Other Names: TBI Procedure: Bone marrow infusion Bone marrow infusion on Day 0 Other Names: HCT Drug: Tacrolimus Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors) Other Names: Prograf Drug: Mycophenolate 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 Other Names: MMF Biological: Donor mesenchymal stem cell infusions Day 60, 100 and 180 (collected during donor BM harvest for graft)
Experimental: Arm C: Re-Transplant with 300 cGy of TBI Epidermolysis bullosa patients treated regardless of original transplant arm with re-transplant using 300 cGy of TBI.	Drug: Thymoglobulin 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 Other Names: ATG anti-thymocyte globulin Drug: Cyclophosphamide 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 Other Names: Cytoxan Drug: Fludarabine 30 mg/m2 IV over 60 minutes days -6 through day -2 Other Names: fludarabine phosphate Fludara Radiation: Total Body Irradiation See arm description for dosing. Other Names: TBI Procedure: Bone marrow infusion Bone marrow infusion on Day 0 Other Names: HCT Drug: Tacrolimus Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors) Other Names: Prograf Drug: Mycophenolate 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 Other Names: MMF Biological: Donor mesenchymal stem cell infusions Day 60, 100 and 180 (collected during donor BM harvest for graft)
Experimental: Arm D: HCT with 200 cGy BID of TBI HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant alone using 200 cGY BID of TBI (400 cGy total).	Drug: Thymoglobulin 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 Other Names: ATG anti-thymocyte globulin Drug: Cyclophosphamide 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 Other Names: Cytoxan Drug: Fludarabine 30 mg/m2 IV over 60 minutes days -6 through day -2 Other Names: fludarabine phosphate Fludara Radiation: Total Body Irradiation See arm description for dosing. Other Names: TBI Procedure: Bone marrow infusion Bone marrow infusion on Day 0 Other Names: HCT Drug: Mycophenolate 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 Other Names: MMF
Experimental: Arm E: HCT plus MSC, 200 cGy BID of TBI HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant plus serial MSC infusions using 200 cGY BID of TBI (400 cGy total)	Drug: Thymoglobulin 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 Other Names: ATG anti-thymocyte globulin Drug: Cyclophosphamide 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 Other Names: Cytoxan Drug: Fludarabine 30 mg/m2 IV over 60 minutes days -6 through day -2 Other Names: fludarabine phosphate Fludara Radiation: Total Body Irradiation See arm description for dosing. Other Names: TBI Procedure: Bone marrow infusion Bone marrow infusion on Day 0 Other Names: HCT Drug: Mycophenolate 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 Other Names: MMF Biological: Donor mesenchymal stem cell infusions Day 60, 100 and 180 (collected during donor BM harvest for graft)
Experimental: Arm F: HCT Alone, 200 cGy BID of TBI HLA-mismatched epidermolysis bullosa patients treated with hematopoietic cell transplant alone using 200 cGy BID of TBI (400 cGy total) + addition of low dose busulfan for recipients of HLA-mismatched bone marrow	Drug: Thymoglobulin 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 Other Names: ATG anti-thymocyte globulin Drug: Cyclophosphamide 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 Other Names: Cytoxan Drug: Fludarabine 30 mg/m2 IV over 60 minutes days -6 through day -2 Other Names: fludarabine phosphate Fludara Radiation: Total Body Irradiation See arm description for dosing. Other Names: TBI Procedure: Bone marrow infusion Bone marrow infusion on Day 0 Other Names: HCT Drug: Tacrolimus Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors) Other Names: Prograf Drug: Mycophenolate 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 Other Names: MMF Drug: Busulfan busulfan IV over 3 hours on days -3 and -2 for HLA-mismatched BM recipients only (Arms F and G)
Experimental: Arm G: HCT plus MSC, 200 cGy HLA-mismatched epidermolysis bullosa patients treated with hematopoietic cell transplant plus serial MSC infusions using 200 cGy BID of TBI (400 cGy total) + addition of low dose busulfan for recipients of HLA-mismatched bone marrow	Drug: Thymoglobulin 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 Other Names: ATG anti-thymocyte globulin Drug: Cyclophosphamide 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 Other Names: Cytoxan Drug: Fludarabine 30 mg/m2 IV over 60 minutes days -6 through day -2 Other Names: fludarabine phosphate Fludara Radiation: Total Body Irradiation See arm description for dosing. Other Names: TBI Procedure: Bone marrow infusion Bone marrow infusion on Day 0 Other Names: HCT Drug: Tacrolimus Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors) Other Names: Prograf Drug: Mycophenolate 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 Other Names: MMF Biological: Donor mesenchymal stem cell infusions Day 60, 100 and 180 (collected during donor BM harvest for graft) Drug: Busulfan busulfan IV over 3 hours on days -3 and -2 for HLA-mismatched BM recipients only (Arms F and G)

Outcome Measures

Primary Outcome Measures

Event-free survival [1 year post-transplant]
An event defined as death or a 50% increase in a patient's IScoreEB from baseline

Secondary Outcome Measures

Percentage change of a patient's iscorEB [1 and 2 year post-transplant]
iscorEB surveys are a validated, standard of care tool used to assess disease status in patients with Epidermolysis Bullosa.
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.
Quality of life [1 year post-transplant]
Measured by the Lansky or Karnofsky score (10-100)
Quality of life [2 years post-transplant]
Measured by the Lansky or Karnofsky score (10-100)
Lymphoid Chimerism [Day 28, 60, 100, 180, and year 1 and 2 post-transplant]
Proportion of lymphoid chimerism at various time-points.
Myeloid Chimerism [Day 28, 60, 100, 180, and year 1 and 2 post-transplant]
Proportion of myeloid chimerism at various time points.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 25 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.