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

Primary Purpose

Epidermolysis Bullosa

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Thymoglobulin

Cyclophosphamide

Fludarabine

Total Body Irradiation

Bone marrow infusion

Tacrolimus

Mycophenolate Mofetil

Donor mesenchymal stem cell infusions

Busulfan

About this trial

This is an interventional treatment trial for Epidermolysis Bullosa

Eligibility Criteria

undefined - 25 Years (Child, Adult)All SexesDoes not accept 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.

Sites / Locations

University of Minnesota Masonic Cancer Center and Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Arm Label

CLOSED TO ACCRUAL Arm A: HCT with 300 cGy of TBI

CLOSED TO ACCRUAL Arm B: HCT plus MSC, 300 cGy of TBI

Arm C: Re-Transplant with 300 cGy of TBI

Arm D: HCT with 200 cGy BID of TBI

Arm E: HCT plus MSC, 200 cGy BID of TBI

Arm F: HCT Alone, 200 cGy BID of TBI

Arm G: HCT plus MSC, 200 cGy

Arm Description

Epidermolysis bullosa patients treated per study regimen with chemotherapy and stem cell transplant without mesenchymal stem cell infusions.

Epidermolysis bullosa patients treated per study regimen with chemotherapy and hematopoietic stem cell transplant with mesenchymal stem cell infusions using 300 cGY of TBI.

Epidermolysis bullosa patients treated regardless of original transplant arm with re-transplant using 300 cGy of TBI.

HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant alone using 200 cGY BID of TBI (400 cGy total).

HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant plus serial MSC infusions using 200 cGY BID of TBI (400 cGy total)

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

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

Outcomes

Primary Outcome Measures

Event-free survival

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

iscorEB surveys are a validated, standard of care tool used to assess disease status in patients with Epidermolysis Bullosa.

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.

Quality of life

Measured by the Lansky or Karnofsky score (10-100)

Quality of life

Measured by the Lansky or Karnofsky score (10-100)

Lymphoid Chimerism

Proportion of lymphoid chimerism at various time-points.

Myeloid Chimerism

Proportion of myeloid chimerism at various time points.

Full Information

NCT ID

NCT02582775

First Posted

October 16, 2015

Last Updated

July 31, 2023

Sponsor

Masonic Cancer Center, University of Minnesota

1. Study Identification

Unique Protocol Identification Number

NCT02582775

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Completed

Study Start Date

March 2016 (Actual)

Primary Completion Date

November 15, 2022 (Actual)

Study Completion Date

July 26, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Masonic Cancer Center, University of Minnesota

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Epidermolysis Bullosa

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

17 (Actual)

8. Arms, Groups, and Interventions

Arm Title

CLOSED TO ACCRUAL Arm A: HCT with 300 cGy of TBI

Arm Type

Experimental

Arm Description

Epidermolysis bullosa patients treated per study regimen with chemotherapy and stem cell transplant without mesenchymal stem cell infusions.

Arm Title

CLOSED TO ACCRUAL Arm B: HCT plus MSC, 300 cGy of TBI

Arm Type

Experimental

Arm Description

Epidermolysis bullosa patients treated per study regimen with chemotherapy and hematopoietic stem cell transplant with mesenchymal stem cell infusions using 300 cGY of TBI.

Arm Title

Arm C: Re-Transplant with 300 cGy of TBI

Arm Type

Experimental

Arm Description

Epidermolysis bullosa patients treated regardless of original transplant arm with re-transplant using 300 cGy of TBI.

Arm Title

Arm D: HCT with 200 cGy BID of TBI

Arm Type

Experimental

Arm Description

HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant alone using 200 cGY BID of TBI (400 cGy total).

Arm Title

Arm E: HCT plus MSC, 200 cGy BID of TBI

Arm Type

Experimental

Arm Description

HLA-matched epidermolysis bullosa patients treated with hematopoietic cell transplant plus serial MSC infusions using 200 cGY BID of TBI (400 cGy total)

Arm Title

Arm F: HCT Alone, 200 cGy BID of TBI

Arm Type

Experimental

Arm Description

Arm Title

Arm G: HCT plus MSC, 200 cGy

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Thymoglobulin

Other Intervention Name(s)

ATG, anti-thymocyte globulin

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

Cytoxan

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

fludarabine phosphate, Fludara

Intervention Description

30 mg/m2 IV over 60 minutes days -6 through day -2

Intervention Type

Radiation

Intervention Name(s)

Total Body Irradiation

Other Intervention Name(s)

TBI

Intervention Description

See arm description for dosing.

Intervention Type

Procedure

Intervention Name(s)

Bone marrow infusion

Other Intervention Name(s)

HCT

Intervention Description

Bone marrow infusion on Day 0

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Other Intervention Name(s)

Prograf

Intervention Description

Day +5 through day +100 with goals of 5-10 ug/L (not used for HLA-identical related donors)

Intervention Type

Drug

Intervention Name(s)

Mycophenolate Mofetil

Other Intervention Name(s)

MMF

Intervention Description

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

Intervention Type

Biological

Intervention Name(s)

Donor mesenchymal stem cell infusions

Intervention Description

Day 60, 100 and 180 (collected during donor BM harvest for graft)

Intervention Type

Drug

Intervention Name(s)

Busulfan

Intervention Description

busulfan IV over 3 hours on days -3 and -2 for HLA-mismatched BM recipients only (Arms F and G)

Primary Outcome Measure Information:

Title

Event-free survival

Description

An event defined as death or a 50% increase in a patient's IScoreEB from baseline

Time Frame

1 year post-transplant

Secondary Outcome Measure Information:

Title

Percentage change of a patient's iscorEB

Description

iscorEB surveys are a validated, standard of care tool used to assess disease status in patients with Epidermolysis Bullosa.

Time Frame

1 and 2 year post-transplant

Title

Transplant-related mortality

Description

Time Frame

180 days post-transplant

Title

Quality of life

Description

Measured by the Lansky or Karnofsky score (10-100)

Time Frame

1 year post-transplant

Title

Quality of life

Description

Measured by the Lansky or Karnofsky score (10-100)

Time Frame

2 years post-transplant

Title

Lymphoid Chimerism

Description

Proportion of lymphoid chimerism at various time-points.

Time Frame

Day 28, 60, 100, 180, and year 1 and 2 post-transplant

Title

Myeloid Chimerism

Description

Proportion of myeloid chimerism at various time points.

Time Frame

Day 28, 60, 100, 180, and year 1 and 2 post-transplant

10. Eligibility

Sex

All

Maximum Age & Unit of Time

25 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jakub Tolar, MD, PhD

Organizational Affiliation

Masonic Cancer Center, University of Minnesota

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Minnesota Masonic Cancer Center and Medical Center

City

Minneapolis

State/Province

Minnesota

ZIP/Postal Code

55455

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

30843184

Citation

Ebens CL, McGrath JA, Tamai K, Hovnanian A, Wagner JE, Riddle MJ, Keene DR, DeFor TE, Tryon R, Chen M, Woodley DT, Hook K, Tolar J. Bone marrow transplant with post-transplant cyclophosphamide for recessive dystrophic epidermolysis bullosa expands the related donor pool and permits tolerance of nonhaematopoietic cellular grafts. Br J Dermatol. 2019 Dec;181(6):1238-1246. doi: 10.1111/bjd.17858. Epub 2019 Jun 28.

Results Reference

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

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