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Autologous Stem Cell Transplantation of Cells Engineered to Express Alpha-Galactosidase A in Patients With Fabry Disease

Primary Purpose

Fabry Disease

Status
Active
Phase
Phase 1
Locations
Canada
Study Type
Interventional
Intervention
Lentivirus Alpha-gal A transduced stem cells
Sponsored by
University Health Network, Toronto
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Fabry Disease focused on measuring autologous stem cell transplant, gene therapy, Fabry disease, lentivirus, haematopoietic stem cell transplant

Eligibility Criteria

18 Years - 50 Years (Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male patients 18-50 years of age at the time of enrollment
  2. Diagnosis of Fabry disease (FD) as defined by very low or absent α-gal A activity
  3. Classic FD Type I phenotype with alpha-galactosidase A (GLA) genotyping
  4. Patients on enzyme replacement therapy (ERT) prior to enrollment
  5. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1
  6. Adequate organ function within 21 days prior to Pre-Treatment Phase:
  7. Willing and capable of signing and giving written informed consent in accordance with Research Ethics Board (REB) requirements
  8. Willing to comply with all procedures outlined in the study protocol, cooperative with the protocol schedule, able to return for safety evaluation, or otherwise likely to complete the study
  9. Willing to abstain from sexual activity or willing to use condoms during sexual intercourse from day of Melphalan administration on day -1 of Phase 3 until after 12 months follow-up post-transplant.
  10. Willing to not donate sperm after receiving Melphalan. Sperm banking will be recommended to any patient who would like to father children in the future.

Exclusion Criteria:

  1. Males with variant Fabry Disease.
  2. Female gender
  3. Use of immunosuppressive agents or any anticoagulant
  4. Ongoing ERT-related infusion associated reactions of moderate-to-severe intensity
  5. Presence of anti-agalsidase immunoglobulin (Ig)G antibodies above a threshold (5-fold above normal;) or evidence of high titre neutralizing antibodies
  6. Blood test positive for Hepatitis B virus (HBV), Hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1 (HTLV-1), human T-cell lymphotropic virus type 1 (HTLV-2), or Venereal Disease Research Laboratory test (VDRL; Transmissible Disease (TD) testing will be done in Pre-Treatment Phase 2 - see section 5.1 for full panel of TD tests. Patients will only be excluded from the study if positive for the TD tests listed here in this exclusion).
  7. Uncontrolled bacterial, viral, or fungal infections
  8. Prior malignancies except resected basal cell carcinoma
  9. Chronic Kidney Disease (CKD) stage >2
  10. History of heart failure or left ventricle ejection fraction (LVEF) <45% or moderate to severe diastolic dysfunction by standard criteria
  11. Arrhythmia: bundle branch block, heart block degree II or III, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, cardiac arrest, pacemaker, implantable cardiac defibrillator
  12. Coronary artery disease with angina, prior myocardial infarction, percutaneous transluminal coronary angioplasty with or without stent, coronary artery bypass graft surgery, moderate to severe valvular heart disease, valve replacement surgery
  13. Uncontrolled hypertension
  14. Diabetes mellitus
  15. Advanced liver disease, liver failure, cirrhosis
  16. Immune deficiency state
  17. Moderate-to-severe chronic obstructive pulmonary disease (COPD)
  18. Any hematological condition with white blood cells (WBC) <3.0 x109/L, platelet count <100 x109/L, and/or hemoglobin <100 g/L
  19. Prior bone marrow transplant (BMT) or organ transplant
  20. Any condition that would preclude use of Melphalan
  21. Use of a drug with cytotoxic or immunosuppressive effect within 60 days of trial entry
  22. Uncontrolled psychiatric disorder
  23. Active chronic infection
  24. Prior tuberculosis
  25. Any other serious concurrent disease
  26. Cognitive impairment that would prevent informed consent
  27. Use of an investigational drug within 30 days of stem cell transplant (SCT)

Sites / Locations

  • Alberta Children's Hospital, University of Calgary
  • QE II Health Sciences Centre
  • Princess Margaret Cancer Centre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment Arm

Arm Description

Patients will receive Health Canada approved transduced autologous CD34+ cell product.

Outcomes

Primary Outcome Measures

Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
Safety measurement will be based on all clinical and laboratory assessment post-baseline. The assessment will be the frequency of clinically notable abnormal vital signs and laboratory values, and the frequency of treatment-related adverse events.

Secondary Outcome Measures

Alpha-gal A enzyme activity levels
Increase in α-gal A enzyme activity within the plasma, leukocytes, and Bone marrow aspirate.
Gb3 levels
Reduction of Gb3 in plasma and urine
lyso-Gb3 levels
Reduction of lyso-Gb3 in plasma and urine
lyso-Gb3 analogue (-28)
Reduction of lyso-Gb3 (-28) in plasma and urine
lyso-Gb3 analogue (-2)
Reduction of lyso-Gb3 (-2) in plasma and urine
lyso-Gb3 analogue (+16)
Reduction of lyso-Gb3 (+16) in plasma and urine
lyso-Gb3 analogue (+34)
Reduction of lyso-Gb3 (+34) in plasma and urine
lyso-Gb3 analogue (+50)
Reduction of lyso-Gb3 (+50) in plasma and urine
vector copy number per genome on the CD34+ cell population
Persistence of LV-transduced cells as measured by quantitative (q)PCR
transduction efficiency
Vector copy number per genome on the CD34+ cell population
transduction efficiency
Number of colonies positive by PCR for the provirus out of number plated in the colony assay

Full Information

First Posted
April 15, 2016
Last Updated
April 20, 2020
Sponsor
University Health Network, Toronto
Collaborators
Ozmosis Research Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02800070
Brief Title
Autologous Stem Cell Transplantation of Cells Engineered to Express Alpha-Galactosidase A in Patients With Fabry Disease
Official Title
Clinical Pilot Study of Autologous Stem Cell Transplantation of Cluster of Differentiation 34 Positive (CD34+) Cells Engineered to Express Alpha-Galactosidase A in Patients With Fabry Disease
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 2016 (undefined)
Primary Completion Date
February 2024 (Anticipated)
Study Completion Date
February 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Health Network, Toronto
Collaborators
Ozmosis Research Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a first-in-human study for the treatment of Fabry disease. Eligible patients will have an autologous stem cell transplantation using CD34+ cells that are transduced with the lentivirus vector containing the human alpha-gal A gene. The researchers of this study would like to see if the re-introduction of transduced cells will help increase the levels of alpha-gal A enzyme levels and to determine the safety and toxicity of autologous stem cell transplantation using CD34+ cells transduced with lentivirus vector containing the alpha-gal A gene. This study's objective is to determine the safety and toxicity of lentivirus alpha-gal A transduced CD34+ cells in adult males with Fabry disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fabry Disease
Keywords
autologous stem cell transplant, gene therapy, Fabry disease, lentivirus, haematopoietic stem cell transplant

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
5 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment Arm
Arm Type
Experimental
Arm Description
Patients will receive Health Canada approved transduced autologous CD34+ cell product.
Intervention Type
Biological
Intervention Name(s)
Lentivirus Alpha-gal A transduced stem cells
Primary Outcome Measure Information:
Title
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
Description
Safety measurement will be based on all clinical and laboratory assessment post-baseline. The assessment will be the frequency of clinically notable abnormal vital signs and laboratory values, and the frequency of treatment-related adverse events.
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Alpha-gal A enzyme activity levels
Description
Increase in α-gal A enzyme activity within the plasma, leukocytes, and Bone marrow aspirate.
Time Frame
5 years
Title
Gb3 levels
Description
Reduction of Gb3 in plasma and urine
Time Frame
5 years
Title
lyso-Gb3 levels
Description
Reduction of lyso-Gb3 in plasma and urine
Time Frame
5 years
Title
lyso-Gb3 analogue (-28)
Description
Reduction of lyso-Gb3 (-28) in plasma and urine
Time Frame
5 years
Title
lyso-Gb3 analogue (-2)
Description
Reduction of lyso-Gb3 (-2) in plasma and urine
Time Frame
5 years
Title
lyso-Gb3 analogue (+16)
Description
Reduction of lyso-Gb3 (+16) in plasma and urine
Time Frame
5 years
Title
lyso-Gb3 analogue (+34)
Description
Reduction of lyso-Gb3 (+34) in plasma and urine
Time Frame
5 years
Title
lyso-Gb3 analogue (+50)
Description
Reduction of lyso-Gb3 (+50) in plasma and urine
Time Frame
5 years
Title
vector copy number per genome on the CD34+ cell population
Description
Persistence of LV-transduced cells as measured by quantitative (q)PCR
Time Frame
5 years
Title
transduction efficiency
Description
Vector copy number per genome on the CD34+ cell population
Time Frame
5 years
Title
transduction efficiency
Description
Number of colonies positive by PCR for the provirus out of number plated in the colony assay
Time Frame
5 years

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male patients 18-50 years of age at the time of enrollment Diagnosis of Fabry disease (FD) as defined by very low or absent α-gal A activity Classic FD Type I phenotype with alpha-galactosidase A (GLA) genotyping Patients on enzyme replacement therapy (ERT) prior to enrollment Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or 1 Adequate organ function within 21 days prior to Pre-Treatment Phase: Willing and capable of signing and giving written informed consent in accordance with Research Ethics Board (REB) requirements Willing to comply with all procedures outlined in the study protocol, cooperative with the protocol schedule, able to return for safety evaluation, or otherwise likely to complete the study Willing to abstain from sexual activity or willing to use condoms during sexual intercourse from day of Melphalan administration on day -1 of Phase 3 until after 12 months follow-up post-transplant. Willing to not donate sperm after receiving Melphalan. Sperm banking will be recommended to any patient who would like to father children in the future. Exclusion Criteria: Males with variant Fabry Disease. Female gender Use of immunosuppressive agents or any anticoagulant Ongoing ERT-related infusion associated reactions of moderate-to-severe intensity Presence of anti-agalsidase immunoglobulin (Ig)G antibodies above a threshold (5-fold above normal;) or evidence of high titre neutralizing antibodies Blood test positive for Hepatitis B virus (HBV), Hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1 (HTLV-1), human T-cell lymphotropic virus type 1 (HTLV-2), or Venereal Disease Research Laboratory test (VDRL; Transmissible Disease (TD) testing will be done in Pre-Treatment Phase 2 - see section 5.1 for full panel of TD tests. Patients will only be excluded from the study if positive for the TD tests listed here in this exclusion). Uncontrolled bacterial, viral, or fungal infections Prior malignancies except resected basal cell carcinoma Chronic Kidney Disease (CKD) stage >2 History of heart failure or left ventricle ejection fraction (LVEF) <45% or moderate to severe diastolic dysfunction by standard criteria Arrhythmia: bundle branch block, heart block degree II or III, atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, cardiac arrest, pacemaker, implantable cardiac defibrillator Coronary artery disease with angina, prior myocardial infarction, percutaneous transluminal coronary angioplasty with or without stent, coronary artery bypass graft surgery, moderate to severe valvular heart disease, valve replacement surgery Uncontrolled hypertension Diabetes mellitus Advanced liver disease, liver failure, cirrhosis Immune deficiency state Moderate-to-severe chronic obstructive pulmonary disease (COPD) Any hematological condition with white blood cells (WBC) <3.0 x109/L, platelet count <100 x109/L, and/or hemoglobin <100 g/L Prior bone marrow transplant (BMT) or organ transplant Any condition that would preclude use of Melphalan Use of a drug with cytotoxic or immunosuppressive effect within 60 days of trial entry Uncontrolled psychiatric disorder Active chronic infection Prior tuberculosis Any other serious concurrent disease Cognitive impairment that would prevent informed consent Use of an investigational drug within 30 days of stem cell transplant (SCT)
Facility Information:
Facility Name
Alberta Children's Hospital, University of Calgary
City
Calgary
State/Province
Alberta
Country
Canada
Facility Name
QE II Health Sciences Centre
City
Halifax
State/Province
Nova Scotia
Country
Canada
Facility Name
Princess Margaret Cancer Centre
City
Toronto
State/Province
Ontario
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
33633114
Citation
Khan A, Barber DL, Huang J, Rupar CA, Rip JW, Auray-Blais C, Boutin M, O'Hoski P, Gargulak K, McKillop WM, Fraser G, Wasim S, LeMoine K, Jelinski S, Chaudhry A, Prokopishyn N, Morel CF, Couban S, Duggan PR, Fowler DH, Keating A, West ML, Foley R, Medin JA. Lentivirus-mediated gene therapy for Fabry disease. Nat Commun. 2021 Feb 25;12(1):1178. doi: 10.1038/s41467-021-21371-5.
Results Reference
derived

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Autologous Stem Cell Transplantation of Cells Engineered to Express Alpha-Galactosidase A in Patients With Fabry Disease

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