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

Fabry Disease Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02800070
• Other study ID #: OZM-074
• Status: Completed
• Phase: Phase 1
• Start date: July 2016
• Est. completion date: April 2024

Study information

• Verified date: April 2024
• Source: University Health Network, Toronto
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: April 2024
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 50 Years

Eligibility

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 a-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)

Related Conditions & MeSH terms

• Fabry Disease

Intervention

Biological:
• Lentivirus Alpha-gal A transduced stem cells

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital, University of Calgary	Calgary	Alberta
Canada	QE II Health Sciences Centre	Halifax	Nova Scotia
Canada	Princess Margaret Cancer Centre	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
University Health Network, Toronto	Ozmosis Research Inc.

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	5 years
Secondary	Alpha-gal A enzyme activity levels	Increase in a-gal A enzyme activity within the plasma, leukocytes, and Bone marrow aspirate.	5 years
Secondary	Gb3 levels	Reduction of Gb3 in plasma and urine	5 years
Secondary	lyso-Gb3 levels	Reduction of lyso-Gb3 in plasma and urine	5 years
Secondary	lyso-Gb3 analogue (-28)	Reduction of lyso-Gb3 (-28) in plasma and urine	5 years
Secondary	lyso-Gb3 analogue (-2)	Reduction of lyso-Gb3 (-2) in plasma and urine	5 years
Secondary	lyso-Gb3 analogue (+16)	Reduction of lyso-Gb3 (+16) in plasma and urine	5 years
Secondary	lyso-Gb3 analogue (+34)	Reduction of lyso-Gb3 (+34) in plasma and urine	5 years
Secondary	lyso-Gb3 analogue (+50)	Reduction of lyso-Gb3 (+50) in plasma and urine	5 years
Secondary	vector copy number per genome on the CD34+ cell population	Persistence of LV-transduced cells as measured by quantitative (q)PCR	5 years
Secondary	transduction efficiency	Vector copy number per genome on the CD34+ cell population	5 years
Secondary	transduction efficiency	Number of colonies positive by PCR for the provirus out of number plated in the colony assay	5 years