Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency

Adenosine Deaminase Deficiency Clinical Trial

Official title:

Phase I/II, Historical Controlled, Open-label, Non-randomised, Single-centre Trial to Assess the Safety and Efficacy of EF1αS-ADA Lentiviral Vector Mediated Gene Modification of Autologous CD34+ Cells From ADA-deficient Individuals

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01380990
• Other study ID #: 10-MI-29
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: November 15, 2012
• Est. completion date: December 23, 2019

Study information

• Verified date: August 2021
• Source: Great Ormond Street Hospital for Children NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a historically controlled, non-randomized Phase I/II clinical trial to assess the safety and efficacy of autologous transplantation of CD34+ hematopoietic stem/progenitor cells (HSPCs), obtained from infants affected by ADA-SCID, following transduction of the HSPCs with a lentiviral vector (LV) carrying the human ADA complementary DNA (cDNA) under the control of the elongation factor 1 alpha shortened (EFS) promoter. Subjects treated in the trial receive the infusion of autologous, transduced cells following marrow cytoreduction with busulfan. The outcomes are compared to those observed in a historical control group of patients who received an allogeneic hematopoietic stem cell transplant (HSCT).

This Phase I/II clinical trial will be performed at Great Ormond Street Hospital (GOSH), London, United Kingdom.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 36
• Est. completion date: December 23, 2019
• Est. primary completion date: December 23, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 15 Years

Eligibility

Gene Therapy (On Trial)

Inclusion Criteria:

1. Diagnosis of ADA-SCID confirmed by DNA sequencing or by confirmed absence of <3% of ADA enzymatic activity in peripheral blood (or for neonates) in umbilical cord blood erythrocytes and/or leukocytes or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of Polyethylene glycol-modified ADA (PEG-ADA) replacement therapy

2. Patients who lack a fully Human leukocyte antigen (HLA)-matched family donor

3. Patients (male or female) <5 years of age OR Patients (male or female) = 5 years to 15 years of age who have preserved thymic function as evidenced by presence of >10 % naïve T cells (CD4+45RA+27+ cells)

4. Parental/guardian signed informed consent

Exclusion Criteria:

1. Cytogenetic abnormalities on peripheral blood

2. Evidence of active malignant disease

3. Known sensitivity to busulfan

4. If applicable, confirmed pregnancy (to be tested in patients above 12 years old)

Gene Therapy (CUP)

A group of patients were treated under CUP (GOSH special license) either because the study was not yet open and patients needed urgent treatment, or because they were outside of the inclusion/exclusion criteria or received Investigational Medicinal Product (IMP) followed a different process (ie, received in two infusions). Patients followed the same protocol steps and study visits.

Historical Control Group

Inclusion Criteria:

1. Diagnosis of ADA-SCID confirmed by DNA sequencing OR by confirmed absence of <3% of ADA enzymatic activity in peripheral blood or (for neonates) in umbilical cord blood erythrocytes and/or leucocytes or in cultured foetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of PEG-ADA replacement therapy

2. Patients (male or female) between 0-18 years at time of treatment

3. Patient treated with allogeneic haematopoietic stem cell transplantation since 2000

Related Conditions & MeSH terms

• Adenosine Deaminase Deficiency
• Severe Combined Immunodeficiencies (SCID)
• Severe Combined Immunodeficiency

Intervention

Genetic:
• Infusion of autologous EFS-ADA LV CD34+ cells
Autologous EFS-ADA LV CD34+ cells (OTL-101*) are infused intravenously

Other:
• Haematopoietic Stem Cell Transplantation (HSCT)
Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH will be collected as comparator group.

Drug:
• Busulfan
Busulfan is used for non-myeloablative conditioning
• Peg-Ada
Peg-Ada enzyme replacement therapy is discontinued at Day +3- (-3/+15 days) after successful engraftment

Locations

Country	Name	City	State
United Kingdom	Great Ormond Street Hospital for Children NHS Foundation Trust	London

Sponsors (2)

Lead Sponsor	Collaborator
Great Ormond Street Hospital for Children NHS Foundation Trust	Orchard Therapeutics

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)	Overall survival is defined as the percentage of subjects alive at 12 months post- treatment with OTL-101* or HSCT	12 months
Primary	Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)	Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.	12 months
Primary	Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils)	Engraftment of transduced cells was assessed using vector gene marking in granulocytes (neutrophils)	36 months
Primary	VCN in Peripheral Blood Mononuclear Cells (PBMCs)	Engraftment of transduced cells was assessed using vector gene marking in PBMCs	36 months
Primary	VCN in CD3+ T Cells	Engraftment of transduced cells was assessed using vector gene marking	36 months
Primary	VCN in CD19+ B Cells	Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells	36 months
Primary	Change From Baseline in CD3+ T Cell Counts (1 Year)	Immune reconstitution was assessed by change in CD3+ T Cell counts over time.	12 months
Primary	Change From Baseline in CD3+ T Cell Counts (3 Years)	Immune reconstitution was assessed by change in CD3+ T Cell counts over time.	36 months
Primary	ADA Activity in Erythrocytes	ADA enzyme activity was assessed as a measure of successful engraftment of genetically modified Hematopoietic stem progenitor cells (HSPCs), as it marks sustained gene expression from the normal ADA transgene.	36 months
Primary	Reduction in Deoxyadenosine Triphosphate (dATP) in Erythrocytes	Decreased dATP levels coincide with increased ADA enzyme activity, detoxification was used as a marker of correction of the defective ADA gene. The threshold for detoxification was <100 µmol/L.	36 months
Primary	Frequency of Vector Integration Into Known Protooncogenes (3 Years)	Vector Integration Site Analysis (VISA) allowed determination of the distribution of vector integration sites in each subject's genome, as well as the relative clonal abundance. VISA was to be considered abnormal for a subject if, in 2 or more instances during the course of follow-up, a single integration site was found to represent >30% of the total integration sites detected.; There were no instances of clonal proliferation in the course of the 36 month follow-up for on-study and CUP subjects; hence, a detailed analysis of the frequency of clonal expansion associated with vector integration near proto-oncogenes was not generated.	36 months
Secondary	OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)	Overall survival (OS) is defined as the percentage of subjects alive at 36 months post- treatment with OTL-101* or HSCT	36 months
Secondary	EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)	Event-free survival is defined as the percentage of subjects alive with no "event", an "event" being the resumption of PEG-ADA ERT or the need for a rescue allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.	36 months
Secondary	Infection Rate	The infections of interest in this study were severe infections or opportunistic infectious episodes, defined as infections requiring hospitalization or prolonging hospitalization and/or documented infections by opportunistic pathogens.	36 months