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

Phase 1

Completed

• Conditions: Adenosine Deaminase Deficiency; Severe Combined Immunodeficiencies (SCID)
• Interventions: Other: Haematopoietic Stem Cell Transplantation (HSCT); Genetic: Infusion of autologous EFS-ADA LV CD34+ cells; Drug: Busulfan; Drug: Peg-Ada

• Registration Number: NCT01380990
• Lead Sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust

Brief 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2011-06-23
• Study First Submitted QC: 2011-06-23
• Study First Posted: 2011-06-27
• Study Start: 2012-11-15
• Primary Completion: 2019-12-23
• Study Completion: 2019-12-23
• Results First Submitted: 2021-02-19
• Status Verified: 2021-08
• Results First Submitted QC: 2021-08-20
• Last Update Submitted: 2021-08-20
• Results First Posted: 2021-09-16
• Last Update Posted: 2021-09-16

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Historical Control Group	Haematopoietic Stem Cell Transplantation (HSCT)	Historical data from ADA-SCID patients who were treated with Hematopoietic Stem Cell Transplantation (HSCT)
Gene Therapy	Peg-Ada	Infusion of autologous EFS-ADA LV CD34+ cells
Gene Therapy	Infusion of autologous EFS-ADA LV CD34+ cells	Infusion of autologous EFS-ADA LV CD34+ cells
Gene Therapy	Busulfan	Infusion of autologous EFS-ADA LV CD34+ cells

Primary Outcome Measures

Name	Time	Method
Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)	12 months	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.
VCN in CD3+ T Cells	36 months	Engraftment of transduced cells was assessed using vector gene marking
VCN in CD19+ B Cells	36 months	Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells
Reduction in Deoxyadenosine Triphosphate (dATP) in Erythrocytes	36 months	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.
Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)	12 months	Overall survival is defined as the percentage of subjects alive at 12 months post- treatment with OTL-101\* or HSCT
VCN in Peripheral Blood Mononuclear Cells (PBMCs)	36 months	Engraftment of transduced cells was assessed using vector gene marking in PBMCs
Frequency of Vector Integration Into Known Protooncogenes (3 Years)	36 months	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.
Change From Baseline in CD3+ T Cell Counts (1 Year)	12 months	Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils)	36 months	Engraftment of transduced cells was assessed using vector gene marking in granulocytes (neutrophils)
Change From Baseline in CD3+ T Cell Counts (3 Years)	36 months	Immune reconstitution was assessed by change in CD3+ T Cell counts over time.
ADA Activity in Erythrocytes	36 months	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.

Secondary Outcome Measures

Name	Time	Method
EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)	36 months	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.
OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)	36 months	Overall survival (OS) is defined as the percentage of subjects alive at 36 months post- treatment with OTL-101\* or HSCT
Infection Rate	36 months	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.

Trial Locations

Locations (1)

Great Ormond Street Hospital for Children NHS Foundation Trust; 🇬🇧 London, United Kingdom