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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Adenosine Deaminase Deficiency, Severe Combined Immunodeficiencies (SCID)

Intervention / Treatment
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* Genetic: Infusion of autologous EFS-ADA LV CD34+ cells
* Other: Haematopoietic Stem Cell Transplantation (HSCT)
* Drug: Busulfan
* Drug: Peg-Ada


Participation Criteria
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Eligibility Criteria
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Gene Therapy (On Trial) Inclusion Criteria: 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 Patients who lack a fully Human leukocyte antigen (HLA)-matched family donor 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) Parental/guardian signed informed consent Exclusion Criteria: Cytogenetic abnormalities on peripheral blood Evidence of active malignant disease Known sensitivity to busulfan 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: 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 Patients (male or female) between 0-18 years at time of treatment Patient treated with allogeneic haematopoietic stem cell transplantation since 2000

Ages Eligible for Study
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Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gene Therapy<br>Infusion of autologous EFS-ADA LV CD34+ cells | Genetic: Infusion of autologous EFS-ADA LV CD34+ cells<br>* Autologous EFS-ADA LV CD34+ cells (OTL-101*) are infused intravenously<br>* Other names: OTL-101*;Drug: Busulfan<br>* Busulfan is used for non-myeloablative conditioning<br>Drug: Peg-Ada<br>* Peg-Ada enzyme replacement therapy is discontinued at Day +3- (-3/+15 days) after successful engraftment<br>|
| Other: Historical Control Group<br>Historical data from ADA-SCID patients who were treated with Hematopoietic Stem Cell Transplantation (HSCT) | Other: Haematopoietic Stem Cell Transplantation (HSCT)<br>* Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH will be collected as comparator group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils) | Engraftment of transduced cells was assessed using vector gene marking in granulocytes (neutrophils) | 36 months | 
| VCN in Peripheral Blood Mononuclear Cells (PBMCs) | Engraftment of transduced cells was assessed using vector gene marking in PBMCs | 36 months | 
| VCN in CD3+ T Cells | Engraftment of transduced cells was assessed using vector gene marking | 36 months | 
| VCN in CD19+ B Cells | Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells | 36 months | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gene therapy, Hematopoietic stem and progenitor cells, Lentiviral vector, ADA-SCID