Phase 2
N=36
Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency
Adenosine Deaminase Deficiency · Severe Combined Immunodeficiencies (SCID)
Bottom Line
View on ClinicalTrials.gov: NCT01380990 ↗Enrolled (actual)
36
Serious AEs
60.0%
Results posted
Sep 2021
Primary outcome: Primary: Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year) — 100; 100; 100; 100 percentage of participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Infusion of autologous EFS-ADA LV CD34+ cells (Genetic); Haematopoietic Stem Cell Transplantation (HSCT) (Other); Busulfan (Drug); Peg-Ada (Drug)
- Age
- Pediatric
- Sex
- All
- Sponsor
- Great Ormond Street Hospital for Children NHS Foundation Trust
- Primary completion
- Dec 2019
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year) |
100; 100; 100; 100; 100 | — |
| PRIMARY Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year) |
100; 100; 100; 100; 100 | — |
| PRIMARY Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils) |
0.240; 0.280 | — |
| PRIMARY VCN in Peripheral Blood Mononuclear Cells (PBMCs) |
0.600; 0.625 | — |
| PRIMARY VCN in CD3+ T Cells |
1.065; 1.160 | — |
| PRIMARY VCN in CD19+ B Cells |
0.880; 1.190 | — |
| PRIMARY Change From Baseline in CD3+ T Cell Counts (1 Year) |
3.58; 3.18 | = 0.002 sig |
| PRIMARY Change From Baseline in CD3+ T Cell Counts (3 Years) |
1.060; 1.090 | — |
| PRIMARY ADA Activity in Erythrocytes |
638.0; 490.5; 86.5; 1.0; 23.0 | — |
| PRIMARY Reduction in Deoxyadenosine Triphosphate (dATP) in Erythrocytes |
50.0; 50.0; 0.0; 114.0; 90.0 | — |
| PRIMARY Frequency of Vector Integration Into Known Protooncogenes (3 Years) |
0; 0 | — |
| SECONDARY OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years) |
100; 100; 100; 88.89; 92.86 | — |
| SECONDARY EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years) |
90.00; 95.00; 80.00; 60.00; 66.67 | =0.645 |
| SECONDARY Infection Rate |
0.14; 0.14; 0.13; 0.17; 0.16 | — |
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.
Eligibility Criteria
Gene Therapy (On Trial)
Inclusion Criteria
- Diagnosis of ADA-SCID confirmed by DNA sequencing or by confirmed absence 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
Data sourced from ClinicalTrials.gov (NCT01380990). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.