Clinical trial NCT01380990: Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Adenosine Deaminase Deficiency
Severe Combined Immunodeficiencies (SCID)
Keywords: Gene therapy
Hematopoietic stem and progenitor cells
Lentiviral vector
ADA-SCID
Lead sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: Orchard Therapeutics
First posted: 2011-06-27
Enrollment: 36
Sex: ALL
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
timeFrame: 12 months
measure: Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
timeFrame: 12 months
measure: Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils)
timeFrame: 36 months
measure: VCN in Peripheral Blood Mononuclear Cells (PBMCs)
timeFrame: 36 months
measure: VCN in CD3+ T Cells
timeFrame: 36 months
measure: VCN in CD19+ B Cells
timeFrame: 36 months
measure: Change From Baseline in CD3+ T Cell Counts (1 Year)
timeFrame: 12 months
measure: Change From Baseline in CD3+ T Cell Counts (3 Years)
timeFrame: 36 months
measure: ADA Activity in Erythrocytes
timeFrame: 36 months
measure: Reduction in Deoxyadenosine Triphosphate (dATP) in Erythrocytes
timeFrame: 36 months
measure: Frequency of Vector Integration Into Known Protooncogenes (3 Years)
timeFrame: 36 months
Secondary outcomes:
measure: OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)
timeFrame: 36 months
measure: EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)
timeFrame: 36 months
measure: Infection Rate
timeFrame: 36 months
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
Study officials:
affiliation: Great Ormond Street Hospital NHS Foundation Trust
name: Claire Booth, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kohn DB, Booth C, Shaw KL, Xu-Bayford J, Garabedian E, Trevisan V, Carbonaro-Sarracino DA, Soni K, Terrazas D, Snell K, Ikeda A, Leon-Rico D, Moore TB, Buckland KF, Shah AJ, Gilmour KC, De Oliveira S, Rivat C, Crooks GM, Izotova N, Tse J, Adams S, Shupien S, Ricketts H, Davila A, Uzowuru C, Icreverzi A, Barman P, Campo Fernandez B, Hollis RP, Coronel M, Yu A, Chun KM, Casas CE, Zhang R, Arduini S, Lynn F, Kudari M, Spezzi A, Zahn M, Heimke R, Labik I, Parrott R, Buckley RH, Reeves L, Cornetta K, Sokolic R, Hershfield M, Schmidt M, Candotti F, Malech HL, Thrasher AJ, Gaspar HB. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021 May 27;384(21):2002-2013. doi: 10.1056/NEJMoa2027675. Epub 2021 May 11.