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

NCT01380990 | Completed Phase 1 Results

• 1 other identifier: 10-MI-29
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Adenosine Deaminase Deficiency; Severe Combined Immunodeficiencies (SCID)

Keywords

Gene therapy; Hematopoietic stem and progenitor cells; Lentiviral vector; ADA-SCID

Outcome Measures

Primary Outcomes (11)

• 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 Outcomes (3)

• OS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)

  36 months

• EvFS of Subjects Treated With IMP With Those of Patients Treated With Allogeneic HSCT (3 Years)

  36 months

• Infection Rate

  36 months

Study Arms (2)

Gene Therapy

EXPERIMENTAL

Infusion of autologous EFS-ADA LV CD34+ cells

Genetic: Infusion of autologous EFS-ADA LV CD34+ cells; Drug: Busulfan; Drug: Peg-Ada

Historical Control Group

OTHER

Historical data from ADA-SCID patients who were treated with Hematopoietic Stem Cell Transplantation (HSCT)

Other: Haematopoietic Stem Cell Transplantation (HSCT)

Interventions

Infusion of autologous EFS-ADA LV CD34+ cells GENETIC

Autologous EFS-ADA LV CD34+ cells (OTL-101\*) are infused intravenously

Also known as: OTL-101*

Gene Therapy

Haematopoietic Stem Cell Transplantation (HSCT) OTHER

Historical data from a database of ADA-SCID patients treated with allogeneic HSCT from GOSH will be collected as comparator group.

Historical Control Group

Busulfan DRUG

Busulfan is used for non-myeloablative conditioning

Gene Therapy

Peg-Ada DRUG

Peg-Ada enzyme replacement therapy is discontinued at Day +3- (-3/+15 days) after successful engraftment

Gene Therapy

Eligibility Criteria

• Age: Up to 15 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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)
• Historical Control Group
• 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

Sponsors & Collaborators

• Great Ormond Street Hospital for Children NHS Foundation Trust: lead
• Orchard Therapeutics: collaborator

Study Sites (1)

Great Ormond Street Hospital for Children NHS Foundation Trust

London, WC1N 3JH, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33974366 DERIVED

MeSH Terms

Conditions

Severe combined immunodeficiency due to adenosine deaminase deficiency; Severe Combined Immunodeficiency

Interventions

Busulfan; pegademase bovine

Condition Hierarchy (Ancestors)

Primary Immunodeficiency Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; DNA Repair-Deficiency Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Dr Claire Booth
• Organization: UCL Institute of Child Health

C.Booth@ucl.ac.uk

+44207 905 2198

Study Officials

• Claire Booth, Dr

  Great Ormond Street Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 23, 2011
• First Posted: June 27, 2011
• Study Start: November 15, 2012
• Primary Completion: December 23, 2019
• Study Completion: December 23, 2019
• Last Updated: September 16, 2021
• Results First Posted: September 16, 2021

Record last verified: 2021-08

Locations

GB (1)