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

Great Ormond Street Hospital for Children NHS Foundation Trust36 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Adenosine Deaminase Deficiency Severe Combined Immunodeficiencies (SCID)

Interventions

Eligibility

Sex: ALLMax age: 15 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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

Time frame: 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.

Time frame: 12 months

Vector Copy Number (VCN) in Granulocytes Fraction (Neutrophils)

Engraftment of transduced cells was assessed using vector gene marking in granulocytes (neutrophils)

Time frame: 36 months

VCN in Peripheral Blood Mononuclear Cells (PBMCs)

Engraftment of transduced cells was assessed using vector gene marking in PBMCs

Time frame: 36 months

VCN in CD3+ T Cells

Engraftment of transduced cells was assessed using vector gene marking

Time frame: 36 months

VCN in CD19+ B Cells

Engraftment of transduced cells was assessed using vector gene marking in CD19+ B Cells

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 36 months

Secondary Outcomes

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

Time frame: 36 months

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

Time frame: 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.

Time frame: 36 months

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes