Autologous Transplantation of Bone Marrow CD34+ Stem/Progenitor Cells After Addition of a Normal Human ADA Complementary DNA (cDNA) by the EFS-ADA Lentiviral Vector for Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency (ADA-SCID)
Trial Snapshot
- Phase
- Phase 1
- Status
- Completed
- Enrollment
- 46
- Locations
- 2
- Primary Endpoint
- Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Study Overview
Brief Summary
The aim of this study is to assess the safety and efficacy of autologous transplantation of hematopoietic stem cells (CD34+ cells) from the bone marrow (BM) of ADA-deficient SCID infants and children following human ADA cDNA transfer by the EFS-ADA lentiviral vector. The level of gene transfer in blood cells and immune function will be measured as endpoints.
Detailed Description
The study is open to twenty (20) infants and children diagnosed with ADA-deficient SCID who did not have a medically eligible, human leukocyte antigen (HLA)-identical sibling donor for bone marrow transplantation. The EFS-ADA lentiviral vector with the human ADA cDNA will be used to transduce autologous CD34+ cells from the bone marrow of these subjects. The subjects will receive 4 mg/kg busulfan prior to re-infusion of their gene-modified cells. Safety is the primary endpoint. During the follow-up phase, the investigators aim to determine whether the cells could engraft and produce mature cells that contain and express the corrected ADA gene in the absence of pegademase bovine (PEG-ADA) enzyme replacement therapy (ERT), which will be withheld at Day +30 following transplant. Efficacy studies to evaluate the level of immune reconstitution, will be performed in the first and second years of the study.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 1 Month to 17 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Children ≥ 1.0 months of age with a diagnosis of ADA-deficient SCID based on A. Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or in cultured fetal cells to levels consistent with ADA-deficient SCID as determined by reference laboratory or confirmed ADA gene mutation(s) known to cause disease , AND
- •B. Evidence of severe combined immunodeficiency based on either:
- •Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, OR
- •Evidence of severe immunologic deficiency in subject prior to institution of immune restorative therapy, based on
- •lymphopenia (absolute lymphocyte count <400 cells/mcL) OR absence or low number of T cells (absolute CD3+ count <300 cells/mcL) OR
- •severely decreased T lymphocyte blastogenic responses to phytohemagglutinin (either <10% of lower limit of normal controls for the diagnostic laboratory, <10% of the response of the normal control of the day, or stimulation index <10)
- •Ineligible for matched sibling allogeneic bone marrow transplantation: absence of a medically eligible HLA-identical sibling, with normal immune function, who may serve as an allogeneic bone marrow donor
- •Signed written informed consent according to guidelines of the Institutional Review Board (IRB) (UCLA Office of Human Research Protection Program and National Human Genome Research Institute (NHGRI) IRB
Exclusion Criteria
- •Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 60 days of entering this trial.
- •Hematologic
- •Anemia (hemoglobin < 10.5 g/dl at < 2 years of age, or < 11.5 g/dl at > 2 years of age).
- •Neutropenia (absolute granulocyte count <500/mm
- •Thrombocytopenia (platelet count < 150,000/mm3, at any age).
- •International Normalised Ratio (INR) or Prothrombin Time (PT) > 2 times the upper limits of normal or Partial Thromboplastin Time (PTT) > 2.33 times the upper limit of normal (patients with a correctable deficiency controlled on medication will not be excluded).
- •Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
- •Prior allogeneic Hematopoietic Stem Cell Transplant (HSCT) with cytoreductive conditioning
- •a. Evidence of infection with HIV-1, hepatitis B, Hepatitis C, or parvovirus B 19 by DNA Polymerase Chain Reaction (PCR) within 90 days prior to bone marrow harvest. If other infection is present, it must be under control (e.g. stable or decreasing viral load) at the time of screening
- •Resting O2 saturation by pulse oximetry < 95% on room air.
- •Chest x-ray indicating active or progressive pulmonary disease.
- •Abnormal electrocardiogram (EKG) indicating cardiac pathology.
- •Uncorrected congenital cardiac malformation with clinical symptomatology.
- •Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
- •Poor cardiac function as evidenced by LV ejection fraction < 40% on echocardiogram.
- •Significant neurologic abnormality by examination.
- •Uncontrolled seizure disorder.
- •Renal insufficiency: serum creatinine >= 1.2 mg/dl, or >= 3+ proteinuria.
- •Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale.
- •Hepatic/GI:
- •Serum transaminases > 5 times the upper limit of normal (ULN).
- •Serum bilirubin > 2 times ULN.
- •Serum glucose > 1.5 times ULN.
- •Intractable severe diarrhea.
- •Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP)
- •Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells
- •Evidence of DFSP expected to be life limiting within the 5 years following the infusion of genetically corrected cells
- •Known sensitivity to Busulfan
- •Expected survival < 6 months.
- •Major congenital anomaly.
- •Ineligible for autologous HSCT by the criteria at the clinical site.
- •Other conditions which in the opinion of the principal investigator and/or co-investigators, contra-indicate the bone marrow harvest, the administration of busulfan, infusion of transduced cells or indicate the patient or patient's parents/primary caregivers inability to follow protocol.
Arms & Interventions
Gene Therapy
Infusion of autologous EFS-ADA Lentiviral (LV) CD34+ cells
Intervention: Infusion of autologous EFS-ADA LV CD34+ (OTL-101) (Genetic)
Gene Therapy
Infusion of autologous EFS-ADA Lentiviral (LV) CD34+ cells
Intervention: busulfan (Drug)
Gene Therapy
Infusion of autologous EFS-ADA Lentiviral (LV) CD34+ cells
Intervention: PEG-ADA ERT (Drug)
Outcomes
Primary Outcomes
Overall Survival (OS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Time Frame: 12 months
Overall survival is defined as the percentage of subjects alive at 12 months post- treatment with OTL-101 or HSCT
Event-free Survival (EvFS) of Subjects Treated With Investigational Medicinal Product (IMP) (1 Year)
Time Frame: 12 months
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 allogeneic Hematopoietic Stem Cell Transplant (HSCT), or death.
Secondary Outcomes
- EvFS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)(24 months)
- Vector Copy Number (VCN) in Peripheral Blood (PB) Granulocytes.(24 months)
- VCN in Peripheral Blood Mononuclear Cells (PBMCs)(24 months)
- ADA Activity in Erythrocytes(24 months)
- Reduction in Deoxyadenosine Nucleotide (dAXP) in Erythrocytes(24 months)
- OS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years)(24 months)
- Change From Baseline in CD3+ T Cell Counts (2 Years)(24 months)
- Number of Single Integration Sites Representing >30% of the Total Integration Sites (2 Years)(24 months)
- Severe Infection Rate Excluding the First Three Months After Treatment(24 months)
Investigators
Donald B. Kohn, M.D.
Principal Investigator
University of California, Los Angeles