Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With Elongation Factor 1 Alpha Shortened (EFS) Lentiviral Vector Encoding for the Human ADA Gene
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|ClinicalTrials.gov Identifier: NCT01852071|
Recruitment Status : Completed
First Posted : May 13, 2013
Results First Posted : September 20, 2021
Last Update Posted : August 3, 2022
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|Condition or disease||Intervention/treatment||Phase|
|ADA-SCID||Genetic: Infusion of autologous EFS-ADA LV CD34+ (OTL-101) Drug: busulfan Drug: PEG-ADA ERT||Phase 1 Phase 2|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||46 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||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)|
|Actual Study Start Date :||August 2, 2013|
|Actual Primary Completion Date :||August 27, 2018|
|Actual Study Completion Date :||August 27, 2018|
Experimental: Gene Therapy
Infusion of autologous EFS-ADA Lentiviral (LV) CD34+ cells
Genetic: Infusion of autologous EFS-ADA LV CD34+ (OTL-101)
autologous EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously
Other Name: OTL-101
Busulfan is used for non-myeloablative conditioning
Drug: PEG-ADA ERT
PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment
- 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.
- OS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years) [ Time Frame: 24 months ]OS is defined as the percentage of subjects alive at 24 months post- treatment with OTL-101 or HSCT
- EvFS of Subjects Treated With Investigational Medicinal Product (IMP) (2 Years) [ Time Frame: 24 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 allogenic Hematopoietic Stem Cell Transplant (HSCT), or death.
- Vector Copy Number (VCN) in Peripheral Blood (PB) Granulocytes. [ Time Frame: 24 months ]Vector copy number in the PB granulocyte fraction that was T cell depleted, is a surrogate for amount of engrafted genetically modified Hematopoietic stem cell (HSC) that are producing granulocytes every 3-5 days. VCN analysis was performed by Droplet Digital PCR (ddPCR) on DNA extracted from peripheral blood granulocytes.
- VCN in Peripheral Blood Mononuclear Cells (PBMCs) [ Time Frame: 24 months ]PBMC VCN is a measure of the accumulation of peripheral blood leukocytes arising from engrafted, genetically modified HSC. VCN analysis was performed by ddPCR on DNA extracted from PBMC.
- ADA Activity in Erythrocytes [ Time Frame: 24 months ]ADA enzyme activity measured to assess the amount of functional gene product produced from the normal ADA transgene delivered by EFS-ADA LV; persistence of ADA enzyme activity over time demonstrates successful engraftment and differentiation of genetically modified HSC.
- Reduction in Deoxyadenosine Nucleotide (dAXP) in Erythrocytes [ Time Frame: 24 months ]Decreased dAXP levels coincide with increased ADA enzyme activity, detoxification was used to demonstrate functional ADA enzyme production from the introduced ADA transgene. The threshold for detoxification was <100 μmol/L.
- Change From Baseline in CD3+ T Cell Counts (2 Years) [ Time Frame: 24 months ]Immune reconstitution was assessed by change in CD3+ T Cell counts at baseline to Month 24.
- Number of Single Integration Sites Representing >30% of the Total Integration Sites (2 Years) [ Time Frame: 24 months ]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.
- Severe Infection Rate Excluding the First Three Months After Treatment [ Time Frame: 24 months ]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. Infections that took place in the first 3 months of follow-up post treatment were excluded from calculations to avoid possible bias introduced in the data by the effects of conditioning.
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|Ages Eligible for Study:||1 Month to 17 Years (Child)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
-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
- Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 60 days of entering this trial.
- 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/mm3.
- 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.
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01852071
|United States, California|
|Mattel Children's Hospital, UCLA|
|Los Angeles, California, United States, 90095|
|United States, Maryland|
|Mark O. Hatfield Clinical Research Center, NIH|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Donald B Kohn, MD||University of California, Los Angeles|
Documents provided by Donald B. Kohn, M.D., University of California, Los Angeles:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||Donald B. Kohn, M.D., Principal Investigator, University of California, Los Angeles|
|Other Study ID Numbers:||
U01AI100801 ( U.S. NIH Grant/Contract )
2P01HL073104 ( U.S. NIH Grant/Contract )
0910-1006 ( Other Identifier: OBA-RAC )
|First Posted:||May 13, 2013 Key Record Dates|
|Results First Posted:||September 20, 2021|
|Last Update Posted:||August 3, 2022|
|Last Verified:||August 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
hematopoietic stem cell
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating