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Trial record 1 of 1 for:    NCT01852071
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Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With 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
Last Update Posted : April 13, 2020
Sponsor:
Collaborators:
National Institute of Allergy and Infectious Diseases (NIAID)
National Human Genome Research Institute (NHGRI)
National Heart, Lung, and Blood Institute (NHLBI)
University of California, Los Angeles
Information provided by (Responsible Party):
Orchard Therapeutics

Tracking Information
First Submitted Date  ICMJE May 7, 2013
First Posted Date  ICMJE May 13, 2013
Last Update Posted Date April 13, 2020
Actual Study Start Date  ICMJE August 2, 2013
Actual Primary Completion Date August 27, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 2, 2020)
  • Assess safety by recording clinical toxicities. [ Time Frame: 2 years ]
    Safety will be assessed by recording clinical adverse events.
  • Assess safety by determining absence or presence of exposure to replication-competent lentivirus (RCL) [ Time Frame: 2 years ]
    Replication-competent lentivirus exposure will be assessed by polymerase chain reaction (PCR) to VSV-G protein.
  • Assess safety by evaluating the absence or development of monoclonal expansion or leukoproliferative complications from vector insertional effects [ Time Frame: 2 years ]
    Monoclonal expansion of blood cells by vector-mediated activity will be assessed by nrLAM-PCR
  • Overall survival [ Time Frame: 1 year ]
    Overall survival will be assessed as the proportion of subjects alive.
  • Event-free survival [ Time Frame: 1 year ]
    Event-free survival will be assessed by determining the numbers of subjects who remain alive with adequate immune reconstitution and do not need an allogeneic hematopoietic stem cell transplant or re-institution of enzyme replacement therapy.
Original Primary Outcome Measures  ICMJE
 (submitted: May 8, 2013)
  • Assess safety by recording clinical toxicites. [ Time Frame: 2 years ]
    Safety will be assessed by recording clinical adverse events.
  • Assess safety by determing absence or presence of exposure to replication-competent lentivirus (RCL) [ Time Frame: 2 years ]
    Replication-competent lentivirus exposure will be assessed by Western blot analysis for antibodies to VSV-G protein.
  • Assess safety by evaluating the absence or development of monoclonal expansion or leukoproliferative complications from vector insertional effects [ Time Frame: 2 years ]
    Monoclonal expansion of blood cells by vector-mediated activity will be assessed by nrLAM-PCR
  • Overall survival [ Time Frame: 2 years ]
    Overall survival will be assessed
  • Event-free survival [ Time Frame: 2 years ]
    Event-free survival will be assessed by determing the numbers of subjects who remain alive with adequate immune reconstitution and do not need an allogeneic hematopoietic stem cell transplant or re-institution of enyzme replacement therapy.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 2, 2020)
  • Overall survival [ Time Frame: 2 years ]
    Overall survival will be assessed as the proportion of subjects alive.
  • Event-free survival [ Time Frame: 2 years ]
    Event-free survival will be assessed by determining the numbers of subjects who remain alive with adequate immune reconstitution and do not need an allogeneic hematopoietic stem cell transplant or re-institution of enzyme replacement therapy.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2013)
  • Determine the frequency of gene marking in peripheral blood cells [ Time Frame: 2 years ]
    The frequency of peripheral blood cells containing the EFS-ADA transferred human ADA cDNA will be determined by qPCR as an index of gene transduction and engraftment of hematopoietic stem cells.
  • Quantify clonal diversity of vector integrants [ Time Frame: 2 Years ]
    The clonal diversity of vector integration sites will be determined using nrLAM-PCR
  • Quantify ADA enzyme activity in peripheral blood mononuclear cells [ Time Frame: 2 years ]
    The ADA eznymatic activity in peripheral blood mononuclear cells will be measured by biochemical assay.
  • Quantify total adenine nucleotides in erythrocytes [ Time Frame: 2 years ]
    The levels of adenine nucleotides in erythrocytes will be measured by HPLC.
  • Determine absolute lymphocytes on complete blood count [ Time Frame: 2 years ]
    The absolute lymphocyte counts (ALC) on complete blood count will be measured as an index of immune reconstitution.
  • Quantify the absolute numbers T, B, and NK lymphocytes [ Time Frame: 2 years ]
    The absolute numbers of T, B and NK lymphocytes will be determined using flow cytometry as an index of immune reconstitution
  • Assess lymphocyte mitogenic proliferation [ Time Frame: 2 years ]
    The proliferative responses of lymphocyte to mitogen stimulation will be quantified as an index of immune reconstitution.
  • Measure quantitative immunoglobulins by class [ Time Frame: 2 years ]
    The levels of immunglobulin classes (IgG, IgM, IgA) will be quantified as an index of immune reconstitution
  • Quantify specific antibody responses [ Time Frame: 2 years ]
    The development of specific antibody responses to vaccine antigens will be quantified as an index of immune reconstitution
  • Assess T lymphocyte reconstitution [ Time Frame: 2 years ]
    T lymphocyte reconstitution will be assessed by TCR Vbeta family usage enumeration by flow cytometry and TREC assay
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With EFS Lentiviral Vector Encoding for the Human ADA Gene
Official Title  ICMJE Autologous Transplantation of Bone Marrow CD34+ Stem/Progenitor Cells After Addition of a Normal Human ADA cDNA by the EFS-ADA Lentiviral Vector for Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency (ADA-SCID)
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE ADA-SCID
Intervention  ICMJE
  • 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
  • Drug: busulfan
    Busulfan is used for non-myoablative conditioning
  • Drug: PEG-ADA ERT
    PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment
Study Arms  ICMJE Experimental: Gene Therapy
Infusion of autologous EFS-ADA Lentiviral (LV) CD34+ cells
Interventions:
  • Genetic: Infusion of autologous EFS-ADA LV CD34+ (OTL-101)
  • Drug: busulfan
  • Drug: PEG-ADA ERT
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 13, 2016)
20
Original Estimated Enrollment  ICMJE
 (submitted: May 8, 2013)
10
Actual Study Completion Date  ICMJE August 27, 2018
Actual Primary Completion Date August 27, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

  1. Family history of first order relative with ADA deficiency and clinical and laboratory evidence of severe immunologic deficiency, OR
  2. Evidence of severe immunologic deficiency in subject prior to institution of immune restorative therapy, based on

    1. lymphopenia (absolute lymphocyte count <400 cells/mcL) OR absence or low number of T cells (absolute CD3+ count <300 cells/mcL) OR
    2. 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:

  1. Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 60 days of entering this trial.
  2. Hematologic

    1. Anemia (hemoglobin < 10.5 g/dl at < 2 years of age, or < 11.5 g/dl at > 2 years of age).
    2. Neutropenia (absolute granulocyte count <500/mm3.
    3. Thrombocytopenia (platelet count < 150,000/mm3, at any age).
    4. International Normalised Ratio (INR) or Prothrombin Time (PT) > 2X the upper limits of normal or Partial Thromboplastin Time (PTT) > 2.33X the upper limit of normal (patients with a correctable deficiency controlled on medication will not be excluded).
    5. Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid (if available).
    6. Prior allogeneic Hematopoietic Stem Cell Transplant (HSCT) with cytoreductive conditioning
  3. Infectious

    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

  4. Pulmonary

    1. Resting O2 saturation by pulse oximetry < 95% on room air.
    2. Chest x-ray indicating active or progressive pulmonary disease.
  5. Cardiac

    1. Abnormal electrocardiogram (EKG) indicating cardiac pathology.
    2. Uncorrected congenital cardiac malformation with clinical symptomatology.
    3. Active cardiac disease, including clinical evidence of congestive heart failure, cyanosis, hypotension.
    4. Poor cardiac function as evidenced by LV ejection fraction < 40% on echocardiogram.
  6. Neurologic

    1. Significant neurologic abnormality by examination.
    2. Uncontrolled seizure disorder.
  7. Renal

    1. Renal insufficiency: serum creatinine >= 1.2 mg/dl, or >= 3+ proteinuria.
    2. Abnormal serum sodium, potassium, calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale.
  8. Hepatic/GI:

    1. Serum transaminases > 5X the upper limit of normal (ULN).
    2. Serum bilirubin > 2X ULN.
    3. Serum glucose > 1.5x ULN.
    4. Intractable severe diarrhea.
  9. Oncologic

    1. Evidence of active malignant disease other than dermatofibrosarcoma protuberans (DFSP)
    2. Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years following the infusion of genetically corrected cells
    3. Evidence of DFSP expected to be life limiting within the 5 years following the infusion of genetically corrected cells
  10. Known sensitivity to Busulfan
  11. General

    1. Expected survival < 6 months.
    2. Pregnant.
    3. Major congenital anomaly.
    4. Ineligible for autologous HSCT by the criteria at the clinical site.
    5. 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Month to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01852071
Other Study ID Numbers  ICMJE EFS-ADA
U01AI100801 ( U.S. NIH Grant/Contract )
2P01HL073104 ( U.S. NIH Grant/Contract )
0910-1006 ( Other Identifier: OBA-RAC )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Orchard Therapeutics
Study Sponsor  ICMJE Orchard Therapeutics
Collaborators  ICMJE
  • National Institute of Allergy and Infectious Diseases (NIAID)
  • National Human Genome Research Institute (NHGRI)
  • National Heart, Lung, and Blood Institute (NHLBI)
  • University of California, Los Angeles
Investigators  ICMJE
Principal Investigator: Donald B Kohn, MD University of California, Los Angeles
PRS Account Orchard Therapeutics
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP