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Autologous CD34+ Hematopoietic Stem Cells Transduced ex Vivo With EFS Lentiviral Vector Encoding for the Human ADA Gene

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

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.

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

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : August 2, 2013
Actual Primary Completion Date : August 27, 2018
Actual Study Completion Date : August 27, 2018


Arm Intervention/treatment
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

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




Primary Outcome Measures :
  1. Assess safety by recording clinical toxicities. [ Time Frame: 2 years ]
    Safety will be assessed by recording clinical adverse events.

  2. 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.

  3. 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

  4. Overall survival [ Time Frame: 1 year ]
    Overall survival will be assessed as the proportion of subjects alive.

  5. 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.


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: 2 years ]
    Overall survival will be assessed as the proportion of subjects alive.

  2. 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.



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Ages Eligible for Study:   1 Month to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

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


Locations
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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
Sponsors and Collaborators
Orchard Therapeutics
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
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Principal Investigator: Donald B Kohn, MD University of California, Los Angeles
Publications:
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Responsible Party: Orchard Therapeutics
ClinicalTrials.gov Identifier: NCT01852071    
Other Study ID Numbers: EFS-ADA
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
Last Update Posted: April 13, 2020
Last Verified: April 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Keywords provided by Orchard Therapeutics:
gene therapy
hematopoietic stem cell
ADA-SCID
lentiviral vector
Additional relevant MeSH terms:
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Busulfan
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Antineoplastic Agents
Myeloablative Agonists