Autologous Transplant of EFS-ADA Modified Bone Marrow Cells for ADA-Deficient Severe Combined Immunodeficiency (SCID)

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by University of California, Los Angeles
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Donald B. Kohn, M.D., University of California, Los Angeles
ClinicalTrials.gov Identifier:
NCT01852071
First received: May 7, 2013
Last updated: September 20, 2014
Last verified: September 2014
  Purpose

In this current study, the investigators will determine whether using a lentiviral vector (based on HIV-1) will be more effective and safer at gene transfer to hematopoietic stem cells compared to previous gene transfer vectors based on murine (mouse) retroviruses for ADA-deficient SCID. The level of gene transfer in blood cells and immune function will be measured as endpoints.


Condition Intervention Phase
Severe Combined Immunodeficiency Due to Adenosine Deaminase Deficiency
Genetic: EFS-ADA transduced CD34+ cells from the bone marrow
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: 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 Adenosine Deaminase (ADA)-Deficient Severe Combined Immunodeficiency (SCID)

Resource links provided by NLM:


Further study details as provided by University of California, Los Angeles:

Primary Outcome Measures:
  • Assess safety by recording clinical toxicities. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: Yes ]
    Monoclonal expansion of blood cells by vector-mediated activity will be assessed by nrLAM-PCR

  • Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Overall survival will be assessed

  • Event-free survival [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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:
  • Determine the frequency of gene marking in peripheral blood cells [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    The ADA enzymatic activity in peripheral blood mononuclear cells will be measured by biochemical assay.

  • Quantify total adenine nucleotides in erythrocytes [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The levels of adenine nucleotides in erythrocytes will be measured by HPLC.

  • Determine absolute lymphocytes on complete blood count [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    The levels of immunoglobulin classes (IgG, IgM, IgA) will be quantified as an index of immune reconstitution

  • Quantify specific antibody responses [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    T lymphocyte reconstitution will be assessed by TCR Vbeta family usage enumeration by flow cytometry and TREC assay


Estimated Enrollment: 10
Study Start Date: May 2013
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: May 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Autologous transplant of ADA gene corrected bone marrow
Autologous transplantation of EFS-ADA transduced bone marrow CD34+ cells
Genetic: EFS-ADA transduced CD34+ cells from the bone marrow
Eligible subjects will undergo bone marrow harvest under general anesthesia. The marrow will be processed to isolate CD34+ cells and transduced with the EFS-ADA lentiviral vector. If sufficient cells are obtained, the subjects will undergo marrow cytoreduction with busulfan (4 mg/kg). If the transduced CD34+ final cell product meets all release criteria, the cells will be infused intravenously. PEG-ADA enzyme replacement therapy will be discontinued at day +30. After discharge from the hospital, the subject will be seen for interval history and examination by either their home physician, the principal investigator or a clinical investigator and have blood drawn at months 1, 2, 3, 4, 5, 6, 8, 10, 12, 15, 18, 21, and 24.

Detailed Description:

The study will be open to ten (10) infants and children diagnosed with ADA-deficient SCID who do not have a medically eligible, 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 will determine whether the cells can engraft and produce mature cells that contain and express the corrected ADA gene in the absence of PEG-ADA enzyme replacement therapy (ERT), which will be withheld at Day +30 following transplant. Efficacy studies to evaluate level of immune reconstitution will begin in the first year and will continue in the second year. This Phase I/II clinical trial will be performed at Mattel Children's Hospital, UCLA and at the Mark O. Hatfield Clinical Research Center, NIH.

  Eligibility

Ages Eligible for Study:   1 Month and older
Genders Eligible for Study:   Both
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, 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 IRB (UCLA Office of Human Research Protection Program and National Human Genome Research Institute (NHGRI) Institutional Review Board

Exclusion Criteria:

  1. Age ≤ 1.0 months Appropriate organ function as outlined below must be observed within 8 weeks 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. If ANC< 1,000, absence of myelodysplastic syndrome on bone marrow aspirate and biopsy and normal marrow cytogenetics.
    3. Thrombocytopenia (platelet count < 150,000/mm3, at any age).
    4. PT or PTT > 2X the upper limits 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).
  3. Infectious

    a. Evidence of active opportunistic infection or infection with HIV-1, hepatitis B, Hepatitis C, CMV or parvovirus B 19 by DNA PCR within 30-90 days prior to bone marrow harvest.

  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01852071

Contacts
Contact: Donald B Kohn, MD (310) 794-1964 dkohn1@mednet.ucla.edu
Contact: Kit L Shaw, PhD (310) 267-0584 kshaw@mednet.ucla.edu

Locations
United States, California
Mattel Children's Hospital, UCLA Recruiting
Los Angeles, California, United States, 90095
Contact: Donald B Kohn, MD    310-794-1964    dkohn1@mednet.ucla.edu   
Contact: Kit L Shaw, PhD    (310) 267-0584    kshaw@mednet.ucla.edu   
Principal Investigator: Satiro de Oliveira, MD         
Sub-Investigator: Ami Shah, MD         
Sub-Investigator: Gay M Crooks, MD         
Sub-Investigator: Theodore Moore, MD         
United States, Maryland
Mark O. Hatfield Clinical Research Center, NIH Recruiting
Bethesda, Maryland, United States, 20892
Contact: Fabio Candotti, MD    301-435-2944    fabio@nhgri.nih.gov   
Contact: Robert Sokolic, MD    (301) 451-1498    sokolicr@mail.nih.gov   
Principal Investigator: Fabio Candotti, MD         
Sub-Investigator: Robert Sokolic, MD         
Sponsors and Collaborators
Donald B. Kohn, M.D.
Investigators
Principal Investigator: Donald B Kohn, MD University of California, Los Angeles
  More Information

Publications:
Responsible Party: Donald B. Kohn, M.D., Professor, Depts. of Microbiology, Immunology & Molecular Genetics and Pediatrics, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT01852071     History of Changes
Other Study ID Numbers: IND 15440, U01AI100801, 2P01 HL073104
Study First Received: May 7, 2013
Last Updated: September 20, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of California, Los Angeles:
gene therapy, hematopoietic stem cell, SCID, lentivirus

Additional relevant MeSH terms:
Severe Combined Immunodeficiency
Agammaglobulinemia
Immunologic Deficiency Syndromes
Blood Protein Disorders
DNA Repair-Deficiency Disorders
Hematologic Diseases
Immune System Diseases
Infant, Newborn, Diseases
Lymphatic Diseases
Lymphoproliferative Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on October 23, 2014