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Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan Conditioning

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03311503
Recruitment Status : Recruiting
First Posted : October 17, 2017
Last Update Posted : April 3, 2023
Information provided by (Responsible Party):
David Williams, Boston Children's Hospital

Brief Summary:

This is a phase I/II open label multi-center study in which patients will receive low dose targeted busulfan followed by infusion of autologous CD34+ selected bone marrow or mobilized peripheral blood cells transduced with the G2SCID vector. Subjects will be enrolled over 3 years and be followed for 2 years post-infusion on this protocol, then followed long-term on a separate long-term follow-up protocol.

Enrollment of subjects will be agreed upon by representatives of both sites. Data will be collected uniformly from both sites through an electronic capture system and key laboratory studies will be centralized.

Harvest, cellular manufacturing and infusion will occur at each site using the same SOPs. Key aspects of cellular product characterization will be centralized

Condition or disease Intervention/treatment Phase
Severe Combined Immunodeficiency, X Linked Gene Therapy Biological: autologous CD34+ cell transduced with G2SCID vector Phase 1 Phase 2

Detailed Description:

This is an open labeled, multi-center, phase I/II, cohort study involving a single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) lentiviral vector G2SCID in up to 10 patients with X-linked SCID (SCID-X1) at Boston Children's Hospital and UCLA Mattel Children's Hospital. Patients will receive transduced cells after low dose targeted busulfan pre-conditioning (n=10).

Enrolled subjects will be followed for 2 years after infusion on this protocol. Required long-term monitoring for a total of 15 years after infusion will be performed on a separate protocol.

Single infusion of autologous CD34+ cells transduced with the SIN lentiviral vector rHIV_IL2RGcoG2SCID (hereafter G2SCID) The primary objective is to measure event free survival and T cell immune reconstitution at 1 year post-infusion

Secondary objectives are to measure overall survival, event-free survival, safety related to the procedure, and clinical and laboratory measures of efficacy including humoral immune reconstitution and gene marking after gene transfer.

Exploratory objectives include: molecular characterization of gene transfer, detailed assessment of biomarkers of T and B cell development and function, assessment of infections, nutritional status, growth and development post gene therapy, assessment of T cell receptor and B cell receptor repertoire by next generation sequencing, correlation of busulfan levels with immune outcome and molecular measurements of gene transfer

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: open labeled, multi-center, phase I/II, cohort study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan Conditioning
Actual Study Start Date : January 19, 2018
Estimated Primary Completion Date : April 1, 2025
Estimated Study Completion Date : April 1, 2025

Arm Intervention/treatment
Experimental: Treatment arm
single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) lentiviral vector G2SCID
Biological: autologous CD34+ cell transduced with G2SCID vector
single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) lentiviral vector G2SCID

Primary Outcome Measures :
  1. The primary objective is to measure event free survival [ Time Frame: 1 year post infusion ]
    Events will include death, infusion of unmanipulated back-up product for failure of hematopoietic recovery, and allogeneic transplant performed for poor immune reconstitution

  2. T cell reconstitution [ Time Frame: 1 year post infusion ]
    • CD3+ T cell count ≥300 cells/microliter in peripheral blood
    • Gene marking ≥0.1 copies/cell in sorted CD3+ T cells

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 5 Years   (Child)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   X linked
Accepts Healthy Volunteers:   No

Inclusion Criteria:

- 1. Diagnosis of SCID-X1 based on immunophenotype and lack of T cell function (proliferation to PHA <10% of the lower limit of normal for the laboratory) AND confirmed by a mutation in IL2RG 2. Lack of an HLA identical (A, B, C, DR, DQ) related donor 3. Age 5 years old or younger 4. Signed informed consent 5. Documentation of willingness to follow up for 15 years post-infusion as currently required by the FDA 6. If the patient has previously undergone allogeneic transplant, lack of donor T cell engraftment must be documented.

7. Age at least 8 weeks by the time of busulfan administration

Exclusion Criteria:

  1. Patients with an active, therapy-resistant infection. Infections that are known to be highly morbid in SCID patients will be considered active and therapy-resistant if the infectious agent is repeatedly isolated despite a minimum of 2 weeks of appropriate therapy and is associated with significant organ dysfunction (including but not limited to abnormalities listed below).

    1. Mechanical ventilation including continuous positive airway pressure
    2. Abnormal liver function defined by AST and ALT >10 times the upper range of normal OR Bilirubin >2 mg/dL
    3. Shortening fraction on echocardiogram <25% or ejection fraction <50%
    4. Renal failure defined as glomerular filtration rate <30 ml/min/1.73 m2 or dialysis dependence
  2. Uncontrolled seizure disorder
  3. Encephalopathy
  4. Documented coexistence of any disorder known to affect DNA repair
  5. Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
  6. Patients with evidence of infection with HIV-1
  7. Major (life-threatening) congenital anomalies. Examples of "major (life-threatening) congenital anomalies" include, but are not limited to: unrepaired cyanotic heart disease, hypoplastic lungs, anencephaly or other major central nervous system malformations, other severe non-repairable malformations of the gastrointestinal or genitourinary tracts that significantly impair organ function.
  8. Other conditions which in the opinion of the P.I. or co-investigators, contra-indicate collection and/or infusion of transduced cells or indicate patient's inability to follow the protocol. These may include for example clinical ineligibility to receive anesthesia, severe deterioriation of clinical condition of the patient after collection of bone marrow but before infusion of transduced cells, or documented refusal or inability of the family to return for scheduled visits. There may be other unforeseen rare circumstances that would result in exclusion of the patient, such as sudden loss of legal guardianship


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): NCT03311503

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Contact: Colleen Dansereau 6179197008 colleen.dansereau@childrens.harvard.edu

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United States, California
Mattel Children's Hospital - UCLA Recruiting
Los Angeles, California, United States, 90095
Contact: Donald Kohn, MD    310-825-6708      
United States, Georgia
Emory University/Childrens Healthcare of Atlanta Recruiting
Atlanta, Georgia, United States, 30322
Contact: Shanmuganathan Chandrakasan, MD    404-727-8877    Shanmuganathan.Chandrakasan@emory.edu   
Principal Investigator: Shanmuganathan Chandrakasan, MD         
United States, Massachusetts
Boston Childrens Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Susan Prockop, MD    617-355-3087    Susan.Prockop@childrens.harvard.edu   
Principal Investigator: Susan Prockop, MD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Sharat Chandra, M.D.    513-636-4266    Sharat.Chandra@cchmc.org   
Principal Investigator: Sharat Chandra, M.D.         
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Caridad Martinez, MD    832-822-4242    camartin@texaschildrens.org   
Principal Investigator: Caridad Martinez, MD         
United Kingdom
Great Ormond Street Hospital Recruiting
London, United Kingdom
Contact: Claire Booth, MD       c.booth@ucl.ac.uk   
Principal Investigator: Claire Booth, MD         
Principal Investigator: Adrian Thrasher, MD         
Sponsors and Collaborators
David Williams
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Study Chair: Sung-Yun Pai, MD National Institutes of Health (NIH)
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Responsible Party: David Williams, Chief Scientific Officer, Boston Children's Hospital
ClinicalTrials.gov Identifier: NCT03311503    
Other Study ID Numbers: P00023098
First Posted: October 17, 2017    Key Record Dates
Last Update Posted: April 3, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by David Williams, Boston Children's Hospital:
Gene therapy
Additional relevant MeSH terms:
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Severe Combined Immunodeficiency
X-Linked Combined Immunodeficiency Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Primary Immunodeficiency Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases
Genetic Diseases, X-Linked