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

• ClinicalTrials.gov Identifier: NCT03311503
• Recruitment Status: Recruiting
• First Posted: October 17, 2017
• Last Update Posted: April 3, 2023
• Sponsor: David Williams
• Information provided by (Responsible Party): David Williams, Boston Children's Hospital

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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

Criteria

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

   -

Contacts and Locations

Contacts

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

Locations

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

Investigators

• Study Chair: Sung-Yun Pai, MD; National Institutes of Health (NIH)

More Information

• 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
• Last Update Posted: April 3, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

lentiviral; Gene therapy; busulfan

Additional relevant MeSH terms:

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