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

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

Study Overview

• Status: Active, not recruiting
• Conditions: Gene Therapy; Severe Combined Immunodeficiency, X Linked
• Intervention / Treatment: Biological: autologous CD34+ cell transduced with G2SCID vector

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 Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Colleen Dansereau; Phone Number: 6179197008; Email: colleen.dansereau@childrens.harvard.edu

Study Locations

• United Kingdom
  • London, United Kingdom
    • Great Ormond Street Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • Mattel Children's Hospital - UCLA
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University/Childrens Healthcare of Atlanta
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Childrens Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 5 years (Child)
• Accepts Healthy Volunteers: No

Description

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

   -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary objective is to measure event free survival	Events will include death, infusion of unmanipulated back-up product for failure of hematopoietic recovery, and allogeneic transplant performed for poor immune reconstitution	1 year post infusion
T cell reconstitution	CD3+ T cell count ≥300 cells/microliter in peripheral blood; Gene marking ≥0.1 copies/cell in sorted CD3+ T cells	1 year post infusion

Collaborators and Investigators

• Sponsor: David Williams
• Investigators: Study Chair: Sung-Yun Pai, MD, National Institutes of Health (NIH)

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2018
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: October 12, 2017
• First Submitted That Met QC Criteria: October 12, 2017
• First Posted (Actual): October 17, 2017

Study Record Updates

• Last Update Posted (Actual): September 14, 2023
• Last Update Submitted That Met QC Criteria: September 13, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Gene therapy; busulfan; lentiviral
• Additional Relevant MeSH Terms: Metabolic Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; DNA Repair-Deficiency Disorders; Primary Immunodeficiency Diseases; Severe Combined Immunodeficiency; X-Linked Combined Immunodeficiency Diseases
• Other Study ID Numbers: P00023098

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No