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

Primary Purpose

Severe Combined Immunodeficiency, X Linked, Gene Therapy

Status

Active

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

autologous CD34+ cell transduced with G2SCID vector

About this trial

This is an interventional treatment trial for Severe Combined Immunodeficiency, X Linked focused on measuring lentiviral, Gene therapy, busulfan

Eligibility Criteria

undefined - 5 Years (Child)MaleDoes not accept healthy volunteers

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:

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
Uncontrolled seizure disorder
Encephalopathy
Documented coexistence of any disorder known to affect DNA repair
Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease
Patients with evidence of infection with HIV-1
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.
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
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Sites / Locations

Mattel Children's Hospital - UCLA
Emory University/Childrens Healthcare of Atlanta
Boston Childrens Hospital
Cincinnati Children's Hospital Medical Center
Texas Children's Hospital
Great Ormond Street Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment arm

Arm Description

single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) lentiviral vector G2SCID

Outcomes

Primary Outcome Measures

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

T cell reconstitution

CD3+ T cell count ≥300 cells/microliter in peripheral blood Gene marking ≥0.1 copies/cell in sorted CD3+ T cells

Secondary Outcome Measures

Full Information

NCT ID

NCT03311503

First Posted

October 12, 2017

Last Updated

September 13, 2023

Sponsor

David Williams

1. Study Identification

Unique Protocol Identification Number

NCT03311503

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

January 19, 2018 (Actual)

Primary Completion Date

October 1, 2025 (Anticipated)

Study Completion Date

October 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

David Williams

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Severe Combined Immunodeficiency, X Linked, Gene Therapy

Keywords

lentiviral, Gene therapy, busulfan

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

open labeled, multi-center, phase I/II, cohort study

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment arm

Arm Type

Experimental

Arm Description

single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) lentiviral vector G2SCID

Intervention Type

Biological

Intervention Name(s)

autologous CD34+ cell transduced with G2SCID vector

Intervention Description

single infusion of autologous CD34+ cells transduced with the self-inactivating (SIN) lentiviral vector G2SCID

Primary Outcome Measure Information:

Title

The primary objective is to measure event free survival

Description

Events will include death, infusion of unmanipulated back-up product for failure of hematopoietic recovery, and allogeneic transplant performed for poor immune reconstitution

Time Frame

1 year post infusion

Title

T cell reconstitution

Description

CD3+ T cell count ≥300 cells/microliter in peripheral blood Gene marking ≥0.1 copies/cell in sorted CD3+ T cells

Time Frame

1 year post infusion

10. Eligibility

Sex

Male

Gender Based

Yes

Gender Eligibility Description

X linked

Maximum Age & Unit of Time

5 Years

Accepts Healthy Volunteers

Eligibility 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: 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). Mechanical ventilation including continuous positive airway pressure Abnormal liver function defined by AST and ALT >10 times the upper range of normal OR Bilirubin >2 mg/dL Shortening fraction on echocardiogram <25% or ejection fraction <50% Renal failure defined as glomerular filtration rate <30 ml/min/1.73 m2 or dialysis dependence Uncontrolled seizure disorder Encephalopathy Documented coexistence of any disorder known to affect DNA repair Diagnosis of active malignant disease other than EBV-associated lymphoproliferative disease Patients with evidence of infection with HIV-1 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. 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 -

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sung-Yun Pai, MD

Organizational Affiliation

National Institutes of Health (NIH)

Official's Role

Study Chair

Facility Information:

Facility Name

Mattel Children's Hospital - UCLA

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

Facility Name

Emory University/Childrens Healthcare of Atlanta

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Boston Childrens Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Cincinnati Children's Hospital Medical Center

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

Facility Name

Texas Children's Hospital

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Great Ormond Street Hospital

City

London

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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