Lentiviral Gene Therapy for X-linked Severe Combined Immunodeficiency

• Register: ClinicalTrials.gov
• Last refreshed on: 23 October 2023
• Main ID: NCT03601286
• Date of registration: 22/02/2018
• Prospective Registration: Yes
• Primary sponsor: Great Ormond Street Hospital for Children NHS Foundation Trust
• Public title: Lentiviral Gene Therapy for X-linked Severe Combined Immunodeficiency
• Scientific title: Phase I/II Study of Lentiviral Gene Transfer for SCID-X1 With Low Dose Targeted Busulfan
• Date of first enrolment: December 21, 2018
• Target sample size: 5
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03601286
• Study type: Interventional
• Study design: Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

United Kingdom

Contacts

• Name: Claire Booth, MBBS, MRCPCH, MSc, PhD

• Name: Adrian Thrasher, Prof
• Affiliation: UCL Great Ormond Street Institute of Child Health

• Name: Claire Booth, Dr

• Name: Claire Booth, Dr
• Affiliation: UCL Great Ormond Street Institute of Child Health

Key inclusion & exclusion 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

4. Signed informed consent

5. Documentation of willingness to follow up for 15 years post-infusion

6. If the patient has previously undergone allogeneic transplant or gene therapy,
insufficiency of graft-derived T cell engraftment must be documented.

7. Age at least 8 weeks of age 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. Previous allogeneic transplant with cytoreductive chemotherapy

8. 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.

9. 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
anaesthesia, severe deterioration 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.



Age minimum: 8 Weeks
Age maximum: 5 Years
Gender: Male

Health Condition(s) or Problem(s) studied

Severe Combined Immunodeficiency, X-Linked

Intervention(s)

Drug: Lentiviral vector transduced CD34+ cells

Primary Outcome(s)

Measure T cell immune reconstitution; gene marking [Time Frame: 1 year]

Measure T cell immune reconstitution: CD3+ T cell count [Time Frame: 1 year]

Measure event-free survival after 1 year after gene transfer [Time Frame: 1 year]

Secondary Outcome(s)

Determine Freedom from immunoglobulin substitution for at least 9 months [Time Frame: 2 years post-infusion of gene therapy]

Calculate percentage of naïve and memory T cell subsets [Time Frame: up to 2 years post-infusion of gene therapy]

Haematopoietic recovery after receipt of busulfan [Time Frame: up to 6 weeks post-infusion of gene therapy]

Measure proliferation of lymphocytes to phytohaemagglutinin determined by titrated thymidine incorporation reconstitution [Time Frame: up to 2 years post-infusion of gene therapy]

Measure absolute numbers of T, B and NK lymphocytes [Time Frame: up to 2 years post-infusion of gene therapy]

Measure antigen specific antibody titres to tetanus toxoid reconstitution [Time Frame: up to 2 years post-infusion of gene therapy]

Enumeration of absolute lymphocyte count determined by routine complete reconstitution [Time Frame: up to 2 years post-infusion of gene therapy]

Measure overall survival [Time Frame: 2 years]

Measure T cell receptor excision circles (TREC) [Time Frame: up to 2 years post-infusion of gene therapy]

Measure event-free survival [Time Frame: 2 years]

Measure laboratory results which correlates with efficacious immune reconstitution [Time Frame: up to 2 years post-infusion of gene therapy]

Incidence of adverse events related to gene therapy [Time Frame: up to 2 years post-infusion of gene therapy]

Measure serum immunoglobulin levels reconstitution [Time Frame: up to 2 years post-infusion of gene therapy]

Measure T cell receptor Vb family usage [Time Frame: up to 2 years post-infusion of gene therapy]

Measure clonal diversity of vector integrants [Time Frame: up to 2 years post-infusion of gene therapy]

To assess the efficacy of stem cell transduction/engraftment by measuring the frequency of gene marking in peripheral blood cells [Time Frame: up to 2 years post-infusion of gene therapy]

Secondary ID(s)

16IC17

Source(s) of Monetary Support

Please refer to primary and secondary sponsors