Phase I/II Clinical Trial Stem Cell Gene Therapy in RAG1-Deficient SCID

Severe Combined Immunodeficiency Due to RAG1 Deficiency Clinical Trial

— RAG1-SCID  

Official title:

Phase I/II Clinical Trial of Autologous Hematopoietic Stem Cell Gene Therapy in RAG1-Deficient Severe Combined Immunodeficiency

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04797260
• Other study ID #: L20.067
• Status: Recruiting
• Phase: N/A
• Start date: July 23, 2021
• Est. completion date: December 31, 2029

Study information

• Verified date: April 2024
• Source: Leiden University Medical Center
• Contact: Arjan C Lankester, Prof. Dr.
• Phone: 0031715264871
• Email: A.Lankester[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a prospective, non-randomized, open-label, two-centre phase I/II intervention study designed to treat children up to 24 months of age with RAG1-deficient SCID with an indication for allogeneic hematopoietic stem cell transplantation but lacking an HLA-matched donor. The study involves infusion of autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (hereafter called RAG1 LV CD34+ cells) in five patients with RAG1-deficient SCID.

Description:

Severe combined immunodeficiency (SCID) is a genetically heterogeneous life-threatening disease characterized by severely impaired T cell development with or without impaired natural killer (NK) and B cell development or function depending on the genetic defect. Mutations in recombination activating genes 1 and 2 (RAG1 and RAG2) represent about 20% of all types of SCID. SCID is a paediatric emergency since it leads to severe and recurrent infections often in combination with protracted diarrhoea and failure to thrive. When left untreated, it is usually fatal within the first year of life. Currently, the only curative treatment option for RAG-deficient SCID is allogeneic hematopoietic stem cell transplantation (HSCT). Despite improvements in HSCT in recent years, this treatment is associated with serious potential complications like graft-versus-host disease which results in an unfavourable outcome, particularly in patients who lack a human leukocyte antigen (HLA)-matched donor. In recent years, gene therapy based on transplantation of autologous gene-corrected hematopoietic stem cells (HSC) has evolved as an effective and safe therapeutic option for X-linked and ADA-deficient forms of SCID. We have recently demonstrated that gene therapy using lentiviral (LV) self-inactivating (SIN) vectors expressing codon-optimized human RAG1 in a mouse model for RAG1-deficient SCID effectively restores T and B cell development and function. In this phase I/II explorative intervention study feasibility, safety and efficacy of gene therapy using gene-corrected autologous CD34+-selected mobilized peripheral blood or bone marrow cells will be investigated in patients with RAG1-deficient SCID with an indication for allogeneic HSCT but lacking an human leukocyte antigen (HLA)-matched donor.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: December 31, 2029
• Est. primary completion date: December 31, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Weeks to 24 Months

Eligibility

Inclusion Criteria:

1. RAG1-deficient SCID as confirmed by genetic analysis

2. Peripheral blood T cells < 300/µL and/or naïve T cells < 1/µL

3. Age < 2 years

4. Age at least 8 weeks by the time of busulfan and fludarabine administration

5. Lack of an available HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)

6. Signed informed consent (parental or guardian)

7. Able to return to the study centre for follow-up (per protocol) during the 2-year study and the 15-year long-term off study review

Exclusion Criteria:

1. Availability of an HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor)

2. RAG1 deficiency with peripheral blood T cells > 300/µL and/or naïve T cells > 1/µL

3. Omenn syndrome

4. Previous allogeneic HSCT

5. Significant organ dysfunction/co-morbidity (including but not limited to the ones listed below):

1. Mechanical ventilation

2. Shortening fraction on echocardiogram <25%

3. Renal failure defined as dialysis dependence

4. Uncontrolled seizure disorder

6. Any other condition that the investigator considers is a contraindication to collection and/or infusion of trans-duced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication f to busulfan, major congenital abnormalities, ineligible to receive anaesthesia, or documented refusal or inability of the family to return for scheduled visits.

7. Human immunodeficiency virus (HIV) infection or Human T-cell Leukemia Virus (HTLV) infection

Related Conditions & MeSH terms

• Immunologic Deficiency Syndromes
• Severe Combined Immunodeficiency
• Severe Combined Immunodeficiency Due to RAG1 Deficiency

Intervention

Genetic:
• Gene therapy
Patients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells).

Locations

Country	Name	City	State
Australia	The Royal Childrens Hospital	Melbourne
Italy	Ospedale Pediatrico Bambino Gesù	Roma
Netherlands	Leiden University Medical Center	Leiden
Poland	Wroclaw Medical University	Wroclaw
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Turkey	Erciyes Üniversitesi TIP Fakültesi	Kayseri
United Kingdom	University College London Great Ormond Street	London

Sponsors (3)

Lead Sponsor	Collaborator
Leiden University Medical Center	Horizon 2020 - European Commission, ZonMw: The Netherlands Organisation for Health Research and Development

Countries where clinical trial is conducted

Australia,  Italy,  Netherlands,  Poland,  Spain,  Turkey,  United Kingdom, 

References & Publications (1)

Garcia-Perez L, van Eggermond M, van Roon L, Vloemans SA, Cordes M, Schambach A, Rothe M, Berghuis D, Lagresle-Peyrou C, Cavazzana M, Zhang F, Thrasher AJ, Salvatori D, Meij P, Villa A, Van Dongen JJM, Zwaginga JJ, van der Burg M, Gaspar HB, Lankester A, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility of successful generation of RAG1 LV CD34+ cells	IMP (RAG1 LV CD34+ cells) that meets the release criteria as defined in the IMPD.	2 years
Primary	Safety of RAG1 lentiviral gene therapy	Overall survival and event-free survival (EFS) after infusion of the IMP with events	2 years
Secondary	T cell reconstitution	CD3 T cells > 300/µL and CD4 > 200/µL at 1 year	1 year
Secondary	Thymic function	presence of naïve CD4 T cells at 1 year	1 year
Secondary	T and B cell receptor repertoire	Molecular T and B cell receptor repertoire at 1 year	1 year
Secondary	Immunoglobulin dependence	Immunoglobulin supplementation dependence at 2 years	2 years
Secondary	Persistence of gene marking	Gene marking in myeloid and lymphoid lineages in blood at six months and one year and in bone marrow at one year	1 year
Secondary	Occurrence of Infections	Frequency of serious/invasive infections	2 years
Secondary	Failure to thrive	Recovery from failure to thrive	2 years
Secondary	Quality of life	Quality of life at 2 years (assessed using PedsQL by proxy).	2 years