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

• ClinicalTrials.gov Identifier: NCT04797260
• Recruitment Status: Recruiting
• First Posted: March 15, 2021
• Last Update Posted: April 18, 2024
• Sponsor: Leiden University Medical Center
• Collaborators: ZonMw: The Netherlands Organisation for Health Research and Development; Horizon 2020 - European Commission
• Information provided by (Responsible Party): alankester, Leiden University Medical Center

Tracking Information

• First Submitted Date: March 11, 2021
• First Posted Date: March 15, 2021
• Last Update Posted Date: April 18, 2024
• Actual Study Start Date: July 23, 2021
• Estimated Primary Completion Date: December 31, 2029 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 11, 2021)

• Feasibility of successful generation of RAG1 LV CD34+ cells [ Time Frame: 2 years ]
  IMP (RAG1 LV CD34+ cells) that meets the release criteria as defined in the IMPD.
• Safety of RAG1 lentiviral gene therapy [ Time Frame: 2 years ]
  Overall survival and event-free survival (EFS) after infusion of the IMP with events

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 11, 2021)

• T cell reconstitution [ Time Frame: 1 year ]
  CD3 T cells > 300/μL and CD4 > 200/μL at 1 year
• Thymic function [ Time Frame: 1 year ]
  presence of naïve CD4 T cells at 1 year
• T and B cell receptor repertoire [ Time Frame: 1 year ]
  Molecular T and B cell receptor repertoire at 1 year
• Immunoglobulin dependence [ Time Frame: 2 years ]
  Immunoglobulin supplementation dependence at 2 years
• Persistence of gene marking [ Time Frame: 1 year ]
  Gene marking in myeloid and lymphoid lineages in blood at six months and one year and in bone marrow at one year
• Occurrence of Infections [ Time Frame: 2 years ]
  Frequency of serious/invasive infections
• Failure to thrive [ Time Frame: 2 years ]
  Recovery from failure to thrive
• Quality of life [ Time Frame: 2 years ]
  Quality of life at 2 years (assessed using PedsQL by proxy).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase I/II Clinical Trial Stem Cell Gene Therapy in RAG1-Deficient SCID
• Official Title: Phase I/II Clinical Trial of Autologous Hematopoietic Stem Cell Gene Therapy in RAG1-Deficient Severe Combined Immunodeficiency
• Brief 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.
• Detailed 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.
• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

CD34+ HSC from patient will be obtained by leukapheresis or from bone marrow. After purification, CD34+ cells will be transduced with the SIN-LV-RAG1 vector. Transduced cells will be cryopreserved. Upon confirmation of successful transduction and meeting the release criteria as RAG1 LV CD34+ cells, patient conditioning will be allowed to start. After patient conditioning, cryopreserved RAG1 LV CD34+ cells will be thawed and administered to the patient. In case of failure of hematopoietic reconstitution after infusion of the RAG1 LV CD34+ cells the autologous backup graft will be infused to rescue the patient from aplasia. In addition, a conventional allogeneic HSCT procedure will be scheduled. Patients included in this study will be monitored on protocol during the first two years after infusion of the RAG1 LV CD34+ cells as per study protocol. Follow up as part of the routine clinical care for post-transplant patients will be annual after this, for at least 15 years after infusion.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: 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).

Study Arms

Experimental: Gene therapy

In this arm, 10 patients will be included for gene therarpy

Intervention: Genetic: Gene therapy

• Publications *: 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, Staal FJT, Pike-Overzet K. Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID. Mol Ther Methods Clin Dev. 2020 Mar 31;17:666-682. doi: 10.1016/j.omtm.2020.03.016. eCollection 2020 Jun 12.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 3, 2021): 10
• Original Estimated Enrollment (submitted: March 11, 2021): 5
• Estimated Study Completion Date: December 31, 2029
• Estimated Primary Completion Date: December 31, 2029 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 8 Weeks to 24 Months (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Arjan C Lankester, Prof. Dr.; 0031715264871; A.Lankester@lumc.nl

Contact: Estefania Laney, MSc.; 0031715296242; e.laney@lumc.nl

• Listed Location Countries: Australia, Italy, Netherlands, Poland, Spain, Turkey, United Kingdom

Administrative Information

• NCT Number: NCT04797260
• Other Study ID Numbers: L20.067
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: alankester, Leiden University Medical Center
• Original Responsible Party: alankester, Leiden University Medical Center, Prof. Dr. A. C. Lankester
• Current Study Sponsor: Leiden University Medical Center
• Original Study Sponsor: Same as current

Collaborators

• ZonMw: The Netherlands Organisation for Health Research and Development
• Horizon 2020 - European Commission

Investigators

• Principal Investigator: Arjan C Lankester, Prof.dr.; Leiden University Medical Center

• PRS Account: Leiden University Medical Center
• Verification Date: April 2024