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

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

Study Description
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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.

Condition or disease Intervention/treatment Phase
Severe Combined Immunodeficiency Due to RAG1 Deficiency Genetic: Gene therapy Not Applicable

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
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
Official Title: Phase I/II Clinical Trial of Autologous Hematopoietic Stem Cell Gene Therapy in RAG1-Deficient Severe Combined Immunodeficiency
Actual Study Start Date : July 23, 2021
Estimated Primary Completion Date : December 31, 2029
Estimated Study Completion Date : December 31, 2029

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Gene therapy
In this arm, 10 patients will be included for gene therarpy
 Genetic: Gene therapy
Patients will be infused with autologous CD34+ cells transduced with the pCCL.MND.coRAG1.wpre lentiviral vector (RAG1 LV CD34+ cells).


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. Safety of RAG1 lentiviral gene therapy [ Time Frame: 2 years ]
    Overall survival and event-free survival (EFS) after infusion of the IMP with events


Secondary Outcome Measures :
  1. T cell reconstitution [ Time Frame: 1 year ]
    CD3 T cells > 300/μL and CD4 > 200/μL at 1 year

  2. Thymic function [ Time Frame: 1 year ]
    presence of naïve CD4 T cells at 1 year

  3. T and B cell receptor repertoire [ Time Frame: 1 year ]
    Molecular T and B cell receptor repertoire at 1 year

  4. Immunoglobulin dependence [ Time Frame: 2 years ]
    Immunoglobulin supplementation dependence at 2 years

  5. 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

  6. Occurrence of Infections [ Time Frame: 2 years ]
    Frequency of serious/invasive infections

  7. Failure to thrive [ Time Frame: 2 years ]
    Recovery from failure to thrive

  8. Quality of life [ Time Frame: 2 years ]
    Quality of life at 2 years (assessed using PedsQL by proxy).


Eligibility Criteria
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Ages Eligible for Study:   8 Weeks to 24 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04797260


Contacts
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Contact: Arjan C Lankester, Prof. Dr. 0031715264871 A.Lankester@lumc.nl
Contact: Estefania Laney, MSc. 0031715296242 e.laney@lumc.nl

Locations
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Australia
The Royal Childrens Hospital Not yet recruiting
Melbourne, Australia, 3052
Contact: Rachel Conyers, Dr         
Principal Investigator: Rachel Conyers, Dr         
Italy
Ospedale Pediatrico Bambino Gesù Not yet recruiting
Roma, Italy
Contact: Franco Locatelli, Prof. Dr.         
Principal Investigator: Franco Locatelli, Prof. Dr.         
Netherlands
Leiden University Medical Center Recruiting
Leiden, Netherlands, 2300RC
Contact: Arjan Lankester, prof dr    0031715264131    a.lankester@lumc.nl   
Contact: Estefania Laney, MSc    0031715262806    e.laney@lumc.nl   
Poland
Wroclaw Medical University Recruiting
Wroclaw, Poland, 50-556
Contact: Krysztof Kalwak, Prof. Dr.         
Principal Investigator: Krysztof Kalwak, Prof. Dr.         
Spain
Hospital Universitari Vall d'Hebron Recruiting
Barcelona, Spain, 08035
Contact: Pere Soler-Palacín, Dr         
Principal Investigator: Pere Soler-Palacín, Dr         
Turkey
Erciyes Üniversitesi TIP Fakültesi Recruiting
Kayseri, Turkey
Contact: Musa Karakükcü, Prof. Dr.         
Principal Investigator: Musa Karakükcü, Prof. Dr.         
United Kingdom
University College London Great Ormond Street Not yet recruiting
London, United Kingdom
Contact: Claire Booth, Dr         
Principal Investigator: Clare Booth, Dr.         
Sponsors and Collaborators
Leiden University Medical Center
ZonMw: The Netherlands Organisation for Health Research and Development
Horizon 2020 - European Commission
Investigators
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Principal Investigator: Arjan C Lankester, Prof.dr. Leiden University Medical Center
More Information
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Publications of Results:

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Responsible Party: alankester, Principal Investigator, Leiden University Medical Center
ClinicalTrials.gov Identifier: NCT04797260    
Other Study ID Numbers: L20.067
First Posted: March 15, 2021    Key Record Dates
Last Update Posted: April 18, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by alankester, Leiden University Medical Center:
SCID
RAG1
Gene Therapy
Additional relevant MeSH terms:
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Severe Combined Immunodeficiency
Immunologic Deficiency Syndromes
Immune System Diseases
Primary Immunodeficiency Diseases
 Genetic Diseases, Inborn
Infant, Newborn, Diseases
DNA Repair-Deficiency Disorders
Metabolic Diseases