Clinical trial NCT04797260: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Severe Combined Immunodeficiency Due to RAG1 Deficiency
Keywords: SCID
RAG1
Gene Therapy
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Horizon 2020 - European Commission
First posted: 2021-03-15
Enrollment: 10
Sex: ALL
Minimum age (years): 8
Maximum age (years): 24
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Feasibility of successful generation of RAG1 LV CD34+ cells
timeFrame: 2 years
measure: Safety of RAG1 lentiviral gene therapy
timeFrame: 2 years
Secondary outcomes:
measure: T cell reconstitution
timeFrame: 1 year
measure: Thymic function
timeFrame: 1 year
measure: T and B cell receptor repertoire
timeFrame: 1 year
measure: Immunoglobulin dependence
timeFrame: 2 years
measure: Persistence of gene marking
timeFrame: 1 year
measure: Occurrence of Infections
timeFrame: 2 years
measure: Failure to thrive
timeFrame: 2 years
measure: Quality of life
timeFrame: 2 years
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: The Royal Childrens Hospital
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Wroclaw
country: Poland
facility: Wroclaw Medical University
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Kayseri
country: Turkey
facility: Erciyes Üniversitesi TIP Fakültesi
city: London
country: United Kingdom
facility: University College London Great Ormond Street
Study officials:
affiliation: Leiden University Medical Center
name: Arjan C Lankester, Prof.dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.