Patients with severe combined immunodeficiency (SCID) based on a genetic defect in the Recombinase Activating Gene 1 (RAG1)
Conditions
Interventions
Product Name: RAG1 LV CD34+ cells
Product Code: RAG1 LV CD34+ cells
Pharmaceutical Form: Infusion
INN or Proposed INN: Not obtained
Other descriptive name: Autologous CD34+ cells transduced with a len
Sponsors
Leiden University Medical Center
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. RAG1 deficient SCID as confirmed by genetic analysis 2. Peripheral blood T cells =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. availability of a HLA-matched donor (HLA-identical sibling or 10/10 (A, B, C, DR, DQ) allele-matched (un)related donor) 2. RAG 1 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) a. Mechanical ventilation b. Shortening fraction on echocardiogram <25% c. Renal failure defined as dialysis dependence d. Uncontrolled seizure disorder 6. Any other condition that the investigator considers is a contraindication to collection and/or infusion of transduced cells for that individual or indicate patient's inability to follow the protocol, for example contraindication to busulfan, major congenital abnormalities, ineligible to receive anesthesia, or documented refusal or inability of the family to return for scheduled visits 7. HIV infection or HTLV infection
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objectives of the study are to demonstrate feasibility and safety of gene corrected autologous CD34+-selected hematopoietic stem cell therapy using a lentiviral SIN vector encoding codon-optimized human RAG1 cDNA in patients with RAG1-deficient SCID.;Secondary Objective: To demonstrate efficacy of this therapeutic intervention based on a) T and B cell reconstitution at one year after infusion of the investigational medicinal product, b) event free survival of the patient, and c) persistence of gene marking in myeloid and lymphoid cell lineages in blood and marrow;Primary end point(s): 1. Feasibility of successful generation of an IMP (RAG1 LV CD34+ cells) for RAG1 deficient SCID patients that meets the release criteria as defined in the IMPD. 2. Event free survival (EFS) after infusion of the IMP with events defined as a) failure of engraftment (neutrophils > 500/µL on three consecutive timepoints) within six weeks requiring infusion of the autologous unmanipulated backup stem cell product b) insufficient immune reconstitution within one year after RAG1 LV CD34+ cells infusion requiring allo-SCT c) occurrence of insertional mutagenesis presenting as malignant disease. ;Timepoint(s) of evaluation of this end point: ad 1. After producing the first three and after all five IMPs ad2. At one year after IMP infusion in the first three and at one after infusion of the fifth patient | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Overall survival (at 2 years) - T cell reconstitution (CD3 T cells > 300/µL blood) at 1 year - CD4 reconstitution (CD4 > 200/µL) at 1 year - Thymic function (presence of naïve CD4 T cells) at 1 year - T and B cell receptor molecular repertoire at 1 year - immunoglobulin substitution independence at 2 years - Persistence of gene marking in myeloid and lymphoid lineages in blood and mar-row at six months and one year (> 0.1 VCN) - Frequency of serious/invasive infections - Recovery from failure to thrive - Quality of life at 2 years (assessed using PedQual by proxy). ;Timepoint(s) of evaluation of this end point: see time points in 5.2 per item | — |
Countries
Australia, Germany, Israel, Italy, Netherlands, Poland, Spain, Türkiye, United Kingdom
Contacts
Public ContactTrialbureau Dep of Pediatrics
Leiden University Medical Center
Outcome results
None listed