A Phase 1/2 interventional study of Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene in Beta-Thalassemia, sponsored by IRCCS San Raffaele. Status unknown at 1 site in Italy. Open to participants aged 3 Years to 64 Years. Per ClinicalTrials.gov, last updated 2019-06-28.
Sponsored by IRCCS San Raffaele · Phase 1/2, Interventional, and Treatment
This is a phase I/II study evaluating safety and efficacy of autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene for the treatment of patients affected by transfusion dependent beta-thalassemia
Both adults and pediatric patients will be treated with genetically modified autologous hematopoietic stem cells collected from mobilized peripheral blood (or bone marrow for patients \< 8 years in case mobilization will not be feasible) and transduced with GLOBE lentiviral vector encoding for the human beta-globin gene.
This study will enroll 10 patients allocated in 3 groups, according to age and conditioning regimen:
Patients are included regardless of the beta globin gene mutation, provided an adequate cardiac, renal, hepatic and pulmonary function is demonstrated. Patients with severe iron overload are excluded as well as patients with active viral infections. Pediatric patients can be enrolled only in absence of a human leukocyte antigen (HLA)-identical sibling or a suitable 10/10 matched unrelated donor.
The treated patients will be followed for 2 years. After completion of the 2 years follow up, patients will be enrolled in a long term follow up study and followed up for at least other additional 6 years.
416 studies on the registry are indexed under Thalassemia; 67 are open to participants now.
This study's enrollment of 10 is below the median of 37 across 277 interventional studies indexed under Thalassemia.
Browse Thalassemia studies →IRCCS San Raffaele is the lead sponsor of 443 studies on the registry; 234 are open to participants now.
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Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
Exclusion Criteria:
≥18 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously.
Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
8-17 years (3 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously.
Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
3-7 years (4 subjects) The ATIMP consists of autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the beta-globin gene re-suspended in their final formulation medium. Dosage indications The target dose in the transduced product is 5x10(6) cells/Kg CD34+cells, with a minimum dose of 2x10(6)/Kg and a maximum dose of 20x10(6)/Kg, depending on the yield of cells. The product will be injected intraosseously.
Genetic: Autologous hematopoietic stem cells genetically modified with GLOBE lentiviral vector encoding for the human beta-globin gene
Autologous CD34+ cell enriched fraction containing hematopoietic stem cells (HSC) transduced with the GLOBE lentiviral vector encoding for the human beta-globin gene resuspended in their final formulation medium. The target dose in the transduced product is 5x10\^6 cells/Kg CD34+ cells, with a minimum dose of 2 x 10\^6/Kg and a maximum dose of 20 x 10\^6/Kg, depending on the yield of cells. The product will be injected intraosseously.
Overall survival
Number of patients alive all over the trial
Time frame: 2 years
Achievement of hematological engraftment
Haematological engraftment is defined as first day of neutrophil count \>500/mm3 and platelets \>20,000/mm3 on 3 consecutive blood counts.
Time frame: within day +60 after gene therapy
Safety of the administration of autologous haematopoietic stem cells transduced with LV-GLOBE
* short-term tolerability: the percentage of patients not experiencing short-term (0-24 hours from injection) adverse events (of any grade) and systemic reactions. * absence of Replication Competent Lentivirus (RCL): the percentage of subjects without RCL in the 24 months from injection. * absence of abnormal clonal proliferation: the percentage of subjects without abnormal clonal proliferation in the 24 months from injection.
Time frame: 0-24 months after gene therapy
Short-term safety and tolerability of the different conditioning regimens
The percentage of patients with the following clinical events from day -5 to +100 days from injection: NCI (National Cancer Institute Common Terminology Criteria grading) ≥2 and metabolic/laboratory NCI ≥3.
Time frame: from day -5 (first day of conditioning treatment) to day 100 after gene therapy
Overall safety and tolerability measured by AE recording
The number of AEs (adverse events) and SAEs (serious adverse events) and the percentage of subjects experiencing AEs and SAEs in the 24 months post injection will be summarized by severity and within body system involved.
Time frame: 0-24 months after gene therapy
Polyclonal engraftment
The percentage of subjects with polyclonality of haematopoiesis will be estimated at 6, 12, 18 and 24 months from injection. Polyclonality of haematopoiesis will be defined as \> 1000 unique integration sites retrieved from peripheral blood and/or bone marrow cells.
Time frame: From 6 months to 2 years after gene therapy
Reduction in transfusion frequency up to transfusion independence
Transfusions will be recorded as mLs of blood/kg/months
Time frame: from -7 months before gene therapy to 2 years after gene therapy
Transfusion independence
Transfusion independence is defined as ≤ 1 transfusion in the previous 6 months
Time frame: 9 months, 1, 1.5 and 2 years after gene therapy
Adequate haemoglobin level
Haemoglobin level will be assessed by full blood counts in patients achieving transfusion independence. Adequate haemoglobin is defined as haemoglobin \>9 g/dl in adults and \>10 g/dl in children.
Time frame: 0-24 months after gene therapy
Adequate engraftment of genetically corrected cells
Engraftment will be assessed by vector-specific quantitative Polymerase Chain reaction (PCR) on bone marrow. Adequate engraftment is defined as ≥ 0.15 VCN/genome. (VCN = Vector Copy Number)
Time frame: 6, 12, and 24 months after gene therapy
Transgene expression
Transgene expression will be evaluated by globin chains and/or hemoglobin synthesis on peripheral blood and/or bone marrow samples by HPLC and/or electrophoresis analysis
Time frame: 6, 12, and 24 months after gene therapy
Improvement of health-related quality of life
Health-related quality of life will be assessed by the use of standardized questionnaires
Time frame: 12 and 24 months
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IRCCS San Raffaele