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
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Beta-Thalassemia
- Sponsor
- IRCCS San Raffaele
- Enrollment
- 10
- Locations
- 1
- Primary Endpoint
- Safety of the administration of autologous haematopoietic stem cells transduced with LV-GLOBE
- Last Updated
- 6 years ago
Overview
Brief Summary
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
Detailed Description
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: 1. 3 adults (≥18 years) conditioned with treosulfan and thiotepa 2. 3 elderly children (8-17 years) conditioned with treosulfan and thiotepa 3. 4 younger children (3-7 years) conditioned with treosulfan and thiotepa Enrolment will start in adult patients. Pediatric patients will be included once evidence of preliminary safety and biological efficacy is shown in at least 2 adults. 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.
Investigators
Alessandro Aiuti
Director of Pediatric Clinical Research Unit
IRCCS San Raffaele
Eligibility Criteria
Inclusion Criteria
- •Written informed consent
- •Transfusion-dependent beta-thalassemia (any genotype). Transfusion dependence is defined as receiving ≥ 8 transfusions of blood per year over a minimum of 2 years.
- •Karnofsky Index or Lansky \> 80%
- •Age ≥ 3 years and \< 65 years
- •Adequate cardiac, renal, hepatic and pulmonary functions as evidenced by:
- •Left ventricular ejection fraction (LVEF) greater than 45% by echo and normal ECG or presence of abnormalities not significant for cardiac disease. Absence of severe pulmonary hypertension
- •Diffusing capacity of the lung for carbon monoxide (DLCO) \> 50% and forced expiratory volume in 1 sec (FEV1) and forced expiratory vital capacity (FVC) \> 60% predicted (if non cooperative: pulse oximetry \> 95 % in room air)
- •Serum creatinine \< 1.5 upper limit of normal
- •Absent-mild-moderate liver iron overload on T2\*MRI (less than 12 months before enrolment)
- •Absent-mild-moderate cardiac iron overload T2\*MRI (less than 12 months before enrolment)
Exclusion Criteria
- •Use of other investigational agents within 4 weeks prior to study enrolment (within 6 weeks if use of long-acting agents)
- •Severe, active viral, bacterial, or fungal infection at eligibility evaluation
- •Malignant neoplasia (except local skin cancer or cervical intraepithelial neoplasia) or exceptional family history of familial cancer syndromes
- •Myelodysplasia, cytogenetic alterations associated with neoplasia, or other serious haematological disorder than thalassemia
- •History of uncontrolled seizures
- •Other clinical conditions judged non compatible with the procedure and/or the treatment
- •Positivity for HIV (serology or RNA), and/or HbsAg and/or HBV DNA and/or HCV RNA (or negative HCV RNA but on antiviral treatment) and/or Treponema Pallidum or Mycoplasma active infection
- •Active alcohol or substance abuse within 6 months of the study
- •Pregnancy or lactation
- •Previous allogeneic bone marrow transplantation or gene therapy
Outcomes
Primary Outcomes
Safety of the administration of autologous haematopoietic stem cells transduced with LV-GLOBE
Time Frame: 0-24 months after gene therapy
* 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.
Overall safety and tolerability measured by AE recording
Time Frame: 0-24 months after gene therapy
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.
Reduction in transfusion frequency up to transfusion independence
Time Frame: from -7 months before gene therapy to 2 years after gene therapy
Transfusions will be recorded as mLs of blood/kg/months
Polyclonal engraftment
Time Frame: From 6 months to 2 years after gene therapy
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.
Overall survival
Time Frame: 2 years
Number of patients alive all over the trial
Achievement of hematological engraftment
Time Frame: within day +60 after gene therapy
Haematological engraftment is defined as first day of neutrophil count \>500/mm3 and platelets \>20,000/mm3 on 3 consecutive blood counts.
Short-term safety and tolerability of the different conditioning regimens
Time Frame: from day -5 (first day of conditioning treatment) to day 100 after gene therapy
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.
Secondary Outcomes
- Adequate engraftment of genetically corrected cells(6, 12, and 24 months after gene therapy)
- Transfusion independence(9 months, 1, 1.5 and 2 years after gene therapy)
- Adequate haemoglobin level(0-24 months after gene therapy)
- Transgene expression(6, 12, and 24 months after gene therapy)
- Improvement of health-related quality of life(12 and 24 months)