A Phase 1 Clinical Trail of the Safety and Efficacy of Gene-modified Autologous Hematopoietic Stem Cell (BD211) Intravenous Infusion for the Treatment of Transfusion-dependent β-thalassaemia Patients
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- β-thalassemia
- Sponsor
- Shanghai BDgene Co., Ltd.
- Enrollment
- 9
- Locations
- 3
- Primary Endpoint
- Mean time from BD211 treatment to successful neutrophil engraftment, as well as the number and percentage of participants with successful neutrophil engraftment.
- Status
- Recruiting
- Last Updated
- last year
Overview
Brief Summary
This study will be intented to evaluate the safety, tolerability, and engraftment efficacy after myeloablative preconditioning and transplantation of autologous CD34+ hematopoietic stem cells transduced with a lentiviral vector encoding the human βA-T87Q-globin gene in patients with transfusion-dependent (TDT) β-thalassemia.
Detailed Description
This is an open-label, single-dose study of BD211 in patients with transfusion-dependent β-thalassemia aged 3 to 35 years. It is estimated that 9 subjects will be enrolled. BD211 is a gene modified gene therapy product designed to produce healthy β-globin in red blood cells in beta-thalassemia patients. The total follow-up duration was 18 months, the safe endpoints and effectiveness endpoints will be used to assess the safety and efficacy profiles in patients with transfusion-dependent β-thalassemia.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participants aged 3 years (inclusive) to 18 years (exclusive), with no gender restrictions.
- •Parents/legal guardians have fully understood and voluntarily signed a written informed consent form; and it is recommended that children aged 8 and above be involved in the decision to participate in this clinical trial and obtain a written consent form.
- •Transfusion-dependent β-thalassemia patients. "Transfusion-dependent" is defined as: requiring at least 100 mL/kg of packed red blood cells annually; the genotype can be β0/β0, β0/β+, or β+/β+, diagnosed through hemoglobin studies.
- •Eligible for allogeneic hematopoietic stem cell transplantation, but without a donor or those refusing to undergo allogeneic hematopoietic stem cell transplantation.
- •Have undergone symptomatic treatment for at least the past 2 years and have retained medical records including transfusion history.
- •Stable condition and maintained an appropriate iron chelation regimen.
- •Good status of organ function.
- •Good compliance from the individual and parents/legal guardians, willing to adhere to visit schedules, trial plans, laboratory tests, and other trial procedures as stipulated in this protocol.
- •Willing to participate in long-term follow-up research.
Exclusion Criteria
- •Has a fully HLA-matched hematopoietic stem cell donor and is willing to receive a fully HLA-matched hematopoietic stem cell transplant. Enrollment is otherwise only advised after review by the safety review committee.
- •Positive for antibodies against Human Immunodeficiency Virus 1/2 (HIV-1/HIV-2), Treponema pallidum (TP) specific antibodies, Human T-lymphotropic Virus 1 or 2 (HTLV-1/HTLV-2) antibodies, and Vesicular Stomatitis Virus G (VSV-G).
- •Positive for Hepatitis B Virus (HBV) HbsAg or HBV-DNA; Hepatitis C Virus (HCV) HCAb positive; positive nucleic acid test for Epstein-Barr Virus (EBV) or Cytomegalovirus (CMV).
- •Severe active bacterial, viral, fungal, malarial, or parasitic infections.
- •Has had, or currently has, a malignant, myeloproliferative, or immunodeficiency disorder.
- •Direct relatives with known or suspected hereditary cancer syndromes (including but not limited to breast cancer, colorectal cancer, ovarian cancer, prostate cancer, and pancreatic cancer).
- •Autoimmune diseases that could result in transfusion difficulties.
- •Major organ diseases or abnormal lab tests, including:
- •Liver cirrhosis, fibrosis, or active hepatitis, and/or abnormal liver function tests (Serum total bilirubin (TBIL) ≥ 1.5x Upper Limit of Normal (ULN); Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≥ 2.5x ULN; Alkaline phosphatase ≥ 2.5x ULN).
- •Heart disease, or Left Ventricular Ejection Fraction (LVEF) \< 60%.
Outcomes
Primary Outcomes
Mean time from BD211 treatment to successful neutrophil engraftment, as well as the number and percentage of participants with successful neutrophil engraftment.
Time Frame: 18 months
Definition of successful neutrophil engraftment: A consistent absolute neutrophil count (ANC) recovery of ≥0.5×10\^9/L over three consecutive days.
Proportion of participants achieving transfusion independence (TI)
Time Frame: 18 months
TI defined as "hemoglobin (Hb) ≥ 90g/L without any transfusion of packed red blood cells (pRBCs) for 12 months at any time during the study period after BD211 treatment"; proportion of participants with TI = number of participants with TI ÷ total number of BD211 treatment.
Mean time from BD211 treatment to successful platelet engraftment, as well as the number and percentage of participants with successful platelet engraftment.
Time Frame: 18 months
Definition of successful platelet engraftment: No platelet transfusion for 7 days with platelet counts of ≥20×10\^9/L in three consecutive measurements.
Secondary Outcomes
- Mean Hb values after BD211 treatment(12 months~18months)
- Proportion of participants with 60% and 80% reduction in blood transfusions from baseline(12 months~18months)
- Change in ferritin levels from baseline.(18 months)
- Types, numbers and incidence rate of adverse events (AEs) and serious adverse events (SAEs) that occurred within 18 months after BD211 adminstration.(18 months)
- Mean time required from BD211 treatment (D0) to achieve TI(18 months)
- Incidence of aberrant replication competent lentivirus (RCL) or malignant transformation induced by vector insertion after BD211 treatment.(18 months)
- BD211 transplant-related mortality (TRM) and overall survival (OS) after BD211 treatment.(18 months)
- Total number of days hospitalized from the discharge day from LAFR to 18 months after BD211 administration(18 months)
- Mean duration (days) after participants reached TI(18 months)
- Expression of βA-T87Q globin protein in whole blood(18 months)
- Mean VCN of the BD211 lentivirus vector in peripheral blood(18 months)
- Dose-response relationship(18 months)