A Phase 1 Study of Gene-modified Autologous Hematopoietic Stem Cell (BD211) Treating β-thalassemia Major

Official title

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

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.

Interventions

• Genetic BD211
  Genetically modified CD34+ autologous stem cells were transfused intravenously with single dosing.

Primary outcome measures

• 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]
• 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]
• Proportion of participants achieving transfusion independence (TI) [Time frame: 18 months]

Secondary outcome measures (12)

• BD211 transplant-related mortality (TRM) and overall survival (OS) after BD211 treatment. [Time frame: 18 months]
• Incidence of aberrant replication competent lentivirus (RCL) or malignant transformation induced by vector insertion after BD211 treatment. [Time frame: 18 months]
• Total number of days hospitalized from the discharge day from LAFR to 18 months after BD211 administration [Time frame: 18 months]
• Types, numbers and incidence rate of adverse events (AEs) and serious adverse events (SAEs) that occurred within 18 months after BD211 adminstration. [Time frame: 18 months]
• Mean duration (days) after participants reached TI [Time frame: 18 months]
• Mean time required from BD211 treatment (D0) to achieve TI [Time frame: 18 months]
• Mean Hb values after BD211 treatment [Time frame: 12 months~18months]
• Proportion of participants with 60% and 80% reduction in blood transfusions from baseline [Time frame: 12 months~18months]
• Change in ferritin levels from baseline. [Time frame: 18 months]
• Expression of βA-T87Q globin protein in whole blood [Time frame: 18 months]
• Mean VCN of the BD211 lentivirus vector in peripheral blood [Time frame: 18 months]
• Dose-response relationship [Time frame: 18 months]

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%.
• Kidney diseases, or serum creatinine ≥ 1.5ULN, creatinine clearance rate < 30% of the normal level (measured or calculated by the Cockcroft-Gault equation).
• Endocrine disorders, such as insulin-dependent diabetes, hyperthyroidism, or hypothyroidism.
• Severe iron overload, serum ferritin ≥ 5000 ng/mL.
• Cardiac T2\* < 20 ms, and/or liver iron content (LIC) ≥ 15mg/g liver weight by MRI.
• Significant pulmonary hypertension diagnosed clinically according to guidelines, requiring clinical medical intervention.
• Uncorrected bleeding disorders.
• Severe psychiatric disorders.
• Peripheral blood white cell (WBC) count < 3x10\^9/L or platelets count < 120x10\^9/L.
• Received hydroxyurea treatment within the last 3 months before stem cell collection.
• Used erythropoiesis-stimulating agents within the 3 months prior to HSC collection.
• History of allogeneic transplantation.
• Previously received any type of gene and/or cell therapy.
• Participating in another clinical trial and is within a 30-day screening period.
• Has contraindications to anesthesia.
• Has contraindications to hematopoietic stem cell collection.
• Allergic to the investigational drug or its excipients.
• Any other conditions determined by the investigator as unsuitable for participation in this clinical trial.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 3 centers

• Sun Yat-sen Memorial Hospital — Guangzhou
• The First Affiliated Hospital of Guangxi Medical University — Nanning
• Shanghai Ruijin Hospital, Shanghai Jiaotong University — Shanghai

Identifiers

NCT: NCT06465550 · BD-TDT-211005

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗