Safety and Efficacy of Gene Modified Autologous Hematopoietic Stem Cells to Treat Transfusion-dependent Beta-thalassemia

Safety and Efficacy of Lentiviral Vector Transduction of β-globin Genetically Modified Autologous CD34+ Hematopoietic Stem Cells in Patients With Transfusion-dependent β-thalassemia

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.

Study Overview

• Status: Recruiting
• Conditions: β-thalassemia
• Intervention / Treatment: Genetic: BD211

Detailed Description

This is an open-label, single-dose study of BD211 in patients with transfusion-dependent β-thalassemia aged 3 to 18 years. It is estimated that 10 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 24 months, the safe endpoints and effectiveness endpoints will be used to assess the safety and efficacy profiles in patients with transfusion-dependent β-thalassemia.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chen Jing, M.D.; Phone Number: +86-18930830632; Email: chenjing@scmc.com.cn

Study Locations

• China
  • Shanghai, China, 200127
    • Recruiting
    • Shanghai Children's Medical Centre
    • Contact: Chen Jing, M.D.; Phone Number: +86-18930830632; Email: chenjing@scmc.com.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Ages 3 to 18 years old, including:

   The parents or legal guardians must be able to understand and provide ICFs. If available, it is strongly recommended that children aged ≥8 years in treatment decisions and obtain written ICFs and be clearly documented; Diagnosed as Transfusion Dependent β-thalassemia with any genotype (β0, β+, βE/β0, βS/S, βS/β0, βS/β+), confirmed the Hb analysis. No alfa chain genetic abnormalities. Subjects must stabilize and maintain an appropriate iron chelation regimen. Transfusion-dependent types are defined as requiring at least 100 mL/kg/ year of red blood cells (pRBCs).

2. No eligiblity for allogeneic hematopoietic stem cell transplantation.
3. The treatment of erythrocyte maturation agent luspatercept cannot be financially supported.
4. The subjects' parents/legal guardians must be willing and able to follow the study procedures in the study protocol.
5. Good organs' functions.
6. Having complete medical records including a history of blood transfusions testified subject received treatment and followed up for at least two years prior to screening .

Exclusion Criteria:

1. Availability of voluntary, fully HLA-matched hematopoietic cell donors, unless recommended for inclusion by the Monitoring Committee.
2. HIV-1 and HIV-2 were positive, and / or HTLV-1, HTLV-2 and VSV-G antibodies were positive.
3. An active bacterial, viral, fungal or parasitic infection.
4. Contraindicated for the extraction of bone marrow under anesthesia.
5. Any malignancy, myeloproliferative, or immunodeficient disease and relevant medical history.
6. Peripheral blood white blood cell (WBC) count < 3×10^9/L or platelet count < 120×10^9/L.
7. A history of allo-transplantation.
8. Erythropoietin was used within 3 months prior to HSC cell collection.
9. Immediate family members with known or suspected familial cancer syndromes (including but not limited to breast, colorectal, ovarian, prostate, and pancreatic cancers).
10. Subjects with a diagnosis of major mental illness may had a serious disability to participate in the study.
11. Active recurrent malaria.
12. Had autoimmune diseases that may make blood transfusions difficult.

13. History of major organ injury including:

    Liver disease, transaminase > 3 times the upper limit of normal. (If the liver biopsy does not reveal evidence of widespread bridging fibrosis, cirrhosis, or acute hepatitis, this indicator will not be used as a criterion for the exclusion); Widely bridging fibrosis, histopathological evidence of acute hepatitis or cirrhosis showed in liver biopsy Heart disease, left ventricular ejection fraction < 25%; Kidney disease, creatinine clearance < 30% normal level; Of severe iron overload, confirmed by the study doctor; An heart MRI detection of T2 * < 10 ms; Significant pulmonary hypertension needing clinical medical intervention.

14. There are bleeding diseases that have not been cured.
15. The subject involved with another clinical study in a 30-day screening period.
16. Allergic to the research drug and its excipients.
17. Prior treatment with any type of gene and/or cell therapy.
18. As assessed by the investigator, the subjects or their parents are unable to comply well with the study procedures per protocol.
19. Hydroxyurea treatment within 3 months prior to hematopoietic stem cell collection.
20. Had diseases that interfere with hematopoietic stem cells collections.
21. Any other conditions being ineligible for HSC transplantation determined by the investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BD211 Single-Dose group; Route of Administrate: infusion intravenously. Dosage form: injection solution. Dose: 5×10^6 cells /kg ~ 10×10^6 cells /kg. Frequency of administration: One dosing intravenously. Intervention: Single dose of BD211	Genetic: BD211; Genetically modified CD34+ autologous stem cells were transfused intravenously with single dosing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of treated participants with Transfusion-Dependent β-Thalassemia (TDT) who achieved transfusion independence (TI) for at least 6 months	TI defined as peripheral blood weighted average hemoglobin (Hb) > or = 9 g/dL without packed red blood cell (pRBC) transfusion for 60 days after BD211 treatment, and transfusion is continuously halted for 12 months.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transplant-related mortality in 3 months and 12 months	Transplant related mortality was definedas any death occurring in the study post drug product infusion deemed related to the transplant bythe investigator.	12 months
Overall survival	Overall survival was defined as time from date of BD211 Drug Product infusion (Day 1) to date of death. Overall survival was censored at the date of last visit if the participant was still alive.	24 months
RCL incidence	Subjects blood RCL was detected with specific assay method, and the incidence was calculated at different scheduled timeslots.	24 months
Characterized insertion mutagenesis events that lead to clonal dominance or leukemia	The number of insertion mutagenesis events that characterized clonal dominance or leukemia was collected.	24 months
Frequency and severity of AE	An AE was any untoward medical occurrence associated with the use of a drug in participants, whether or not considered drug related. An AE may include a change in physical signs, symptoms, and/or clinically significant laboratory change occurring in any phase of a clinical study.	24 months
Hb (g/dL) level between 12 and 24 months after BD211 treatment compared with baseline Hb level	Hb (g/dL) in 12, 15, 18, 21 and 24 months after drug product infusion are tested and calculated.	24 months
Parameters of efficacy related to TI achievement after BD211 treatment	including a. Duration to achieve TI; b. Time from BD211 infusion to last transfusion; c. Time to reach TI from BD211 infusion; d. Mean weighted Hb (g/dL) during TI; and e. Proportion of patients achieving TI at 24 month after BD211 treatment.	24 months
Parameters of efficacy related to reduced blood transfusion after BD211 treatment	Including a. Using the transfusion volume from the 2 years prior to the participant's enrollment as a baseline, compared with the transfusion volume between 12 and 24 months after BD211 treatment (mL/kg/month, mL/kg/year), the proportion of participants categorized based on a reduction in transfusion volume of 50%, 75%, 90%, and 100%; b. Using the number of transfusions from the 2 years prior to the participant's enrollment as a baseline, comparing the changes in the volume of pRBC transfusions at 12 and 24 months after BD211 treatment; c. Using the transfusion requirement volume from the 2 years prior to the participant's enrollment as a baseline, comparing the changes in the pRBC transfusion requirement volume at 12 and 24 months after BD211 treatment.	24 months
Parameters of iron overload after BD211 treatment	Including a. Time from the last iron-chelation treatment to the last follow-up within 24 months; b. Decrease in serum ferritin level compared from baseline to 6 months and 12 months after BD211 infusion; c. Number and proportion of participants who did not require iron-chelation treatment for at least 6 months after BD211 infusion; d. Comparison of cardiac MRI T2 values at the end of the 24 month after BD211 treatment with the baseline values.	24 months
Parameters of growth and development after BD211 treatment	Percentage of pediatric participants reaching the standard for bone age, height, and weight at the same age, at baseline and 24 months after BD211 treatment.	24 months
Change in quality of life from baseline	Comparison of Pediatric Quality of Life Inventory (PedQL) scores in pediatric participants at 24 months after BD211 treatment with the scores at baseline.	24 months
Total hospitalizing days at 12, and 24 months (discharge after transplant)	Total hospitalizing days at 12, and 24 months after transplantation were counted.	24 months
Measurement of PD/PK parameters	Including a. The number and percentage of participants, in whom the HbAT87Q containing the βT87Q-globin remains at or above ≥2.0 g/dL for 6 months or longer, at 18 and 24 months after BD211 infusion; b. Average vector copy number (VCN) of the BD211 lentiviral vector in peripheral blood and bone marrow cells within 24 months after BD211 product infusion; c. Dose-response relationship within 24 months after BD211 infusion.	24 months
Neutrophil engraftment and platelet engraftment	Neutrophil engraftment was defined as the first of absolute neutrophil count (ANC) > or = 0.5 ×10^9/ L for 3 consecutive days (or 3 consecutive measurements done on separate days), after a post-transplant value less than (<) 0.5 × 10^9/L. Platelet engraftment was defined as the first of 3 consecutive platelet values > or =20 × 10^9/L for participants on different days with no platelet transfusionsadministered for 7 days immediately preceding. The day of engraftment is the first day of the 3 consecutive platelet measurements.	24 months

Collaborators and Investigators

• Sponsor: Shanghai BDgene Co., Ltd.
• Collaborators: Shanghai Children's Medical Center
• Investigators: Principal Investigator: Chen Jing, M.D., Shanghai Children's Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2023
• Primary Completion (Estimated): March 1, 2026
• Study Completion (Estimated): October 1, 2026

Study Registration Dates

• First Submitted: March 3, 2023
• First Submitted That Met QC Criteria: March 15, 2023
• First Posted (Actual): March 17, 2023

Study Record Updates

• Last Update Posted (Actual): June 14, 2024
• Last Update Submitted That Met QC Criteria: June 13, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Thalassemia; beta-Thalassemia
• Other Study ID Numbers: BD-TDT-211003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No