the Safety and Efficacy Evaluation of HGI-001 Injection in Patients With Transfusion-Dependent β-Thalassemia

the Safety and Efficacy Evaluation of HGI-001 Injection in Patients With Transfusion-Dependent β-Thalassemia(Child)

This is an open label study to evaluate the safety and efficacy of β-globin Restored Autologous Hematopoietic Stem Cells in ß-Thalassemia Major Patients

Study Overview

• Status: Recruiting
• Conditions: β-thalassemia
• Intervention / Treatment: Biological: β-globin restored autologous hematopoietic stem cells

Detailed Description

We will recruit ß-thalassaemia major patients and collect their autologous hematopoietic stem cells, which will be modified with the LentiHBBT87Q system to restore β-globin expression. After conditioning, the autologous hematopoietic stem cells with restored β-globin will be reinfused to the patients and followed up for two years to collect data.

• Study Type: Interventional
• Enrollment (Anticipated): 3
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Haigang Sun; Phone Number: 13823168465; Email: sunhaigang@genomics.cn

Study Locations

• China
  • Guangdong
    • Shenzhen, Guangdong, China
      • Recruiting
      • Shenzhen university General Hospital
      • Contact: Haigang Sun; Phone Number: 13823168465; Email: sunhaigang@genomics.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18-35 years (inclusive), ICF can be provided by the patient and/or legal guardian;
2. Definitively diagnosed with severe TDT without genotype restriction, and a valid test report can be provided;
3. Average transfusion volume > 100 mL/kg/year or transfusion frequency > 8 times/year within 2 years prior to enrollment, or has been definitively diagnosed with TDT;
4. At least 3 months of full volume transfusion (verification of blood transfusion records can be provided) prior to screening, and Hb is maintained at ≥ 9.0 g/dL;
5. Ferritin load < 3000 μg/L, cardiac and liver iron indicates moderate or lesser iron overload; records of iron chelation treatments within 3 months before screening (including prescription or receipt) can be provided;
6. Acceptable organ functions (including heart, liver, kidney, lung and coagulation functions), stable disease condition, and suitable for busulfan pre-treatment and hematopoietic stem cell (HSC) transplantation as judged by the investigator;
7. Meets follow-up requirements, adheres to treatment arrangements, and is able to return to the hospital regularly to undergo various examinations within 2 years after reinfusion of HGI-001 injection.

Exclusion Criteria:

1. Patients with fully HLA-matched donors;
2. Received allogeneic transplantation, which needs to be weighed and evaluated by an expert committee; received other gene therapies;
3. Have previously undergone splenectomy;
4. Uncorrected bleeding disorder;
5. Uncontrolled epilepsy and mental illness;
6. Received hydroxyurea, ruxolitinib, decitabine, or cytarabine within 3 months prior to enrollment;
7. Psychoactive substance abuse, drug or alcohol abuse within 6 months prior to enrollment;
8. Patients with pulmonary hypertension who have not been given effective intervention;
9. Persistent toxicity (≥ CTCAE grade 2) induced by previous treatment;
10. Positive for anti-RBC antibodies in antibody screening;
11. Positive for hepatitis B surface antigen (HBsAg) and HBV DNA copy number > upper limit of normal (ULN) (HBV DNA test not required for patients negative for HBsAg), positive for hepatitis C virus (HCV) antibody, positive human immunodeficiency virus (HIV), or positive for Treponema pallidum antibody (TP-Ab) (subjects who are positive for the antibody due to vaccination can be enrolled). In certain clinical environments/regions, subjects who are positive for other tests can also be excluded from the trial, such as, human lymphocytic virus-1 (HTLV-1) or -2 (HTLV-2), tuberculosis, and toxoplasmosis.
12. Has or has had malignant tumors or myeloproliferative disease or immunodeficiency disease;
13. Immediate family member with or suspected of having a familial cancer (including but not limited to hereditary breast and ovarian cancers, nonpolyposis colorectal cancer, and adenomatous polyposis);
14. Severe bacterial, viral, fungal or parasitic infection;
15. Other illnesses which render the subject unsuitable for participation (e.g., severe liver, kidney or heart disease); Definition of severe liver and kidney disease: a. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or total bilirubin > 3 × ULN; b. Liver magnetic resonance imaging (MRI) indicates significant cirrhosis; c. Liver biopsy indicates cirrhosis, severe fibrosis or active hepatitis (liver biopsy is only performed when liver MRI indicates active hepatitis and significant fibrosis without evidence for cirrhosis); d. Creatinine clearance < 30% of normal;
16. WBC < 3 × 109/L and/or PLT < 100 × 109/L;
17. Has diabetes, abnormal thyroid functions or other endocrine disorder;
18. Participated in other interventional clinical studies within 4 weeks before the trial;
19. Poor adherence or other conditions that renders the subject unsuitable for participation as judged 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: Experimental; Three transfusion-dependent β-thalassaemia subjects aged 18-35 years will be reinfused with β-globin restored autologous hematopoietic stem cells modified with LentiHBBT87Q	Biological: β-globin restored autologous hematopoietic stem cells; β-globin-restored autologous hematopoietic stem cells modified with LentiHBBT87Q

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and severity of AEs	The number and the percentage of adverse events related to transplantation will be summarized according to NCI CTCAE 5.0	0-24 months
Overall survival rate during the clinical trial	Number of patients alive through the whole trial will be record	0-24 months
Overall response rate	Percent of patients with average VCN > 0.1 in peripheral blood mononuclear cells (PBMCs) and average expression of exogenous adult hemoglobin HbAT87Q > 2.0 g/dL	24 months
Incidence of SAEs	The number of SAE related to transplantation will be summarized according to NCI CTCAE 5.0	0-24 months
Transplantation-related fatal and disabling events within day 100 after transplantation	Transplantation-related fatal and disabling events	Day 100
HGI-001 injection-related replicating lentivirus test	The percentage of RCL should be negative in the 24 months after transplant	0-24 months
Change from baseline in Clonal variations containing specific viral integration sites	Evaluation of the percentage of participants without abnormal clonal proliferation and polyclonal engraftment at 6, 12, 18 and 24 months after transplant. More than 1000 VIS retrieved from peripheral blood should be checked.	0-24 months
Number of patients with abnormal hematology and bone marrow cytology within 24 months after reinfusion, and percent of patients with abnormal RBC proliferation	Number of patients with abnormal hematology and bone marrow cytology	0-24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of subjects with successful HSC engraftment	Criteria for successful engraftment: Absolute neutrophil count > 0.5 × 10 9 /L for 3 consecutive days; platelet count is maintained at > 20 × 10 9 /L for 7 consecutive days without platelet transfusion	1 month
Change in transfusion volume or frequency	Change in average annual transfusion volume or frequency from baseline or change in percentage	0-24 Months
Transfusion-free survival	the time when a subject meets the TI criteria and maintains transfusion-free survival	0-24 Months
Treatment response rate	Percent of patients with average VCN > 0.1 in PBMCs and average expression of exogenous adult hemoglobin HbAT87Q > 2.0 g/dL after reinfusion of HGI-001 injection	12 Months
Transfusion improvement rate	Percent of subjects with ≥ 30% decrease in the average annual (0-12 months, 12-24 months) transfusion volume or frequency from baseline after reinfusion of HGI-001 injection	0-24 Months
Transfusion independence (TI) rate	Percent of subjects who do not require transfusion for at least 12 consecutive months after reinfusion of HGI-001 injection and have a weighted average Hb of ≥ 9.0 g/dL	0-24 Months
Changes in VCN and exogenous adult HbAT87Q expression	Vector copy number	0-24 Months
Changes in cardiac iron load after reinfusion of HGI-001 injection	T2 MRI	0-24 Months
Changes in liver iron load after reinfusion of HGI-001 injection	T2 MRI	0-24 Months
Changes in serum ferritin after reinfusion of HGI-001 injection	serum ferritin	0-24 Months
Changes use of iron chelation medications after reinfusion of HGI-001 injection	iron chelation medications	0-24 Months

Collaborators and Investigators

• Sponsor: Shenzhen Hemogen
• Investigators: Principal Investigator: Li Yu, Shenzhen university General Hospital; Principal Investigator: Chao Liu, PHD, Shenzhen Hemogen

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2022
• Primary Completion (Anticipated): August 1, 2024
• Study Completion (Anticipated): August 1, 2025

Study Registration Dates

• First Submitted: February 28, 2023
• First Submitted That Met QC Criteria: May 8, 2023
• First Posted (Actual): May 18, 2023

Study Record Updates

• Last Update Posted (Actual): May 18, 2023
• Last Update Submitted That Met QC Criteria: May 8, 2023
• Last Verified: May 1, 2023

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: HGI-001-CTP

Drug and device information, study documents

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