Base-edited Autologous Hematopoietic Stem Cell Transplantation in Treating Patients With β-thalassemia Major

Study Overview
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Brief Summary
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The goal of this open label, single-arm clinical study is to learn about the safety and efficacy of base-edited autologous hematopoietic stem cell transplantation(CS-101) in treating patients with β-thalassemia major.

Detailed Description
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CS-101 is an autologous CD34+ cell suspension modified by ex vivo base editing technology, removing the inhibitory effect of BCL11A on the γ-globin coding gene, inducing the production of γ-globin chains, increasing the concentration of fetal hemoglobin (HbF) in the blood, compensating for the loss of adult hemoglobin (HbA) to treat transfusion-dependent type/ Major β - thalassemia. The therapy addresses two major challenges in the treatment of the disease: lack of matching donors and graft-versus-host responses commonly seen in allogeneic hematopoietic stem cell transplantation. The study consists of the following five phases: Screening phase: Sign informed consent, complete screening assessments, and confirm the eligibility for enrollment; Baseline: check the subject's baseline status; Mobilization, collection and manufacturing phase: mobilize, collect autologous CD34+ cells and manufacture, release and transport CS-101 product; Conditioning and treatment phase: including myeloablation and CS-101 product infusion; Follow-up phase: 180 days post-infusion.

Official Title
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Evaluation and Promotion of Key Technologies of Base-edited Autologous Hematopoietic Stem Cell Transplantation in Treating Patients With β-thalassemia Major

Conditions
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Beta-Thalassemia

Intervention / Treatment
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* Biological: CS-101 injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 6 to 17 years old(inclusive) male or female subjects at the time of informed consenting Diagnosis of β-thalassemia, genotypes include but are not limited to β+β0, βEβ0, β0β0, etc Generally in good condition, Karnofsky performance score≥60 points for subjects≥16 years old at the time of autologous hematopoietic stem cell collection, or Lansky Play-Performance score≥60 points for subjects under 16 years old, or equivalent clinical evaluation as the investigator site's common practice Exclusion Criteria: Treatment with other investigational medications or other experimental interventions 30 days prior to signing informed consent or within 6 half-lives of the drug, whichever is longer. Subjects who have received or are receiving thalidomide and/or Luspatercept, when their drug-drug interaction on the efficacy and safety of CS-101 cannot be ruled out, unless at least there are 3 test results showing the total hemoglobin level before transfusion is below 9g/dL in the past 6 months before screening. Previously received allogeneic hematopoietic stem cell transplantation or gene(edited) therapy. Subjects have available related fully matching donors and are eligible and prepared for allogeneic hematopoietic stem cell transplantation. Those with active infections, including but not limited to: HIV, hepatitis B, hepatitis C, cytomegalovirus, Epstein-Barr virus and treponema pallidum test positive, or known tuberculosis, parasitic infection, etc. who are judged by the investigator to be unsuitable to participate in this study Echocardiography results with ejection fraction below 45% Advanced liver disease, defined as aspartate aminotransferase (AST), alanine aminotransferase (ALT) >3 × upper limit of normal (ULN) or baseline International Normalized Ratio (INR) >1.5 × ULN MRI during the screening period showed heavy iron overload and is judged by the investigator to be unable to participate in the study.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CS-101 injection<br>Autologous CD34+(cluster of differentiation 34) hematopoietic stem cell suspension modified by in vitro base editing technique | Biological: CS-101 injection<br>* Autologous CD34+ hematopoietic stem cell suspension modified by in vitro base editing technique<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of adverse events(AEs) as assessed by CTCAE v5.0 |  | From signing informed consent to 180 days post-CS-101 infusion | 
| Occurrence of engraftment | Subjects with engraftment is defined as neutrophil engrafted | within 42 days post-CS-101 infusion | 
| Time to neutrophil and platelet engraftment | Time to neutrophil engraftment is defined as first day of 3 consecutive measurements of absolute neutrophil count≥0.5×10^9/L on three different days; Time to platelet engraftment is defined as first day of 3 consecutive measurements of absolute platelet count≥20×10^9/L on three different days and without platelet transfusion | Days post-CS-101 infusion | 
| Occurrence of transplant-related death |  | baseline to 100 days post-CS-101 infusion | 
| Occurrence of all-cause death |  | From signing informed consent to 180 days post-CS-101 infusion | 
| Occurrence of achieving transfusion reduction for at least 3 consecutive months |  | From 3 months post -CS-101 infusion to 3 months post -CS-101 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of achieving transfusion independence for at least 3 consecutive months |  | From 3 months up to 180 days post-CS-101 infusion | 
| Time to last red blood cell(RBC) transfusion |  | Days post-CS-101 infusion | 
| Change in total hemoglobin(Hb) concentration over time |  | up to 180 days post-CS-101 infusion | 
| Change in fetal hemoglobin(HbF) concentration over time |  | up to 180 days post-CS-101 infusion | 
| Chimerism level in Peripheral blood and bone marrow | Proportion of alleles with intended genetic modification in peripheral blood leukocytes and bone marrow over time | up to 180 days post-CS-101 infusion |