A Phase 2 Safety and Efficacy Study Evaluating CS-101 in Participants With β-Thalassemia Major

Official title

A Single-arm, Open-label Phase II Clinical Trial: Evaluating the Safety and Efficacy of a Single Dose of CS-101 Injection in Participants With β-thalassemia Major

Overview

The goal of this open label, single-arm clinical study is to learn about the safety and efficacy of CS-101 in treating patients with β-Thalassemia Major

Detailed description

CS-101 is an autologous CD34+(Cluster of differentiation 34) cell suspension, edited by ex vivo base editing technology, which modifies the BCL11A binding site in HBG(Hemoglobin Subunit Gamma) promoter, so that it loses the ability to bind to BCL11A, which can re-induce the production of γ-globin chain and increase the concentration of HbF(fetal hemoglobin) in the blood, compensating for the function of missing HbA(adult hemoglobin) to achieve clinical cure. The therapy addresses two major challenges in the current treatment of the disease: lack of matching donors and graft-versus-host diseases in allogeneic hematopoietic stem cell transplantation.

Interventions

• Genetic CS-101 injection
  Autologous CD34+ hematopoietic stem cell suspension modified by ex vivo base editing technique

Primary outcome measures

• AEs(Adverse Events) and SAEs(Serious Adverse Events) after CS-101 infusion [Time frame: Up to 16 months post-CS-101 infusion]
• Overall survival [Time frame: Up to 16 months post-CS-101 infusion]
• Proportion of Subjects with engraftment [Time frame: Within 42 days post-CS-101 infusion]
• Time to neutrophil engraftment [Time frame: Up to 16 months post-CS-101 infusion]
• Time to platelet engraftment [Time frame: Up to 16 months post-CS-101 infusion]
• Incidence of transplant-related mortality [Time frame: Up to 100 days post-CS-101 infusion]
• Proportion of subjects achieving transfusion independence for at least 12 consecutive months [Time frame: Up to 16 months post-CS-101 infusion]

Secondary outcome measures (5)

• Proportion of subjects achieving transfusion independence for at least 6 consecutive months [Time frame: Up to 16 months post CS-101 Infusion]
• Changes in targeted editing efficiency in peripheral blood nucleated cells over time [Time frame: Up to 16 months post CS-101 infusion]
• Changes in targeted editing efficiency in bone marrow nucleated cells over time [Time frame: Up to 16 months post CS-101 infusion]
• Change in fetal hemoglobin(HbF) concentration over time [Time frame: Up to 16 months post CS-101 infusion]
• Change in total hemoglobin(Hb) concentration over time [Time frame: Up to 16 months post CS-101 infusion]

Eligibility criteria

Inclusion criteria

• Voluntarily signed informed consent. Male or female participants aged 12 to 35 years (inclusive). The participant or their legally authorized representative must sign the informed consent. If the participant is under 18 years of age, their legally authorized representative must also sign the informed consent.
• Diagnosed with β-thalassemia major (transfusion-dependent). Received at least 8 units of red blood cell transfusions within 12 months prior to screening, and documented hemoglobin level ≤ 70 g/L pre-transfusion.
• Good general condition: Karnofsky score (≥16 years of age) ≥ 60, or Lansky Play-Performance score (<16 years of age) ≥ 60.
• For females of childbearing potential: From the start of the screening, highly effective contraception or complete abstinence (if this is their usual lifestyle), and agree to maintain such contraception throughout the study.
• For males of childbearing potential: Use condoms or other methods to ensure effective contraception for sexual partners continuously from mobilization through the study period.

Exclusion criteria

• Received other investigational products or other experimental interventions within 30 days prior to signing informed consent or within 6 elimination half-lives of the drug (whichever is longer).
• Received or is receiving thalidomide, hydroxyurea, and/or luspatercept within 3 months prior to screening.
• Previous received allogeneic hematopoietic stem cell transplantation, gene therapy, or gene-editing therapy; or participants who can be maintained with standard therapy.
• Participants with a matched sibling donor, or with a matched unrelated / haploidentical related donor and judged by the investigator to have no high-risk factors for allogeneic hematopoietic stem cell transplantation.
• Participants with coexisting α-thalassemia with more than 2 α-globin chain gene deletions or non-deletional mutations.
• Known hypersensitivity to drugs used during autologous hematopoietic stem cell transplantation, excipients, or devices, judged by the investigator to be ineligible for this study.
• Infection with HIV, cytomegalovirus, Epstein-Barr virus, or Treponema pallidum during screening; active HBV or HCV infection (participants with stable hepatitis B after treatment (HBV-DNA negative) and cured hepatitis C (HCV-RNA negative) may be included). Known active bacterial, viral, fungal, or parasitic infection.
• Echocardiographic ejection fraction < 50%.
• Laboratory abnormalities: AST or ALT > 3 × upper limit of normal (ULN); or International normalized ratio (INR) > 1.5 × ULN.
• Cardiac severe iron overload detected by MRI during screening, judged by the investigator to be unsuitable for hematopoietic stem cell transplantation.
• Current or history of malignancy.
• Participants with known neurological consciousness disorders, psychological problems, or psychiatric diseases judged by the investigator to be unable to comply with study procedures.
• Participants with known history of uncontrolled seizures judged by the investigator to be ineligible for this study.
• Uncontrolled bleeding disorders.
• Leukocyte count < 3 × 10⁹/L and/or platelet count < 100 × 10⁹/L not due to hypersplenism.
• Participants with other severe cardiovascular, pulmonary, renal, gastrointestinal, hepatic diseases, and/or other organ disorders judged by the investigator to be ineligible for this study.
• Pregnant or lactating females; females of childbearing potential with a positive serum pregnancy test.
• Received live or live-attenuated vaccine within 90 days prior to myeloablation.
• Participants with autoimmune diseases

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

• The First Affiliated Hospital of Guangxi Medical University — Nanning
• Children's Hospital of Fudan University — Shanghai
• Ruijin Hospital Shanghai JiaoTong University School of Medicine — Shanghai

Identifiers

NCT: NCT07489196 · CS-101-09

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗