A Phase 1/2/3 Study of the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) in Subjects With Transfusion-Dependent β-Thalassemia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 59
- 试验地点
- 14
- 主要终点
- Proportion of participants achieving transfusion independence for at least 12 consecutive months (TI12)
研究概览
简要总结
This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in participans with transfusion-dependent β-thalassemia (TDT). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 35 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by
- •Documented homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Participants can be enrolled based on historical data, but a confirmation of the genotype using the study central laboratory will be required before busulfan conditioning
- •History of at least 100 mL/kg/year or ≥10 units/year of packed RBC transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through re-screening
- •Eligible for autologous stem cell transplant as per investigator's judgment
排除标准
- •A willing and healthy 10/10 Human Leukocyte Antigen (HLA)-matched related donor is available per investigator's judgement
- •Prior allo-HSCT
- •Participants with associated α-thalassemia and >1 alpha deletion or alpha multiplications
- •Participants with sickle cell beta thalassemia variant
- •Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator
- •White blood cell (WBC) count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism
- •Other protocol defined Inclusion/Exclusion criteria may apply.
研究组 & 干预措施
CTX001
CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Participants will receive a single infusion of CTX001 through a central venous catheter.
干预措施: CTX001 (Biological)
结局指标
主要结局
Proportion of participants achieving transfusion independence for at least 12 consecutive months (TI12)
时间窗: From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion]
Incidence of transplant-related mortality (TRM)
时间窗: Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion
Proportion of participants with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)
时间窗: Within 42 days after CTX001 infusion
Time to neutrophil and platelet engraftment
时间窗: Days post-infusion to engraftment
Frequency and severity of collected adverse events (AEs)
时间窗: Signing of informed consent through Month 24 visit
All-cause mortality
时间窗: Signing of informed consent through Month 24 visit
次要结局
- Proportion of participants achieving transfusion independence for at least 6 consecutive months (TI6)(From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion)
- Proportion of participants achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized volume of RBC transfusions after Month 10 after CTX001 infusion(From Month 10 up to 24 months post-CTX001 infusion)
- Relative reduction from baseline in annualized volume of RBC transfusions after Month 10 after CTX001 infusion(From Month 10 up to 24 months post-CTX001 infusion)
- Duration of transfusion free in participants who have achieved TI12(From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion)
- Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time(Day 1 CTX001 infusion through Month 24 visit)
- Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time(Day 1 CTX001 infusion through Month 24 visit)
- Change in fetal hemoglobin concentration over time(Baseline (pre-transfusion) through Month 24 visit)
- Change in total hemoglobin concentration over time(Baseline (pre-transfusion) through Month 24 visit)
- Change in health-related quality of life (HRQoL) from baseline over time using EuroQol Questionnaire (5 dimensions - 5 levels of severity - EQ-5D-5L)(Screening visit through Month 24 visit)
- Change in health-related quality of life (HRQoL) from baseline over time using the Functional assessment of cancer therapy-bone marrow transplant questionnaire (FACT-BMT)(Screening visit through Month 24 visit)
- Change in patient reported outcome (PRO) over time assessed using EQ-5D-Youth (EQ-5D-Y)(Screening visit through Month 24 visit)
- Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)(Screening visit through Month 24 visit)
- Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload(Screening visit through Month 24 visit)
- Proportion of participants receiving iron chelation therapy(1 month post-CTX001 infusion through Month 24 visit)