A First-in-patient Phase I/II Clinical Study to Investigate the Safety, Tolerability and Efficacy of Genome-edited Hematopoietic Stem and Progenitor Cells in Subjects With Severe Complications of Sickle Cell Disease
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 4
- 试验地点
- 3
- 主要终点
- Fetal hemoglobin (HbF) expression 6 months after hematopoietic stem cell transplant (HSCT)
研究概览
简要总结
This study evaluated a genome-edited, autologous, hematopoietic stem and progenitor cell (HSPC) product - OTQ923 to reduce the biologic activity of BCL11A, increasing fetal hemoglobin (HbF) and reducing complications of sickle cell disease.
详细描述
CADPT03A12101 was a multicenter, multi-part, first-in-human, proof-of-concept, open label non-randomized, clinical study in Sickle Cell Disease (SCD) subjects. This study included apheresis of mobilized hematopoietic stem and progenitor cells (HSPCs), ex vivo CRISPR/Cas9-mediated genome editing and expansion, followed by myeloablative conditioning and autologous hematopoietic stem cell transplant (HSCT) with follow-up for a minimum of one year and up to two years.
The study was divided into the following parts:
- Part A - Adult subjects were dosed with OTQ923.
- Part B - Assessment of OTQ923 in pediatric patients, however Part B was not opened.
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
盲法说明
The is an open-label study.
入排标准
- 年龄范围
- 2 Years 至 40 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female subjects age 2-40 years inclusive
- •Confirmed diagnosis of sickle cell disease with globin typing (e.g. HbSS, HbSC, HbS/β0-thalassemia or others)
- •Performance status >70% (Karnofsky for subjects >16 years of age and Lansky for subjects <16 years of age)
- •At least one of the following indicators of disease severity as defined in the protocol - Vaso-occlusive pain crisis, Acute chest syndrome, Recurrent priapism, prior stroke, receive chronic transfusions, Red cell alloimmunization
- •Subjects, who have failed, not tolerated or refused hydroxyurea therapy.
排除标准
- •Available matched related donor for HSCT
- •Clinically significant active infection
- •Seropositive for HIV or HTLV
- •Active known malignancy, myelodysplasia, abnormal cytogenetics or immunodeficiency
- •Prior HSCT or gene therapy
- •Known hepatic cirrhosis, bridging hepatic fibrosis or active hepatitis
- •Protocol defined iron overload
- •Cerebrovascular procedure within one year, including pial synangiosis for Moyamoya
- •Severe or progressive arteriopathy or cerebrovascular disease, including Moyamoya
- •Other protocol defined inclusion/exclusion criteria may apply
研究组 & 干预措施
OTQ923
Single intravenous infusion of OTQ923 Part A - Adults treated with OTQ923; Part B - Children age 2-17 treated with OTQ923 based on review of data from Part A by Health agency after a formal interim analysis.
干预措施: OTQ923 (Biological)
结局指标
主要结局
Fetal hemoglobin (HbF) expression 6 months after hematopoietic stem cell transplant (HSCT)
时间窗: at 6 months
Assessment of HbF expression will be done by measuring total fetal hemoglobin over time.
Time to reach absolute neutrophil count (ANC) ≥500/μL for 3 consecutive days
时间窗: up to 24 months
Time to engraftment is defined as first of 3 consecutive days when an absolute neutrophil count (ANC) ≥500/μL after receiving OTQ923 was reached.
Number of participants with adverse events and serious adverse events
时间窗: up to 24 months
Number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.
次要结局
- Number of participants with treatment induced anti-Cas9 humoral and cellular immunogenicity(up to 24 months)
- Transplant-related mortality(up to 24 months)
- Overall Survival(up to 24 months)
- Durability of hematologic engraftment(up to 24 months)
- Proportion of subject to achieve 30% of total HbF at 12 months(12 months)
- Time to achieve 30% total HbF(up to 24 months)
- Time to peak total HbF(up to 24 months)
- Percentage of edited WBC and bone marrow cells by time points(up to 24 months)
- Number of participants with change from baseline of annualized VOC rate by 65%(Baseline, 12 months)
- Number of participants with change from baseline of annualized SCD complications (aggregate of VOC, ACS, priapism and stroke) and if relevant, rate of transfusion by 65%(Bseline, 12 months)
- Evaluation of effect on patient-reported outcomes from baseline and post-HSCT with age appropriate patient reported measures(up to 24 months)