Gene Transfer For Patients With Sickle Cell Disease Using A Gamma Globin Lentivirus Vector: An Open-Label Phase 1 / 2 Pilot Study
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 7
- 试验地点
- 2
- 主要终点
- Incidence of Grade 4 infection
研究概览
简要总结
The purpose of this Phase 1/2 study is to determine the feasibility and safety of stem cell collection and gamma-globin gene transfer, and success of gene correction in subjects with sickle cell disease
详细描述
This study will assess the feasibility, safety and efficacy of gene transfer using ARU-1801 (CD34+ cells transduced with the gamma-globin lentiviral vector). Gene transfer will occur ex-vivo into CD34+ enriched human bone marrow or plerixafor-mobilized peripheral blood hematopoietic stem cells (HSC) collected from subjects with severe sickle cell disease (SCD). Subjects will undergo reduced intensity chemotherapy conditioning with single-dose melphalan to facilitate engraftment of ex-vivo ARU-1801 via IV infusion. Subjects will return to the study site at regular intervals for follow-up for 2 years after the ARU-1801 infusion. It is anticipated that a separate long-term follow-up (LTFU) clinical study will be initiated, in which all subjects completing the 2 year study visit will be asked to consent and enroll, and will followed for a further 13 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Supportive Care
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 45 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
结局指标
主要结局
Incidence of Grade 4 infection
时间窗: From infusion (Day 0) to 15 years
Incidence of Grade 4 infection following infusion of transduced cell product uncontrolled for ≥14 days
Incidence of Grade 4 neutropenia
时间窗: From date of chemotherapy clearance visit to 15 years post-infusion of transduced cells
Incidence of Grade 4 neutropenia lasting \>1 month following melphalan
Incidence of Grade 3 or 4 organ toxicity
时间窗: From screening to 15 years post-infusion of transduced cells
Incidence of Grade 3 or 4 organ toxicity attributable to study procedures
Incidence of Serious Adverse Events (SAEs)
时间窗: From screening to 15 years post-infusion of transduced cells
Incidence of death due to study procedures
时间窗: From screening to 15 years post-infusion of transduced cells
≥8x10⁶kg viable CD34+ cells
时间窗: Up to Year 2
Number of subjects with a total number of CD34+ cells recovered from all collections combined (mobilized peripheral blood and bone marrow) of at least ≥8x10⁶kg viable CD34+ cells
Incidence of Grade 3 allergic reaction
时间窗: From infusion (Day 0) to 15 years
Incidence of Grade 3 allergic reaction associated with infusion of transduced cell product
Time to neutrophil recovery
时间窗: From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells
Number of days from melphalan-induced nadir to the first of 3 consecutive absolute neutrophil counts ≥500 cells/µL
Time to platelet recovery
时间窗: From ≥36 hours before Day 0 to 2 years post-infusion of transduced cells
Number of days from melphalan-induced nadir to the first of 3 consecutive platelet counts \>50,000 cells/µL and independent of platelet transfusion for ≥7 days consecutive days.
Incidence of Adverse Events (AEs)
时间窗: From screening to 15 years post-infusion of transduced cells
Incidence of hematological malignancy
时间窗: From infusion (Day 0) to 15 years
Incidence of hematological malignancy due to vector insertion
Incidence of hematological cancer
时间窗: From screening to 15 years post-infusion of transduced cells
Incidence of hematological cancer related to investigational product or study medications/procedures
≥4x10⁶ CD34+ cells/kg body weight transduced
时间窗: Up to Year 2
Proportion of subjects for which a minimum of 4x10⁵ CD34+ cells/kg body weight from all collections combined have been successfully transduced
Bone marrow aspirates with ≥1% gene-marked cells
时间窗: Infusion (Day 0) to 1 year
Number of subjects with bone marrow aspirates at 1-year post-infusion with ≥1% gene-marked cells
次要结局
- Quantity of Hb (hemoglobin) subtypes(Months 6, 12, 18, 24 and year 3, 4, 5)
- Presence of vector copies in white blood cell fraction(Days 30, 60, 90, Months 4, 5, 6, 9, 12, 18, 21, 24)
- Change in proportion of antisickling/sickling hemoglobin(Baseline to Month 6 through 12)
- Percentage of F-retics (fetal hemoglobin content in reticulocytes)(Months 6, 12, 18, 24, 36)
- Presence of gene-marked colony-forming unit cells (CFU-c) in bone marrow (BM) indicting gene transfer(Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36)
- Number of annualized vaso-occlusive episodes (VOEs) pre-transplant versus post-transplant(Baseline to year 15)
- Percentage of F-RBC (fetal hemoglobin content in red blood cells)(Months 6, 12, 18, 24, 36)
- Frequency of opioid use pre-transplant versus post-transplant(Baseline to year 15)
- Change in QoL (Quality of Life)(Baseline, month 4, 5, 6, 12 and 24 and year 3, 4, 5)
- Presence of vector copies in bone marrow(Prior to ARU-1801 infusion, month 6, 12, 18, 24 and 36)