A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy in Subjects With β-Thalassemia Major by Transplantation of Autologous CD34+ Cells Transduced Ex Vivo With a Lentiviral βA-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 19
- 试验地点
- 6
- 主要终点
- Percentage of Participants With Sustained Production of >=2.0 Grams Per Deciliter (g/dL) of Hemoglobin A (HbA) Containing βA-T87Q-globin (HbAT87Q) for the Six Months Between Month 18 and Month 24
研究概览
简要总结
This is a non-randomized, open label, multi-site, single-dose, phase 1/2 study in up to 18 participants (including at least 3 adolescents between 12 and 17 years of age, inclusive) with β-thalassemia major. The study will evaluate the safety and efficacy of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product [autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human βA-T87Q-globin gene].
详细描述
Subject participation for this study will be 2 years. Subjects who enroll in this study will be asked to participate in a subsequent long-term follow up study that will monitor the safety and efficacy of the treatment they receive for up to 13 years post-transplant.
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
- •Participants between 12 and 35 years of age, inclusive, at the time of consent/assent, and able to provide written consent/assent, if applicable.
- •Diagnosis of β-thalassemia major and a history of at least 100 mL/kg/year of pRBCs or ≥8 transfusions of pRBCs per year for the prior 2 years.
- •Eligible for allogeneic bone marrow transplant.
- •Treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.
排除标准
- •Positive for presence of human immunodeficiency virus type 1 or 2 (HIV 1 and HIV 2).
- •A white blood cell (WBC) count <3 × 10^9/L, and / or platelet count <100 × 10^9/L if not due to hypersplenism.
- •Uncorrected bleeding disorder.
- •Any prior or current malignancy or myeloproliferative or immunodeficiency disorder.
- •Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome and familial adenomatous polyposis).
- •Receipt of an allogeneic transplant.
- •Advanced liver disease, including persistent aspartate transaminase (AST), alanine transaminase (ALT), or total bilirubin value >3 × the upper limit of normal, liver biopsy demonstrating cirrhosis, extensive bridging fibrosis, or active hepatitis.
- •Kidney disease with a calculated creatinine clearance <30% normal value.
- •Uncontrolled seizure disorder.
- •Diffusion capacity of carbon monoxide (DLco) <50% of predicted (corrected for hemoglobin).
- •A cardiac T2* <10 ms by magnetic resonance imaging (MRI).
- •Any other evidence of severe iron overload that, in the Investigator's opinion, warrants exclusion.
- •Clinically significant pulmonary hypertension, as defined by the requirement for ongoing pharmacologic treatment or the consistent or intermittent use of supplemental home oxygen.
- •Participation in another clinical study with an investigational drug within 30 days of Screening.
- •Any prior or current malignancy or myeloproliferative disorder.
- •Prior receipt of gene therapy.
结局指标
主要结局
Percentage of Participants With Sustained Production of >=2.0 Grams Per Deciliter (g/dL) of Hemoglobin A (HbA) Containing βA-T87Q-globin (HbAT87Q) for the Six Months Between Month 18 and Month 24
时间窗: Month 18 to Month 24
Percentage of participants with sustained production of \>=2.0 grams per deciliter (g/dL) of hemoglobin A (HbA) containing βA-T87Q-globin (HbAT87Q) for 6 months (Month 18 to Month 24) was reported.
Percentage of Participants Who Achieved Transfusion Independence (TI)
时间窗: From time of drug product infusion up to 24 months
TI was defined as a weighted average hemoglobin (Hb) \>= 9 g/dL without any packed red blood cells (pRBC) transfusions for a continuous period of \>=12 months at any time during the study after LentiGlobin BB305 Drug Product infusion. Percentage of participants who achieved TI from time of drug product infusion up to 24 months was reported.
次要结局
- Percentage Change From Baseline in Average Annual Packed Red Blood Cells (pRBC) Transfusion Volume at Month 24(Baseline, Month 24)
- Overall Survival(From time of drug product infusion up to 24 months)
- Duration of Transfusion Independence (TI)(From time of drug product infusion up to 24 months)
- Weighted Average Hemoglobin (Hb) During Period of Transfusion Independence (TI)(From time of drug product infusion up to 24 months)
- Number of Participants With Integration Site Analysis (ISA) With >30% Clonal Contribution(From time of drug product infusion up to 24 months)
- Percentage Change From Baseline in Annualized Number of Packed Red Blood Cells (pRBC) Transfusions at Month 24(Baseline, Month 24)
- Time to Neutrophil Engraftment(From time of drug product infusion up to 24 months)
- Time to Platelet Engraftment(From time of drug product infusion up to 24 months)
- Percentage of Participants Detected With Replication-competent Lentivirus (RCL)(From time of drug product infusion up to 24 months)
- Percentage of Participants Who Achieved Transfusion Independence (TI) at Month 18 and Month 24(Month 18, Month 24)
- Weighted Average Nadir Hemoglobin (Hb)(Baseline, Month 6 to Month 24)
- Transplant-related Mortality(Through 100 and 365 days post-LentiGlobin BB305 Drug Product infusion)
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)(From signing of informed consent to 24 months after the drug product infusion)
- Time From LentiGlobin BB305 Drug Product Infusion to Last pRBC Transfusion Prior to Achieving Transfusion Independence (TI)(From time of drug product infusion up to 24 months)
- Time From LentiGlobin BB305 Drug Product Infusion to Achieving Transfusion Independence (TI)(From time of drug product infusion up to 24 months)
- Number of Participants With Successful Neutrophil Engraftment(From time of drug product infusion up to 24 months)
- Number of Participants With Successful Platelet Engraftment(From time of drug product infusion up to 24 months)