A Phase 1 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy in Subjects With β-Thalassemia Major by Transplantation of Autologous CD34+Stem Cells Transduced With a Lentiviral Vector Encoding βA-T87Q-Globin
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Evaluate the success and kinetics of HSC engraftment.
研究概览
简要总结
This is a Phase 1,open label,safety,and efficacy study in subjects with non-β0/β0 TDT β-thalassemia Major by transplanting BD211 drug product which is for autologous use only,via a single IV administration.
详细描述
After collection of mobilised peripheral blood samples, the patient's autologous cells,enriched for CD34+ HSCs, undergo ex vivo transduction with lentiviral vector encoding βA-T87Q-globin to BD211 finished product,which is then infused intravenously into the patient after myeloablative busulfan conditioning to prepare bone marrow "niches" for engraftment of the HSCs.
After discharge, subjects will be followed monthly, at a minimum, for 6 months and thereafter every 3 months for the remainder of the 24 months post-transplant.
Evaluation will include Routine and special biological testing at regular intervals, collection of AEs and concomitant medications, and evaluation of disease specific biological and clinical parameters.
Subjects will then be enrolled in a long-term follow-up protocol with annual evaluations for an additional 13 years post-transplant.
The long-term follow-up study will focus on long-term safety, with an emphasis on integration site analysis, and long-term efficacy.
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
- 5 Years 至 35 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •5 to 35 years of age.
- •Be eligible for allogeneic HSCT based on institutional medical guideline, but without a matched related donor.
- •Transfusion-dependent β-Thalassemia Major, regardless of the genotype, with the diagnosis confirmed by Hb studies. Subjects must be stable and maintained on an appropriate iron chelation regimen. Transfusion dependence is defined as requiring at least 100 mL/kg/year of packed red blood cells(pRBCs).
- •Have been treated and followed for at least the past 2 years in a specialized center that maintained detailed medical records, including transfusion history.
- •Be willing and able, in the Investigator's opinion, to comply with the study procedures outlined in the study protocol. If a pediatric subject, the subject's parent/legal guardian also must be willing and able to comply with the study procedures outlined in the study protocol.
排除标准
- •Availability of a willing matched HLA-identical sibling hematopoietic cell donor.
- •Positive for presence of human immunodeficiency virus, human T-lymphotropic virus, vesicular stomatitis virus G antibody.
- •Clinically significant, active bacterial, viral, fungal, or parasitic infection.
- •A white blood cell (WBC) count<3x109/L and/or platelet count<120x109/L
- •Receipt of an allogeneic transplant.
- •Receipt of erythropoietin within 3 months before HSCT harvest.
- •Contraindication to anesthesia for bone marrow harvesting.
- •Any of prior or current malignancy, myeloproliferative or immunodeficiency disorder.
- •Active relapsing malaria
- •Immediate family member with a known or suspected Familial Cancer Syndrome.
- •Diagnosis of significant psychiatric disorder of the subject that could seriously impede the ability to participate in the study.
- •Pregnancy or breastfeeding in a postpartum female or absence of adequate contraception for fertile subjects.
- •Any other condition that would render the subject ineligible for HSCT, as determined by the attending transplant physician.
- •History of major organ damage.including Liver, Heart, Kidney disease, pulmonary hypertension ,severe iron overload, which in the opinion of the physician is grounds for exclusion.
- •Participation in another clinical study with an investigational drug within 30 days of screening.
- •Hydroxyurea therapy within 3 months before hematopoietic stem cell collection.
- •An assessment by the Investigator that the subject or parents of the subject will not comply with the study procedures outlined in the study protocol.
- •Subjects who have the desire to become a parent within the 27-month study period.
- •Prior receipt of gene therapy.
结局指标
主要结局
Evaluate the success and kinetics of HSC engraftment.
时间窗: At multiple timepoints after infusion for 24 months.
Three consecutive absolute neutrophil counts≥500 cells/uL, three consecutive platelet values ≥20 e9/L, measure blood samples monthly after BD211 drug product infusion.
Incidence of transplant-related mortality through 100 days post-transplant.
时间窗: Up to 100 days post-HSCT.
Incidence of transplant-related mortality through 100 days post-transplant.
Overall survival of maintenance phase.
时间窗: Up to 24 months post-HSCT.
Overall survival up to 24 months post-HSCT.
Post-transplant blood samples for replication competent lentivirus (RCL) testing.
时间窗: At multiple timepoints after infusion for 24 months.
The testing of any subject positivity will be considered an SAE and suspend the inclusion of new subjects.
Assessment of Clonal dominance or leukemia/lymphoma and other malignancies.
时间窗: At multiple timepoints after infusion for 24 months.
Using peripheral blood of subjects for integration site analysis via LAM-PCR \& deep sequencing.
Incidence of treatment- related adverse events.
时间窗: Up to 24 months after BD211 drug product infusion.
According to the requirements of the National Cancer Institute Common Terminology Standards for Adverse Events (NCI CTCAE) version 5.0, monitor laboratory parameters and the frequency and severity of clinical AEs.
次要结局
- Quantify gene transfer efficiency and expression of BD211 drug product.(Up to 24 months after engraftment.)
- Quantify the hematopoietic chimerism resulting from treatment with BD211 drug product.(Up to 24 months after engraftment.)
- HbAT87Q in peripheral blood(Up to 24 months after engraftment.)
- Reduction of RBC transfusion requirements from baseline(Up to 24 months after engraftment.)
- Duration of transfusion independence (months).(Up to 24 months after engraftment.)
- Weighted average Hemoglobin(Up to 24 months after engraftment.)
- Changes of liver iron burden from baseline(Up to 24 months after engraftment.)
- Changes of cardiac iron burden from baseline(Up to 24 months after engraftment.)