ET3-201: Phase 1 Study of Hematopoietic Stem Cell Transplantation (HSCT) Gene Therapy Incorporating a Lentiviral Vector (LV) Encoding a High Expressing Factor VIII Transgene for Treatment of Severe Hemophilia A
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 7
- 主要终点
- Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.
研究概览
简要总结
This is a first-in-human, non-randomized, open label, single treatment, Phase 1 study in approximately 7 patients with severe hemophilia A. The study will evaluate gene therapy by transplantation of autologous CD34+ hematopoietic stem cells transduced ex vivo with the CD68-ET3 lentiviral vector.
详细描述
Eligible subjects will undergo CD34+ hematopoietic stem cell collection. These cells will be transduced ex vivo with CD68-ET3 lentiviral vector and subsequently, following a conditioning regimen of busulfan and anti-thymocyte globulin, the transduced cells will be infused to patients. After completion of study treatment, patients are followed up periodically for up to 15 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
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Able to provide informed consent for the protocol approved by the Institutional Review Board.
- •Male subjects who are >= 18 years of age.
- •Diagnosis of severe hemophilia A (<1 IU/dL factor VIII activity) based on one-stage coagulation assay.
- •Documented history of more than 150 days of factor VIII treatment.
- •Average of at least 4 bleeds requiring treatment per year over the prior three years, or at least 4 bleeds per year during the 3 years preceding the initiation of prophylaxis, or evidence of joint damage (knee, elbow or ankle) on physical or radiographic examination thought to be related to hemophilia.
- •Performance status (Karnofsky score) of at least
- •Willingness to use effective barrier contraception or limit sexual intercourse to postmenopausal, surgically sterilized, or contraception-practicing partners, for 12 weeks (3 months) after transplantation.
- •Willing and able to comply with the requirements of the protocol.
排除标准
- •History of spontaneous central nervous system bleeding within the last 5 years.
- •Significant functional deficits in major organs which would interfere with successful outcome following autologous stem cell transplant, the following guidelines will be utilized:
- •Cardiac: There should be no evidence of significant cardiac dysfunction (resting left ventricular ejection fraction of < 50%) and no marked cardiomegaly. There should not be uncontrollable hypertension.
- •Renal: GFR < 60 mL/min/1.73m2 per local institutional standard such as CKD-EPI creatinine equation or equivalent.
- •Hepatic: There should be no evidence of hepatic dysfunction which is defined as a serum total bilirubin of > 1.5 mg/dL and AST/ALT > 3X the upper limit of normal.
- •Hematologic: Absolute neutrophil counts (ANC) <1000/ µL or platelets counts < 150,000/µL.
- •Pulmonary function with a corrected carbon monoxide diffusing capacity (cDLCO) < 50% predicted.
- •History of a fVIII inhibitor (> 0.4 Bethesda Units/mL) including at least 2 measurements done at least a week apart or any single titer > 5 BU/mL.
- •Subjects who have had prior cellular based therapy or gene editing/ gene therapy including a previous stem cell transplant.
- •Subjects with any evidence of active infection or any immunosuppressive disorder, including currently detectable HIV viral load
- •Subjects who are RPR, anti-HTLV-1 and II antibody, CMV PCR, VZV antibody and HSV PCR positive at screening.
- •Subjects who have allergic reactions or hypersensitivity to any of the drugs used in the study (i.e., anti-thymocyte globulin, plerixafor, G-CSF, busulfan, levetiracetam) or to the constituents of the investigational product formulation.
- •Evidence of hepatitis B active infection or chronic carrier based on a positive Hepatitis B DNA testing at screening.
- •Positive (detectable viral load per local institutional standard) for the presence of Hepatitis C virus (HCV). Subjects who are positive for anti-HCV antibody are eligible as long as they have a negative undetectable HCV viral load at screening.
- •Subjects diagnosed with any history of clinically relevant coagulation or bleeding disorder other than hemophilia A.
- •Use of medication(s) that can affect hemostasis (e.g. aspirin, ibuprofen and non-COX-2 selective non-steroid anti-inflammatory drugs).
- •Subjects with a history of a malignancy (except surgically resected non-melanoma skin cancer) or subjects with a family history of a known cancer syndrome in a first degree relative.
- •Planned surgery within 6 months of enrollment (other than study procedures).
- •Treatment with any live vaccines or systemic immunosuppressive agents, not including corticosteroids within 30 days before CD68-ET3-LV CD34+ infusion.
- •Treatment with any investigational product within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to enrollment.
- •History of autoimmune disease (e.g., inflammatory bowel disease, systemic lupus erythematosus, vasculitis).
- •Concurrent enrollment in another clinical study, which might interfere with the requirements of this study or have the potential to impact the evaluation of safety and efficacy of CD68-ET3-LV CD34+- unless it is a non-interventional observational study.
- •Any condition in the opinion of the Study Investigators that will negatively impact the subject's ability to safely undergo an autologous stem cell transplant.
- •Any reason in the opinion of the Study Investigators that will negatively impact the subject's ability to complete the clinical trial per the trial protocol.
研究组 & 干预措施
Autologous HSCT CD68-ET3-LV gene therapy
G-CSF/Plerixafor mobilization and apheresis will be used for collection of hematopoietic stem cells and subjects will receive transplantation of autologous CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector encoding the human factor VIII gene.
干预措施: Gene therapy (Drug)
Autologous HSCT CD68-ET3-LV gene therapy
G-CSF/Plerixafor mobilization and apheresis will be used for collection of hematopoietic stem cells and subjects will receive transplantation of autologous CD34+ hematopoietic stem cells transduced with CD68-ET3 lentiviral vector encoding the human factor VIII gene.
干预措施: Biological (Other)
结局指标
主要结局
Number of study participants experiencing serious adverse events (SAEs) following treatment through 12 weeks.
时间窗: 12 weeks
As assessed by physical examination, vital signs, clinical labs, and FVIII inhibitor levels (Bethesda assay). Serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; Life-threatening event; Required or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly.
Severity of serious adverse events following administration of CD68-ET3-LV CD34+ as assessed by NCI Common Toxicity Criteria for Adverse Events (CTCAE) Version 5.0.
时间窗: 12 weeks
Serious adverse events
Duration of the serious adverse events following administration of CD68-ET3-LV CD34+.
时间窗: 12 weeks
As assessed by stop and end dates of the SAEs
次要结局
- Time to absolute neutrophil count (ANC) recovery.(Measured up to 5 years.)
- Time to platelet recovery.(Measured up to 5 years.)
- Anti-human factor VIII inhibitor titer(Measured up to 5 years.)
- Immune response to ET3 as measured by modified Bethesda assay incorporating ET3i spiked into fVIII-deficient plasma(Measured up to 5 years.)
- Vector copy number of circulating genetically modified cells as determined by real time PCR(Measured up to 5 years.)
- Clonality of circulating genetically modified cells as determined by LAM-PCR and insertion site analysis using DNA sequencing of LAM-PCR products(Measured up to 5 years.)
- Survival of autologous HSCT CD68-ET3-LV gene therapy.(Up to 12 weeks following treatment)