Clinical Research of Gene Therapy for Refractory B-Cell Non-Hodgkin Lymphoma Using Autologous T Cells Expressing a Chimeric Antigen Receptor Specific to the CD19 Antigen
试验速览
- 阶段
- 1 期
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Toxicity Profile
研究概览
简要总结
The purpose of this study is to evaluate the safety, efficacy and blood kinetics of autologous T cells genetically modified to express anti-CD19 Chimeric Antigen Receptor in patients with relapsed or refractory B-Cell Non-Hodgkin Lymphoma.
详细描述
Peripheral blood (up to 600 mL) will be collected from a subject after obtaining a written informed consent and completing the 1st registration. Peripheral blood mononuclear cells (PBMCs) and plasma are obtained from the blood, and T cells contained in the PBMCs are transduced with anti-CD19 CAR gene by using SFG-1928z retroviral vector. Anti-CD19 CAR expressing T cells (CD19-CAR-T) will be expanded using a medium containing autologous plasma. After the T cells pass in quality control tests, the subject will go into 2nd registration. Subjects will be hospitalized and administered Cyclophosphamide on Day -2 or Bendamustine on Day -3 to Day -2 intravenously as Pre-treatment, and then subjects will receive 1st infusion of CD19-CAR-T on Day 0 and Day 1 (Day 1：1/3 dose, Day 2：2/3 dose) as a split dose. In case the sufficient cell number of CD19-CAR-T is manufactured, DLT is not observed after CD19-CAR-T infusion, certain clinical effect is observed and additional treatment is preferable, the necessity of 2nd infusion will be assessed. In the case that 2nd infusion is necessary, it is allowed to infuse at appropriate timing.
This study is conducted based on the 3+3 dose escalation scheme. Three subjects are enrolled in each group of Dose Level. If one of the 3 subjects show DLT during DLT assessment period, another 3 subjects will be added; therefore, decision as to whether the next Dose Level can follow or not is made based on the results obtained from the total of 6 subjects.
The investigator assesses the tumor shrinkage effect of CD19-CAR-T in accordance with "Revised response criteria malignant lymphoma", at 12 week after the 1st infusion of CD19-CAR-T (or at the time of termination). The investigator also assesses the safety during the follow-up period. Long-term follow-up study is conducted at frequency of once a year for 15 years after the 1st infusion of CD19-CAR-T in reference to guidelines of FDA.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Relapsed or refractory B-NHL.
- •Evaluable region can be identified by CT scan and is positive by FDG-PET.
- •20 ≤ age ≤ 70 years at the time of informed consent.
- •ECOG performance status of 0-
- •Well preserved main organ functions.
- •Life expectancy ≥3 months after informed consent.
- •Written informed consent.
排除标准
- •Other active malignancy.
- •CNS infiltration of lymphoma.
- •History of allogeneic stem cell transplantation.
- •Already participated in a clinical trial in which CD19-CAR-T are administered within 24 weeks.
- •Concurrent use of systemic steroids or immunosuppressive agents.
- •Concurrent severe heart disease.
- •History of severe cerebrovascular disease or sequela including paralysis.
- •Known active or severe infection.
- •HIV seropositive status.
- •HBsAg-positive or both HBcAb and HBV-DNA positive.
- •Active hepatitis C.
- •Psychiatric disorder or drug addiction that affects the ability of informed consent.
- •Pregnant or breastfeeding women, women who may be pregnant and women desiring to become pregnant. Men who desire impregnating a woman are also excluded (excluded: in case when sperm is cryopreserved prior to gene therapy and a child is born by using the sperm).
- •Any other patients judged by the investigators to be inappropriate for the subject of this study.
研究组 & 干预措施
Dose Level -1
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
干预措施: Cyclophosphamide or Bendamustine (Drug)
Dose Level -1
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
干预措施: Dose Level -1 (Genetic)
Dose Level 1
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
干预措施: Cyclophosphamide or Bendamustine (Drug)
Dose Level 1
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
干预措施: Dose Level 1 (Genetic)
Dose Level 2
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
干预措施: Cyclophosphamide or Bendamustine (Drug)
Dose Level 2
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
干预措施: Dose Level 2 (Genetic)
Dose Level 3
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
干预措施: Cyclophosphamide or Bendamustine (Drug)
Dose Level 3
Cyclophosphamide or Bendamustine as Pre-treatment, and in combination with CD19-CAR-T. In case when sufficient cell number of CD19-CAR-T has been manufactured, the physician judges whether the 2nd infusion of CD19-CAR-T should be performed based on the condition of the subject.
干预措施: Dose Level 3 (Genetic)
结局指标
主要结局
Toxicity Profile
时间窗: 12 weeks
Confirm clonality by linear amplification mediated (LAM)-PCR.
Quality test of CD19-CAR-T
时间窗: Before administration
Transduction efficiency, viability, sterility and potency.
次要结局
- Lymphocyte subset analysis of CD19-CAR-T(12 weeks)
- Human anti-mouse antibody (HAMA) test(12 weeks)
- Tumor shrinkage effect(12 weeks)
研究者
Keiya Ozawa
Professor
Jichi Medical University