An Open, Single-arm, Phase 1 Study to Evaluate the Safety/Preliminary Effectiveness and Determine the Maximal Tolerated Dose of B7-H3-targeting CAR-T Cell Therapy in Treating Recurrent Glioblastomas
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Safety：Incidence and severity of adverse events
研究概览
简要总结
This is an open, single-arm, dose-escalation and multiple-dose study to evaluate the safety, tolerability and preliminary effectiveness of B7-H3-targeting Chimeric Antigen Receptor-T (CAR-T) cell therapy on patients with recurrent glioblastomas. The study also plan to explore the Maximum Tolerated Dose (MTD) and determine the Recommended Phase II Dose (RP2D) of the CAR-T cell therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, aged 18-75 years (including 18 and 75 years old)；
- •Patients with relapsed glioblastoma, as confirmed by positron emission tomography (PET) or histologic pathology；
- •A >= 30% staining extent of B7-H3 in his/her primary/recurrent tumor tissue by the immunochemical method;
- •Karnofsky scale score>=50
- •Availability in collecting peripheral blood mononuclear cells (PBMCs) ；
- •Adequate laboratory values and adequate organ function;
- •Patients with childbearing/fathering potential must agree to use highly effective contraception；
排除标准
- •Pregnant or breastfeeding females；
- •Contraindication to bevacizumab；
- •Within 5 days before the CAR-T cell infusion, subjects receiving systemic administration of steroids with dosage more than 10mg/d prednisone or the equivalent doses of other steroids ( not including inhaled corticosteroid)；
- •Comorbid with Other uncontrolled malignancy；
- •Active immunodeficiency virus (HIV) or hepatitis B virus or hepatitis C virus or tuberculosis infection;
- •Subjects receiving the placement of a carmustine slow-release wafer within 6 months before the enrollment;
- •Autoimmune diseases;
- •Receiving long-term immunosuppressive treatment after organ transplantation;
- •Severe or uncontrolled psychiatric diseases or condition that could increase adverse events or interfere the evaluation of outcomes;
- •Not recovered from the toxicities or side effects by previous treatment;
- •Subjects who have participated the other interventional trial within one month before the enrollment, or have received other CAR-T cell therapies or gene-modified cell therapy before enrollment.
- •Subjects with medical conditions that affect signing the written informed consent or complying with the research procedures, the medical conditions including, but not limited to cardio-cerebral vascular diseases, renal dysfunction/failure, pulmonary embolism, coagulation disorders, active systemic infection, uncontrolled infection et. al; or patients who are unwilling or unable to comply with the research procedures; these
- •Subjects with other conditions that would interfere trial participation at the investigator's discretion.
研究组 & 干预措施
CAR-T cell therapy
Dose-escalation phase:
A "3+3" dose-escalation design is used to determine MTD & R2PD. Anti-B7-H3 autologous CAR-T cells were given biweekly to patients at the following doses for each cycle, and 4 cycles as one course. Dose1: 3 patients at a dose of 20 million cells for each cycle. Dose 2: 3 patients at a dose of 60 million cells for each cycle. Dose 3: 3 patients at a dose of 150 million cells for each cycle. Dose 4: 3 patients at a dose of 450 million cells for each cycle. Dose 5: 3 patients at a dose of 900 million cells for each cycle.
R2PD confirmation phase:
Determine the R2PD based on the results from the previous dose-escalation study; Treat another 12 patients with anti-B7-H3 autologous CAR-T cells biweekly at the R2PD to further confirm the safety of R2PD.
At each dose phase, if the patients show tolerate and response to the treatment, these patients would receive several courses of treatment at PI's discretion.
干预措施: B7-H3-targeting CAR-T cells (Biological)
结局指标
主要结局
Safety：Incidence and severity of adverse events
时间窗: three months post CAR-T cells infusion
To evaluate the possible adverse events occurred within three months after B7-H3 CAR-T cell infusion, including the incidence and severity of symptoms such as cytokine release syndrome and neurotoxicity
Incidence of Dose Limiting Toxicity (DLT)
时间窗: three months post CAR-T cells infusion
To evaluate the DLT incidence occurred within three months after B7-H3 CAR-T cells infusion
次要结局
- Efficacy：Overall survival rate at 12 months(12 months post CAR-T cells infusion)
- Efficacy：objective remission rate(1, 2, 3, 4, 5, 6 months post CAR-T cells infusion)
- pharmacokinetics：Cmax(Samples collected pre-injection, and 1, 2, 3, 5, 7, 9, 11,13 days post the first injection; Samples collected pre-injection, and 2, 7, 13 days post re-injections)
- pharmacokinetics：Tmax(Samples collected pre-injection, and 1, 2, 3, 5, 7, 9, 11,13 days post the first injection; Samples collected pre-injection, and 2, 7, 13 days post re-injections)
- pharmacokinetics：AUC(Sample taken pre-injection, and 1, 2, 3, 5, 7, 9, 11,13 days post the first injection; Sample taken pre-injection, and 2,7,13 days post re-injections)
研究者
Yang Zhang
Clinical Professor
Beijing Tiantan Hospital