A Pilot Study of Chimeric Antigen Receptor (CAR) T Cells Targeting B7-H3 Antigen in Treating Patients With Recurrent and Refractory Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Overall survival (OS)
研究概览
简要总结
This is a pilot phase I study to evaluate the safety and efficacy on B7-H3 CAR-T in between Temozolomide cycles in treating patients with glioblastoma that has come back or does not respond to the standard treatment. The antigen B7-H3 is highly expressed in glioblastoma of a subset of patients. B7-H3 CAR-T, made from isolated patient peripheral blood mononuclear cells, can specifically attack patient glioblastoma cells that expressing B7-H3.
详细描述
Background
- B7-H3 is expressed in 70% of patients with glioblastoma
- B7-H3 is not expressed in normal tissues especially not in central nervous system. Therefore, it is an attractive GBM target for CAR-T therapy
- The investigators constructed a retroviral vector encoding a chimeric antigen receptor (CAR) targeting B7-H3, which can mediate CAR transfer into patient T cells with high efficiency.
Objectives
- To evaluate the safety and tolerability intratumoral/intracerebroventricular injection of B7-H3 CAR-T when used in between Temozolomide cycles
- To compare the overall survival (OS) and progression-free survival (PFS) of R/R GBM patients treated with B7-H3 CAR-T in between Temozolomide cycles to the historical Temozolomide data
- To access the pharmacokinetics and pharmacodynamics of B7-H3 CAR-T in between Temozolomide cycles
Design
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documented informed consent of the participant and/or legally authorized representative.
- •Histologically confirmed diagnosis of World Health Organization (WHO) classification grade IV glioblastoma (GBM).
- •Clinical Pathology confirms B7-H3 positive tumor expression by immunohistochemistry (IHC) at the initial tumor presentation or recurrent disease (H-score >= 50).
- •Relapsed/refractory disease confirmed by radiographic evidence after standard therapy.
- •Suitable for the surgery of the placement of the Ommaya catheter.
- •Eastern Cooperative Oncology Group (ECOG) =0 or 1 (need to be confirmed before intratumoral or intracerebroventricular injection)
- •>= 8 weeks after completion of front-line radiation therapy
- •>= 6 weeks after completion of nitrourea chemotherapy
- •>= 14 days after completion of Temozolomide or other chemotherapy
- •2 weeks of wash-out time after completion of targeted therapy with related adverse events (AE) on baseline (4 weeks for Bevacizumab).
- •Patients with other chronic AEs are in the investigator's judgement
- •Blood cell count： White blood count (WBC) >= 2000/μL；Neutrophil count >= 1500/μL；Platelets >= 100 x 103/μL；Hemoglobin >= 9.0 g/dL
- •Serum Creatinine <= 1.5×ULN or Creatinine Clearance Rate (Cockcroft and Gault) > 30 mL/min/1.73 m2
- •Alanine Transaminase (ALT) <= 5×ULN and total bilirubin < 2.0mg/dL
- •Lung function: Oxygen (O2) saturation >= 92% on room air and < CTCAE grade 1 dyspnea
- •Heart function: Left ventricular ejection fraction (LVEF) >= 40% by multigated acquisition (MUGA) scan or echocardiogram
- •Normal coagulation function: prothrombin time (PT)，activated partial thromboplastin time (APTT) and international normalized ratio (INR)
- •Good blood vessel condition for leukapheresis
- •Women of childbearing potential (WOCBP): negative urine or serum pregnancy test
- •Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity within one year after B7-H3 CAR-T infusion
排除标准
- •Other active malignancy in the past 2 years except non-melanoma skin cancer, completely surgical removed low grade tumor, posttherapeutic limited-stage prostate cancer, biopsy confirmed in situ cervical carcinoma, PAP test confirmed squamous intraepithelial lesions
- •Participant is undergoing or planning to take other anti-tumor therapies
- •Participant is systematic steroid-dependent, or is expecting to be treated with systematic steroid
- •Active immunodeficiency virus (HIV) or hepatitis B or hepatitis C virus infection
- •Active infection from fungi, bacteria and/or viruses
- •Known history of the following cardiac diseases in the past 6 months:
- •New York Heart Association (NYHA) defined grade III or IV heart failure, cardiac angioplasty, myocardial infarction, unstable angina and other clinically significant heart diseases
- •Known history and/or clinically evident central nerve system diseases: seizure, epileptic seizure, aphasia, paralysis, stroke, severe brain damage, dementia, Parkinson's Disease, cerebellar diseases, organic brain syndrome and psychiatric disorders
- •Autoimmune diseases
- •Pregnant or breastfeeding females
- •Therapeutic doses of corticosteroid within 7 days before leukapheresis or 72 hours before B7-H3 CAR-T infusion
- •Cytotoxic chemotherapy without lymphocytotoxicity within 1 week before leukapheresis except that the treatment has been stopped for more than 3 half-lives of the drug
- •Lymphocytotoxic chemotherapy (cyclophosphamide, Ifosfamide and bendamustine) within 2 weeks before leukapheresis
- •Other clinical trials drugs within 4 weeks before leukapheresis except that the drug has no effect or the disease has progressed, and the treatment has been stopped for more than 3 half-lives of the drug
- •Radiotherapy within 6 weeks before leukapheresis
- •Prior trials of CAR-T or other cell therapy
- •Any other condition that would, in the investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures
- •Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
研究组 & 干预措施
B7-H3 CAR-T
Patients will received regular cycles of Temozolomide treatment with 5 days of treatment and 23 days of interval. 3 infusions of B7-H3 CAR-T with 1-2 weeks of interval will be used in between cycles of Temozolomide treatment. Temozolomide treatment during B7-H3 CAR-T infusions will be stopped and resumed after CAR-T infusion.
干预措施: B7-H3 CAR-T (Drug)
B7-H3 CAR-T
Patients will received regular cycles of Temozolomide treatment with 5 days of treatment and 23 days of interval. 3 infusions of B7-H3 CAR-T with 1-2 weeks of interval will be used in between cycles of Temozolomide treatment. Temozolomide treatment during B7-H3 CAR-T infusions will be stopped and resumed after CAR-T infusion.
干预措施: Temozolomide (Drug)
结局指标
主要结局
Overall survival (OS)
时间窗: 2 years, up to 15 years if necessary
Kaplan Meier methods will be used to estimate median OS
Incidence and type of adverse events
时间窗: 12 weeks
Number of Participants With Treatment-Related Adverse Events and Types of adverse events as Assessed by CTCAE v4.0
Maximum tolerated dose (MTD)
时间窗: 12 weeks
The highest dose of B7-H3 CAR-T that does not cause targeted dose limiting toxicity
Progression-free survival (PFS)
时间窗: 2 years, up to 15 years if necessary
Kaplan Meier methods will be used to estimate median PFS. Progression is defined by Response Assessment in Neuro-Oncology (RANO) criteria
次要结局
- Disease response (ORR, CR, PR, DOR)(2 years, up to 15 years if necessary)
- The pharmacokinetics (PK) of B7-H3 CAR-T(12 weeks)