An Open, Single-center, Exploratory Clinical Trial to Evaluate the Safety and Efficacy of mRNA CAR-mesothelin T Cells in Patients With Advanced Refractory Solid Tumors
试验速览
- 阶段
- 1 期
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- SIAEs and SAEs
研究概览
简要总结
The goal of this clinical trial is to study the safety, efficacy, and pharmacokinetics of mRNA-engineered anti-Mesothelin (MESO) Chimeric Antigen Receptor T-Cell (CAR-T cells) therapy in patients with mesothelin expression-positive, advanced solid tumors that have failed at least first-line or second-line therapy.
详细描述
This phase I study is being conducted to establish safety, pharmacokinetics, and preliminary efficacy of intravenous (IV) mRNA electroporated fully-humanized anti-MESO re-directed autologous T cell administration in patients with chemotherapy-refractory metastatic solid tumors.
The study will adopt the "3+3" dose escalation design exploring two doses of 1×109 and 3×109. The administration is planned to infuse 3 times a week for 2 consecutive weeks.
• The subjects will receive a total dose of 1x109 RNA transduced anti-MESO CAR-T cells in the first week, following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m2/day and fludarabine 30 mg/m2/day given over 3 days by intravenous infusion. If there is no obvious dose-limiting toxicity (DLT) after the first week of infusion, three times consecutive infusions of 1x109 anti-MESO CAR-T cells each time is planned in the second week. Each subject needs to be observed for at least 2 weeks (14 days) after completing the last infusion. Lymphodepleting chemotherapy will not be repeated prior to additional infusions of anti-MESO CAR-T cells.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ability to understand and the willingness to provide written informed consent.
- •Advanced pancreatic cancer, ovarian cancer, malignant mesothelioma, gastric cancer, bowel cancer, etc., diagnosed by histopathological or cytological examination, but not limited to subjects with various advanced solid tumors.
- •IHC test showed Mesothelin positive expression at least 1+ in tumor tissue
- •Age no less than 18 years.
- •Life expectancy greater than 3 months.
- •According to the RECIST (Response Evaluation Criteria in Solid Tumors) standard, there must be measurable lesions.
- •Evidence of metastatic disease and failure of at least 1 prior chemotherapy for metastatic disease. During the last treatment or after the treatment, the disease progressed and was confirmed (the investigator judged according to the RECIST 1.1 standard).
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 during the screening period and before apheresis.
- •Adequate liver/bone marrow function.
- •Female subjects must meet the following conditions: infertility or fertility and use high-efficiency contraceptive measures.
- •Male subjects agree to use approved contraceptive methods (e.g. birth control pills, barrier device, intrauterine device, abstinence) during the study and for 3 months following the last dose of the study cell infusion. Moreover, all men are absolutely prohibited from donating sperm within 1 year after receiving the last study treatment infusion.
排除标准
- •Participated in any other trial in which receipt of an investigational study drug occurred within 28 days prior to entry into the study.
- •Received any anticancer medication in the 2 weeks prior to receiving their first dose of study treatment, including but not limited to surgery, systemic chemotherapy, radiotherapy, intervention, etc.
- •Uncontrolled thyroid dysfunction (serum thyroid hormone determination TT4, TT3, FT3, FT4, and serum thyroid-stimulating hormone TSH) are not suitable for enrolling in the study;
- •Pregnant or breastfeeding female, or not willing to take contraception measures during the study.
- •Any uncontrollable active infection, including but not limited to active tuberculosis; HBV infection (including HBsAg positive, or HBcAb positive and HBV DNA positive); HIV, syphilis, hepatitis C positive or suffering from other fatal viruses, Bacterial disease
- •Administrated with steroids (5 mg/day or more dexamethasone, or equivalent hormone drugs) within the past two weeks;
- •Other uncontrolled diseases may cause abnormal death of the patient;
- •Active autoimmune disease (including but not limited to: systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, etc.) requiring immunosuppressive therapy within the past 4 weeks.
- •Previously allergic to immunotherapy, tocilizumab, cyclophosphamide, fludarabine, and other related drugs, previous history of severe allergies, to research product excipients (such as human serum albumin, DMSO, and dextran 40 ); people who have a history of penicillin allergy and have a positive skin test at the time of screening.
- •Congestive heart failure, uncontrolled cardiac arrhythmia, etc.
- •Uncontrollable massive ascites, that cannot be drained by standard methods;
- •Intestinal obstruction or CT suggesting omental cake-like peritoneal metastasis, or repeated uncontrollable incomplete intestinal obstruction.
- •Have received any genetic engineering modified T cell therapy (including CAR T, TCR T cell).
- •Uncontrolled brain metastasis or mental illness.
- •Suffered from other uncured malignant tumors within the past 3 years or at the same time.
- •The blood oxygen saturation ≤95% at the time of screening and before apheresis.
- •Can't be followed up or obey protocol.
- •The investigator believes that it is not appropriate to participate in the trial.
结局指标
主要结局
SIAEs and SAEs
时间窗: 4 weeks after the last infusion
Incidence of AEs of Special Interest and Serious Adverse Events
TRAEs
时间窗: 4 weeks after the last infusion
Incidence of Treatment Related Adverse Events
DLTs
时间窗: 4 weeks after the last infusion
Incidence of dose-limiting toxicities
TEAEs
时间窗: 4 weeks after the last infusion
Incidence of Treatment Emergent Adverse Event
次要结局
- PFS by IRC(24 weeks after the last infusion)
- TEAEs,TRAEs, SIAEs and SAEs(12 weeks after the last infusion)
- DCR by IRC(12 weeks after the last infusion)
- DOR by IR(12 weeks after the last infusion)
- PFS by IR(24 weeks after the last infusion)
- ORR by IRC(12 weeks after the last infusion)
- QOL(12 weeks after the last infusion)
- Cmax(4 weeks after the last infusion)
- ORR by IR(12 weeks after the last infusion)
- DCR by IR(12 weeks after the last infusion)
- TTR by IR(12 weeks after the last infusion)
- OS(52 weeks after the last infusion)
- HACA(4 weeks after the last infusion)
- AUC(4 weeks after the last infusion)
研究者
Jun Zhang
Chief of Department of Oncology
Ruijin Hospital