Phase I/II Study of Pan-T Booster Co-expressing MSLN CAR T Cell Therapy in Advanced/Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 15
- 试验地点
- 1
- 主要终点
- Incidence of treatment related adverse events
研究概览
简要总结
In preclinical study, investigators have demonstrated that the newly developed pan-T booster (harbouring CD40 agonist and one T cell costimulator agonist) co-expressing MSLN CAR T cell possess more powerful antitumor activity than previously reported MSLN-CAR T cells. In this clinical trial, enrolled patients receive an initial dose of pan-T booster co-expressing MSLN CAR T cells at 1×10^6 cells/kg based on the basic principle of dose escalation design, in order to evaluate the safety, feasibility, pharmacokinetics/pharmacodynamics, and efficacy of pan-T booster co-expressing MSLN CAR T cell in vivo.
详细描述
In this study, investigators have developed a novel CAR T cell system targeting mesothelin (MSLN) antigen, termed as Pan-T booster (harbouring CD40 agonist and one T cell costimulator agonist) co-expressing MSLN CAR T cell. Preclinical study demonstrated that this novel pan-T booster co-expressing MSLN CAR T cell possess more powerful antitumor activity than previously reported MSLN-CAR T cells. In this clinical trial, enrolled patients receive an initial dose of pan-T booster co-expressing MSLN CAR T cells at 1×10^6 cells/kg based on the basic principle of dose escalation design, in order to evaluate the safety, feasibility, pharmacokinetics/pharmacodynamics, and efficacy of pan-T booster co-expressing MSLN CAR T cell in vivo. The level of CAR-T cell expansion and the duration of expansion are important determining factors for subsequent dose escalation infusions (3×10^6 cells/kg and 6×10^6 cells/kg). Repeated infusion, immune checkpoint inhibitor (such as anti-PD1/PD-L1) or local therapy (radiotherapy) are allowed when patients achieve clinical benefit and the level of CAR-T cell expansion declines to low level.
In the 3 patients receiving the first dose treatment, we observed high levels of expansion of both total T cells and CAR T cells in the PB after CAR T cell infusion (CAR T > 300 per microliter, total T cells reaching 10 times the number of CAR T cells), one patient experienced a grade 2 pulmonary toxicity and transient liver dysfunction during the CAR T cell expansion period (infusion 14 days later), transient marked enlargement of the spleen, and required to be treated with glucocorticoids and ruxolitinib to control T cell toxicity. Efficacy monitoring showed that some target lesion clearance or reduction could be achieved within 2-4 weeks after CAR T infusion. Based on these observations, it was concluded that low-dose CAR T infusion (CAR+T cells 1×10^6 cells/kg) could achieve the sufficient level of CAR T cell expansion, and the initially planned CAR T dose escalation was dispensable. Subsequent patients after May 10th, 2024, will all be treated using 1×10^6 cells/kg dose.
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
- •Age from 18 to 75 years with estimated life expectancy >3 months.
- •Histopathological confirmed advanced or metastatic solid tumors failed to at least first-line treatment or initially diagnosed advanced/metastatic solid tumors that have no NCCN guideline recommended standard first-line therapy. Mesothelin antigen expression percentage >＝10%.
- •Have at least one measurable target lesion.
- •Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 6 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor rebiopsy in the process of this study.
- •Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to <= grade 1 toxicity.
- •Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment.
- •Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs.
- •Previous treatment with anti-PD-1/PD-L1 antibodies are allowed.
- •Ability to understand and sign a written informed consent document.
- •Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and up to 90 days after the last dose of the drug.
排除标准
- •Active, known or suspected autoimmune diseases.
- •Known brain metastases or active central nervous system (CNS). Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
- •Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
- •History of severe hypersensitive reactions to other monoclonal antibodies.
- •History of allergy or intolerance to study drug components.
- •Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
- •History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
- •Uncontrolled intercurrent illness, including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
- •History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
- •Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented.
- •Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
- •Vaccination within 30 days of study enrollment.
- •Active bleeding or known hemorrhagic tendency.
- •Subjects with unhealed surgical wounds for more than 30 days.
- •Being participating any other trials or withdraw within 4 weeks.
研究组 & 干预措施
Pan-T booster co-expressing MSLN CAR T cell
Before the infusion of pan-T booster co-expressing MSLN CAR T cells, all enrolled patients need to undergo conditioning chemotherapy consisting of albumin-bound paclitaxel, cyclophosphamide, and fludarabine.
干预措施: Pan-T booster co-expressing MSLN CAR T cell (Biological)
Pan-T booster co-expressing MSLN CAR T cell
Before the infusion of pan-T booster co-expressing MSLN CAR T cells, all enrolled patients need to undergo conditioning chemotherapy consisting of albumin-bound paclitaxel, cyclophosphamide, and fludarabine.
干预措施: Albumin-bound paclitaxel (Drug)
Pan-T booster co-expressing MSLN CAR T cell
Before the infusion of pan-T booster co-expressing MSLN CAR T cells, all enrolled patients need to undergo conditioning chemotherapy consisting of albumin-bound paclitaxel, cyclophosphamide, and fludarabine.
干预措施: Cyclophosphamide (Drug)
Pan-T booster co-expressing MSLN CAR T cell
Before the infusion of pan-T booster co-expressing MSLN CAR T cells, all enrolled patients need to undergo conditioning chemotherapy consisting of albumin-bound paclitaxel, cyclophosphamide, and fludarabine.
干预措施: Fludarabine (Drug)
结局指标
主要结局
Incidence of treatment related adverse events
时间窗: Up to 12 months since the initiation of MSLN targeted CAR T cell therapy
Treatment related adverse events are defined as any medical events since the initiation of MSLN targeted CAR T cell therapy . CRS or CRES will be graded based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria, and the others will be graded by CTCAE V5.0
Incidence of dose limiting toxicities (DLTs)
时间窗: Up to 28 days since the initiation of MSLN targeted CAR T cell therapy
Dose limiting toxicities are defined as MSLN targeted CAR T cell therapy related adverse events within the first 28 days that meet the following criteria: grade 3 or higher CRS or CRES, and any other grade 4 adverse events.
次要结局
- Objective response rate (ORR)(Up to 3 years)
- Progression Free Survival (PFS)(Up to 3 years)
- Overall Survival (OS)(Up to 3 years)
- Time to response (TTR)(Up to 3 years)
- Duration of response (DOR)(Up to 3 years)
- Number and copy number of MSLN targeted CAR T cell(Up to 3 years)
研究者
Han weidong
Director of Biotherapeutic Department
Chinese PLA General Hospital