A Multicenter, Open-label, Phase Ia/Ib Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of TSN084 Tablets in Patients With Advanced Malignant Tumors.
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 114
- 试验地点
- 2
- 主要终点
- Dose limiting toxicity (DLT)
研究概览
简要总结
TSN084 is a novel type II kinase inhibitor with demonstrated anti-tumor effects in vitro and in vivo and targets multiple tyrosine kinases, such as c-MET, FLT3, TRK and serine/threonine kinase CDK8/19. This phase 1a/1b study is conducted to assess the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT), to evaluate the pharmacokinetics, safety and preliminary anti-tumor activity of TSN084 in advanced or metastatic malignancies in China.
详细描述
The phase 1a part will begin with an exploration of TSN084 dose and regimen to determine the maximum tolerated dose (MTD) and/or recommended dose for further investigation (i.e., RP2D). In Phase 1b part, separate cohorts of patients with different histological diagnosis will be evaluated for the clinical activity and efficacy of TSN084 at the recommended dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men or women ≥18 years old.
- •The subject fully understands the requirements of the study and voluntarily signs the written informed consent.
- •Be able to comply with the medication requirements of the study and all study related procedures and evaluations; not deemed as potentially unreliable and/or uncooperative.
- •Meeting the requirements of tumor types shown below. Phase Ia Study: Histological or cytological diagnosis of locally advanced, relapsed, or metastatic malignancies, not amenable to standard therapy or for which no standard therapy is available.
- •Phase Ib study: Histological or cytological diagnosis of the locally advanced, relapsed, or metastatic selected malignancies not amenable to standard therapy (disease progression or intolerance), or unable to receive standard therapy/no standard therapy is available. Malignancies with targeted mutations are preferred, including but not limited to MET exon 14 skipping mutation and MET amplification.
- •Survival expectations are ≥ 12 weeks.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 for Phase Ia, while 0 to 2 for Phase Ib.
- •Patients with adequate organ function at the time of screening.
- •Male and female patients of childbearing potential must agree to use effective methods of contraception.
排除标准
- •Patients with active brain metastases, except that their central nervous system (CNS) tumor metastases are confined to the supratentorial or cerebellum, have been adequately treated (surgery or radiotherapy), have maintained radiographic stability for at least 4 weeks, and do not require corticosteroids to control symptoms.
- •Other malignancies (other than non-melanoma basal cell carcinoma or squamous cell carcinoma of the skin, breast/cervical carcinoma in situ, superficial bladder carcinoma that have received radical treatment and no evidence of disease recurrence) within 5 years prior to initiation of TSN084 treatment;
- •Any arterial thromboembolic event, including myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack, occurred within 6 months prior to enrolment;
- •Uncontrolled third space effusion requiring repeated drainage, such as pleural effusion, ascites, pericardial effusion, etc. (Patients who do not need drainage effusion or have no significant increase in effusion after 3 days of cessation of drainage can be included).
- •Has active gastrointestinal disease or other disease, or other factors such as surgical resection that may significantly affect drug absorption, metabolism, or excretion.
- •Pregnant or lactating women.
- •Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.
- •HIV infected patients (HIV 1/2 antibody positive).
- •Known active syphilis infection, or active tuberculosis.
- •A history of drug abuse or drug use.
研究组 & 干预措施
Experimental: Phase 1a
Dose Escalation/Evaluation
干预措施: TSN084 (Drug)
Experimental: Phase 1b
TSN084 recommended Phase 2 dose administered to separate cohorts of patients with selected malignancies harboring mutations including but not limited to MET exon14 skipping mutation and MET amplification.
干预措施: TSN084 (Drug)
结局指标
主要结局
Dose limiting toxicity (DLT)
时间窗: 28 days
Number of patients with dose limiting toxicity, to determine the MTD and/or RP2D
Incidence of Treatment-Emergent Adverse Events (TEAE)
时间窗: Up to 3 years
Incidence of TEAE, Serious Adverse Event (SAE), their relationship with the investigational product and severity. Adverse events will be graded according to NCI-CTCAE V5.0.
次要结局
- Maximum plasma concentration (Cmax)(28 days)
- Time to Cmax (Tmax)(28 days)
- Area under the concentration versus time curve from time 0 to the last measurable concentration (AUC 0-t)(28 days)
- Objective response rate (ORR)(Up to 3 years)
- Duration of response (DoR)(Up to 3 years)
- Disease control rate (DCR)(Up to 3 years)
- Time to response (TTR)(Up to 3 years)
- Progression free survival (PFS)(Up to 3 years)
- Overall survival (OS)(Up to 3 years)