Phase 1/2 Study of TSN1611 in Subjects With Advanced Solid Tumors Harboring KRAS G12D Mutation
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 440
- 试验地点
- 34
- 主要终点
- Dose limiting toxicities (DLTs) in phase 1 part
研究概览
简要总结
The study is a first-in-human (FIH), open-label, multi-center phase 1/2 study of TSN1611 in subjects with KRAS G12D mutant advanced solid tumors. This study will consist of a phase 1 dose escalation part and phase 2 dose expansion part. This study will evaluate the efficacy of TSN1611 at RP2D(s) through ORR using RECIST version 1.1, and determine and confirm the MTD/RP2D for TSN1611 in combination with cetuximab, in combination with cetuximab and mFOLFOX6, in combination with gemcitabine and albumin-bound paclitaxel in subjects with selected solid tumors.
详细描述
Phase 1 Part of TSN1611 Monotherapy:
The phase 1 part will evaluate the prespecified dose levels of TSN1611. Dose escalation will continue until up to the highest planned dose or the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is determined. Dose optimization could be performed as indicated by the emerging data.
Phase 2 Part of TSN1611 Monotherapy:
hase 2 part of TSN1611 monotherapy will evaluate the efficacy and safety of TSN1611 as monotherapy at the RP2D until disease progression or unacceptable toxicity in separate groups of patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer, or other solid tumors, harboring KRAS G12D mutations.
Phase 1b/2 Part of TSN1611 Combination Therapy:
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 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects must meet all the following inclusion criteria to be eligible for participation in this study:
- •The subject fully understands the requirements of the study and voluntarily signs the ICF.
- •At least 18 years of age at the time of informed consent.≤ 75 years of age for Cohort B and C.
- •Life expectancy of 3 months or more.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or
- •Phase 1 part (1a/1b) of Monotherapy:
- •Subjects with histologically or cytologically confirmed locally advanced or metastatic solid tumor harboring KRAS G12D mutation; subjects must be refractory or intolerable to standard treatment, or have no standard treatment available, or the subject is ineligible or declines standard treatment.
- •Phase 2 part of TSN1611 Monotherapy:
- •Subjects with histologically or cytologically confirmed locally advanced or metastatic PDAC、CRC and NSCLC harboring KRAS G12D mutation; According to the requirements of different combined cohorts, the number of previous treatments is taken into account.
- •Patients with adequate cardiac, liver, renal function, etc.
排除标准
- •Subjects will be excluded if they meet any of the following criteria:
- •Leptomeningeal disease or Active central nervous system (CNS) metastases.
- •Prior systemic anti-cancer treatment within 21 days or 5 half-lives (whichever is shorter will be used as the criteria) prior to the first dose of study drug.
- •Radical radiation within 4 weeks prior to the first dose of study drug; palliative radiotherapy within 1 week prior to the first dose of study drug.
- •Any unresolved Grade 2 or higher toxicity from previous anticancer therapy except alopecia.
- •Has participated in a study of investigational agent and received the investigational agent within 21 days or 5 half-lives, if known (whichever is shorter) prior to the first dose of study drug.
- •History of interstitial lung disease (ILD), drug induced IDL, or current active pneumonitis, radiation pneumonitis requiring therapeutic intervention, or uncontrolled other lung disease.
- •Any of the following in the past 6 months: myocardial infarction, unstable angina, symptomatic congestive heart failure, stroke or transient ischemic attack, pulmonary embolism.
- •Prior treatment with KRAS G12D targeted therapy.
- •Has a history or current evidence of any severe condition, concurrent therapy, or laboratory abnormality that might confound the interpretation of the study results, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the investigator.
研究组 & 干预措施
Phase 1: Dose-finding/evaluation of TSN1611 monotherapy
The phase 1 part will evaluate the prespecified sequential dose levels of TSN1611 in subjects with KRAS G12D mutant advanced solid tumors to determine the recommended dose of TSN1611 for further investigation.
干预措施: TSN1611 (Drug)
Phase 2: Dose expansion of TSN1611 monotherapy
Phase 2 part will evaluate the efficacy and safety of TSN1611 as monotherapy at the recommended dose level in separate groups of patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer, or other solid tumors, harboring KRAS G12D mutations.
干预措施: TSN1611 (Drug)
Dose of Phase 1b/2 part of TSN1611 combination therapy-Cohort A
Cohort A: TSN1611 combined with cetuximab treating subjects with advanced solid tumors harboring KRAS G12D mutation:
干预措施: TSN1611 (Drug)
Dose of Phase 1b/2 part of TSN1611 combination therapy-Cohort B
Cohort B: TSN1611 combined with GnP regimen (i.e., gemcitabine and nab-paclitaxel) treating subjects with advanced PDAC with KRAS G12D mutation who received no prior systemic treatment in the advanced setting.
干预措施: TSN1611 (Drug)
Dose of Phase 1b/2 part of TSN1611 combination therapy-Cohort C
Cohort C: TSN1611 combined with cetuximab and mFOLFOX6 regimen (i.e., fluorouracil, leucovorin, oxaliplatin) treating subjects with advanced CRC with KRAS G12D mutation who received no prior systemic treatment in the advanced setting.
干预措施: TSN1611 (Drug)
结局指标
主要结局
Dose limiting toxicities (DLTs) in phase 1 part
时间窗: 21 days
To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose(s) (RP2D\[s\]) of TSN1611 as monotherapy in subjects with KRAS G12D mutant advanced solid tumors.
Objective response rate (ORR) in phase 2 part
时间窗: Up to 3 years
To evaluate the anti-tumor activity of TSN1611 using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
次要结局
- Progression free survival (PFS)(Up to 3 years)
- Adverse events(Up to 3 years)
- Maximum blood concentrations (Cmax)(9 weeks)
- Duration of response (DOR)(Up to 3 years)
- Overall survival(Up to 3 years)
- Area under the plasma concentration-time curve (AUC)(9 weeks)
- Time to maximum blood concentration (Tmax)(9 weeks)
- Time to response (TTR)(Up to 3 years)
- Disease control rate (DCR)(Up to 3 years)