A Study to Evaluate the Safety and Tolerability of the Covalent Phosphoinositide-3-Kinase (PI3K)-Alpha Inhibitor, TOS-358, in Adult Subjects With Select Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 241
- 试验地点
- 36
- 主要终点
- Determine the rate of dose-limiting toxicities (DLTs)
研究概览
简要总结
The goal of this clinical trial is to evaluate the safety and efficacy of TOS-358 in women with HR+ HER2- metastatic breast cancer whose tumors have a mutation in PIK3CA and who meet all other study enrollment criteria. The main questions it aims to answer are:
- Phase 1a: what is the maximum tolerated dose and recommended dose for phase 2?
- Phase 1a: how safe and tolerable is TOS-358 at different dose levels when taken orally once or twice per day?
- Phase 1b: how safe and effective is TOS-358 when given with standard of care medicines for HR+HER2- metastatic breast cancer (fulvestrant and CDK4/6i)
详细描述
This study will be conducted in two parts: a dose finding portion to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of TOS-358 administered orally on once a day (QD) and twice daily (BID) schedules, and a dose expansion portion to evaluate safety and tolerability in tumor-specific cohorts administered TOS-358 at the recommended phase 2 dose and schedule.
Women with histologically confirmed diagnosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2) negative breast cancer with known PIK3CA mutations or amplifications and who meet all of the eligibility criteria will be enrolled in the study.
In the dose finding portion of the study, TOS-358 will be evaluated as a single-agent at multiple dose levels administered orally until disease progression, unacceptable toxicity, or until meeting any other reason for discontinuation as specified in the protocol. In the Phase 1b portion, TOS-358 will be combined with fulvestrant +/- CDK4/6i.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Locally advanced, recurrent, or metastatic HR +/HER2- breast cancer
- •Up to 3 prior lines of therapy for metastatic disease
- •Willing and able to provide written informed consent for this study
- •Adults ≥ 18 years old at time of consent
- •Known PIK3CA mutations or amplifications as determined at a CAP/CLIA-certified or equivalently accredited diagnostic laboratory using a validated test
- •Measurable or evaluable disease by RECIST 1.1
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Life expectancy ≥ 6 months, as determined by the investigator
- •Adequate bone marrow, liver, and kidney function within 14 days prior to first dose of investigational product
- •Fasting plasma glucose <= 140 mg/dL AND hemoglobin A1c (HbA1c) <= 7.0%
- •Available archived or fresh tumor tissue sample for detection of PIK3CA mutation by central laboratory test
排除标准
- •Has an established diagnosis of diabetes mellitus type 1 or has uncontrolled diabetes mellitus type 2
- •Known active central nervous system (CNS) metastases
- •PTEN mutations
研究组 & 干预措施
TOS-358 + fulvestrant
TOS-358 + fulvestrant at standard dosing
干预措施: TOS-358 (Drug)
TOS-358 + fulvestrant
TOS-358 + fulvestrant at standard dosing
干预措施: Fulvestrant (Drug)
TOS-358 + fulvestrant + CDK4/6i
TOS-358 + fulvestrant + CDK4/6i
干预措施: TOS-358 (Drug)
TOS-358 + fulvestrant + CDK4/6i
TOS-358 + fulvestrant + CDK4/6i
干预措施: Fulvestrant (Drug)
TOS-358 + fulvestrant + CDK4/6i
TOS-358 + fulvestrant + CDK4/6i
干预措施: Palbociclib (Drug)
TOS-358 + fulvestrant + CDK4/6i
TOS-358 + fulvestrant + CDK4/6i
干预措施: Ribociclib (Drug)
TOS-358
PIK3CA covalent inhibitor
干预措施: TOS-358 (Drug)
结局指标
主要结局
Determine the rate of dose-limiting toxicities (DLTs)
时间窗: First 21 days of treatment
Incidence and severity of adverse events (AEs) and specific laboratory abnormalities graded according to NCI CTCAE v5
时间窗: Start of treatment to 30 days after last dose
次要结局
- ORR and duration of tumor control(Up to 24 months)