A Phase 1/2 Study of Avutometinib (VS-6766) in Combination With Sotorasib With or Without Defactinib in Patients With KRAS G12C Mutant Non-Small Cell Lung Cancer (NSCLC)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 153
- 试验地点
- 35
- 主要终点
- Part B: To determine the efficacy of the RP2D and/or Alt-RP2D identified from Part A
研究概览
简要总结
This study will assess the safety and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C Non-Small Cell Lung Cancer (NSCLC) in patients who have been exposed to prior G12C inhibitor and those who have not been exposed to prior G12C inhibitor.
详细描述
This is a multicenter, non-randomized, open-label Phase 1/2 study designed to evaluate safety and tolerability and efficacy of avutometinib (VS-6766) in combination with sotorasib with or without defactinib in patients with KRAS G12C mutant NSCLC.
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
- •Male or female patients ≥ 18 years of age
- •Histologic or cytologic evidence of NSCLC
- •Known KRAS G12C mutation
- •Either exposed or not exposed to a KRAS inhibitor to be included in Part A (avutometinib + sotorasib + defactinib) and not exposed to KRAS inhibitor to be included in Part B (avutometinib + sotorasib + defactinib), Cohort 1
- •Received at least 1 dose of a G12C inhibitor to be included in Part B, Cohort 2 (avutometinib + sotorasib + defactinib)
- •Must have received appropriate treatment with at least one prior systemic regimen, but no more than 2 prior regimens, for Stage 3B-C or 4 NSCLC
- •Measurable disease according to RECIST 1.1
- •An Eastern Cooperative Group (ECOG) performance status ≤ 1
- •Adequate organ function
- •Adequate recovery from toxicities related to prior treatments
- •Agreement to use highly effective method of contraceptive
排除标准
- •Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy
- •History of prior malignancy, with the exception of curatively treated malignancies
- •Major surgery within 4 weeks, minor surgery within 2 weeks (excluding placement of vascular access)
- •History of treatment with a direct and specific inhibitor of MEK
- •Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy
- •Symptomatic brain metastases requiring steroids or other local interventions.
- •Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy
- •Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active
- •Active skin disorder that has required systemic therapy within the past year
- •History of rhabdomyolysis
- •Concurrent ocular disorders
- •Concurrent heart disease or severe obstructive pulmonary disease
- •Inability to swallow oral medications
- •Female patients that are pregnant or breastfeeding
- •Previously treated with sotorasib and were dose reduced due to toxicity
研究组 & 干预措施
avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor exposed
To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients
干预措施: avutometinib and sotorasib and defactinib (Drug)
avutometinib (VS-6766)+sotorasib
To determine the recommended phase 2 dose (RP2D) for avutometinib (VS 6766) in combination with sotorasib in KRAS G12C inhibitor naïve and exposed patients
干预措施: avutometinib and sotorasib (Drug)
avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor naïve
To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients
干预措施: avutometinib and sotorasib (Drug)
avutometinib (VS-6766)+sotorasib - KRAS G12C inhibitor exposed
To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor exposed patients
干预措施: avutometinib and sotorasib (Drug)
avutometinib (VS-6766)+sotorasib+defactinib
To determine the recommended phase 2 dose (RP2D) for avutometinib (VS-6766) in combination with sotorasib and defactinib in KRAS G12C inhibitor exposed patients
干预措施: avutometinib and sotorasib and defactinib (Drug)
avutometinib (VS-6766)+sotorasib+defactinib - KRAS G12C inhibitor naive
To determine the efficacy of the RP2D identified from Part A in KRAS G12C inhibitor naïve patients
干预措施: avutometinib and sotorasib and defactinib (Drug)
结局指标
主要结局
Part B: To determine the efficacy of the RP2D and/or Alt-RP2D identified from Part A
时间窗: From start of treatment to confirmation of response; 16 weeks
Confirmed overall response rate per RECIST 1.1
Part A: To determine RP2D for avutometinib in combination with sotorasib and the Alt-RP2D for avutometinib in combination with sotorasib and defactinib
时间窗: From start of treatment to confirmation of RP2D; 28 days
Assessment of Dose-limiting toxicities (DLTs)
次要结局
- Frequency and severity adverse events (AEs) and Serious Adverse Events (SAEs)(24 months)
- Progression Free Survival (PFS)(24 months)
- Overall Survival (OS)(Up to 5 years)
- Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites half-life(10 weeks)
- Duration of Response (DOR)(Time from the first documentation of response to first documentation of progressive disease or death due to any cause, greater than or equal to 6 months)
- Disease Control Rate (DCR)(Greater than or equal to 8 weeks)
- Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites - Tmax(10 weeks)
- Plasma Pharmacokinetics (PK) of avutometinib, sotorasib, defactinib and relevant metabolites -AUC(10 weeks)