A Phase 1/2, Open-label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Sotorasib (AMG 510) Monotherapy in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation and Sotorasib (AMG 510) Combination Therapy in Subjects With Advanced NSCLC With KRAS p.G12C Mutation (CodeBreaK 100)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Amgen
- 入组人数
- 713
- 试验地点
- 228
- 主要终点
- Primary: Number of subjects with treatment-related adverse events
研究概览
简要总结
Evaluate the safety and tolerability of sotorasib in adult subjects with KRAS p.G12C mutant advanced solid tumors.
Estimate the maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) in adult subjects with KRAS p.G12C mutant advanced solid tumors.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men or women greater than or equal to 18 years old.
- •Pathologically documented, locally-advanced or metastatic malignancy with, KRAS p.G12C mutation identified through molecular testing.
排除标准
- •Active brain metastases from non-brain tumors.
- •Myocardial infarction within 6 months of study day
- •Gastrointestinal (GI) tract disease causing the inability to take oral medication.
研究组 & 干预措施
Phase 1 combination arm with sotorasib and anti PD-1/L1
Additional subjects will be enrolled into the combination arm with sotorasib in combination with an anti (PD-1/L1)
干预措施: Anti PD-1/L1 (Drug)
Phase 1 combination arm with sotorasib and anti PD-1/L1
Additional subjects will be enrolled into the combination arm with sotorasib in combination with an anti (PD-1/L1)
干预措施: sotorasib (Drug)
Phase 1 Dose Exploration Part 1 monotherapy
Cohorts with food effect and alternative dosing regimens
Enrollment into the dose exploration cohorts may be from any eligible solid tumor type. Dose escalation will begin with 2-4 subjects treated at the lowest planned dose level of 180 mg. If no DLT is observed, dose escalation will continue to the next planned dose cohort
干预措施: sotorasib (Drug)
Phase 1 Dose Expansion Part 2 monotherapy
Upon completing the dose exploration part of the study, dose expansion may proceed with 3 groups consisting of subjects with KRAS p.G12C mutant advanced solid tumors. Dose expansion in these 3 groups may be done concurrently
干预措施: sotorasib (Drug)
Phase 1 monotherapy treatment naive advanced NSCLC
Separate cohort of part 1 dose expansion subjects to evaluate the safety and clinical activity of sotorasib administered orally once daily in subjects with previously untreated advanced non-small cell lung cancer (NSCLC). Drug-drug interaction will be evaluated in 6 of the subjects enrolled in the treatment naive cohort by adding Midazolam alone on Day -1 and in combination with sotorasib on Day 15 of Cycle 1, where each cycle is 21 days.
干预措施: sotorasib (Drug)
Phase 1 monotherapy treatment naive advanced NSCLC
Separate cohort of part 1 dose expansion subjects to evaluate the safety and clinical activity of sotorasib administered orally once daily in subjects with previously untreated advanced non-small cell lung cancer (NSCLC). Drug-drug interaction will be evaluated in 6 of the subjects enrolled in the treatment naive cohort by adding Midazolam alone on Day -1 and in combination with sotorasib on Day 15 of Cycle 1, where each cycle is 21 days.
干预措施: Midazolam (Drug)
Phase 2 monotherapy dose comparison
Subjects with NSCLC will be enrolled in a dose comparison study evaluating safety and efficacy
干预措施: sotorasib (Drug)
Phase 1 Does escalation and Expansion monotherapy BID
BID 2L+solid tumors (fed state)
干预措施: sotorasib (Drug)
结局指标
主要结局
Primary: Number of subjects with treatment-related adverse events
时间窗: 24 Months
Treatment-related adverse events will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Number of subjects with grade ≥3 treatment-emergent adverse events
时间窗: 24 Months
Grade ≥3 treatment-emergent adverse events will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Primary: Number of subjects with adverse events of interest
时间窗: 24 Months
Adverse events of interest will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Primary: Number of subjects with clinically significant changes in physical examination results
时间窗: Baseline to 24 Months
Physical examinations will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1
Primary: Number of subjects with clinically significant changes on electrocardiograms (ECGs)
时间窗: Baseline to 24 Months
ECGs will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Number of subjects with clinically significant changes in clinical laboratory values
时间窗: Baseline to 24 Months
Abnormal clinical laboratory values will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Number of subjects with dose-limiting toxicities (DLTs)
时间窗: 21 Days
DLTs will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria
时间窗: 24 Months
ORR will be a primary outcome measure in the following group: * Phase 1 monotherapy treatment naïve advanced NSCLC * Phase 2 monotherapy * Phase 2 monotherapy dose comparison
Primary: Duration of response (DOR) as assessed by RECIST 1.1 criteria
时间窗: 24 Months
DOR will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Disease control as assessed by RECIST 1.1 criteria
时间窗: 24 Months
Disease control will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria
时间窗: 24 Months
Duration of SD will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Time to response (TTR) as assessed by RECIST 1.1 criteria
时间窗: 24 Months
TTR will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Number of subjects with serious adverse events
时间窗: 24 Months
Serious adverse events will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Primary: Number of subjects with treatment-emergent adverse events
时间窗: 24 Months
Treatment-emergent adverse events will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC * Phase 2 monotherapy dose comparison
Primary: Number of subjects with treatment-related adverse events
时间窗: 24 Months
Treatment-related adverse events will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Number of subjects with grade ≥3 treatment-emergent adverse events
时间窗: 24 Months
Grade ≥3 treatment-emergent adverse events will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Primary: Number of subjects with serious adverse events
时间窗: 24 Months
Serious adverse events will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Primary: Number of subjects with adverse events of interest
时间窗: 24 Months
Adverse events of interest will be a primary outcome measure in the following group: \- Phase 2 monotherapy dose comparison
Primary: Number of subjects with clinically significant changes in vital signs
时间窗: Baseline to 24 Months
Vital signs will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Number of subjects with clinically significant changes in physical examination results
时间窗: Baseline to 24 Months
Physical examinations will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1
Primary: Number of subjects with clinically significant changes on electrocardiograms (ECGs)
时间窗: Baseline to 24 Months
ECGs will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Number of subjects with clinically significant changes in clinical laboratory values
时间窗: Baseline to 24 Months
Abnormal clinical laboratory values will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Number of subjects with dose-limiting toxicities (DLTs)
时间窗: 21 Days
DLTs will be a primary outcome measure for the following groups: * Phase 1 Dose Exploration Part 1 monotherapy * Phase 1 Dose Expansion Part 2 monotherapy * Phase 1 combination arm with sotorasib and anti PD-1/L1 * Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria
时间窗: 24 Months
ORR will be a primary outcome measure in the following group: * Phase 1 monotherapy treatment naïve advanced NSCLC * Phase 2 monotherapy * Phase 2 monotherapy dose comparison
Primary: Duration of response (DOR) as assessed by RECIST 1.1 criteria
时间窗: 24 Months
DOR will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Disease control as assessed by RECIST 1.1 criteria
时间窗: 24 Months
Disease control will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria
时间窗: 24 Months
Duration of SD will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
Primary: Time to response (TTR) as assessed by RECIST 1.1 criteria
时间窗: 24 Months
TTR will be a primary outcome measure in the following group: \- Phase 1 monotherapy treatment naïve advanced NSCLC
次要结局
- Secondary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Plasma concentration (Cmax) of sotorasib(15 Weeks)
- Secondary: Impact of treatment on disease-related symptoms and health related quality of life (HRQOL) as assessed by EORTC QLQ-C30(24 Months)
- Secondary: Time to achieve Cmax (Tmax) of sotorasib(15 Weeks)
- Secondary: Area under the plasma concentration-time curve (AUC) of sotorasib(15 Weeks)
- Secondary: Area under the plasma concentration-time curve (AUC) of midazolam(16 Days)
- Secondary: Clearance of midazolam from the plasma(16 Days)
- Secondary: Terminal half-life (t1/2) of midazolam(16 Days)
- Secondary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Severity (PGIS)(24 Months)
- Secondary: Duration of response (DOR) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Time to response (TTR) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by non-small cell lung cancer symptom assessment questionnaire (NSCLC SAQ) for NSCLC(24 Months)
- Secondary: Overall survival (OS)(24 Months)
- Secondary: sotorasib exposure and QTc interval relationship(24 Months)
- Secondary: Progression-free survival (PFS) at 6 months(6 Months)
- Secondary: Progression-free survival (PFS) at 12 months(12 Months)
- Secondary: Overall survival (OS) at 12 months(12 Months)
- Secondary: Number of subjects with treatment-emergent adverse events(24 Months)
- Secondary: Progression-free survival (PFS) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Number of subjects with grade ≥3 treatment-emergent adverse events(24 Months)
- Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Change (PGIC) in cough, dyspnea and chest pain for NSCLC(24 Months)
- Secondary: Treatment-related symptoms and impact on the subject as assessed by selected questions from the Patient-reported Outcome of the Common Terminology Criteria for Adverse Events (PRO-CTCAE library)(24 Months)
- Secondary: Change from baseline in physical function as assessed by EORTC QLQ-C30(Baseline to 24 Months)
- Secondary: Plasma concentration (Cmax) of sotorasib(15 Weeks)
- Secondary: Plasma concentration (Cmax) of midazolam(16 Days)
- Secondary: Time to achieve Cmax (Tmax) of sotorasib(15 Weeks)
- Secondary: Area under the plasma concentration-time curve (AUC) of sotorasib(15 Weeks)
- Secondary: Area under the plasma concentration-time curve (AUC) of midazolam(16 Days)
- Secondary: Clearance of midazolam from the plasma(16 Days)
- Secondary: Terminal half-life (t1/2) of midazolam(16 Days)
- Secondary: Objective response rate (ORR) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Duration of response (DOR) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Disease control as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Progression-free survival (PFS) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Duration of stable disease (SD) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Depth of response (best percentage change from baseline in lesion sum diameters) as assessed by RECIST 1.1 criteria(Baseline to 24 Months)
- Secondary: Time to response (TTR) as assessed by RECIST 1.1 criteria(24 Months)
- Secondary: Overall survival (OS)(24 Months)
- Secondary: sotorasib exposure and QTc interval relationship(24 Months)
- Secondary: Progression-free survival (PFS) at 6 months(6 Months)
- Secondary: Progression-free survival (PFS) at 12 months(12 Months)
- Secondary: Overall survival (OS) at 12 months(12 Months)
- Secondary: Number of subjects with treatment-emergent adverse events(24 Months)
- Secondary: Number of subjects with grade ≥3 treatment-emergent adverse events(24 Months)
- Secondary: Impact of treatment on disease-related symptoms and health related quality of life (HRQOL) as assessed by EORTC QLQ-C30(24 Months)
- Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by disease-specific modules Quality-of-Life Questionnaire Lung Cancer Module (QLQ LC13)(24 Months)
- Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by non-small cell lung cancer symptom assessment questionnaire (NSCLC SAQ) for NSCLC(24 Months)
- Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Severity (PGIS)(24 Months)
- Secondary: Impact of treatment on disease-related symptoms and HRQOL as assessed by Patient Global Impression of Change (PGIC) in cough, dyspnea and chest pain for NSCLC(24 Months)
- Secondary: Treatment-related symptoms and impact on the subject as assessed by EORTC QLQ-C30(24 Months)
- Secondary: Treatment-related symptoms and impact on the subject as assessed by selected questions from the Patient-reported Outcome of the Common Terminology Criteria for Adverse Events (PRO-CTCAE library)(24 Months)
- Secondary: Treatment-related symptoms and impact on the subject as assessed by a single item about symptom bother, item GP5 of the Functional Assessment of Cancer Therapy - General (FACT-G)(24 Months)
- Secondary: Change from baseline in physical function as assessed by EORTC QLQ-C30(Baseline to 24 Months)