A Phase 2 Trial of Adagrasib Monotherapy and in Combination With Pembrolizumab and a Phase 3 Trial of Adagrasib in Combination With Pembrolizumab Versus Pembrolizumab in Patients With Advanced Non-Small Cell Lung Cancer With KRAS G12C Mutation
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 626
- 试验地点
- 1,469
- 主要终点
- Phase 2: To evaluate the efficacy of Adagrasib monotherapy and in combination with pembrolizumab administered to patients having advanced/metastatic NSCLC.
研究概览
简要总结
The Phase 2 portion of this study evaluates the efficacy and safety of MRTX849 monotherapy and in combination with pembrolizumab in cohorts of patients with advanced NSCLC with KRAS G12C mutation and any PD-L1 TPS and who are candidates for first-line treatment.
The Phase 3 portion of the study compares the efficacy of adagrasib in combination with pembrolizumab versus pembrolizumab in patients with unresectable, locally advanced or metastatic squamous or nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS >=50% and who are candidates for first line treatment.
详细描述
The Phase 2 portion of this study will evaluate the efficacy and safety of MRTX849 as monotherapy and in combination with pembrolizumab. There will be 3 cohorts of patients, all of whom have KRAS G12C mutation, have advanced or metastatic NSCLC, and are candidates for first-line treatment. 2 cohorts have PD-L1 TPS score <1% and are randomized to MRTX849 monotherapy or MRTX849 in combination with pembrolizumab. The 3rd cohort has PD-L1 TPS score of 1% or higher and is treated with MRTX849 and pembrolizumab
The Phase 3 portion of the study will randomize patients with squamous or nonsquamous NSCLC with KRAS G12C mutation and TPS >=50% in the first-line setting to adagrasib plus pembrolizumab or pembrolizumab. Primary efficacy objective is to compare efficacy between experimental and comparator arms. Secondary and exploratory objectives include evaluation of secondary efficacy endpoints, safety and tolerability, adagrasib PK, PROs, and correlative genomic biomarkers for the combination regimen in the study population.
MRTX849 is an orally available small molecule inhibitor of KRAS G12C, and Pembrolizumab (KEYTRUDA®) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
研究设计
- 研究类型
- Interventional
- 分配方式
- 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
- All
- 接受健康志愿者
- 否
入选标准
- •Phase 2: Histologically confirmed diagnosis of unresectable or metastatic NSCLC with KRAS G12C mutation and any PD-L1 TPS
- •Phase 3: Histologically confirmed diagnosis of unresectable or metastatic squamous or nonsquamous NSCLC with KRAS G12C mutation and PD-L1 TPS>=50%
- •Phase 3: Presence of measurable disease per RECIST1.1
- •Phase 3: CNS Inclusion - Based on screening brain imaging, patients must have one of the following:
- •No evidence of brain metastases
- •Untreated brain metastases not needing immediate local therapy
- •Previously treated brain metastases not needing immediate local therapy
排除标准
- •Phase 2 and Phase 3: Prior systemic treatment for locally advanced or metastatic NSCLC including chemotherapy, immune checkpoint inhibitor therapy, or a therapy targeting KRAS G12C mutation (e.g., AMG 510).
- •Phase 2: Active brain metastases
- •Phase 3: Patients with known central nervous system (CNS) lesions must not have any of the following:
- •Any untreated brain lesions > 2.0 cm in size
- •Any brainstem lesions
- •Ongoing use of systemic corticosteroids for control of symptoms of brain lesions at a total daily dose of > 10 mg of prednisone (or equivalent) prior to randomization.
- •Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain lesions notwithstanding CNS-directed therapy
- •Phase 3: Radiation to the lung > 30 Gy within 6 months prior to the first dose of study treatment
研究组 & 干预措施
Phase 2 Cohort 1a: PD-L1 TPS <1%
Cohort 1a: Adagrasib twice daily (BID) in combination with pembrolizumab
干预措施: Adagrasib (Drug)
Phase 2 Cohort 2: PD-L1 TPS ≥1%
Cohort 2: Adagrasib BID in combination with pembrolizumab
干预措施: Adagrasib (Drug)
Phase 2 Cohort 1b: PD-L1 TPS <1%
Cohort 1b: Adagrasib BID monotherapy
干预措施: Adagrasib (Drug)
Phase 3 Cohort 3 Investigational Arm
Adagrasib BID in combination with pembrolizumab
干预措施: Adagrasib (Drug)
Phase 3 Cohort 4 Comparator Arm
Pembrolizumab
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Phase 2: To evaluate the efficacy of Adagrasib monotherapy and in combination with pembrolizumab administered to patients having advanced/metastatic NSCLC.
时间窗: 22 months
Objective Response Rate (ORR) as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
Phase 3: To compare efficacy of Adagrasib in combination with pembrolizumab versus pembrolizumab
时间窗: 36 months
Progression Free Survival per RECIST 1.1 by Blinded Independent Central Review (BICR) and Overall Survival
次要结局
- Phase 2: To characterize the safety and tolerability of study treatments in selected populations(22 months)
- Phase 2: Duration of Response(22 months)
- Phase 2: Progression Free Survival(22 months)
- Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations(22 months)
- Phase 2: To evaluate the pharmacokinetics (PK) of study treatments by measuring blood plasma MRTX849 and potential metabolite concentrations.(22 months)
- Phase 3: To evaluate the PK of adagrasib administered in the study population(36 months)
- Phase 3: To evaluate health-related quality of life (HRQOL) and lung cancer specific symptoms in the study population(36 months)
- Phase 3: Progression Free Survival per RECIST 1.1 by Investigator(36 months)
- Phase 3: Objective Response Rate (ORR) per RECIST 1.1 by Investigator and BICR(36 months)
- Phase 3: To evaluate the safety and tolerability in the study population(36 months)
- Phase 3: Duration of Response (DOR) per RECIST 1.1 by Investigator and BICR(36 months)
- Phase 2: To evaluate secondary efficacy endpoints using the study treatment in selected populations(12 months)