A Phase Ib/II, Open-Label, Multicenter Study Evaluating the Safety, Activity, and Pharmacokinetics of Divarasib as a Single Agent or in Combination With Other Anti-Cancer Therapies in Patients With Previously Untreated Advanced Or Metastatic Non-Small Cell Lung Cancer With a KRAS G12C Mutation
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 320
- 试验地点
- 72
- 主要终点
- Percentage of Participants with Adverse Events (AEs)
研究概览
简要总结
The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and activity of single-agent divarasib or combined with other anti-cancer therapies in participants with previously untreated, advanced or metastatic non-small cell lung cancer (NSCLC).
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
- •Confirmation of Biomarker eligibility
- •Pre-treatment tumor tissue along with an associated pathology report is required for all participants enrolled on study. Representative tumor specimens must be in formalin-fixed, paraffin embedded (FFPE) blocks (preferred) or 15 unstained, freshly cut, serial slides. Although 15 slides are required, if only 10 slides are available, the participant may be eligible for the study following consultation with the Sponsor.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
- •Histologically or cytologically documented locally advanced unresectable or metastatic NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy
- •No prior systemic treatment for advanced unresectable or metastatic NSCLC
- •Measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.
- •Additionally, for participants in cohort D, measurable brain metastases defined as at least 5 millimeters and twice the slice thickness, but less than 20 mm, that is asymptomatic and does not require local therapy at the time of enrollment.
排除标准
- •Known concomitant second oncogenic driver with available targeted treatment
- •Squamous cell histology NSCLC
- •Symptomatic, untreated, or actively progressing CNS metastases (Cohorts A, B, and C)
- •Prior treatment with a KRAS G12C inhibitor
- •Known hypersensitivity to any of the components of divarasib or pembrolizumab; or known hypersensitivity to pemetrexed, carboplatin, or cisplatin (Cohort B only)
- •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis, active tuberculosis, significant cardiovascular disease within 3 months prior to initiation of study treatment
- •History of malignancy other than NSCLC within 5 years prior to initiation of study treatment, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate more >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer
- •Uncontrolled tumor related pain, pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures, uncontrolled or symptomatic hypercalcemia
- •Co-morbid condition that is an absolute contraindication to treatment with corticosteroids
- •Inability or unwillingness to take prophylactic treatments such as corticosteroids, anti-emetics, folic acid, or vitamin B12 supplementation.
- •Participants with brain metastases for whom complete surgical resections is clinically appropriate
研究组 & 干预措施
Cohort B - Combination Dose Finding + Dose Expansion
Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed.
干预措施: Divarasib (Drug)
Cohort C - Dose Expansion
Participants enrolled in this cohort will receive one dose level of divarasib QD.
干预措施: Divarasib (Drug)
Cohort A - Combination Dose Finding + Dose Expansion
Participants will be enrolled in different cohorts to receive divarasib (different dose levels will be evaluated) once a day (QD) combined with pembrolizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W).
During the expansion stage, some participants are planned to be randomized to one divarasib combination dose level; other participants are planned to be randomized to another divarasib combination dose level. Divarasib will be given in combination with pembrolizumab.
干预措施: Divarasib (Drug)
Cohort A - Combination Dose Finding + Dose Expansion
Participants will be enrolled in different cohorts to receive divarasib (different dose levels will be evaluated) once a day (QD) combined with pembrolizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W).
During the expansion stage, some participants are planned to be randomized to one divarasib combination dose level; other participants are planned to be randomized to another divarasib combination dose level. Divarasib will be given in combination with pembrolizumab.
干预措施: Pembrolizumab (Drug)
Cohort B - Combination Dose Finding + Dose Expansion
Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed.
干预措施: Carboplatin (Drug)
Cohort B - Combination Dose Finding + Dose Expansion
Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed.
干预措施: Pembrolizumab (Drug)
Cohort D - Dose Expansion
Participants enrolled in this cohort will receive one dose level of divarasib QD.
干预措施: Divarasib (Drug)
Cohort B - Combination Dose Finding + Dose Expansion
Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed.
干预措施: Cisplatin (Drug)
Cohort B - Combination Dose Finding + Dose Expansion
Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed.
干预措施: Pemetrexed (Drug)
结局指标
主要结局
Percentage of Participants with Adverse Events (AEs)
时间窗: Baseline until 60 days after the final dose of study treatment or until initiation of another anti-cancer therapy, whichever occurs first (up to approximately 5 years)
次要结局
- Change from Baseline in Symptomatic Side Effects, as Assessed Through use of the PRO-CTCAE(Baseline up to approximately 5 years)
- Objective Response Rate (ORR)(Approximately 5 years)
- Duration of Response (DOR)(Approximately 5 years)
- Progression Free Survival (PFS)(Approximately 5 years)
- Number of Participants Reporting Presence, Frequency, Severity, and/or Degree of Interference with Daily Function of Symptomatic Side Effects as Assessed Through the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE)(Approximately 5 years)
- Change from Baseline in Symptomatic Side Effects, as Assessed Through use of the PRO-CTCAE(Baseline up to approximately 5 years)
- Percentage of Participants Reporting "Frequent" or "Almost Constant" Diarrhea During the First Three Cycles of Treatment According to the PRO-CTCAE Criteria(Approximately 5 years)
- Percentage of Participants Reporting "Severe" or "Very Severe" Nausea or Vomiting During the First Three Cycles of Treatment According to the PRO-CTCAE(Approximately 5 years)
- Frequency of Participant's Response of the Degree they are Troubled with Treatment Symptoms, as Assessed Through use of the Single-item European Organisation for Research and Treatment of Cancer (EORTC) Item List 46 (IL46)(Approximately 5 years)
- Plasma or CSF Concentration of Divarasib at Specified Timepoints(Approximately 5 years)
- Identification of Divarasib Recommended Dose(Approximately 5 years)
- Central Nervous System (CNS) Response(Approximately 5 years)