A Phase 1/2, Open-Label, Safety, Pharmacokinetic and Preliminary Efficacy Study of Oral Rociletinib in Patients With Previously Treated Mutant EGFR Non-Small Cell Lung Cancer (NSCLC)
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 612
- 试验地点
- 49
- 主要终点
- Dose Limiting Toxicity (DLT) Incidence
研究概览
简要总结
Rociletinib is a novel, potent, small molecule irreversible tyrosine kinase inhibitor (TKI) that selectively targets mutant forms of the epidermal growth factor receptor (EGFR) while sparing wild-type (WT) EGFR. The purpose of the study is to evaluate the pharmacokinetic (PK) and safety profile of oral rociletinib; to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of oral rociletinib; to assess the safety and efficacy of rociletinib in previously treated NSCLC patients known to have the T790M EGFR mutation.
详细描述
Lung cancer remains the most common cancer worldwide with non-small cell lung cancer accounting for 85% of cases. Cytotoxic chemotherapy has been the mainstay of patients with NSCLC; however, survival rates remain low and toxicity is significant. Molecularly targeted therapies have proven to be superior to chemotherapy for NSCLC patients whose tumors have mutations in EGFR. Recent studies have established tyrosine kinase inhibitors (TKIs) as the gold standard for treating EGFR-mutation-positive NCSLC. However, patients on TKIs eventually progress, and in approximately 50% of cases, progression is due to development of an additional mutation called T790M. There are currently no approved therapies for patients who progress on TKIs. Rociletinib may provide an effective therapy for a patient population with few alternative treatment options. Nonclinical data demonstrate that rociletinib inhibits T790M. It is anticipated that rociletinib may promote cell death in tumor cells with the T790M mutation, thus providing possible therapeutic benefit in patients who have developed T790M-mediated resistance to first generation TKIs.
This is a two-part, open-label study of oral rociletinib administered daily in previously treated NSCLC patients who have documented evidence of an activating mutation in the EGFR gene and have failed treatment with an EGFR inhibitor such as erlotinib, gefitinib or afatinib.
This study will include 2 parts:
Phase 1: Dose-escalation Period with 21-day cycles; optional Treatment Extension Period starting on Day 22
Phase 2: Evaluation of activity and safety in patients with the T790M EGFR mutation who have:
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Rociletinib 1000 mg BID HBr formulation
Rociletinib hydrobromide (HBr) dose 1000 mg twice a day (BID)
干预措施: Rociletinib (Drug)
Rociletinib <900 mg BID FB formulation
Rociletinib free base (FB) dose <900 mg twice a day (BID)
干预措施: Rociletinib (Drug)
Rociletinib 900 mg BID FB formulation
Rociletinib free base (FB) dose 900 mg twice a day (BID)
干预措施: Rociletinib (Drug)
Rociletinib 500 mg BID HBr formulation
Rociletinib hydrobromide (HBr) dose 500 mg twice a day (BID)
干预措施: Rociletinib (Drug)
Rociletinib 625 mg BID HBr formulation
Rociletinib hydrobromide (HBr) dose 625 mg twice a day (BID)
干预措施: Rociletinib (Drug)
Rociletinib 750 mg BID HBr formulation
Rociletinib hydrobromide (HBr) dose 750 mg twice a day (BID)
干预措施: Rociletinib (Drug)
结局指标
主要结局
Dose Limiting Toxicity (DLT) Incidence
时间窗: Cycle 1 Day 1 to Cycle 1 Day 21
The number of Phase 1 patients who experienced dose limiting toxicities after one cycle (21 days) of study drug.
Percentage of T790M Positive Patients With Confirmed Response Per Investigator
时间窗: Cycle 1 Day 1 to End of Treatment, up to approximately 42 months
Percentage of patients with a T790M mutation (determined by central lab) with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.
Duration of Response (DOR) in T790M Positive Patients According to RECIST Version 1.1 as Determined by Investigator Assessment
时间窗: Cycle 1 Day 1 to End of Treatment, up to approximately 36 months
Duration of Response in patients with a T790M mutation (determined by central lab) with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.
次要结局
- QTcF Values Post Baseline by Daily Dose(Screening to End of Treatment, up to approximately 42 months)
- Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)(Cycle 1 Day 1 to End of Treatment, up to approximately 42 months)
- PK Profile of Rociletinib - Cmax(Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days)
- PK Profile of Rociletinib - Tmax(Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days)
- PK Profile of Rociletinib - AUC 0-24(Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days)
- Food Effect on PK of Rociletinib - T 1/2(Day -7 prior to Cycle 1 Day 1, or approximately 7 days)
- PK Profile of Rociletinib - T 1/2(Cycle 1 Day 1 to Cycle 1 Day 15, or approximately 15 days)
- Overall Survival (OS) Determined by Investigator Assessment(Cycle 1 Day 1 to date of death, assessed up to 42 months)
- Food Effect on PK of Rociletinib - AUC 0-24(Day -7 prior to Cycle 1 Day 1, or approximately 7 days)
- Food Effect on PK of Rociletinib - Cmax(Day -7 prior to Cycle 1 Day 1, or approximately 7 days)
- Food Effect on PK of Rociletinib - Tmax(Day -7 prior to Cycle 1 Day 1, or approximately 7 days)
- Food Effect on PK of Rociletinib - C24(Day -7 prior to Cycle 1 Day 1, or approximately 7 days)
- Objective Response Rate (ORR), Duration of Response (DOR) and Progression-Free Survival (PFS) Per RECIST Version 1.1 as Determined by IRR(Cycle 1 Day 1 to End of Treatment / End of Follow-up)
- QTcF Value Change From Baseline(Screening to End of Treatment, up to approximately 42 months)