A Phase Ib, Open-Label, Multicenter Study to Evaluate the Safety, Pharmacokinetics, and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Nivolumab in Patients With NRAS-Mutant Advanced Melanoma Who Have Received Anti-PD-1/PD-L1 Therapy
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 65
- 试验地点
- 25
- 主要终点
- Percentage of Participants With Adverse Events
研究概览
简要总结
This study will evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib plus nivolumab in patients with NRAS-mutant advanced melanoma who have received anti-PD-1/PD-L1 therapy.
详细描述
The study will evaluate three treatment regimens in three arms: a belvarafenib monotherapy arm (Belva arm); a belvarafenib plus cobimetinib arm (Belva + Cobi arm) in an initial dose-finding phase followed by an expansion phase and a belvarafenib plus cobimetinib plus nivolumab arm (Belva + Cobi + Nivo arm) in a run-in phase followed by an expansion phase.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •ECOG Performance Status of 0 or 1
- •Histologically confirmed, metastatic (recurrent or de novo Stage IV) or unresectable locally advanced (Stage III) cutaneous melanoma, that has progressed on or after treatment with anti-PD-1 or anti-PD-L1 therapy. Patients may have received up to two lines of systemic cancer therapy. Treatment with anti-PD-1/PD-L1 in the adjuvant setting is acceptable. Patients must have progressed disease at study entry
- •Documentation of NRAS mutation-positive within 5 years prior to screening
- •Tumor specimen availability
- •Adequate hematologic and end-organ function
- •Measurable disease per RECIST v1.1
排除标准
- •Prior treatment with a pan-RAF inhibitor
- •Treatment with systemic immunotherapy agents (e.g., anti-CTLA4, anti-PD(L)1, cytokine therapy, investigational therapy, etc.) within 28 days prior to C1D1
- •Symptomatic, untreated, or actively progressing CNS metastases
- •History or signs/symptoms of clinically significant cardiovascular disease
- •Known clinically significant liver disease
- •History of autoimmune disease or immune deficiency
- •Prior treatment with a MEK inhibitor (cobimetinib arm)
- •History of or evidence of retinal pathology on ophthalmologic examination (cobimetinib arm)
- •History of immune-related AE attributed to prior anti-PD(L)1 therapy that resulted in permanent discontinuation of anti-PD(L)1 therapy (nivolumab arm)
研究组 & 干预措施
Belvarafenib Plus Cobimetinib
Recommended dose (RD) and schedule of belvarafenib and cobimetinib selected based on the safety data, tolerability, pharmacokinetics, and anti-tumor activity tested in dose-finding phase followed by an expansion phase.
干预措施: Cobimetinib (Drug)
Belvarafenib Plus Cobimetinib Plus Nivolumab
Recommended dose (RD) and schedule of belvarafenib and cobimetinib plus nivolumab IV infusion every 4 weeks (Q4W) in a run-in phase followed by an expansion phase
干预措施: Nivolumab (Drug)
Belvarafenib Monotherapy
Twice daily (BID), continuous dosing.
干预措施: Belvarafenib (Drug)
结局指标
主要结局
Percentage of Participants With Adverse Events
时间窗: From Cycle 1, Day 1 Up to 4 Years
Severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0
Percentage of Participants With Dose Limiting Toxicity (DLTs)
时间窗: 28 Days from Cycle 1, Day 1
次要结局
- Objective response rate (ORR) according to RECIST v1.1(Up to Approximately 4 Years)
- Progression free survival (PFS) according to RECIST v1.1(Up to Approximately 4 Years)
- Duration of response (DOR) according to RECIST v1.1(Up to Approximately 4 Years)
- Overall survival (OS)(Up to Approximately 4 Years)
- Plasma concentration of belvarafenib at specified timepoints(Up to 30 Days After the Final Dose of Study Drug)
- Plasma concentration of cobimetinib at specified timepoints(Up to 30 Days After the Final Dose of Study Drug)