A Phase I/II, Open-label, Dose Escalation Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of RAF265 (CHIR-265)Administered Orally to Patients With Locally Advanced or Metastatic Melanoma.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 104
- 试验地点
- 11
- 主要终点
- Maximum tolerated dose
研究概览
简要总结
The purpose of this study is to determine the safety profile, pharmacokinetics, pharmacodynamics and maximum tolerated dose of RAF265 in patients with locally advanced and metastatic melanoma.
Phase II portion of study (dose expansion) has been cancelled with Amendment 7 as of Dec 2011.
详细描述
The Ras/Raf/MEK/ERK pathway plays a prominent role in controlling several key cellular functions including growth, proliferation and survival. B-Raf is a member of the Ras/Raf/MEK/ERK pathway and is frequently mutated in melanoma resulting in activation of the MAPK pathway. RAF265 is a novel, orally active, small molecule with potent inhibitory activity against B-Raf kinase and additional antiangiogenic activity through inhibition of vascular endothelial growth factor receptor type 2 (VEGFR-2) in non-clinical studies.
The primary objectives of this study are to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and the safety profile of RAF265 when administered orally to subjects with locally advanced or metastatic melanoma; to determine the plasma pharmacokinetics (PKs) of orally administered RAF265; and to evaluate potential pharmacodynamic effects of RAF265 using tumor biopsies, peripheral blood samples, and tumor imaging.
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
- •Confirmed diagnosis of melanoma, locally advanced AJCC Stage IIIB to metastatic Stage IV
- •Measurable disease - at least one lesion measured in at least one dimension as ≥ 20 mm with conventional techniques or ≥ 10 mm with spiral computed tomography (CT) scan
- •ECOG performance status of 0 or 1
- •No concurrent anticancer or investigational therapy for at least 4 weeks prior to enrollment
- •No major surgery for at least 4 weeks prior to enrollment
排除标准
- •Significant cardiac disease or other significant medical/psychiatric disease
- •History of primary central nervous system tumor or brain metastases
- •History of melena, hematemesis, or hemoptysis within the last 3 months
- •Previous therapy with certain molecularly targeted agents
研究组 & 干预措施
RAF265 - Arm 1
Patients received 10mg RAF265 as a once weekly dose until progressive disease was confirmed.
干预措施: RAF265 (Drug)
RAF265 - Arm 2
RAF265 is given as a single "PK run-in" dose, a single loading dose on day 1 of cycle 1, followed by once daily maintenance doses.
干预措施: RAF265 (Drug)
RAF265 - Arm 3
Patients were treated with once weekly dosing of RAF265
干预措施: RAF265 (Drug)
RAF265 - Arm 4
Patients with locally advanced or metastatic melanoma will utilize a dose close to or at the MTD/RPTD of the liquid formulation that was determined in Arm 2.
干预措施: RAF265 (Drug)
RAF265 - Arm 5
RAF265 was administered as a continuous dose for 2 weeks followed by a dose holiday of 1 week.
干预措施: RAF265 (Drug)
结局指标
主要结局
Maximum tolerated dose
时间窗: at the end of dose escalation
Dose limiting toxicities
时间窗: during the PK run-in phase and first cycle (28 day cycle)
Safety profile
时间窗: throughout the study
Evaluate potential pharmacodynamic effects
时间窗: throughout the study
Pharmacokinetic profile
时间窗: throughout the study
次要结局
- Evaluate whether somatic mutations in BRAF and N-RAS genes are associated with modulation of pharmacodynamic markers and clinical response(throughout the study)
- Determine the response rate for BRAF mutant patients(Every 2 months)
- Determine the recommended phase two dose(at the end of dose escalation)