A Phase I, Open-Label, Multicenter, 3- Period, Fixed-Sequence Study to Investigate the Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 12
- 主要终点
- Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Area under the concentration-time curve (AUC)
研究概览
简要总结
This open-label, multicenter, 3-period, fixed-sequence study will evaluate the effect of multiple oral doses of vemurafenib on the pharmacokinetics of a single oral dose of tizanidine in participants with BRAFV600 mutation-positive metastatic malignancies. Participants will receive a single oral dose of tizanidine on Day 1, vemurafenib orally twice daily on Days 2 to 21, and tizanidine and vemurafenib on Day 22. Eligible participants will have the option to continue treatment with vemurafenib as part of an extension study (NCT01739764).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults 18 to 70 years of age, inclusive
- •Unresectable Stage IIIc or IV metastatic melanoma positive for the BRAFV600 mutation or other malignant tumor type which harbors a V600 activating mutation of BRAF, as determined by Cobas 4800 BRAFV600 Mutation Test or a DNA sequencing method
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
- •Life expectancy greater than or equal to (>/=) 12 weeks
- •Participant has not consumed tobacco or nicotine-containing products for 42 days prior to first dose of study drug, and must agree to refrain from such products while on study
- •Adequate hematologic, renal and liver function
排除标准
- •Prior treatment with vemurafenib or other BRAF inhibitor within 42 days of Day 1
- •History of or current clinically significant cardiac or pulmonary dysfunction, including current uncontrolled Grade >/= 2 hypertension or unstable angina
- •Current dyspnea at rest due to complications of advanced malignancy or any requirement for supplemental oxygen
- •Active central nervous system lesions (participants with radiographically unstable, symptomatic lesions)
- •Participants with CYP1A2 gene mutation (-3113G->A), either in one or two alleles
- •Allergy or hypersensitivity to vemurafenib or tizanidine formulations
- •Current severe uncontrolled systemic disease
- •Inability or unwillingness to swallow pills
- •History of malabsorption or other condition that would interfere with enteral absorption of study treatment
- •History of clinically significant liver disease (including cirrhosis), current alcohol abuse, or human immunodeficiency (HIV) infection requiring antiretroviral treatment, acquired immune deficiency syndrome (AIDS)-related illness, or active hepatitis B or C
- •Pregnant or breastfeeding women
研究组 & 干预措施
Pharmacokinetic Population
All participants will receive a 3-period treatment including single-dose tizanidine on Day 1, twice-daily vemurafenib on Days 2 to 21, and both agents together on Day 22.
干预措施: Tizanidine (Drug)
Pharmacokinetic Population
All participants will receive a 3-period treatment including single-dose tizanidine on Day 1, twice-daily vemurafenib on Days 2 to 21, and both agents together on Day 22.
干预措施: Vemurafenib (Drug)
结局指标
主要结局
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Area under the concentration-time curve (AUC)
时间窗: Pre-dose and up to 12 hours post-dose
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Maximum plasma concentration (Cmax)
时间窗: Pre-dose and up to 12 hours post-dose
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Time to maximum plasma concentration (Tmax)
时间窗: Pre-dose and up to 12 hours post-dose
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Terminal half-life (t1/2)
时间窗: Pre-dose and up to 12 hours post-dose
Pharmacokinetics of tizanidine under conditions of vemurafenib steady-state exposure: Apparent clearance (CL/F)
时间窗: Pre-dose and up to 12 hours post-dose
次要结局
- Safety: Incidence, nature and severity of adverse events and serious adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0(Up to approximately 9 months)