A Phase I Open Label Safety Study to Evaluate the Pharmacokinetic Profile and Tolerance of Mibefradil Dose Finding in Subjects With Recurrent High-Grade Glioma Undergoing Standard, Repeated Temozolomide Treatment
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 7
- 主要终点
- Dose-limiting toxicity
研究概览
简要总结
RATIONALE: Mibefradil dihydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.
PURPOSE: This phase I trial is studying the best dose of mibefradil dihydrochloride when given together with temozolomide in treating patients with glioma.
详细描述
OBJECTIVES:
Primary
- Determine the maximum-tolerated dose (MTD) of mibefradil dihydrochloride administered prior to five days of temozolomide (TMZ) at 150-200 mg/m² in subjects with progressive or recurrent high-grade glioma.
Secondary
- Assess the safety of mibefradil dihydrochloride administered prior to five days of TMZ at 150-200 mg/m² when the mibefradil dihydrochloride dose is escalated from a starting dose of 100 mg/day, given four times a day for seven consecutive days.
- Determine the pharmacokinetic profile of mibefradil.
- Determine the steady state levels of mibefradil dihydrochloride on the last day of dosing.
- Assess the severity and frequency of adverse events for tested mibefradil dihydrochloride dose levels including cumulative toxicity and/or tolerance to adverse effects.
- Estimate the number and type of radiographic responses to treatment with mibefradil dihydrochloride and temozolomide.
- Assess the potential effect of mibefradil dihydrochloride on tumor metabolism as determined by Fluorothymidine Positron Emission Tomography (FLT PET) scans with the radiotracer [18F]-3'-fluoro-3'-deoxy-L-thymidine (dose-expansion cohort only).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（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
Dose Finding and Dose Expansion
DOSE FINDING 4 Levels
For all Levels:
Cycle 1 Mibefradil QID dosing, Days 1-8 (to accommodate PKs) (*2 doses on Days 1 and 8) Temozolomide daily at 150-200 mg/m2, Days 9-13;
Cycles 2+ Mibefradil QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
DOSE EXPANSION 28-day cycles FLT PET scans, Baseline x2, Day 7 Mibefradil MTD determined at Dose Finding QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
干预措施: temozolomide (Drug)
Dose Finding and Dose Expansion
DOSE FINDING 4 Levels
For all Levels:
Cycle 1 Mibefradil QID dosing, Days 1-8 (to accommodate PKs) (*2 doses on Days 1 and 8) Temozolomide daily at 150-200 mg/m2, Days 9-13;
Cycles 2+ Mibefradil QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
DOSE EXPANSION 28-day cycles FLT PET scans, Baseline x2, Day 7 Mibefradil MTD determined at Dose Finding QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
干预措施: 3'-deoxy-3'-[18F]fluorothymidine (Other)
Dose Finding and Dose Expansion
DOSE FINDING 4 Levels
For all Levels:
Cycle 1 Mibefradil QID dosing, Days 1-8 (to accommodate PKs) (*2 doses on Days 1 and 8) Temozolomide daily at 150-200 mg/m2, Days 9-13;
Cycles 2+ Mibefradil QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
DOSE EXPANSION 28-day cycles FLT PET scans, Baseline x2, Day 7 Mibefradil MTD determined at Dose Finding QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
干预措施: pharmacological study (Other)
Dose Finding and Dose Expansion
DOSE FINDING 4 Levels
For all Levels:
Cycle 1 Mibefradil QID dosing, Days 1-8 (to accommodate PKs) (*2 doses on Days 1 and 8) Temozolomide daily at 150-200 mg/m2, Days 9-13;
Cycles 2+ Mibefradil QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
DOSE EXPANSION 28-day cycles FLT PET scans, Baseline x2, Day 7 Mibefradil MTD determined at Dose Finding QID, Days 1-7 Temozolomide daily at 150-200 mg/m2, Days 8-12
干预措施: Mibefradil (Drug)
结局指标
主要结局
Dose-limiting toxicity
时间窗: 2 years
Maximum-tolerated dose of mibefradil dihydrochloride
时间窗: 2 years
Determine the maximum tolerated dose (MTD) of mibefradil administered prior to five days of temozolomide (TMZ) at 150-200 mg/m2 in subjects with progressive or recurrent high grade glioma.
次要结局
- Toxicity and adverse events according to CTCAE v. 4.0(2 years)
- Biological activity of treatment determined by radiographic response(3 years)
- Pharmacokinetics of mibefradil dihydrochloride as measured by the steady-state maximum plasma concentration (Cmax)(Day 8)
- Potential effect of mibefradil dihydrochloride on tumor metabolism as determined by [F-18]FLT PET scans in the dose-expansion cohort(6 months)