Phase I/II Adaptive Randomized Trial of Bevacizumab Versus Bevacizumab Plus Vorinostat in Adults With Recurrent Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 96
- 试验地点
- 1
- 主要终点
- Progression Free Survival (PFS) at 6 Months
研究概览
简要总结
The goal of this Phase I portion of this clinical research study is to find the highest tolerable dose of bevacizumab with or without vorinostat, that can be given to patients with malignant gliomas. The safety of these drug combinations will also be studied.
The goal of this Phase II part of this clinical research study is to learn if bevacizumab when given with or without vorinostat can help to control malignant gliomas. The safety of these drug combinations will also be studied.
详细描述
Background
- Glioblastoma (GBM) is the most common primary brain tumor. With optimal treatment, consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor progression within one year of diagnosis despite treatment. At progression, treatment options are limited and mostly ineffective.
- Given the importance of angiogenesis in GBM, anti-angiogenic therapy is a promising strategy in recurrent GBM. Bevacizumab, the first angiogenesis inhibitor approved against cancer by FDA based on improved survival of advanced colon cancer patient, has recently been studied in the GBM.
- The present study aims to determine the potential of vorinostat, an HDAC inhibitor plus bevacizumab, versus bevacizumab alone, in an attempt to increase the anti-angiogenic effects of VEGF by blocking the evasive resistance by combination with vorinostat and to also not only provide the potential of the independent effects of both agents but also the potential for synergy.
Objectives
- To determine the maximum tolerated dose (MTD) of vorinostat plus bevacizumab in adult patients with malignant glioma.
- To determine the efficacy of vorinostat plus bevacizumab versus bevacizumab alone in patients with recurrent WHO grade IV glioma (glioblastoma and gliosarcoma) as determined by progression free survival (PFS) using an adaptive randomization phase II trial design.
Eligibility
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 99 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
Bevacizumab
10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.
干预措施: bevacizumab (Drug)
Vorinostat and Bevacizumab
Vorinostat: 400 mg/day by mouth on days 1 to 7 and days 15 to 21 of a 28 day cycle.
Bevacizumab: 10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.
干预措施: vorinostat (Drug)
Vorinostat and Bevacizumab
Vorinostat: 400 mg/day by mouth on days 1 to 7 and days 15 to 21 of a 28 day cycle.
Bevacizumab: 10 mg/kg/dose by vein on days 1 and 15 of a 28 day cycle.
干预措施: bevacizumab (Drug)
结局指标
主要结局
Progression Free Survival (PFS) at 6 Months
时间窗: Baseline until disease progression or death due to any cause, up to six months
PFS is time measured in months to disease progression as assessed at six months from participant registration. Assessments continue every 8 weeks up to 28 days after last dose (follow-up), anticipated trial length one year. Participants must be assessed at least 4 weeks after surgery to begin treatment in the adaptive randomized Phase 2 portion of the trial. PFS in participants in the surgical arm determined from the date of randomization to the treatment arms and not from the date of registration in the trial. Study outcome measure period ended June 2015.
Maximum Tolerated Dose (MTD) of Oral Vorinostat Used With Bevacizumab
时间窗: 28 day, cycle 1
MTD defined as the dose level at which 1/6 patients experience dose limiting toxicity (DLT), using conventional Phase I design where the MTD was selected using a 3+3 accrual design at each dose level until MTD was determined. Toxicities will be graded according to the Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.
次要结局
- Mean Symptom Interference at the Time of Clinical Evaluation(Baseline, (cycle 2), week 8 (cycle 4), and end of therapy, approximately week 52 (cycle 12))
- Overall Survival (OS)(up to 30 months.)
- Time to Progression (TTP)(3, 6, and 12 months from patient registration)
- Effects of Bevacizumab With and Without Vorinostat Upon Biomarkers of Angiogenesis Vascular Endothelial Growth Factor (VEGF), Placental Growth Factor (PIGF), and Basic Fibroblast Growth Factor (bFGF)(Baseline before treatment, Cycle 1 Day 2, day 15 (pre-infusion and post-infusion), Cycle 2 (pre-infusion))
- Effects of Bevacizumab With and Without Vorinostat Upon Biomarkers of Angiogenesis Stromal Cell-derived Factor α (SDF1α), and Angiopoietin 1 (Ang 1) and 2 (Ang 2) by Enzyme-linked Immunosorbent Assay (ELISA)(Baseline before treatment, Cycle 1 Day 2, day 15 (pre-infusion and post-infusion), Cycle 2 (pre-infusion))
- Percentage of Patients Rating Their Symptoms to be 7 or Greater on a 0-10 Scale Using the Mean Severity of the MD Anderson Symptom Inventory-Brain Tumor Module (MDSAI-BT) Self Reporting Tool(Baseline, week 4, week 8, and end of therapy, approximately week 52 (cycle 12))
- Number of Participants With Serious and Non-Serious Adverse Events(Phase I adverse events collected within 4 week (28 day) cycle. Phase II evaluated for adverse events after each cycle for first 2 cycles and subsequently after each 2 cycles of treatment prior to initiating the next cycle.)
- Mean Symptom Severity Using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) Self Reporting Tool(Baseline, week 4 (cycle 2), week 8 (cycle 4), and end of therapy, approximately week 52 (cycle 12))
- Radiological Response(End of therapy, approximately)
研究者
Mark Gilbert, M.D.
Principal Investigator
National Cancer Institute (NCI)