Phase I/II Trial of Concurrent RAD001 (Everolimus) With Temozolomide/Radiation Followed by Adjuvant RAD001/Temozolomide in Newly Diagnosed Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 279
- 试验地点
- 36
- 主要终点
- Phase I: Number of Patients With Dose-limiting Toxicity (DLT)
研究概览
简要总结
RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. 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. Radiation therapy uses high energy x-rays to kill tumor cells. Giving everolimus together with temozolomide and radiation therapy may kill more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of everolimus when given together with temozolomide and radiation therapy and to see how well it works in treating patients with newly diagnosed glioblastoma multiforme.
详细描述
OBJECTIVES:
Primary
- To define the maximum tolerated dose of everolimus (up to an established dose of 10 mg/day) when combined with concurrent radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I)
- To determine the efficacy of everolimus in combination with radiotherapy and temozolomide followed by adjuvant everolimus in combination with temozolomide, as measured by progression-free survival, in these patients. (Phase II)
Secondary
- To characterize the safety profile of everolimus in combination with radiotherapy and temozolomide in these patients. (Phase I)
- To determine the overall survival of these patients. (Phase II)
- To further evaluate the safety profile of everolimus in combination with radiotherapy and temozolomide in these patients. (Phase II)
- To determine if activation of the Akt/mTOR axis predicts response to everolimus. (Phase II)
- To determine if there is an association between tumor MGMT gene methylation status and response to everolimus. (Phase II)
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 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
Ph I: RT + TMZ + RAD001 2.5 mg/day
Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: concurrent temozolomide (Drug)
Ph I: RT + TMZ + RAD001 2.5 mg/day
Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: Radiation therapy (Radiation)
Ph I: RT + TMZ + RAD001 2.5 mg/day
Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: concurrent RAD001 2.5 mg/day (Drug)
Ph I: RT + TMZ + RAD001 2.5 mg/day
Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: post-radiation RAD001 10 mg/day (Drug)
Ph I: RT + TMZ + RAD001 2.5 mg/day
Radiation therapy (RT), concurrent temozolomide (TMZ), and concurrent RAD001 2.5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: post-radiation temozolomide (Drug)
Ph I: RT + TMZ + RAD001 5 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: concurrent temozolomide (Drug)
Ph I: RT + TMZ + RAD001 5 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: Radiation therapy (Radiation)
Ph I: RT + TMZ + RAD001 5 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: concurrent RAD001 5 mg/day (Drug)
Ph I: RT + TMZ + RAD001 5 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: post-radiation RAD001 10 mg/day (Drug)
Ph I: RT + TMZ + RAD001 5 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 5 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: post-radiation temozolomide (Drug)
Ph I: RT + TMZ + RAD001 10 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: concurrent RAD001 10 mg/day (Drug)
Ph I: RT + TMZ + RAD001 10 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: concurrent temozolomide (Drug)
Ph I: RT + TMZ + RAD001 10 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: Radiation therapy (Radiation)
Ph I: RT + TMZ + RAD001 10 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: post-radiation RAD001 10 mg/day (Drug)
Ph I: RT + TMZ + RAD001 10 mg/day
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: post-radiation temozolomide (Drug)
Ph II: RT + TMZ
Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
干预措施: concurrent temozolomide (Drug)
Ph II: RT + TMZ
Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
干预措施: Radiation therapy (Radiation)
Ph II: RT + TMZ
Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
干预措施: post-radiation RAD001 10 mg/day (Drug)
Ph II: RT + TMZ
Radiation therapy and concurrent temozolomide followed by post-radiation temozolomide
干预措施: post-radiation temozolomide (Drug)
Ph II: RT + TMZ + RAD001
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: concurrent RAD001 10 mg/day (Drug)
Ph II: RT + TMZ + RAD001
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: concurrent temozolomide (Drug)
Ph II: RT + TMZ + RAD001
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: Radiation therapy (Radiation)
Ph II: RT + TMZ + RAD001
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: post-radiation RAD001 10 mg/day (Drug)
Ph II: RT + TMZ + RAD001
Radiation therapy, concurrent temozolomide, and concurrent RAD001 10 mg/day followed by post-radiation temozolomide and post-radiation RAD001 10 mg/day.
干预措施: post-radiation temozolomide (Drug)
结局指标
主要结局
Phase I: Number of Patients With Dose-limiting Toxicity (DLT)
时间窗: From start of treatment to eight weeks.
DLT is defined as any of the following events occurring during the first 8 weeks of treatment with RAD001 and temozolomide and attributable to the study drugs: any grade 3 or 4 thrombocytopenia, grade 4 anemia, or grade 4 neutropenia lasting more than 7 days; any non-hematologic grade 3 or greater adverse event (AE), excluding alopecia, despite maximal medical therapy; any grade 4 radiation-induced skin changes; failure to recover from adverse events to be eligible for re-treatment with RAD001 and temozolomide within 14 days of the last dose of either drug; or any episode of non-infectious pneumonitis grade 2, 3, or 4 of any duration. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE
Phase II: Progression-free Survival (PFS)
时间窗: Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months.
Using the Response Assessment in Neuro- Oncology (RANO) criteria, the progression is defined by any of the following: \> 25% increase in sum of the products of perpendicular diameters of enhancing lesions compared to the smallest tumor measurement obtained either at baseline (if no decrease) or best response, on stable or increasing doses of corticosteroids; Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared to baseline scan or best response following initiation of therapy, not due to co-morbid events; Any new lesion; Clear clinical deterioration not attributable to other causes apart from the tumor or changes in corticosteroid dose; Failure to return for evaluation due to death or deteriorating condition; Clear progression of non-measurable disease. PFS time is defined as time from registration to date of progression, death, or last known follow-up (censored). PFS rates are estimated using the Kaplan-Meier method.
次要结局
- Phase II: Overall Survival (OS)(Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months.)
- Phase I: Distribution of Worst Adverse Event Grade(Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months.)
- Phase II: Distribution of Worst Adverse Event Grade(Analysis occured after 134 events (progression or death) were reported. Patients were followed from randomization to death or study termination whichever occurs first, up to 36.7 months.)