A Phase I/II Trial of Hydroxychloroquine in Conjunction With Radiation Therapy and Concurrent and Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma Multiforme
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 92
- 试验地点
- 9
- 主要终点
- (Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ)
研究概览
简要总结
RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine and 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 hydroxychloroquine 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 hydroxychloroquine when given together with radiation therapy and temozolomide and to see how well they work in treating patients with newly diagnosed glioblastoma multiforme.
详细描述
OBJECTIVES:
Primary
- Determine the maximum tolerated dose of hydroxychloroquine when administered in combination with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma multiforme. (Phase I)
- Assess the toxicity of this regimen in these patients. (Phase I)
- Determine the overall survival of patients treated with this regimen. (Phase II)
Secondary
- Assess the frequency of toxicity of this regimen in these patients. (Phase II)
- Evaluate the pharmacokinetics and pharmacodynamics of this regimen in these patients.
- Correlate the average change in autophagic vesicles from baseline with genotype, toxicity, and clinical outcomes.
- Correlate the presence of TP53 and PTEN genes and BECN1 with toxicity and clinical outcomes.
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 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
Phase 1: RT+TMZ+HCQ 200 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Starting dose of HCQ is 200mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: hydroxychloroquine (Drug)
Phase 1: RT+TMZ+HCQ 200 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Starting dose of HCQ is 200mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: temozolomide (Drug)
Phase 1: RT+TMZ+HCQ 200 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Starting dose of HCQ is 200mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: pharmacological study (Other)
Phase 1: RT+TMZ+HCQ 200 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT. Starting dose of HCQ is 200mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: Radiation (Radiation)
Phase 1: RT+TMZ+HCQ 400 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 400 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: hydroxychloroquine (Drug)
Phase 1: RT+TMZ+HCQ 400 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 400 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: temozolomide (Drug)
Phase 1: RT+TMZ+HCQ 400 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 400 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: pharmacological study (Other)
Phase 1: RT+TMZ+HCQ 400 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 400 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: Radiation (Radiation)
Phase 1: RT+TMZ+HCQ 600 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 600 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: hydroxychloroquine (Drug)
Phase 1: RT+TMZ+HCQ 600 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 600 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: temozolomide (Drug)
Phase 1: RT+TMZ+HCQ 600 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 600 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: pharmacological study (Other)
Phase 1: RT+TMZ+HCQ 600 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 600 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: Radiation (Radiation)
Phase 1: RT+TMZ+HCQ 800 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 800 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: hydroxychloroquine (Drug)
Phase 2: RT + TMZ + HCQ MTD
Phse 2: daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and concomitant temozolomide for 6wks during RT. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
Other: pharmacological study (PK)
Pts will continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 2
Radiation (RT)
干预措施: pharmacological study (Other)
Phase 1: RT+TMZ+HCQ 800 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 800 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: temozolomide (Drug)
Phase 1: RT+TMZ+HCQ 800 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 800 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: pharmacological study (Other)
Phase 1: RT+TMZ+HCQ 800 mg
Phse I: daily hydroxychloroquine (HCQ) on 1st day of RT and concomitant temozolomide for 6wks during RT, 800 mg. After 6 wks, 4 wkd of HCQ alone daily. this will complete 10 week cycle. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
cohorts of three pts: dose levels: 200, 400, 800mg. NO dose escalation beyond 800mg.
Other: pharmacological study (PK)
pts continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 1
Radiation (RT)
干预措施: Radiation (Radiation)
Phase 2: RT + TMZ + HCQ MTD
Phse 2: daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and concomitant temozolomide for 6wks during RT. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
Other: pharmacological study (PK)
Pts will continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 2
Radiation (RT)
干预措施: hydroxychloroquine (Drug)
Phase 2: RT + TMZ + HCQ MTD
Phse 2: daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and concomitant temozolomide for 6wks during RT. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
Other: pharmacological study (PK)
Pts will continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 2
Radiation (RT)
干预措施: temozolomide (Drug)
Phase 2: RT + TMZ + HCQ MTD
Phse 2: daily hydroxychloroquine (HCQ) (MTD 600mg) on 1st day of RT and concomitant temozolomide for 6wks during RT. After 6 weeks, 4 weeks of HCQ alone daily. Complete 10 week cycle -Initiation Phase
Maintenance cycles 1-6 HCQ daily TMZ D 1-5 150-200mg/m2 every 28 days. Cycles 7+ mono therapy of HCQ daily, every 28 days.
Other: pharmacological study (PK)
Pts will continue on treatment until tumor progression. PKs - correlatives will be collected in Phase 2
Radiation (RT)
干预措施: Radiation (Radiation)
结局指标
主要结局
(Phase I) Maximum Tolerated Dose (MTD) of Hydroxychloroquine (HCQ)
时间窗: 10 weeks
Number of participants who tolerated doses of HCQ without dose limiting toxicity. The highest dose at which participants did not experience dose limiting toxicity was determined as the MTD.
(Phase II) Overall Survival
时间窗: 2 years
Number of months alive after end of study participation
(Phase I) Number of Participants Who Experienced Dose Limiting Toxicity (DLT)
时间窗: 10 weeks
Dose limiting toxicity defined as: Any DLT must be a toxicity considered at least possibly related to HCQ. DLTs will include any possibly, probably, or definitely HCQ-related Grade 3 or 4 toxicity. Known or reasonably suspected TMZ hematological toxicities will not be considered dose limiting unless the treating physician considers the toxicity to be exacerbated by HCQ. Nonhematological toxicities: Any Grades 3-4 severity (except nausea and vomiting without sufficient antiemetic prophylaxis)
次要结局
- (Phase II) Number of Participants With Grade 3 and 4 Toxicity(up to 2 years)
- Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition(up to 9 weeks)
- Pharmocodynamics as Determined by Number of Participants With Autophagy Inhibition in Relation to Maximal Concentration (Cmax) of HCQ(up to 9 weeks)
- Pharmacokinetics (PK) of Hydroxychloroquine as Measured by Lag Time (Tlag)(up to 276 days)
- PK of Hydroxychloroquine as Measured by Oral Clearance (Liters/Hour) From Central Compartment (CL/F)(up to 276 days)
- PK of Hydroxychloroquine as Measured by Volume of Distribution of Central Compartment (V/F)(up to 276 days)
- PK of Hydroxychloroquine as Measured by Distribution Volume of Peripheral Compartment (V2/F)(up to 276 days)
- PK of Hydroxychloroquine as Measured by First-order Absorption Rate Constant (Ka)(up to 276 days)