Phase II Study of Bevacizumab Plus Irinotecan (Camptosar™) in Children With Recurrent, Progressive, or Refractory Malignant Gliomas, Diffuse/Intrinsic Brain Stem Gliomas, Medulloblastomas, Ependymomas and Low Grade Gliomas
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 97
- 试验地点
- 11
- 主要终点
- Objective Response Rate Sustained for ≥ 8 Weeks
研究概览
简要总结
This phase II trial is studying how well giving bevacizumab together with irinotecan works in treating young patients with recurrent, progressive, or refractory glioma, medulloblastoma, ependymoma, or low grade glioma. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of glioma by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with irinotecan may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in pediatric patients with recurrent, progressive, or refractory malignant glioma (Stratum A [closed to accrual as of 4/21/2009]) or recurrent/progressive/refractory intrinsic brain stem glioma (Stratum B [closed to accrual as of 4/21/2009]).
II. Estimate the rates of objective response observed prior to disease progression during the first four courses of treatment with bevacizumab and irinotecan hydrochloride in patients with recurrent or progressive medulloblastoma (Stratum C [closed to accrual as of 10/27/2009]) or recurrent or progressive ependymoma (Stratum D [closed to accrual as of 7/29/2010]).
III. Estimate the sustained disease stabilization rate associated with bevacizumab and irinotecan in patients with recurrent or progressive low grade glioma (Stratum E [closed to accrual as of 7/29/2010]).
SECONDARY OBJECTIVES:
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
- — 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed high-grade glioma (WHO grade III or IV) at any site within the brain, including the following:
- •Anaplastic astrocytoma
- •Glioblastoma multiforme (including giant cell and gliosarcoma subtypes)
- •Anaplastic oligodendroglioma
- •Anaplastic ganglioglioma
- •Anaplastic oligoastrocytoma
- •Diffuse brain stem glioma
- •Histologic confirmation not required
- •Histologically confirmed medulloblastoma
- •Histologically confirmed ependymoma
- •Primary spinal cord malignant glioma with measurable metastatic disease within the brain
- •Histologic confirmation required
- •Neuraxis dissemination allowed provided there is bidimensionally measurable disease within the brain and spinal cord
- •Low grade glioma at any site within the brain with or without spinal cord disease
- •Recurrent, progressive, or refractory disease (must have received prior chemoradiotherapy)
- •No more than 2 prior chemotherapy regimens following relapse
- •Bidimensionally measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 2 planes
- •If there is spinal cord disease as well, response assessment will be based only upon the measurable tumor in the brain
- •No diffuse gliomatosis cerebri with < 1 discrete, measurable lesion
- •No evidence of new symptomatic CNS hemorrhage (> grade 2) within the past 2 weeks
- •No central non-cerebellar PNET's (e.g., cerebral PNET or pineoblastoma)
- •No spinal cord tumors only
- •Karnofsky performance status (PS) 50-100% (> 16 years of age) OR Lansky PS 50-100% (≤ 16 years of age)
- •Absolute neutrophil count ≥ 1,500/mm³ (unsupported)
- •Platelet count ≥ 100,000/mm³ (unsupported)
- •Hemoglobin > 8 g/dL (support allowed)
- •Creatinine normal
- •BUN < 25 mg/dL
- •Bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •ALT and AST ≤ 3 times ULN
- •Neurological deficits must be stable for ≥ 1 week prior to study entry
- •No active renal, cardiac (congestive cardiac failure, myocarditis), or pulmonary disease
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception during and for ≥ 6 months after completion of study treatment
- •No clinically significant unrelated systemic illness that would preclude study treatment, including any of the following:
- •Serious infections
- •Significant cardiac, pulmonary, hepatic, or other organ dysfunction
- •No uncontrolled systemic hypertension, defined as systolic blood pressure (BP) and/or diastolic BP > 95th percentile for age
- •No stroke, myocardial infarction, or unstable angina within the past 6 months
- •No clinically significant peripheral vascular disease
- •No significant traumatic injury within the past 6 weeks
- •No evidence of bleeding diathesis, coagulopathy, or PT INR > 1.5
- •Urine protein/creatinine ratio ≤ 1.0
- •No abdominal fistula or gastrointestinal perforation within the past 6 months
- •No serious nonhealing wound, ulcer, or bone fracture
- •At least 3 weeks since prior myelosuppressive anticancer chemotherapy (6 weeks for nitrosoureas)
- •At least 7 days since prior investigational or biologic agents (3 weeks if patient experienced ≥ grade 2 myelosuppression or if agent has a prolonged half-life)
- •More than 7 days since prior minor surgery
- •More than 12 weeks since prior craniospinal or focal irradiation to primary tumor or other sites
- 另有 11 项未显示
排除标准
- 未提供
研究组 & 干预措施
Arm I
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment.
干预措施: Bevacizumab (Biological)
Arm I
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment.
干预措施: Fludeoxyglucose F-18 (Radiation)
Arm I
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and irinotecan hydrochloride IV over 90 minutes on day 16 or 17 for course 1. Patients receive bevacizumab and irinotecan hydrochloride on days 1 and 15 for all subsequent courses. Treatment repeats every 4 weeks for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Patients undergo MRIs of the brain, magnetic resonance perfusion/diffusion, and fludeoxyglucose F 18 positron emission tomography at baseline and periodically during treatment.
干预措施: Irinotecan Hydrochloride (Drug)
结局指标
主要结局
Objective Response Rate Sustained for ≥ 8 Weeks
时间窗: From day 1 of treatment up to 24 weeks
Objective response is either a complete response or a partial response observed during the first four courses of treatment and sustained for 8 weeks. The objective response rate will be reported separately for patients with recurrent/progressive malignant glioma(Stratum A), recurrent/progressive instrinsic brain stem tumors(Stratum B), recurrent/progressive medulloblastoma(Stratum C), and recurrent/progressive ependymoma(Stratum D). CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size. This outcome measures is not defined for the Stratum E in the protocol.
Sustained Disease Stabilization Rate Associated With Bevacizumab and Irinotecan in Patients With Recurrent or Progressive Low-grade Glioma (Stratum E)
时间窗: From day 1 of treatment up to 24 weeks
Disease stabilization is defined as a complete response(CR) or partial response(PR) observed during the first four courses and sustained for 8 weeks; or stable disease (SD) sustained for 6 courses characterized by SD at the end of course 2, at the end of course 4 and at the end of course 6. CR is complete disappearance of all enhancing tumor. PR is \>= 50% reduction in tumor size. SD is at least stable and maintenance corticosteroid dose not increased in neurologic examination.
次要结局
- Change in Perfusion Ratio Between the Baseline and Day 15 Brain Imaging(Baseline and day 15)
- Association of Log-transformed Tumor Volume Based on FLAIR With Progression-free Survival (PFS) Using Hazard Ratio Estimates(From start of treatment until the earliest of progressive disease, death, second malignancy or off study OR up to 2 years)
- Correlation of the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline With the Change in Perfusion From Magnetic Resonance Imaging(Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1)
- Number of Study Participants With Grade 3 or 4 Treatment-related Toxicity(From day 1 of treatment until off study)
- Progression-free Survival(From start of treatment up to 2 years)
- Change in Diffusion Ratio Between the Baseline and Day 15 Brain Image(Baseline and day 15)
- Association of Log-transformed Tumor Diffusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates(From start of treatment until the earliest of progressive disease, death, second malignancy or off study)
- Cumulative Incidence of Sustained Objective Responses(From the first imaging after treatment up to 2 years)
- Systemic Clearance(Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1)
- Number of Patients With High VEGF-A Expression at Baseline(Baseline)
- Number of Patients With High VEGF-R2 Expression at Baseline(Baseline)
- Association of Log-transformed Tumor Enhancing Volume With Progression-free Survival (PFS) Using Hazard Ratio Estimates(From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years)
- Volume of Distribution(Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1)
- Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) From Baseline to Day-15(Baseline and 24-48 hours after the 2nd dose of Bevacizumab in course 1)
- Progression-free Survival Hazard Ratio by Carbonic Anhydrase 9 (CA9) Expression(From start of treatment until the earliest of progressive disease, death, second malignancy or off study)
- Progression-free Survival Hazard Ratio by VEGF-A Expression(From start of treatment until the earliest of progressive disease, death, second malignancy or off study)
- Association of Log-transformed Volume of Cystic Necrosis With Progression-free Survival (PFS) Using Hazard Ratio Estimates(From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years)
- Descriptive Statistics for the Change of Perfusion in Magnetic Resonance Imaging Concurrently Measured With the Change in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC)(Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1)
- Number of Patients With High Hypoxia Inducible Factor-2alpha Expression at Baseline(Baseline)
- Number of Patients With High Carbonic Anhydrase 9 Expression at Baseline(Baseline)
- Progression-free Survival Hazard Ratio by Hypoxia Inducible Factor-2alpha Expression(From start of treatment until the earliest of progressive disease, death, second malignancy or off study)
- Association of Log-transformed Tumor Perfusion Ratio With Progression-free Survival (PFS) Using Hazard Ratio Estimates(From start of treatment until the earliest of progressive disease, death, second malignancy or off study, OR up to 2 years)
- Terminal Half-life(Baseline, Course 1 Day 1, Course 1 Day 15, Course 2 Day 1, Course 3 Day 1, Course 4 Day 1, and Course 5 Day 1)
- Descriptive Statistics for the Changes in Vascular Endothelial Growth Factor Receptor-2 (VEGF-R2) Expression in Peripheral Blood Mononuclear Cells (PBMC) Concurrently Measured With the Changes in Perfusion From Magnetic Resonance Imaging(Baseline and Day 15 (after 2 doses of Bevacizumab) of course 1)
- Progression-free Survival Hazard Ratio by VEGF-R2 Expression(From start of treatment until the earliest of progressive disease, death, second malignancy or off study)