A Randomized Phase II/III Study of Vorinostat and Local Irradiation OR Temozolomide and Local Irradiation OR Bevacizumab and Local Irradiation Followed by Maintenance Bevacizumab and Temozolomide in Children With Newly Diagnosed High-Grade Gliomas
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 101
- 试验地点
- 132
- 主要终点
- Maximum Tolerated Dose (MTD) of Vorinostat
研究概览
简要总结
This randomized phase II/III trial is studying vorinostat, temozolomide, or bevacizumab to see how well they work compared with each other when given together with radiation therapy followed by bevacizumab and temozolomide in treating young patients with newly diagnosed high-grade glioma. Vorinostat 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. 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. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether giving vorinostat is more effective then temozolomide or bevacizumab when given together with radiation therapy in treating glioma.
详细描述
PRIMARY OBJECTIVES:
I. To identify the dose of vorinostat that is feasible when given in combination with radiotherapy (RT) in patients with newly diagnosed high-grade gliomas (HGG). II. To compare 1-year event-free survival of patients with newly diagnosed HGG treated with vorinostat (using MTD) versus bevacizumab versus temozolomide when given in combination with RT followed by maintenance therapy with bevacizumab and temozolomide. (Phase II) III. To compare the event-free survival of patients with newly diagnosed HGG treated with the superior chemoradiotherapy (from phase II portion) versus temozolomide given in combination with RT followed by maintenance chemotherapy with bevacizumab and temozolomide. (Phase III)
SECONDARY OBJECTIVES:
I. To evaluate the anti-tumor activity, as measured by event-free survival (EFS), progression-free survival (PFS), and overall survival (OS), of patients with newly diagnosed HGG treated with vorinostat, bevacizumab, or temozolomide when given in combination with RT followed by maintenance chemotherapy with bevacizumab and temozolomide. II. To define and evaluate the toxicities of each of the treatment arms of the study.
III. To conduct gene expression profiling and SNP arrays in patients with newly diagnosed HGG.
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
- 3 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed high-grade glioma
- •Anaplastic astrocytoma
- •Glioblastomamultiforme
- •Gliosarcoma
- •Primary spinal cord malignant glioma allowed
- •No oligodendroglioma oroligoastrocytoma
- •Patient must have histological verification of diagnosis
- •No M+ disease (defined as evidence of neuraxis dissemination)
- •No positive CSF cytology
- •ECOG performance status (PS) 0-2
- •Karnofsky PS 50-100% (patients > 16 years of age)
- •Lansky PS 50-100% (patients ≤ 16 years of age)
- •ANC ≥ 1,000/μL
- •Platelet count ≥ 100,000/μL
- •Hemoglobin ≥ 8.0 mg/dL (transfusion independent)
- •Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age and/or gender as follows:
- •0.4 mg/dL (1 month to < 6 months of age)
- •0.5 mg/dL (6 months to < 1 year of age)
- •0.6 mg/dL (1 to < 2 years of age)
- •0.8 mg/dL (2 to < 6 years of age)
- •1.0 mg/dL (6 to < 10 years of age)
- •1.2 mg/dL (10 to < 13 years of age)
- •1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
- •1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
- •Proteinuria < 2+ OR urine; protein ratio (UPC) ≤ 0.5
- •If UPC > 0.5, a 24-hour urine protein should be obtained and level should be < 1,000 mg of protein
- •Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •ALT < 2.5 times ULN
- •Serum albumin ≥ 2 g/dL
- •PT INR ≤ 1.5 times ULN
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception during all study therapy and for ≥ 6 months after completion of bevacizumab
- •Hypertension well controlled (≤ 95^th percentile for age and height if patient is ≤ 17years) by stable doses of medication allowed
- •For patients > 17 years, systolic blood pressure (BP) ≤ 150 mm Hg or diastolic BP ≤ 100 mm Hg)
- •Seizure disorder allowed provided patient is well-controlled and on nonenzyme-inducing anticonvulsants
- •No history of myocardial infarction, severe or unstable angina, clinically significant peripheral vascular disease, ≥ grade 2 heart failure, or serious and inadequately controlled cardiac arrhythmia
- •No known bleeding diathesis or coagulopathy
- •No prior arterial thromboembolic events, including transient ischemic attacks orcerebrovascular accidents
- •No prior diagnosis of a deep venous thrombosis, including pulmonary embolism, and no known thrombophilic condition (e.g., protein S, protein C, antithrombin III deficiency, Factor V Leiden or Factor II G202'0A mutation, homocysteinemia, or antiphospholipid antibody syndrome)
- •No history of an abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
- •No serious or non-healing wound, ulcer, or bone fracture
- •No evidence of significant postoperative intracranial hemorrhage, defined as > 1 cm of blood on postoperative MRI scan (potentially in addition to the postoperative scan) obtained within the past 14days
- •No history of allergic reaction to Chinese hamster ovary cell products or other recombinanthuman antibodies
- •No more than 31 days since definitive surgery
- •Must not have received any prior chemotherapy, radiotherapy, immunotherapy, or bone marrow transplant
- •More than 7 days since major surgical procedure and recovered
- •For patients scheduled to receive bevacizumab:
- •More than 28 days since major procedure
- •More than 14 days since intermediate procedure
- 另有 6 项未显示
排除标准
- 未提供
研究组 & 干预措施
Arm I (vorinostat, Phase II Arm A)
Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Bevacizumab (Biological)
Arm I (vorinostat, Phase II Arm A)
Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Temozolomide (Drug)
Arm I (vorinostat, Phase II Arm A)
Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at the maximum-tolerated dose determined in the feasibility study. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Vorinostat (Drug)
Arm II (temozolomide, Phase II Arm B)
Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Bevacizumab (Biological)
Arm II (temozolomide, Phase II Arm B)
Patients undergo RT as in the feasibility arm and receive temozolomide PO once daily for 42 days by day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Temozolomide (Drug)
Arm III (Bevacizumab, Phase II Arm)
Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Bevacizumab (Biological)
Arm III (Bevacizumab, Phase II Arm)
Patients undergo RT as in the feasibility arm and receive bevacizumab IV over 30-90 minutes on days 22 and 36. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Temozolomide (Drug)
Arm IV (temozolomide, Phase 3 Arm B)
Patients undergo RT as in the Arm II and receive temozolomide PO once daily for 42 days beginning on day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Bevacizumab (Biological)
Arm IV (temozolomide, Phase 3 Arm B)
Patients undergo RT as in the Arm II and receive temozolomide PO once daily for 42 days beginning on day 5 of RT. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Temozolomide (Drug)
Arm V (vorinostat/bevacizumab, Phase 3, Chemoradiotherapy)
Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Bevacizumab (Biological)
Arm V (vorinostat/bevacizumab, Phase 3, Chemoradiotherapy)
Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Temozolomide (Drug)
Arm V (vorinostat/bevacizumab, Phase 3, Chemoradiotherapy)
Patients receive treatment as in phase II, arm I or phase II, arm III, whichever was established as superior in phase II. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Vorinostat (Drug)
Feasibility (vorinostat)
Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Bevacizumab (Biological)
Feasibility (vorinostat)
Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Temozolomide (Drug)
Feasibility (vorinostat)
Patients undergo RT 5 days a week for 6 weeks and receive vorinostat at 230 mg/m2/day. In the event of 2 or more DLTs, participants will de-escalate to vorinostat at 180 mg/m2/day. Patients receive Maintenance therapy of bevacizumab 10mg/kg/dose every 2 weeks and temozolomide 200 mg/m2/dose Days 1-5, for up to twelve cycles in the absence of progressive disease and unacceptable toxicities.
干预措施: Vorinostat (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD) of Vorinostat
时间窗: 10 weeks
The dose of vorinostat in mg/sq m/day to be administered with combination chemotherapy and radiation therapy.
Event-free Survival
时间窗: 1 year after enrollment
Time from enrollment to disease progression, diagnosis of a second malignant neoplasm, death or last follow-up, whichever occurs first. Disease progression is evaluated according to the COG criteria for measurement of brain tumors and is defined to be a ≥ 25% increase in the product of perpendicular diameters of ANY target lesion, taking as reference the smallest product observed since the start of treatment; OR the appearance of one or more new lesions, OR worsening neurologic status not explained by causes unrelated to tumor progression (e.g., anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) PLUS any increase in tumor cross-sectional area (or tumor volume).
次要结局
- Overall Survival(1 year after enrollment)
- Cumulative Incidence of Disease Progression in Each Treatment Arm(1 year after enrollment)