A Randomized Phase II Trial of Bevacizumab With Irinotecan or Bevacizumab With Temozolomide in Recurrent Glioblastoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 123
- 试验地点
- 93
- 主要终点
- Number of Participants With Predicted Overall Survival (OS) at 12 Months
研究概览
简要总结
This randomized phase II trial is studying the side effects and how well giving bevacizumab together with irinotecan or temozolomide works in treating patients with recurrent or refractory glioblastoma multiforme or gliosarcoma. 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 tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as irinotecan and temozolomide, 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 or temozolomide may kill more tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. Determine the efficacy of bevacizumab and irinotecan hydrochloride, in terms of 6-month progression-free survival rate, in patients with recurrent or refractory intracranial glioblastoma multiforme or gliosarcoma.
II. Determine the adverse event profile and tolerability of bevacizumab and temozolomide in these patients.
SECONDARY OBJECTIVES:
I. Determine the efficacy of bevacizumab and temozolomide, in terms of 6-month progression-free survival rate, in patients previously treated with temozolomide.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma
- •Original histology of low-grade glioma with subsequent histological diagnosis of GBM or gliosarcoma allowed
- •Recurrent or refractory disease, meeting all of the following criteria:
- •Must have received prior temozolomide
- •Pathologic or imaging confirmation of tumor progression or regrowth required
- •Confirmation of true progressive disease (rather than radiation necrosis) by positron emission tomography, thallium scanning, MRI spectroscopy, or surgical documentation required for patients who received prior interstitial brachytherapy, Gliadel wafer, or stereotactic radiosurgery
- •Unequivocal radiographic evidence of tumor progression by MRI within the past 14 days (while on a stable dose of steroids for ? 5 days)
- •No acute intratumoral hemorrhage on MRI
- •Patients with MRI demonstrating old hemorrhage or subacute blood after a neurosurgical procedure (biopsy or resection) are eligible
- •Karnofsky performance status 70-100%
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception during and for at least 6 months after completion of bevacizumab therapy
- •Systolic blood pressure ? 160 mm Hg or diastolic blood pressure ? 90 mm Hg (antihypertensive medication allowed)
- •Able to undergo brain MRI scans with intravenous gadolinium
- •Absolute neutrophil count ? 1,500 cells/mm?
- •Platelet count ? 100,000 cells/mm?
- •Hemoglobin ? 10 g/dL (transfusion or other intervention allowed)
- •WBC ? 3,000 cells/mm?
- •AST < 2 times upper limit of normal
- •Bilirubin ? 1.6 mg/dL
- •Creatinine < 1.5 mg/dL
- •Urine protein:creatinine ratio ? 0.5 by urinalysis OR total urinary protein < 1,000 mg by 24-hour urine collection
- •INR < 1.4 (for patients not on warfarin)
- •No patients with severely impaired renal function (i.e., estimated glomerular filtration rate < 30 mL/min or on dialysis)
- •No other prior invasive malignancy, except nonmelanomatous skin cancer or carcinoma in situ of the cervix, unless the patient has been disease free and off therapy for that disease for ? 3 years
- •No severe, active comorbidity, defined as any of the following:
- •Transmural myocardial infarction or unstable angina within the past 6 months
- •Evidence of recent myocardial infarction or ischemia manifested as ST elevation of ? 2 mm by EKG performed within the past 14 days
- •New York Heart Association class II-IV congestive heart failure requiring hospitalization within the past 12 months
- •History of stroke or transient ischemic attack within the past 6 months
- •Cerebrovascular accident within the past 6 months
- •Serious and inadequately controlled cardiac arrhythmia
- •Significant vascular disease (e.g., aortic aneurysm or history of aortic dissection)
- •Clinically significant peripheral vascular disease
- •Evidence of bleeding diathesis or coagulopathy
- •Serious or nonhealing wound, ulcer, or bone fracture
- •Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 28 days
- •Acute bacterial or fungal infection requiring intravenous antibiotics at the time of study entry
- •Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 14 days
- •Acquired immune deficiency syndrome (AIDS)
- •No significant traumatic injury within the past 28 days
- •No known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
- •No condition that impairs the ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication; requirement for IV alimentation; prior surgical procedures affecting absorption; or active peptic ulcer disease)
- •No disease that would obscure toxicity or dangerously alter drug metabolism
- •No concurrent major surgical procedures
- •Recovered from prior therapy
- •Recent resection of recurrent or progressive tumor allowed provided the following criteria are met:
- •Failed prior radiotherapy that was completed ? 42 days ago
- •Residual disease after resection of recurrent glioblastoma is not mandated
- 另有 16 项未显示
排除标准
- 未提供
研究组 & 干预措施
Arm I (bevacizumab and temozolomide)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral temozolomide once daily on days 1-21.
干预措施: Bevacizumab (Biological)
Arm I (bevacizumab and temozolomide)
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral temozolomide once daily on days 1-21.
干预措施: Temozolomide (Drug)
Arm II (bevacizumab & irinotecan hydrochloride)
Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15.
干预措施: Bevacizumab (Biological)
Arm II (bevacizumab & irinotecan hydrochloride)
Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15.
干预措施: Irinotecan Hydrochloride (Drug)
结局指标
主要结局
Number of Participants With Predicted Overall Survival (OS) at 12 Months
时间窗: 2 and 8 weeks posttreatment, and every 2 months until 96wks
Magnetic Resonance Imaging with Spectroscopy (MRS or MRSI) metabolic tumor ratios will be used to predict 12-month overall survival (OS). Ratios of NAA/Cho, Cho/Cr, NAA/Cr measured at 2 weeks and 8 weeks and every 2 months until 96wks were used to predict survival, and time to death, evaluated at 96wks, is the determinate of OS at 12 months. Subjects will not be analyzed by arm.
Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Irinotecan Hydrochloride Arm
时间窗: From randomization to six months.
Progression defined as ≥ 25% increase in the size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable or increased. Percentage is calculated by taking the number of patients who have survived 6 months without progression of study disease after study registration in the numerator. The denominator consists of all patients except those who were found retrospectively to be ineligible or who were lost to follow-up after less than 6 months.
Count/Percentage of Patients Discontinuing Treatment Due to Treatment-related Medical Complications(Bevacizumab and Temozolomide Arm)
时间窗: From randomization to end of treatment (treatment can continue up to 24 months for patients with stable or responding tumor).
This endpoint determines tolerability of this treatment arm. If tolerable, then the secondary endpoint of treatment efficacy for this arm occurs. Percentage is calculated by taking the number of patients who did not stop bevacizumab and temozolomide treatment due to medical complications in the numerator. The denominator consists of all patients except those who were found retrospectively to be ineligible or who did not begin treatment.
Number of Participants With Predicted Progression-free Survival at 6 Months (PFS-6)
时间窗: 2 and 8 weeks posttreatment, and every 2 months until 96wks
Magnetic Resonance Imaging with Spectroscopy (MRS or MRSI) metabolic tumor ratios will be used to predict 6-month progression-free survival (PFS-6) over all study participants. Ratios of NAA/Cho, Cho/Cr, NAA/Cr measured at 2 weeks and 8 weeks and every 2 months until 96wks were used to predict survival, and time to progression, evaluated at 96wks, is the determinate of PFS at 6months (PFS-6). Subjects will not be analyzed by arm.
次要结局
- Accuracy of Local PFS 6-mo Interpretation Using Central Review PFS-6 as the Reference Standard(baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment)
- Patients' Best Objective Response (Complete Response, Partial Response, Stable Disease, Progression)(From randomization to death or last follow-up. Patients were followed up to 62.9 months.)
- Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to Patient Response(2 weeks following initiation of protocol treatment (T1))
- Predictive Value of CBV and Lac/NAA in Assessing 6-month Progression-free Survival(2 weeks following initiation of protocol treatment (T1))
- Change in Perfusion MRI Markers at Week 2 as Predictors of 12mo Overall Survival (OS)(Baseline and 2 Weeks)
- Change in Perfusion MRI Markers at Week 8 as Predictors of 12mo Overall Survival (OS)(Baseline and 8 weeks)
- Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Temozolomide Arm(From randomization to six months.)
- Agreement Between Local Interpretation and Central Interpretation of Standard MRI(baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment)
- Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to N-acetylaspartate (NAA) (Lac/NAA) Ratio(2 weeks following initiation of protocol treatment (T1) and at 8 weeks following chemotherapy with bevacizumab (T2))
- Change in Perfusion MRI Markers at Week 16 as Predictors of 12mo Overall Survival (OS)(Baseline and 16 Weeks)