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.
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. II. Determine the efficacy of bevacizumab and irinotecan hydrochloride, in terms of objective response, in patients with measurable disease. III. Determine the efficacy of bevacizumab and temozolomide, in terms of objective response, in patients with measurable disease who were previously treated with temozolomide. IV. Determine the toxicity profile and tolerability of bevacizumab and irinotecan hydrochloride in these patients. TERTIARY OBJECTIVES: I. Assess the potential role of perfusion MRI and magnetic resonance spectroscopy imaging as an early indicator of response to therapy after 2 weeks of treatment with bevacizumab. II. Assess the potential role of perfusion MRI and magnetic resonance spectroscopy imaging as a prognostic indicator based on images taken at baseline, at 2 weeks, and after 2 courses of study treatment. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (\< 50 vs \>= 50 years of age) and Karnofsky performance status (70-80% vs 90-100%). Patients are randomized to 1 of 2 treatment arms with a 2:1 ratio (arm I:arm II). ARM I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral temozolomide once daily on days 1-21. ARM II: Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15. In both arms, treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. All patients undergo MRI at baseline and at every 2 courses (no 2-week MRI) per standard of care until progression or discontinuation of treatment to assess areas of breakdown of the blood-brain barrier. Patients undergo an additional MRI after study therapy. Consenting patients also undergo diffusion and perfusion MRI and magnetic resonance spectroscopic imaging for correlative studies. After completion of study therapy, patients are followed up for at least 1 month.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
123
Mobile Infirmary Medical Center
Mobile, Alabama, United States
Fairbanks Memorial Hospital
Fairbanks, Alaska, United States
Arizona Oncology Services Foundation
Scottsdale, Arizona, United States
Alta Bates Summit Medical Center-Herrick Campus
Berkeley, California, United States
Mills-Peninsula Medical Center
Burlingame, California, United States
Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Irinotecan Hydrochloride Arm
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.
Time frame: From randomization to six months.
Count/Percentage of Patients Discontinuing Treatment Due to Treatment-related Medical Complications(Bevacizumab and Temozolomide Arm)
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.
Time frame: From randomization to end of treatment (treatment can continue up to 24 months for patients with stable or responding tumor).
Number of Participants With Predicted Progression-free Survival at 6 Months (PFS-6)
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.
Time frame: 2 and 8 weeks posttreatment, and every 2 months until 96wks
Number of Participants With Predicted Overall Survival (OS) at 12 Months
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.
Time frame: 2 and 8 weeks posttreatment, and every 2 months until 96wks
Count/Percentage of Patients Progression-free at 6 Months for Bevacizumab and Temozolomide Arm
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.
Time frame: From randomization to six months.
Patients' Best Objective Response (Complete Response, Partial Response, Stable Disease, Progression)
Tumor size measured in millimeters and is the largest crosssectional area using perpendicular measurements of contrast enhancing abnormality. Complete response (CR): Complete disappearance of all enhancing tumor on consecutive MRI scans at least 1 month apart, off corticosteroids, and neurologically stable or improved. Partial response (PR): ≥ 50% decrease in size of enhancing tumor on consecutive MRI scans at least 1 month apart, corticosteroids stable or reduced, and neurologically stable or improved. Progressive disease (PD): ≥ 25% increase in the size of enhancing tumor or any new tumor; or neurologically worse, and steroids stable or increased. Stable disease (SD): Does not qualify for CR, PR, or PD.
Time frame: From randomization to death or last follow-up. Patients were followed up to 62.9 months.
Agreement Between Local Interpretation and Central Interpretation of Standard MRI
Local and central interpretations of the standard MRI were assessed for progression and survival at all available imaging (baseline visit, week 2, and after every 2 cycles of treatment, and at termination of treatment). Patients who suffer clinical progression without radiographic confirmation of progression were considered to have progressive disease in determination of PFS-6. Subjects participated in the MR substudies regardless of therapeutic intervention
Time frame: baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment
Accuracy of Local PFS 6-mo Interpretation Using Central Review PFS-6 as the Reference Standard
Local reads were treated as the test and central reads were treated as the reference standard. Thus, a participant meeting the definition of progression on any standard MRI central interpretation (baseline visit, week 2, after every 2 cycles of treatment, and at termination of treatment) was considered positive for PFS-6. Therefore, a true positive is defined as a positive local interpretation for a subject with a positive central read.
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John Muir Medical Center-Concord Campus
Concord, California, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
Marin General Hospital
Greenbrae, California, United States
Sutter Cancer Research Consortium
Novato, California, United States
California Pacific Medical Center-Pacific Campus
San Francisco, California, United States
...and 83 more locations
Time frame: 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
Aim not included in final (February 10, 2009) protocol (removed from section 2).
Time frame: 2 weeks following initiation of protocol treatment (T1) and at 8 weeks following chemotherapy with bevacizumab (T2)
Correlation of Degree of Cerebral Blood Volume (CBV) and Lactate (Lac) to Patient Response
Aim not included in final (February 10, 2009) protocol (removed from section 2)
Time frame: 2 weeks following initiation of protocol treatment (T1)
Predictive Value of CBV and Lac/NAA in Assessing 6-month Progression-free Survival
Aim not included in final (February 10, 2009) protocol (removed from section 2)
Time frame: 2 weeks following initiation of protocol treatment (T1)
Change in Perfusion MRI Markers at Week 2 as Predictors of 12mo Overall Survival (OS)
To assess the potential role of perfusion MRI as a prognostic indicator for 12-month OS based on the change in MRI markers evaluated before treatment and 2 weeks following initiation of protocol treatment. Percent change in mean tumor relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI normalized to white matter (nRCBV) and standardized rCBV (sRCBV) between baseline and week 2 are the prognostic indicators.
Time frame: Baseline and 2 Weeks
Change in Perfusion MRI Markers at Week 8 as Predictors of 12mo Overall Survival (OS)
To assess the potential role of perfusion MRI as a prognostic indicator for 12-month OS based on the change in MRI markers evaluated before treatment and 8 weeks following initiation of protocol treatment. Percent change in mean tumor relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI normalized to white matter (nRCBV) and standardized rCBV (sRCBV) between baseline and week 8 are the prognostic indicators.
Time frame: Baseline and 8 weeks
Change in Perfusion MRI Markers at Week 16 as Predictors of 12mo Overall Survival (OS)
To assess the potential role of perfusion MRI as a prognostic indicator for 12-month OS based on the change in MRI markers evaluated before treatment and 16 weeks following initiation of protocol treatment. Percent change in mean tumor relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast (DSC) MRI normalized to white matter (nRCBV) and standardized rCBV (sRCBV) between baseline and week 16 are the prognostic indicators.
Time frame: Baseline and 16 Weeks