Bevacizumab and Irinotecan or Temozolomide in Treating Patients With Recurrent or Refractory Glioblastoma Multiforme or Gliosarcoma

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Phase II Trial of Bevacizumab With Irinotecan or Bevacizumab With Temozolomide in Recurrent Glioblastoma

Conditions
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Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Neoplasm

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Irinotecan Hydrochloride
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 More than 28 days since prior surgery or open biopsy More than 7 days since prior core or needle biopsy At least 28 days since prior investigational agents At least 14 days since prior vincristine At least 42 days since prior nitrosoureas At least 21 days since prior procarbazine At least 28 days since other prior cytotoxic therapy At least 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin [except radiosensitizers]) At least 14 days since prior enzyme-inducing antiepileptic drugs (EIAEDs) Concurrent non-hepatic EIAEDs allowed No other concurrent CYP3A4 inducers, such as rifampin or Hypericum perforatum (St. John's wort) Concurrent full-dose anticoagulants (e.g., warfarin or low molecular weight heparin) allowed provided all of the following criteria are met: No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) In-range INR (usually between 2 and 3) on a stable dose of oral anticoagulants or on a stable dose of low molecular weight heparin No concurrent highly active antiretroviral therapy No concurrent prophylactic use of growth factors

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (bevacizumab and temozolomide)<br>Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and oral temozolomide once daily on days 1-21. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Temozolomide<br>* Given orally<br>* Other names: Temomedac;|
| Experimental: Arm II (bevacizumab & irinotecan hydrochloride)<br>Patients receive bevacizumab IV as in Arm I followed by irinotecan hydrochloride IV over 90 minutes on days 1 and 15. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 2 and 8 weeks posttreatment, and every 2 months until 96wks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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 | 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. | 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). | 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) | 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) | 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. | 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. | 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. | Baseline and 16 Weeks |