Bevacizumab and Sorafenib in Treating Patients With Recurrent Glioblastoma Multiforme

Study Overview
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Brief Summary
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RATIONALE: 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. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab and sorafenib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving bevacizumab together with sorafenib may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects and how well giving bevacizumab together with sorafenib works in treating patients with recurrent glioblastoma multiforme.

Detailed Description
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OBJECTIVES: Primary Identify the clinical efficacy of bevacizumab and sorafenib, as measured by 6-month progression-free survival, in patients with recurrent glioblastoma multiforme. Secondary Assess time to progression of this patient population. Assess overall survival of this patient population. OUTLINE: This is a multicenter study. Patients receive oral sorafenib once daily on days 1-14 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and plasma sample collection at baseline and then periodically during study treatment for translational research studies. Translational research studies include analysis of circulating endothelial cells and circulating endothelial progenitor cells by flow cytometry and measurement of angiogenic proteins in plasma by ELISA. DNA and buffy coat are extracted and collected from the blood samples for pharmacogenetic studies. Quality of life is assessed at baseline, prior to every other treatment course, and at the end of treatment. After completion of study treatment, patients are followed at 28-42 days, every 3 months for 5 years, and then annually for 10 years.

Official Title
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Phase II Trial of Bevacizumab in Combination With Sorafenib in Recurrent Glioblastoma Multiforme

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Biological: bevacizumab
* Drug: sorafenib tosylate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed glioblastoma multiforme as determined by pre-registration central pathology review Gliosarcoma allowed Must have evidence of tumor progression by MRI or CT scan following radiotherapy or the most recent anti-tumor therapy No more than 1 chemotherapy regimen for progressive or recurrent disease Bidimensionally measurable or evaluable disease by MRI or CT scan No evidence of CNS hemorrhage on baseline CT or MRI Patients with T1 hyperintensity confined to the surgical cavity which is felt likely due to post surgical blood contaminating the intracavity cerebrospinal fluid or irrigation that have not yet absorbed and which is not felt to clinically or radiographically represent new spontaneous hemorrhage are eligible Patients with old blood products or hemosiderin without a history of spontaneous bleeding are eligible PATIENT CHARACTERISTICS: ECOG performance status 0-2 ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin > 9.0 g/dL Total bilirubin ≤ 1.5 times upper limit of normal AST ≤ 3 times upper limit of normal Creatinine ≤ upper limit of normal Urine protein:creatinine ratio < 1 OR urine protein < 1,000 mg by 24-hour urine collection Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for six months after completion of study treatment Able to complete questionnaire(s) alone or with assistance Willing to return to NCCTG enrolling institution for follow-up Willing to provide mandatory blood samples for research purposes Not immunocompromised (other than that related to the use of corticosteroids) No known HIV positivity No concurrent uncontrolled illness including, but not limited to, the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements No inadequately controlled hypertension (i.e., systolic blood pressure [BP] > 150 mm Hg or diastolic BP > 100 mm Hg while on antihypertensive medications) Patients with well-controlled hypertension are eligible No myocardial infarction or unstable angina within the past 6 months No congestive heart failure requiring the use of ongoing maintenance therapy for life-threatening ventricular arrhythmias No New York Heart Association class II-IV congestive heart failure No significant vascular disease (e.g., aortic aneurysm or aortic dissection) No peripheral arterial thrombosis within the past 6 months No stroke or transient ischemic attack within the past 6 months No history of hypertensive crisis or hypertensive encephalopathy No evidence of bleeding diathesis (greater than normal risk of bleeding) or coagulopathy (in the absence of therapeutic anticoagulation) No active or recent history of hemoptysis (i.e., ≥ ½ teaspoon of bright red blood per episode) within the past 30 days No serious, nonhealing wounds, ulcers, or bone fractures No condition that impairs the ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation) No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months No significant traumatic injury within the past 28 days No known hypersensitivity to any of the components of sorafenib or bevacizumab No other active malignancy within the past 3 years, except nonmelanoma skin cancer or carcinoma in situ of the cervix Patients with a history of prior malignancy must not be receiving specific treatment (other than hormonal therapy) for that malignancy No co-morbid systemic illness or other concurrent severe disease that, in the judgment of the investigator, would make the patient inappropriate for entry into this study or significantly interfere with the proper assessment of safety and toxicity of the prescribed study regimen PRIOR CONCURRENT THERAPY: See Disease Characteristics At least 12 weeks since prior radiotherapy More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) More than 2 weeks since prior small molecule cell cycle inhibitors At least 1 week since prior fixed-dose corticosteroids (or no corticosteroids) No prior intratumoral chemotherapy, stereotactic radiosurgery or interstitial brachytherapy unless there is a separate lesion on MRI that is not part of the prior treatment field OR there is proof of recurrent disease based on biopsy, MRI spectroscopy, or PET scan No prior antiangiogenic therapy No prior surgical procedures affecting absorption More than 7 days since prior core biopsy or other minor surgical procedures Placement of a vascular access device is allowed More than 28 days since prior major surgical procedure or open biopsy No concurrent major surgical procedure No other concurrent investigational agents No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin, fosphenytoin, carbamazepine, phenobarbital, or primidone) No other concurrent potent CYP3A4 inducers (e.g., rifampin or St. John's wort) No concurrent therapeutic anticoagulation with warfarin Prophylactic anticoagulation (i.e., low-dose warfarin) for venous or arterial access devices allowed provided the INR < 1.5 Therapeutic anticoagulation with low molecular weight heparin allowed

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib + Bevacizumab/Group A<br>Patients receive oral sorafenib 400 mg (200 mg twice daily) days 1-5 and 8-12 and 5 mg/kg bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days. Patients undergo blood and plasma sample collection at baseline and then periodically during study treatment for translational research studies. Translational research studies include analysis of circulating endothelial cells and circulating endothelial progenitor cells by flow cytometry and measurement of angiogenic proteins in plasma by ELISA. DNA and buffy coat are extracted and collected from the blood samples for pharmacogenetic studies. Quality of life is assessed at baseline, prior to every other treatment course, and at the end of treatment. After completion of study treatment, patients are followed at 28-42 days, every 3 months for 5 years, and then annually for 10 years. | Biological: bevacizumab<br> <br> Drug: sorafenib tosylate<br> <br> |
| Experimental: Sorafenib + Bevacizumab /Group B<br>Patients receive oral sorafenib 200 mg once daily on days 1-14 and 5 mg/kg bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 14 days. Patients undergo blood and plasma sample collection at baseline and then periodically during study treatment for translational research studies. Translational research studies include analysis of circulating endothelial cells and circulating endothelial progenitor cells by flow cytometry and measurement of angiogenic proteins in plasma by ELISA. DNA and buffy coat are extracted and collected from the blood samples for pharmacogenetic studies. Quality of life is assessed at baseline, prior to every other treatment course, and at the end of treatment. After completion of study treatment, patients are followed at 28-42 days, every 3 months for 5 years, and then annually for 10 years. | Biological: bevacizumab<br> <br> Drug: sorafenib tosylate<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-month Progression-free Survival | Primary Endpoint: 6-month progression free survival (PFS6): The proportion of successes will be estimated using the binomial point estimator (number of successes divided by the total number of evaluable patients) and the binomial 95% confidence interval estimated. To be classified as a success, an evaluable patient must be alive and progression-free 6 months after registration to the study. Patients who die prior to 6 months after study registration will be considered to have failed. Progression is defined as a >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan. | at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression | Time to progression (TTP) is defined to be the length of time from study registration to a) date of disease progression as defined by section 11.0 of the protocol, or b) last follow-up. If a patient dies without documentation of disease progression, the patient will be considered to have had a tumor progression at the time of death unless there is sufficient documented evidence to conclude no progression occurred prior to death. Time to progression curves were compared via the log-rank test. Progression is defined as a >25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions or unequivocal increase in size of contrast enhancement or increase in mass effect as agreed upon independently by primary physician and quality control physicians: appearance of new lesions compared to pretreatment MRI and/or CT scan. | Time from study registration to a) date of disease progression, or b) last follow-up; Up to 15 years | 
| Overall Survival | Overall survival (OS) is defined as the length of time from date of registration to a) date of death due to any cause or b) last follow-up. | Time from date of registration to a) date of death due to any cause or b) last follow-up; Up to 15 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma, recurrent adult brain tumor