Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Bevacizumab and Sorafenib in Treating Patients With Recurrent Glioblastoma Multiforme

Basic Trial Information

Objectives

Primary

1. Identify the clinical efficacy of bevacizumab and sorafenib, as measured by 6-month progression-free survival, in patients with recurrent glioblastoma multiforme.
2. Assess the safety and toxicity of this regimen in this patient population.

Secondary

1. Assess time to progression and overall survival of this patient population.
2. Assess the utility of dynamic contrast-enhanced MRI as a predictor of response to this treatment regimen.
3. Determine the relationship between tumor biomarkers and circulating biomarkers of vascular response and clinical outcome in patients treated with this regimen.
4. Assess the impact of treatment on the patient’s quality of life using the FACTBr.
5. Bank leftover tissue and blood products (i.e., plasma, DNA, and buffy coat) for future research studies.

Entry Criteria

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

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

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

Expected Enrollment

Outcomes

6-month progression-free survival
Safety, toxicity, and adverse events

Time to progression
Overall survival
Quality of life as assessed by the FACT-Br at baseline, prior to every other treatment course, and at the end of treatment
Utility of dynamic contrast-enhanced MRI as a predictor of response
Relationship between tumor biomarkers and circulating biomarkers of vascular response and clinical outcome

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.

Galanis E, Jaeckle KA, Anderson S, et al.: NCCTG phase II trial of bevacizumab in combination with sorafenib in recurrent GBM. [Abstract] J Clin Oncol 28 (Suppl 15): A-2018, 2010.

Trial Contact Information

Trial Lead Organizations

North Central Cancer Treatment Group

Evanthia Galanis, MD, Protocol chair		Ph: 507-284-3559

Registry Information
Official Title		Phase II Trial of Bevacizumab in Combination with Sorafenib in Recurrent Glioblastoma Multiforme
Trial Start Date		2008-09-12
Trial Completion Date		2009-02-03 (estimated)
Registered in ClinicalTrials.gov		NCT00621686
Date Submitted to PDQ		2008-02-12
Information Last Verified		2010-04-24
NCI Grant/Contract Number		CA25224

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