Bevacizumab, Temozolomide, and External Beam Radiation Therapy as First-Line Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

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. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x-rays to kill tumor cells. Giving bevacizumab together with temozolomide and radiation therapy may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects and how well giving bevacizumab together with temozolomide and external beam radiation therapy works when given as first-line therapy in treating patients with newly diagnosed glioblastoma multiforme or gliosarcoma.

Detailed Description
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OBJECTIVES: Primary To investigate the safety and tolerability of bevacizumab in combination with temozolomide and external beam fractionated regional radiotherapy as first-line treatment in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. (Pilot phase) To estimate the overall survival of patients treated with this regimen. (Expansion phase) Secondary To further investigate the safety and tolerability of this regimen in these patients. (Expansion phase) To isolate DNA, RNA, and protein from frozen and paraffin-embedded archival tumor samples for evaluations, such as immunohistochemical pathway profiling of vascular endothelial growth factor (VEGF)-dependent angiogenic pathways, gene expression microarray, and O-6 methylguanine DNA methyltransferase (MGMT) promoter methylation status to define important molecular features of treatment response. OUTLINE: This is a multicenter study. Patients undergo external beam fractionated regional radiotherapy once daily 5 days a week for 6 weeks and receive concurrent oral temozolomide once daily for 6 weeks. Patients also receive bevacizumab IV over 30-90 minutes every 2 weeks beginning on the first day of radiotherapy and continuing in the absence of disease progression or unacceptable toxicity. Beginning 2-5 weeks after completion of radiotherapy, patients receive oral temozolomide on days 1-5. Treatment with temozolomide repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Blood and frozen and paraffin-embedded tumor tissue samples are collected for biomarker and genetic analysis. After completion of study treatment, patients are followed up periodically.

Official Title
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Phase II Trial of Bevacizumab in Combination With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly-diagnosed Glioblastoma Multiforme

Conditions
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Brain and Central Nervous System Tumors

Intervention / Treatment
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* Biological: bevacizumab
* Drug: temozolomide
* Radiation: external beam radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma. Prior histologic diagnosis of low-grade glioma allowed provided it has been upgraded to GBM after repeat resection Has undergone surgery to collect tumor tissue 3-6 weeks ago Measurable or assessable disease is not required Karnofsky performance status 60-100% Life expectancy > 8 weeks White Blood Cell (WBC) ≥ 3,000/mm³ Absolute Neutrophil Count (ANC) ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 10 g/dL (transfusion allowed) Serum Glutamate Oxaloacetate Transaminase (SGOT) < 2.5 times upper limit of normal (ULN) Bilirubin < 2.5 times ULN INR (international normalized ratio) ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy) aPTT (activated partial thromboplastin time) ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy) Creatinine < 1.5 mg/dL Urine protein:creatinine ratio < 1.0 Negative pregnancy test Fertile patients must use effective contraception More than 28 days since prior major surgical procedures or open biopsy (other than craniotomy) More than 7 days since prior minor surgical procedures (e.g., placement of PortoCath (port-a-cath - a port placed under the subjects skin), stereotactic biopsy, fine-needle aspirations, or core biopsies) More than 4 weeks since prior and no concurrent participation in another experimental drug study. Prior or concurrent corticosteroids, anti-epileptic drugs, analgesics, or other drugs to treat symptoms or prevent complications are allowed Concurrent full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin) allowed Exclusion Criteria: unstable angina BP > 150/100 mm Hg New York Heart Association (NYHA) class II-IV congestive heart failure myocardial infarction within the past 6 months stroke within the past 6 months clinically significant peripheral vascular disease evidence of bleeding diathesis or coagulopathy intracerebral abscess within past 6 months abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months serious, non-healing wound, ulcer, or bone fracture Any wound requiring surgical intervention (including scalp wounds requiring cranioplasty) allowed provided the wound is clean and without further infection post-surgical intervention significant traumatic injury within the past 28 days concurrent serious uncontrolled medical illness including, but not limited to, the following: Ongoing or active infection requiring IV antibiotics Psychiatric illness/social situation that would limit compliance with study requirements Disorders associated with significant immunocompromised state (e.g., HIV, systemic lupus erythematosus) other cancer within the past 3 years, except nonmelanoma skin cancer or carcinoma in situ of the cervix disease that would obscure toxicity or dangerously alter drug metabolism significant medical illness that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate study therapy prior radiotherapy to the brain prior cytotoxic or non-cytotoxic drug therapy or experimental drug therapy for the brain tumor prior Gliadel wafers concurrent participation in any other clinical trial concurrent GM-CSF (granulocyte-macrophage colony-stimulating factor) concurrent stereotactic radiosurgery or brachytherapy concurrent major surgical procedure other concurrent anticancer therapy, including chemotherapy, hormonal therapy, radiotherapy, or immunotherapy

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: bevacizumab, temozolomide, external beam radiation<br> | Biological: bevacizumab<br> <br> Drug: temozolomide<br> <br> Radiation: external beam radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 2 years | 
| Progression-free Survival at 6 Months | participants who were alive and disease progression free at 6 months | 6 months | 
| Radiographic Response (When Evaluable) | Radiation therapy (RT) median from diagnosis to RT. Patients will have brain MRI evaluation of response and progression every 8 weeks starting from the day 56 scan obtained 2 weeks after completion of radiation and daily temozolomide and assessment will be conducted on a 7-point scale. This scale is expected to be more useful in this study because many newly-diagnosed patients are likely not to have evaluable disease due to gross total resections. Determination of whether progression occurs based on the day 56 scan will take into account the untreated window between baseline MRI and day of 1 of study. 7 Point Likert Scale: 3 to -3, 3 means complete resolution of tumor, and -3 means new lesion. A -2 or -3 assessment will be taken as tumor progression. complete resolution of tumor: 3 tumor resolved 3 tumor definitely smaller: 2 tumor probably smaller: 1 tumor unchanged: 0 tumor probably worse: -1 tumor definitely worse: -2 New Lesion: -3 | 2 years | 
| Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status | IDH1 and MGMT methylation are important independent prognostic biomarkers that have to be included in a Cox regression model. In addition, subgroup analysis could reveal differential sensitivities to the treatment arm. The MGMT promoter methylation status, IDH1 mutation status were not available for all of the control samples. Therefore, only the samples with both info available were included in the analysis. Baseline analysis results are included in the Baseline Characteristics module. | 2 years | 

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