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

Phase 2

Completed

Conditions: Brain and Central Nervous System Tumors

Interventions: Biological: bevacizumab
Drug: temozolomide
Radiation: external beam radiation therapy

Registration Number: NCT01013285

Lead Sponsor: Jonsson Comprehensive Cancer Center

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 70

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
bevacizumab, temozolomide, external beam radiation	bevacizumab	-
bevacizumab, temozolomide, external beam radiation	external beam radiation therapy	-
bevacizumab, temozolomide, external beam radiation	temozolomide	-

Primary Outcome Measures

Name	Time	Method
Overall Survival	2 years

Secondary Outcome Measures

Name	Time	Method
Radiographic Response (When Evaluable)	2 years	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
Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status	2 years	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.
Time to Disease Progression	2 years	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.
Progression-free Survival at 6 Months	6 months	participants who were alive and disease progression free at 6 months