Clinical trial NCT01013285: Bevacizumab, Temozolomide, and External Beam Radiation Therapy as First-Line Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma
Official title: Phase II Trial of Bevacizumab in Combination With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly-diagnosed Glioblastoma Multiforme
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Brain and Central Nervous System Tumors
Keywords: adult giant cell glioblastoma
adult gliosarcoma
adult glioblastoma
Lead sponsor: Jonsson Comprehensive Cancer Center
Sponsor class: OTHER
First posted: 2009-11-13
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival
timeFrame: 2 years
Secondary outcomes:
measure: Time to Disease Progression
timeFrame: 2 years
measure: Progression-free Survival at 6 Months
timeFrame: 6 months
measure: Radiographic Response (When Evaluable)
timeFrame: 2 years
measure: Median Overall Survival (OS) Based on the MGMT Promoter Methylation Status
timeFrame: 2 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA)
state: California
Study officials:
affiliation: Ronald Reagan University of California, Los Angeles (UCLA) Medical Center
name: Albert Lai, MD
role: PRINCIPAL_INVESTIGATOR
References: