Conditions: Glioblastoma Multiforme
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 62
Healthy volunteers: no

Brief summary:
This study is being conducted to help determine whether the addition of Avastin (an anti-cancer drug), when given along with temozolomide during the monthly cycles that follow radiation, is able to delay tumor growth, shrink tumors, or impact how long people with GBM live. This study is sponsored by Genentech, Inc., the manufacturer of Avastin.

Avastin is the experimental drug being administered in this research study. Avastin binds a protein called vascular endothelial growth factor, or VEGF. VEGF is produced by tumors and circulates in the blood. One of VEGF's main roles is to support the growth of new blood vessels. During cancer, VEGF promotes the growth of blood vessels that bring nutrients to tumor cells and help them grow. Avastin binds to VEGF, which then prevents VEGF from functioning. In laboratory studies, Avastin prevented the growth of several different types of cancer cells grown in animals. Avastin was approved by the Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer in combination with chemotherapy. Avastin has not been approved by the FDA for the treatment of GBM and is, therefore, considered experimental. Avastin is currently undergoing testing (alone and in combination with another anti-cancer drug, irinotecan) in persons with GBM that have come back after conventional treatment.

Temozolomide (Temodar) is an anti-cancer drug that works by interfering with the growth of cells (including cancer cells) by stopping their division. Temozolomide was approved by the U.S. FDA for the treatment of newly diagnosed GBM in 2005.

Avastin and temozolomide are currently being used together in several research studies involving people with newly diagnosed GBM. Limited information is available about either the safety or effectiveness of this drug combination.

Detailed description:
The study consists of the following: 1) a screening period of up to 28 days; 2) a treatment period of radiation with daily temozolomide that lasts approximately 6 weeks, 3) a study treatment period that will last until either your tumor grows or you experience unacceptable side effects; and 4) a 30-day follow-up period after treatment has ended. Additionally, basic information concerning your condition will be collected every 2 months after the follow-up period for the rest of your life.

During this study, Dr. Nicholas and his research team will collect information about you for the purposes of this research. This includes name, address, dates (i.e., date of birth, date of consent), telephone number, and medical record number. Slides of your tumor tissue that were used to diagnose your GBM will be sent to a pathologist to confirm the diagnosis of GBM. After this review has been completed your slides will be returned to the hospital that provided them. Preserved samples of your tumor will also be sent for a test to determine how effective the temozolomide might be in your case. Any remaining tissue will be returned to the hospital that provided it.

Screening phase (following diagnosis of GBM at surgery) To determine if you are eligible to participate in this study, you will undergo a screening process that will involve the following

* Assessment of your cancer by magnetic resonance imaging (MRI) of your brain using an intravenous (in your vein) contrast material
* Recording of your general medical, surgical and cancer history
* Physical examination, including measurement of your blood pressure, height and weight
* Evaluation of your performance status (your ability to carry on daily activities)
* Neurologic examination (how well your nerves and muscles work)
* Blood sample for laboratory tests (approximately 2 to 3 tablespoons) to evaluate your blood counts, liver, and kidney function
* Serum pregnancy test if you are a woman of childbearing potential
* Urine sample
* Recording of any medications taken within the past 14 days

Radiation and daily temozolomide chemotherapy You will begin radiation treatment within 5 weeks of surgery. You will take temozolomide orally once daily (seven days a week) during radiation treatments (which occur Monday - Friday and last approximately six weeks). You will take a medication to prevent a rare form of pneumonia (pneumocystis carinii) that can occur when temozolomide is given on a daily basis. That may be either in pill form or inhaled. During radiation treatment you will be seen every two weeks by a study doctor at which time you will be asked how you are tolerating the treatment. A physical examination, (including neurological evaluation), will be performed. Blood tests (1-2 tablespoons) will be performed to assure that you are not having any side-effects from the chemotherapy.

Post-radiation treatment Two to four weeks after completing radiation you will have a brain MRI scan. Beginning four weeks after radiation ends, the study drug and temozolomide will begin. The study drug (Avastin) will be administered by IV infusion (through a vein) every 2 weeks. Temozolomide will be taken orally for five consecutive days of every 28 days. In other words, you will receive two intravenous infusions of Avastin and five days of temozolomide every 28 days. This constitutes a treatment cycle. These cycles will continue indefinitely. The dose of Avastin will be based upon your weight during screening and will remain the same throughout the study. The temozolomide dose during radiation will be based on your height and weight at screening. During the study phase, temozolomide will be dosed according to your height and weight at the beginning of each treatment cycle. The dose may be delayed for up to four weeks if your blood counts are low. If temozolomide still cannot be given because your blood counts are low for longer than four weeks, the temozolomide will be stopped but the Avastin may still be continued.

Your first dose of Avastin will be given as over 90 minutes. If you tolerate the 90 minute infusion well, infusions in the future may be given over a shorter period of time. However, if you do not tolerate the shorter infusion time, future infusions will be given over the longer period that you previously tolerated. If you experience any problems during or following the infusion, you will be monitored by trained staff until it is considered safe for you to leave.

The dose of Avastin that you receive may be stopped or slowed based on how well you tolerate the treatment. If you must stop treatment because of unfavorable side effects, you may be able to restart treatment once the side effect has improved or resolved. Your doctor will discuss with you whether it is in your best interest to continue treatment. If you stop study drug treatment, you should continue to return to be evaluated as explained below.

Temozolomide will be taken at bedtime on an empty stomach (at least 2 hours after any meal). Prior to each dose of temozolomide, you will take an anti-nausea pill (ondansetron, granisetron, or dolasetron) to reduce nausea and vomiting.

The treatment cycles described above will continue until: 1) your tumor grows, 2) you have unacceptable side effects, 3) you choose to withdraw from this research study, or 4) your participation is ended by Dr. Nicholas or Genentech.

During the first treatment day of each 28 day cycle you will receive Avastin. Your blood pressure will be monitored, and you will have a physical examination, a neurologic examination, and an evaluation of your performance status (how well you are functioning in daily activities). On the same day, you will begin temozolomide chemotherapy. You will have a blood sample drawn for laboratory tests (approximately 2-3 tablespoons), and a urine sample taken. You will be asked by the study doctor about any health problems you have and medications you take. Additional blood samples may be drawn at the discretion of your doctor as part of your standard care.

On day 14 of every treatment cycle you will return to the clinic to receive an infusion of Avastin. At that time, your blood pressure will be taken, and you will have a physical examination and an evaluation of your performance status. On day 21 of each cycle you will have blood work (1-2 tablespoons) to see how well you are tolerating the treatment. Every 8 weeks (after every 2 cycles immediately prior to your next cycle) you will have an MRI of your brain to determine measurements of your tumor.

Arms:
arm 1: This is an open-label, single arm, multi-center, phase II study involving 48 subjects with newly diagnosed supra-tentorial GBM. Following surgery, subjects with radiographically evaluable disease will receive external beam radiotherapy (59.4 - 60 Gy in 30 - 33 fractions) with daily temozolomide (75 mg/m2). Two to three weeks later, subjects will begin treatment with temozolomide (150-200 mg/m2 daily for five of 28 consecutive days) in conjunction with Avastin (10 mg/kg, every 14 days).

Interventions: intervention 1: Bevacizumab and Temozolomide
Intervention descriptions: intervention 1: This is an open-label, single arm, multi-center, phase II study involving 48 subjects with newly diagnosed supra-tentorial GBM. Following surgery, subjects with radiographically evaluable disease will receive external beam radiotherapy (59.4 - 60 Gy in 30 - 33 fractions) with daily temozolomide (75 mg/m2). Two to three weeks later, subjects will begin treatment with temozolomide (150-200 mg/m2 daily for five of 28 consecutive days) in conjunction with Avastin (10 mg/kg, every 14 days).

Protocol document: