Glyburide vs Placebo as Prophylaxis Against Cerebral Edema in Patients Receiving Radiosurgery for Brain Metastases (RAD 1502/UAB 1593)

Many patients with cancer that has spread to the brain have side effects caused by swelling
around the tumors. A common treatment for this swelling is a medicine called dexamethasone.
Dexamethasone is a steroid. Long-term use of steroids has several known side effects.

Recent studies have shown that a drug commonly used in to control high blood sugar in
diabetes, called glyburide, can decrease brain swelling in patients with brain damage or
stroke. Animal studies have shown that this drug may also reduce swelling from tumors in the
brain. Researchers are interested in whether glyburide could treat brain swelling as well as
dexamethasone with fewer side effects.

This study is being done to see whether glyburide is safe to be used in patients without
diabetes in combination with receiving SRS for brain metastases. This study will also find
out if glyburide will decrease brain swelling in patients that get radiosurgery (SRS) for
brain metastases. This study will also find out if taking glyburide will decrease the chance
of needing steroids due to brain swelling that is causing symptoms. It is not yet known, but
it is the investigators' hope that glyburide will both decrease brain swelling and lessen the
chance of needing steroids.

Inclusion Criteria:

- Patients with 1-10 newly diagnosed brain metastases deemed to be eligible for
radiosurgery.

- Subject must have cytologically or histologically confirmed malignancy (this is the
original malignancy, not the brain metastases).

- A diagnostic contrast-enhanced MRI of the brain must be performed within 60 days prior
to registration. The contrast-enhancing intraparenchymal brain tumor must be well
circumscribed and must have a maximum diameter of ≤ 4.0 cm in any direction on the
enhanced scan. If multiple lesions are present and one lesion is at the maximum
diameter, the other(s) must not exceed 3.0 cm in maximum diameter.

- History and physical with neurological examination, height, and weight within 14 days
prior to registration

- No dexamethasone use (or any other corticosteroid use with the purpose of treating
cerebral edema) starting 5 days prior to the treatment planning MRI. Patients may be
tapered to meet this criterion if deemed safe by the treating physician.

- Women of child-bearing potential (e.g. not post-menopausal or permanently sterilized
women) must have a negative pregnancy test obtained within 14 days prior to
registration. This is to prevent potential harm to the fetus by glyburide and
radiotherapy.

- CBC with differential and CMP including Liver Function Tests (LFTs) obtained within 14
days prior to registration and meeting the following requirements:

- Creatinine Clearance ≥ 50 mL/min.

- Total Bilirubin < 1.5 x the upper limit of normal (ULN).

- ALT and AST ≤ 2.5 x ULN.

- Glucose ≥ 80 mg/dL.

- Hemoglobin ≥ 7 mg/dL.

- Absolute Neutrophil Count > 100 cells/mm3.

- For the Randomized Portion only: Subject must have at least 2 of the following risk
factors: {For the Pilot Portion, it is not required that patients have the risk
factors mentioned in Inclusion Criteria 9.}

- Pretreatment Edema/Tumor ratio (≥ 35:1) as contoured on a baseline MRI obtained
at most 60 days prior to registration. Patients are allowed to have Whole Brain
Radiotherapy (WBRT) or corticosteroid use between the time of pretreatment MRI
and SRS (as long as the corticosteroids can be safely tapered at least 5 days
prior to the treatment planning MRI and WBRT is at least 4 days prior to
registration).

- Greater than 40 pack year history of smoking cigarettes.

- Whole Brain Radiotherapy at least 4 days and no more than 1 year prior to
registration.

- RPA Class III.

Exclusion Criteria:

- Known sulfonylurea treatment within 7 days prior to registration. Sulfonylureas
include glyburide/glibenclamide (Diabeta, Glynase); glyburide plus metformin
(Glucovance); glimepiride (Amaryl); repaglinide (Prandin); nateglinide (Starlix);
glipizide (Glucotrol, GlibeneseR, MinodiabR); gliclazide (DiamicronR); tolbutamide
(Orinase, Tolinase); and glibornuride (Glutril).

- Leptomeningeal metastases.

- Known allergy to sulfa or specific allergy to sulfonylurea drugs.

- Use of VEGF inhibitors within 10 days prior to registration.

- Patients receiving an investigational drug within 10 days prior to registration

- Allergy to gadolinium.

- Type 1 diabetes mellitus or Type 2 diabetes mellitus actively receiving treatment.

- Cognitive impairment that precludes a patient from acting as his or her own agent to
provide informed consent.

- Concurrent use of Bosentan.

- Any major medical illnesses or psychiatric impairments that in the treating
physician's opinion will prevent administration or completion of protocol therapy (
which may include patients who are elderly, debilitated, or malnourished persons
and/or those with renal, hepatic or adrenal insufficiency).

- Pregnant or breast feeding women due potential damage to the fetus

- Patients treated on any other therapeutic clinical protocols within 10 days prior to
registration or during participation in the study.

- Inability to undergo MRI or SRS (e.g. due to safety reasons such as presence of a
pacemaker).

- Deemed by the treating physician to be unable to eat regular meals.

- Patients currently on beta blockers.

- Patients with a known diagnosis of ongoing alcoholism/alcohol abuse.