FMISO PET Study of Glioblastoma

This study does not add any additional treatment to patients with malignant glioma who are
already scheduled to receive bevacizumab monotherapy. All treatment decisions will be at the
discretion of the treating physician. There will be no change in the diagnosis or management
of the patient based on any procedures or tests carried out as a part of this study.

If the participant chooses to take part in this research study each treatment cycle will last
28 days.

- Day 1-The participant will have the following procedures done before they can receive
bevacizumab:

- An assessment of the participant's tumor by Vascular MRI (Magnetic Resonance
Imaging) and FMISO-PET scans

- Blood pregnancy test for women of childbearing potential.

- Day 14:The participant will have the following procedures done after they receive
bevacizumab:

- An assessment of the participant's tumor by Vascular MRI (Magnetic Resonance
Imaging) and FMISO-PET scans before the participant have received bevacizumab

- Blood pregnancy test for women of childbearing potential.

- Day 28: The participant will have the following procedures done after they receive
bevacizumab:

- An assessment of the participant's tumor by Vascular MRI (Magnetic Resonance
Imaging) and FMISO-PET scans after the participant has received bevacizumab

- Blood pregnancy test for women of childbearing potential.

FMISO-PET Scans:

- The participant will have the scans performed in Charlestown, MA at the Martinos Center.
The participant will be injected with two separate intravenous (IV) injections (listed
below). Intravenous means a need will be injected into a vein in the participant's arm.

- FMISO for PET scan and a contrast dye for the MRI scan

- Drawing blood to assess the radioactivity of FMISO

- The PET scan will take approximately 60-75 minutes. The participant will receive one
injection of FMISO. Following the injection of the radiotracer, blood samples will be
taken from the second IV line. The tracer is given through a vein (IV) and travels
through the participant's blood and collects in organs and tissues. The participant will
need to wait nearby as the tracer is absorbed by the their body. This takes about 90
minutes. Then, the participant will lie on a narrow table that slides into a large
tunnel-shaped scanner. The PET will pick up signals from the tracer and a computer will
change the signals into 3D pictures that will be displayed on a monitor for the
participant's study doctor to read.

MRI Scan:

- MRI scans will last about 60-75 minutes. This will occur at the same time as the PET
scan. The participant will be injected with contrast dye twice during the MRI scan. The
participant will have 3 MRI scans (prior to starting treatment, day 1 of treatment and
day 14 of treatment) that would not have routinely been performed if the participant
were not participating in this study.

- Blood samples will be collected during both scans in order to measure how the
participant blood vessels are processing the radiotracer FMISO and how well it is being
delivered to the tumor tissue.

- The participant will be assessed for side effects via clinic visit or phone call about
24 hours after each of the visits above.

Planned Follow-up: The investigators would like to call the participant every 3 months for
three years after the 28 day visit to see how they are doing and if the participant is
experiencing any side effects. If the participant is removed from the study due to an
unacceptable side effect, the participant will be followed until it has been resolved.

Inclusion Criteria:

- Participants must have histologically confirmed glioblastoma and evidence of
recurrence. Patients with low-grade tumors who have progressed to glioblastoma are
eligible.

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as >
10 mm. See section 10 for the evaluation of measureable disease.

- Only patients for whom their neuro-oncologist has planned to give bevacizumab as
monotherapy are eligible for this study

- Age > 18 years. Because no dosing or adverse event data are currently available on the
use of FMISO in participants <18 years of age, children are excluded from this study
but will be eligible for future pediatric trials.

- Life expectancy of greater than 3 months.

- Karnofsky performance status > 60 (see Appendix A).

- Participants must have normal organ and marrow function as defined below:

- Leukocytes > 3,000/mcL

- Absolute neutrophil count > 1,500/mcL

- Platelets > 100,000/mcL

- Total bilirubin within normal institutional limits

- AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits or creatinine clearance > 60
mL/min/1.73 m2 for subjects with creatinine levels about institutional normal.

- Patient must be able to undergo MRI and PET scans.

- Patients must be maintained on a stable corticosteroid regimen for 5 days prior each
MR-PET scan.

- The effects of FMISO on the developing human fetus are unknown. For this reason and
because radiopharmaceuticals agents are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to temozolomide or FMISO.

- Participants who have already received anti-VEGF or experimental anti-angiogenic
therapy for glioblastoma.

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because FMISO is a radiopharmaceutical
agent with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk of adverse events in nursing infants secondary to treatment
of the mother with radiopharmaceutical agents, breastfeeding should be discontinued if
the mother is treated with radiopharmaceutical agents. These potential risks may also
apply to other agents used in this study.

- HIV-positive individuals on combination antiretroviral therapy are ineligible because
of the potential for pharmacokinetic interactions with FMISO. In addition, these
individuals are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in participants
receiving combination antiretroviral therapy when indicated.

- Patients who are no suitable to undergo MRI or use gadolinium contrast due to:

- Claustrophobia

- Presence of metallic objects or implanted medical devices in body (i.e. cardiac
pacemaker, aneurysm clips, surgical clips, prostheses, artificial hearts, valves
with steel parts, metal fragments, shrapnel, tattoos near the eye, or steel
implants)

- Sickle cell disease

- Renal failure

- Reduced renal function, as determined by creatinine clearance < 30 mL/min based
on a serum creatinine level obtained within 28 days prior to registration