Trial Information

Assessment of Primary and Metastatic Brain Tumor Hypoxia With 18F-Fluoromisonidazole, [18F]Fluoro-2-deoxy-D-glucose (FDG) and [15O]Water (H215O)

Malignant Brain Tumors (Primary and Metastatic) Despite significant advances in the
understanding of brain tumor biology and genetics as well as improvements in surgical
techniques, radiotherapy administration, and chemotherapy methods, many brain tumors remain
incurable. Many brain tumors are highly infiltrative neoplasms, and are therefore unlikely
to be cured by local treatments such as surgery, focal radiotherapy, radiosurgery or
brachytherapy.

Rationale and Goals of Study The preliminary efficacy of the radiopharmaceutical,
1H-1-(3-[18F]-fluoro-2-hydroxy-propyl)-2-nitro-imidazole [18F]-fluoromisonidazole,
[18F]FMISO, FMISO (fluoromisonidazole), a radiopharmaceutical that directly assess tumor
hypoxia using Positron Emission Tomography(PET) will be assessed.

This preliminary/exploratory clinical study will investigate [F-18]FMISO in 30 evaluable
patients with newly diagnosed primary brain tumor or brain metastasis. We expect that up to
35 -40 total patients may be enrolled in this study. This will assure that 30 evaluable
patients (patients who have complete imaging results and blood metabolism data available for
data analysis). In certain patients the blood metabolism data is not acceptable for final
analysis typically due to difficulty in drawing it rapidly enough due to the vein collapsing
during the rapid sampling required.

When possible we will also correlate FMISO uptake with the typical in-vitro test used to
assess proliferation, Ki-67 (protein) and other experimental assessments of hypoxia. This
correlation will be made whenever possible in those patients where tumor tissue is obtained
as part of standard care.

OBJECTIVES:

Primary Objective of Study - Synopsis The primary objective of this study is to determine
the association of FMISO PET (positron emission tomography) uptake (hypoxic volume [HV]),
highest tumor:blood ratio [T/Bmax]), FDG ([18F]-2 fluoro-2-deoxy-d-glucose) uptake, and
tumor blood flow/perfusion determined with H2O (water) and MRI and correlate these
variables with overall survival (OS) and time to progression (TTP) in participants with
newly diagnosed primary brain tumors or brain metastases.

The Hypotheses to be Tested

Three exploratory hypotheses will be studied. These include:

1. The first hypothesis to be tested is that increased FMISO PET uptake (hypoxic volume
[HV], highest tumor:blood ratio [T/Bmax]) is correlated with a shorter overall survival
and a shorter time to progression. An exploratory evaluation assessing combinations of
PET imaging variables such as hypoxic volume [HV], highest tumor:blood ratio [T/Bmax],
FDG-SUV, FDG quantitative parameters and blood flow as well as MR (magnetic resonance)
perfusion and blood volume will be assessed to see if they correlate with survival and
time to progression.

2. A second hypothesis to be tested is that FMISO is safe and non toxic in the dose
administered in this study in patients with primary and metastatic brain tumors. This
will be assessed in the first 10 patients enrolled in the study. Even though there have
been numerous published studies using FMISO in humans in several different tumor types
little human safety data has been published. Laboratory tests (except urinalysis) will
be repeated at approximately 24 hours in the first 10 and compared to the screening
values.

3. A third exploratory hypothesis to be tested is that FMISO uptake (hypoxic volume [HV],
highest tumor:blood ratio [T/Bmax]) will correlate with increased FDG uptake and
possibly with reduced blood flow/perfusion as determined with H215O PET imaging and MRI