A Phase II Study of BAY 43-9006 (Sorafenib) in Metastatic, Androgen-Independent Prostate Cancer

BAY 43-9006 (Sorafenib) is a potent inhibitor of wild-type and mutant b-Raf and c-Raf kinase
isoforms in vitro. In addition, this agent also inhibits p38, c-kit, vascular endothelial
growth factor receptor 2 (VEGFR-2) and platelet-derived growth factor receptor beta
(PDGFR-beta) affecting tumor growth as well as possibly promoting apoptosis by events
downstream of c-Raf. At this time, over 500 patients have been treated with this drug with
tolerable side effects.

The primary objective of this study is to determine if BAY 43-9006 (Sorafenib) is associated
with a 50% 4 month probability of progression free survival in patients with metastatic
androgen independent prostate cancer (AIPC) as determined by clinical, radiographic, and
prostatic specific antigen (PSA) criteria.

The secondary objective of this study will be demonstration of biologic effect by the drug in
the patient and on the tumor (when possible). Correlative studies will be conducted on
serially obtained tissue biopsies, bone marrow biopsies, and white blood cell collections.
These laboratory correlates will include elucidation of activation of components of the
Raf-extracellular-signal regulated kinase (ERK)-methyl ethyl ketone (MEK) and angiogenesis
pathways using protein microarray technologies developed by the National Cancer Institute
(NCI)/Food and Drug Administration (FDA) clinical proteomics program.

Per Amendment D, a secondary objective of this study will also be to determine the time to
progression measured by clinical and radiographic criteria. The 22 patients treated on the
first stage of this protocol will be retrospectively evaluated with respect to this secondary
endpoint possible. Please refer to the statistics section for further details.

The combination of correlated clinical and laboratory endpoints with emphasis on molecular
signaling will provide new information on the anti-tumor effects helping to characterize its
role in the treatment of androgen independent prostate cancer (AIPC).

- INCLUSION CRITERIA

Patients must have histopathological confirmation of prostate cancer by the Laboratory of
Pathology of the National Cancer Institute (NCI) or Pathology Department of the National
Naval Medical Center prior to entering this study. Patients whose pathology specimens are
no longer available may be enrolled in the trial if the patient has a clinical course
consistent with prostate cancer and available documentation from an outside pathology
laboratory of the diagnosis. In cases where original tissue blocks or archival biopsy
material is available, all efforts should be made to have the material forwarded to the
research team for use in correlative studies.

Patients must have metastatic progressive androgen-independent prostate cancer. There must
be radiographic evidence of disease after primary treatment with either surgery or
radiotherapy that has continued to progress despite hormonal agents. Progression requires
that a measurable lesion is expanding, new lesions have appeared, and/or that prostatic
specific antigen (PSA) is continuing to rise on successive measurements. Patients on
flutamide must have disease progression at least 4 weeks after withdrawal. Patients on
bicalutamide or nilutamide must have progression at least 6 weeks after withdrawal.

Patients may have had no more than 1 previous cytoxic chemotherapeutic line.

Because no dosing or adverse event data are currently available on the use of BAY 43-9006
(Sorafenib) in patients less than 18 years of age, children are excluded from this study.

Patients must have a life expectancy of more than 3 months.

Patients must have a performance status of 0 to 2 according to the Eastern Cooperative
Oncology Group (ECOG) criteria.

Patient must have adequate organ function as defined below:

Leukocytes greater than or equal to 3,000/microL

Absolute neutrophil count greater than or equal to 1,500/microL

Platelets greater than or equal to 100,000/microL

Total bilirubin less than or equal to 1.5 X institutional upper limits of normal

Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase(SGOT) and alanine
aminotransferase (ALT)/serum glutamic pyruvic transaminase(SGPT) less than or equal to 2.5
X institutional upper limit of normal

Creatinine less than or equal to 1.5 X institutional upper limits of normal OR:

Creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with
creatinine levels above institutional normal.

Patients must have recovered from any acute toxicity related to prior therapy, including
surgery. Toxicity should be less than or equal to grade 1 or returned to baseline.

Hormonal profile: all patients who have not undergone bilateral surgical castration must
continue suppression of testosterone production by appropriate usage of gonadotropin
releasing hormone (GnRH) agonists.

Patients must not have other invasive malignancies (within the past two years with the
exception of non-melanoma skin cancers or non-invasive bladder cancer).

Patients must be able to understand and sign an informed consent form.

Concurrent use of bisphosphonates will be allowed for patients with known bone metastases

Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin),
non-steroidal anti-inflammatory drug (NSAIDs), and other maintenance medications prior to
study entry will be allowed to continue their supportive therapies.

The effects of BAY 43-9006 (Sorafenib) on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason and because Raf-kinase inhibitors are known
to be teratogenic, men must agree to use adequate contraception (abstinence; hormonal or
barrier method of birth control) prior to study entry and for the duration of study
participation.

EXCLUSION CRITERIA

Patients who have had chemotherapy or radiotherapy (including radioisotopes) within 4 weeks
(6 weeks for nitrosoureas or mitomycin C, greater than 3 months for suramin) prior to
entering the study or those who have not recovered from adverse events due to agents
administered more than 4 weeks earlier.

Patients may not be receiving any other investigational agents.

Patients with known brain metastases are excluded from this clinical trial because of their
poor prognosis and because they often develop progressive neurologic dysfunction that would
confound the evaluation of neurologic and other adverse events.

History of allergic reactions attributed to compounds of similar chemical or biologic
composition to BAY 43-9006 (Sorafenib)

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.

Hypertension as defined by systolic blood pressure in excess of 170 mmHg or diastolic
pressure in excess of 100 mmHg. Patients with a history of hypertension that is well
controlled on medication will not be excluded. Patients may not be on either verapamil or
diltiazem while on study. Use of calcium channel blocker should be discouraged.

Patients with immune deficiency are at increased risk of lethal infections when treated
with marrow-suppressive therapy. Therefore, human immunodeficiency virus (HIV)-positive
patients receiving combination anti-retroviral therapy are excluded from the study because
of possible pharmacokinetic interactions with BAY 43-9006 (Sorafenib). Appropriate studies
will be undertaken in patients receiving combination anti-retroviral therapy when
indicated.

History of bleeding diathesis

Patients on therapeutic anticoagulation are at increased risk from bleeding while on BAY
43-9006 (Sorafenib). Prophylactic anticoagulation (i.e. low dose warfarin) of venous or
arterial access devices is allowed provided that the requirements for prothrombin time
(PT), International normalized ratio (INR) or partial thromboplastin time (PTT) are met: PT
less than 1.1 x institutional upper limit of normal; INR less than 1.1; PTT within the
institutional limits of normal. These requirements will only be made upon those patients on
warfarin.

INCLUSION OF WOMEN AND MINORITIES

Men of all races and ethnic groups are eligible for this trial. Women are excluded by the
nature of the disease.