Sorafenib Tosylate and Gene Expression Analysis in Patients Undergoing Surgery For High-Risk Localized Prostate Cancer

PRIMARY OBJECTIVES:

I. To compare the gene expression changes (transcript profiles) between pre- and
post-treatment tumor specimens in order to determine the molecular impact of multi-kinase
inhibition on prostate cancer. While this analysis will initially be targeted to tumor cells,
gene expression changes in the surrounding stromal tissue may also be analyzed.

SECONDARY OBJECTIVES:

I. To determine if specific downstream protein effectors (i.e. ERK, AKT, and S6- kinase) of
Sorafenib kinase targets are affected by changes in protein phosphorylation by
immunohistochemistry.

II. To provide evidence that Sorafenib has significant anti-tumor effect by comparison of
pre- and post-treatment immunohistochemical markers of apoptosis (caspase-3), cell
proliferation (Ki-67), and angiogenesis (microvessel density).

III. To determine the pathologic complete response rate, defined as absence of cancer in the
prostatectomy specimen.

IV. To determine rates of positive surgical margins, extracapsular extension, seminal vesicle
and lymph node involvement with tumor in comparison with Memorial Sloan Kettering
pre-operative nomogram predictions.

V. To determine the percentage of patients with a >= 25% and >= 50% decline in PSA while
receiving Sorafenib.

VI. To determine tissue Sorafenib levels in prostate tumors after treatment and correlate
with molecular, clinical, and/or pathologic outcomes.

VII. To describe changes in overall histology after treatment with Sorafenib and correlate
with molecular and clinical outcomes.

VIII. To determine if patients with baseline alterations in phospho-ERK, phospho-AKT, and
phospho-S6-kinase expression correlate with treatment related molecular, clinical, and/or
pathologic outcomes.

IX. To collect tissue samples for future analysis of correlative biomarkers of prognosis or
treatment response.

X. To collect frozen plasma for future analysis of correlative biomarkers of treatment
response (no genetic analysis will be performed on these specimens).

OUTLINE:

Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days 1-14. Treatment
repeats every 2 weeks for 3 courses in the absence of disease progression or unacceptable
toxicity. Beginning 1 or 2 days after completion of sorafenib tosylate, patients undergo
radical prostatectomy on approximately day 43.

After completion of study treatment, patients are followed up for 6-10 weeks.

Inclusion Criteria:

- Histologically confirmed adenocarcinoma of the prostate

- Radical prostatectomy and lymph node dissection planned as primary therapy in a
patient with acceptable surgical risk (e.g., cardiovascular, pulmonary, and functional
status)

- 10 year or longer life expectancy

- Any of the following high-risk features: Clinical stage T2b (palpable bilateral
involvement) OR surgically resectable T3 OR PSA >= 20 ng/ml OR overall Gleason grade
>= 8

- No evidence of bone metastases on bone scan

- No evidence of lymph nodes >= 2 cm in diameter on pelvic CT scan

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

- Hemoglobin >= 9.0 g/dl

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Total bilirubin =< 1.5 x ULN

- ALT =< 2.5 x the ULN

- AST =< 2.5 x the ULN

- INR =< 1.5 and aPTT within normal limits

- Creatinine =< 1.5 x ULN or creatinine clearance > 60mL/min/1.73 m^2

- Men must agree to use adequate contraception (abstinence, hormonal in female partner,
or barrier method of birth control) prior to study entry, for the duration of study
participation, and for at least two weeks after stopping treatment

- Signed informed patient consent

Exclusion Criteria:

- Prior therapy for prostate cancer including conventional androgen deprivation therapy,
radiotherapy (external beam or brachytherapy), cryotherapy, and/or cytotoxic
chemotherapy

- Any known metastasis; patients with neurological symptoms must undergo a CT scan/MRI
of the brain to exclude brain metastasis

- Significant active medical illness which in the opinion of the investigator would
preclude protocol treatment

- Another malignancy, other than non-melanoma skin cancer, during the past 5 years

- History of bleeding diathesis or unexpected surgical bleeding

- Patients with active coagulopathy

- Cardiac disease: Congestive heart failure > class II NYHA; patients must not have
unstable angina (anginal symptoms at rest) or new onset angina (began within the last
3 months) or myocardial infarction within the past 6 months

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- Uncontrolled hypertension, as defined by systolic blood pressure consistently in
excess of 150 mmHg, or diastolic pressure consistently in excess of 90 mmHg

- Thrombolic or embolic events such as a cerebrovascular accident including transient
ischemic attacks within the past 6 months

- Pulmonary hemorrhage/bleeding event >= CTCAE Grade 2 within 4 weeks of first dose of
study drug

- Any other hemorrhage/bleeding event >= CTCAE Grade 3 within 4 weeks of first dose of
study drug

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sorafenib

- Patients may not be concurrently receiving any chemotherapy, immunotherapy, hormonal
therapy, or molecular targeted agents to treat their prostate cancer

- Patients may not be receiving any other investigational agents

- Therapeutic anticoagulation with heparin, low-molecular weight heparin, or warfarin
within the last 4 weeks

- Patients may not be using rifampin, digoxin, quinidine, ketoconazole, itraconazole,
cyclosporine, carbamazepine, phenytoin, phenobarbital, St. John's Wart, or products
containing grapefruit juice

- Patients may not be using bevacizumab or any other drugs that target VEGF or VEGF
receptors

- Active clinically significant infections (>= grade 2 NCI-CTCAE version 3.0); patients
may enroll after infection resolves

- HIV-positive patients receiving combination anti-retroviral therapy because of
possible pharmacokinetic interactions with Sorafenib

- Any condition that impairs patient's ability to swallow whole pills

- Any malabsorption problem