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

Study Overview
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Brief Summary
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This phase II trial is studying sorafenib tosylate and gene expression in patients undergoing surgery for high-risk localized prostate cancer. Sorafenib tosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Studying samples of blood and tumor tissues in the laboratory from patients with prostate cancer may help doctors learn more about changes that occur in DNA after treatment with sorafenib tosylate

Detailed Description
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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.

Official Title
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A Phase II Study of Sorafenib (Nexavar®) Prior to Radical Prostatectomy in Patients With High-Risk Localized Prostate Cancer

Conditions
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Adenocarcinoma of the Prostate, Stage II Prostate Cancer, Stage III Prostate Cancer

Intervention / Treatment
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* Drug: sorafenib tosylate
* Genetic: microarray analysis
* Other: immunohistochemistry staining method
* Genetic: gene expression analysis
* Procedure: needle biopsy
* Procedure: therapeutic conventional surgery
* Other: laboratory biomarker analysis
* Genetic: western blotting
* Genetic: RNA analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (enzyme inhibitor) 48hr stop<br>Patients receive sorafenib tosylate PO BID on days 1-14. Treatment repeats every 2 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Beginning 2 days after completion of sorafenib tosylate, patients undergo radical prostatectomy on approximately day 43. | Drug: sorafenib tosylate<br>* Given PO<br>* Other names: SFN;Genetic: microarray analysis<br>* Correlative studies<br>* Other names: gene expression profiling;Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Genetic: gene expression analysis<br>* Correlative studies<br>Procedure: needle biopsy<br>* Correlative studies<br>* Other names: puncture biopsy;Procedure: therapeutic conventional surgery<br>* Undergo prostatectomy<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: western blotting<br>* Correlative studies<br>* Other names: Western Blot;Genetic: RNA analysis<br>* Correlative studies<br>|
| Experimental: Treatment (enzyme inhibitor) 24hr stop<br>tients receive sorafenib tosylate PO BID on days 1-14. Treatment repeats every 2 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Beginning 1 day after completion of sorafenib tosylate, patients undergo radical prostatectomy on approximately day 43. | Drug: sorafenib tosylate<br>* Given PO<br>* Other names: SFN;Genetic: microarray analysis<br>* Correlative studies<br>* Other names: gene expression profiling;Other: immunohistochemistry staining method<br>* Correlative studies<br>* Other names: immunohistochemistry;Genetic: gene expression analysis<br>* Correlative studies<br>Procedure: needle biopsy<br>* Correlative studies<br>* Other names: puncture biopsy;Procedure: therapeutic conventional surgery<br>* Undergo prostatectomy<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: western blotting<br>* Correlative studies<br>* Other names: Western Blot;Genetic: RNA analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy as Assessed by Number of Patients With Changes Across Transcript Profiles by Microarray Analysis in Prostate Cancer Specimens, Specifically Those With Complete Pathologic Response. | Determined by changes across transcript profiles, by microarray analysis, in pre- versus post-treatment prostate cancer specimens (minimum 50 day time frame between these). Proportion of patients with complete pathologic response. | Pre- versus post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Complete Pathologic Response | Proportion of Patients with at least 50% decline in PSA on Day 1 of Cycle 2, Day 1 of Cycle 3, and on day of radical prostatectomy. | Day 1 of cycles 2 and 3, and day of radical prostatectomy. Each cycle is 2 weeks. | 
| Number of Participants With at Least 25% Reduction in PSA | Proportion of Patients with at least 25% decline in PSA on Day 1 of Cycle 2, Day 1 of Cycle 3, and on day of radical prostatectomy. | Day 1 of cycles 2 and 3 and on the day of radical prostatectomy. Each cycle is 2 weeks. |