Study of Sunitinib Malate in Patients With Newly Diagnosed Prostate Cancer Prior to Prostatectomy

Study Overview
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Brief Summary
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The purpose of this study is to look at blood and tissue samples for changes following the use of Sunitinib malate. Additionally, we would like to find out if the drug, Sunitinib malate, is safe and works in men with prostate cancer. Sunitinib malate , also known as Sutent, is approved by the U.S. Food and Drug Administration (FDA), for treatment of tumors of intestines and kidney but it is being tested in research studies for use in men with prostate cancer.

Detailed Description
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Eligible patients will be treated with 50 mg once daily for four weeks followed by one to two weeks off treatment prior to undergoing radical prostatectomy. Patients with palpable disease (cT2-3) and patients with 3 or more positive prostatic biopsies from one lobe may undergo an additional study of IFP monitoring before treatment and during week 4 of study treatment. Safety and tolerability of Sunitinib malate therapy at this dose and schedule in this patient population will be assessed. Extensive correlative science evaluations, including assessment of physiologic, cellular, molecular and genetic changes during treatment with Sunitinib malate, will be performed

Official Title
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Investigator-Initiated Pilot Study of Sunitinib Malate in Patients With Newly Diagnosed Prostate Cancer Prior to Prostatectomy

Conditions
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Prostate Cancer, Prostatectomy

Intervention / Treatment
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* Drug: Sunitinib Malate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic evidence of adenocarcinoma of the prostate deemed candidates for curative RRP Intermediate or high risk, clinically localized disease Adequate organ function Patients must be surgically sterile or must agree to use effective contraception during the period of therapy Select imaging to rule out metastasis will be done as clinically indicated Signed and date informed consent document Exclusion Criteria: Prior treatment for prostate cancer Major surgery or radiation therapy within 4 weeks of starting the study treatment NCI CTCAE grade 3 hemorrhage within 4 weeks of starting therapy History of or known metastatic prostate cancer Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack, or pulmonary embolism. Ongoing cardiac dysrhythmias of NCI CTCAE grade 2 or greater QTc interval > 500 msec on baseline EKG Hypertension that cannot be controlled by medications (>150/100 mm Hg despite optimal medical therapy). Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication Known active infection Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. QOL, are allowed. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sunitinib Malate<br>Sunitinib Malate 50mg capsule by mouth once daily for 4 weeks | Drug: Sunitinib Malate<br>* Sunitinib Malate 50mg capsule by mouth once daily for 4 weeks<br>* Other names: Sutent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Apoptotic Indices Before and After Treatment | Pathologic changes will be described using immuno-histochemical techniques (assessment of apoptotic/proliferative indices and microvessel density (MVD)) using paraffin-embedded samples and freshly cut slides from the block which are deparaffinized and rehydrated through graded alcohol, where applicable. Antigen retrieval will be accomplished by microwaving in citrate buffer from 5 to 7 minutes for the Ki-67 and MVD analysis. Mean difference in %apoptosis (measured as %TUNEL positive cells per high powered field) between pre and post treatment will be reported. | Baseline and 4 weeks | 
| Change in Proliferation Indices Before and After Treatment | Pathologic changes will be described using immuno-histochemical techniques (assessment of apoptotic/proliferative indices and microvessel density (MVD)) using paraffin-embedded samples and freshly cut slides from the block which are deparaffinized and rehydrated through graded alcohol, where applicable. Antigen retrieval will be accomplished by microwaving in citrate buffer from 5 to 7 minutes for the Ki-67 and MVD analysis. Mean difference in %proliferation (Ki67 positive nuclei out of total nuclei) between pre and post treatment will be reported. | Baseline and 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Experiencing Grade ≥4 Hematologic or Grade ≥3 Non-hematologic Toxicity | Adverse events were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 and were converted to version 4.0 for the purposes of ClinicalTrials.gov reporting. | 4 years | 
| Change in Pathologic (Microvessel Density). | Pathologic changes will be described using immuno-histochemical techniques (assessment of microvessel density (MVD)) using paraffin-embedded samples and freshly cut slides from the block which are deparaffinized and rehydrated through graded alcohol, where applicable. Antigen retrieval will be accomplished by microwaving in citrate buffer from 5 to 7 minutes for the MVD analysis. Results are reported as the difference in pre and post MVD. Units for MVD are number of CD31 cells per high powered field. | Baseline and 4 weeks | 
| Change in Systemic Parameters Before and After Sunitinib Malate Treatment. | We evaluated candidate biomarkers of this pathway to predict for pharmacodynamic response to Sunitinib malate. In addition, a 7 ml plasma sample was collected at baseline and again at 4 weeks on all patients to assess possible biomarkers of response. Reported is the mean percent change in plasma concentration for each marker between 4 weeks and baseline. | Baseline and 4 weeks | 
| Protein Levels and Activation Status of PDGFR in Prostate Cancer Tissue. | We will perform immunohistochemistry staining on snap frozen specimens for endothelial and pericyte cell staining as previously described (42). Frozen prostate tumor biopsies are sectioned at 6μm thickness and fixed with acetone for 10 minutes. Endogenous peroxidase activity is quenched with 3% hydrogen peroxide for 15 min and then blocked with 5% normal serum. The slides are incubated with the primary antibody (1;100) overnight at 4 C°, and washed with PBS. Negative controls will be included by omission of the primary antibody. Biotinylated donkey antimouse antibody (1:1000, v/v) will be applied for 30 min at room temperature, followed by application of ABC kit (Vector Lab, Inc., Burlingame, USA). Slides are again washed in PBS and the color is developed by 5 min incubation with diaminobenzidine (DAB) solution. Slides are then counterstained with hematoxylin. Mean protein levels are presented. | 4 years | 
| Difference in Gene Expression Patterns Using Microarray Analysis | Microarray data of 21 specimens from men enrolled who have undergone a prostatectomy and study treatment were compared to data from 21 prostatectomy only specimens. We used previously developed genomic signatures to measure the deregulation of oncogenic pathways built using Bayesian Probit models for 'metagene' factors from a singular value decomposition of top differentially expressed genes. A Monte Carlo Markov Chain was used to generate the predicted probabilities of pathway activity in normalized samples. We predicted the activity of these pathways, leading to the generation of probability measures that have previously reflected the state of pathway activity. These probability scores are interpreted as gene expression values to describe pathway activity patterns. A probability near 0 indicates a low chance of pathway activity; a probability near 1 indicates a higher likelihood of activity. Differences (treatment - control) in mean probability for each pathway are reported. | 4 years | 
| Interstitial Fluid Pressure (IFP) | Measure Interstitial fluid pressure (IFP) pre-treatment and during treatment to indirectly measure the effect of Sunitinib malate on transcapillary transport and correlate with other biologic evidence of treatment effect.Eligible patients who sign consent will undergo a baseline transrectal ultrasound (TRUS)-guided measurement of tumor IFP. Participants will then begin treatment with daily oral Sunitinib malate with biweekly monitoring for response and toxicity. After 4 weeks of therapy, patients undergo a repeat TRUS and tumor IFP measurement. Following a 1 to 2 week wash out period, patients undergo prostatectomy with pathologic tissue collection. This will be performed as a means to evaluate whether Sunitinib malate has the ability to decrease tumor IFP, and whether this correlates with other tr | 4 years |