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

Primary Purpose

Prostate Cancer, Prostatectomy

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Sunitinib Malate
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prostate Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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.

Sites / Locations

  • Duke University Medical Center
  • MD Anderson, University of Texas

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sunitinib Malate

Arm Description

Sunitinib Malate 50mg capsule by mouth once daily for 4 weeks

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
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

Full Information

First Posted
May 4, 2008
Last Updated
July 31, 2014
Sponsor
Duke University
Collaborators
Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT00672594
Brief Title
Study of Sunitinib Malate in Patients With Newly Diagnosed Prostate Cancer Prior to Prostatectomy
Official Title
Investigator-Initiated Pilot Study of Sunitinib Malate in Patients With Newly Diagnosed Prostate Cancer Prior to Prostatectomy
Study Type
Interventional

2. Study Status

Record Verification Date
May 2014
Overall Recruitment Status
Completed
Study Start Date
July 2006 (undefined)
Primary Completion Date
September 2012 (Actual)
Study Completion Date
September 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
Pfizer

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostate Cancer, Prostatectomy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sunitinib Malate
Arm Type
Experimental
Arm Description
Sunitinib Malate 50mg capsule by mouth once daily for 4 weeks
Intervention Type
Drug
Intervention Name(s)
Sunitinib Malate
Other Intervention Name(s)
Sutent
Intervention Description
Sunitinib Malate 50mg capsule by mouth once daily for 4 weeks
Primary Outcome Measure Information:
Title
Change in Apoptotic Indices Before and After Treatment
Description
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.
Time Frame
Baseline and 4 weeks
Title
Change in Proliferation Indices Before and After Treatment
Description
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.
Time Frame
Baseline and 4 weeks
Secondary Outcome Measure Information:
Title
Number of Patients Experiencing Grade ≥4 Hematologic or Grade ≥3 Non-hematologic Toxicity
Description
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.
Time Frame
4 years
Title
Change in Pathologic (Microvessel Density).
Description
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.
Time Frame
Baseline and 4 weeks
Title
Change in Systemic Parameters Before and After Sunitinib Malate Treatment.
Description
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.
Time Frame
Baseline and 4 weeks
Title
Protein Levels and Activation Status of PDGFR in Prostate Cancer Tissue.
Description
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.
Time Frame
4 years
Title
Difference in Gene Expression Patterns Using Microarray Analysis
Description
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.
Time Frame
4 years
Title
Interstitial Fluid Pressure (IFP)
Description
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
Time Frame
4 years

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel J George, MD
Organizational Affiliation
Duke University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
MD Anderson, University of Texas
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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