Sorafenib Tosylate and Gene Expression Analysis in Patients Undergoing Surgery For High-Risk Localized Prostate Cancer
Study Details
Study Description
Brief Summary
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
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- 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:
-
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.
-
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).
-
To determine the pathologic complete response rate, defined as absence of cancer in the prostatectomy specimen.
-
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.
-
To determine the percentage of patients with a >= 25% and >= 50% decline in PSA while receiving Sorafenib.
-
To determine tissue Sorafenib levels in prostate tumors after treatment and correlate with molecular, clinical, and/or pathologic outcomes.
-
To describe changes in overall histology after treatment with Sorafenib and correlate with molecular and clinical outcomes.
-
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.
-
To collect tissue samples for future analysis of correlative biomarkers of prognosis or treatment response.
-
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Treatment (enzyme inhibitor) 48hr stop 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
Given PO
Other Names:
Genetic: microarray analysis
Correlative studies
Other Names:
Other: immunohistochemistry staining method
Correlative studies
Other Names:
Genetic: gene expression analysis
Correlative studies
Procedure: needle biopsy
Correlative studies
Other Names:
Procedure: therapeutic conventional surgery
Undergo prostatectomy
Other: laboratory biomarker analysis
Correlative studies
Genetic: western blotting
Correlative studies
Other Names:
Genetic: RNA analysis
Correlative studies
|
| Experimental: Treatment (enzyme inhibitor) 24hr stop 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
Given PO
Other Names:
Genetic: microarray analysis
Correlative studies
Other Names:
Other: immunohistochemistry staining method
Correlative studies
Other Names:
Genetic: gene expression analysis
Correlative studies
Procedure: needle biopsy
Correlative studies
Other Names:
Procedure: therapeutic conventional surgery
Undergo prostatectomy
Other: laboratory biomarker analysis
Correlative studies
Genetic: western blotting
Correlative studies
Other Names:
Genetic: RNA analysis
Correlative studies
|
Outcome Measures
Primary Outcome Measures
- 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. [Pre- versus post-treatment]
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.
Secondary Outcome Measures
- Number of Participants With Complete Pathologic Response [Day 1 of cycles 2 and 3, and day of radical prostatectomy. Each cycle is 2 weeks.]
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.
- Number of Participants With at Least 25% Reduction in PSA [Day 1 of cycles 2 and 3 and on the day of radical prostatectomy. Each cycle is 2 weeks.]
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.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium | Seattle | Washington | United States | 98109 |
Sponsors and Collaborators
- University of Washington
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Evan Yu, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 6307
- NCI-2010-00604
Study Results
Participant Flow
| Recruitment Details | Subjects were screened and enrolled at a single site in Seattle, Washington, United States. |
|---|---|
| Pre-assignment Detail | Five subjects were screened for this study, deemed eligible and enrolled. |
| Arm/Group Title | 48 Hour Drug Stop Point | 24 Hour Drug Stop Point |
|---|---|---|
| Arm/Group Description | Sorafenib 400mg taken orally twice per day for 41 days prior to radical prostatectomy. Last dose of study drug is the morning dose 2 days prior to surgery. | Sorafenib 400mg taken orally twice per day for 42 days prior to radical prostatectomy. Last dose of study drug is the morning dose the day prior to surgery. |
| Period Title: Overall Study | ||
| STARTED | 5 | 0 |
| COMPLETED | 5 | 0 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | 48 Hour Drug Stop Point | 24 Hour Drug Stop Point | Total |
|---|---|---|---|
| Arm/Group Description | Sorafenib 400mg taken orally twice per day for 41 days prior to radical prostatectomy. Last dose of study drug is the morning dose 2 days prior to surgery. | Sorafenib 400mg taken orally twice per day for 42 days prior to radical prostatectomy. Last dose of study drug is the morning dose the day prior to surgery. | Total of all reporting groups |
| Overall Participants | 5 | 0 | 5 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
NaN
|
0
0%
|
| Between 18 and 65 years |
4
80%
|
0
NaN
|
4
80%
|
| >=65 years |
1
20%
|
0
NaN
|
1
20%
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
0%
|
0
NaN
|
0
0%
|
| Male |
5
100%
|
0
NaN
|
5
100%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
0
0%
|
0
NaN
|
0
0%
|
| Not Hispanic or Latino |
4
80%
|
0
NaN
|
4
80%
|
| Unknown or Not Reported |
1
20%
|
0
NaN
|
1
20%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
NaN
|
0
0%
|
| Asian |
0
0%
|
0
NaN
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
NaN
|
0
0%
|
| Black or African American |
0
0%
|
0
NaN
|
0
0%
|
| White |
5
100%
|
0
NaN
|
5
100%
|
| More than one race |
0
0%
|
0
NaN
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
NaN
|
0
0%
|
| Region of Enrollment (Count of Participants) | |||
| United States |
5
100%
|
5
Infinity
|
|
| Baseline PSA (ng/mL) [Median (Full Range) ] | |||
| Median (Full Range) [ng/mL] |
14.76
|
14.76
|
|
| Gleason Score at Diagnosis (units on a scale) [Median (Full Range) ] | |||
| Median (Full Range) [units on a scale] |
7
|
7
|
|
Outcome Measures
| Title | 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. |
|---|---|
| Description | 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. |
| Time Frame | Pre- versus post-treatment |
Outcome Measure Data
| Analysis Population Description |
|---|
| Data not collected |
| Arm/Group Title | 48 Hour Drug Stop Point | 24 Hour Drug Stop Point |
|---|---|---|
| Arm/Group Description | Sorafenib 400mg taken orally twice per day for 41 days prior to radical prostatectomy. Last dose of study drug is the morning dose 2 days prior to surgery. | Sorafenib 400mg taken orally twice per day for 42 days prior to radical prostatectomy. Last dose of study drug is the morning dose the day prior to surgery. |
| Measure Participants | 0 | 0 |
| Title | Number of Participants With Complete Pathologic Response |
|---|---|
| Description | 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. |
| Time Frame | Day 1 of cycles 2 and 3, and day of radical prostatectomy. Each cycle is 2 weeks. |
Outcome Measure Data
| Analysis Population Description |
|---|
| One patient did not have lab samples collected on day of radical prostatectomy. |
| Arm/Group Title | 48 Hour Drug Stop Point | 24 Hour Drug Stop Point |
|---|---|---|
| Arm/Group Description | Sorafenib 400mg taken orally twice per day for 41 days prior to radical prostatectomy. Last dose of study drug is the morning dose 2 days prior to surgery. | Sorafenib 400mg taken orally twice per day for 42 days prior to radical prostatectomy. Last dose of study drug is the morning dose the day prior to surgery. |
| Measure Participants | 5 | 0 |
| Day 1 of Cycle 2 |
0
0%
|
|
| Day 1 of Cycle 3 |
0
0%
|
|
| Day of Radical Prostatectomy |
0
0%
|
| Title | Number of Participants With at Least 25% Reduction in PSA |
|---|---|
| Description | 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. |
| Time Frame | Day 1 of cycles 2 and 3 and on the day of radical prostatectomy. Each cycle is 2 weeks. |
Outcome Measure Data
| Analysis Population Description |
|---|
| One patient did not have lab samples collected on day of radical prostatectomy. |
| Arm/Group Title | 48 Hour Drug Stop Point | 24 Hour Drug Stop Point |
|---|---|---|
| Arm/Group Description | Sorafenib 400mg taken orally twice per day for 41 days prior to radical prostatectomy. Last dose of study drug is the morning dose 2 days prior to surgery. | Sorafenib 400mg taken orally twice per day for 42 days prior to radical prostatectomy. Last dose of study drug is the morning dose the day prior to surgery. |
| Measure Participants | 5 | 0 |
| Day 1 of Cycle 2 |
0
0%
|
|
| Day 1 of Cycle 3 |
0
0%
|
|
| Day of Radical Prostatectomy |
1
20%
|
Adverse Events
| Time Frame | Reported Adverse Events (AEs) include events starting on or after Day 0 and on or before Day 113 | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | If a subject experienced more than 1 of a given AE, the subject is counted only once for that AE. | |||
| Arm/Group Title | 48 Hour Drug Stop Point | 24 Hour Drug Stop Point | ||
| Arm/Group Description | Sorafenib 400mg taken orally twice per day for 41 days prior to radical prostatectomy. Last dose of study drug is the morning dose 2 days prior to surgery. | Sorafenib 400mg taken orally twice per day for 42 days prior to radical prostatectomy. Last dose of study drug is the morning dose the day prior to surgery. | ||
All Cause Mortality |
||||
| 48 Hour Drug Stop Point | 24 Hour Drug Stop Point | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| 48 Hour Drug Stop Point | 24 Hour Drug Stop Point | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/5 (0%) | 0/0 (NaN) | ||
Other (Not Including Serious) Adverse Events |
||||
| 48 Hour Drug Stop Point | 24 Hour Drug Stop Point | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/5 (100%) | 0/0 (NaN) | ||
| Ear and labyrinth disorders | ||||
| Tinnitus | 1/5 (20%) | 0/0 (NaN) | ||
| Gastrointestinal disorders | ||||
| Constipation | 1/5 (20%) | 0/0 (NaN) | ||
| Diarrhea | 2/5 (40%) | 0/0 (NaN) | ||
| General disorders | ||||
| pain, gastrointestinal, oral cavity, esophagus | 1/5 (20%) | 0/0 (NaN) | ||
| pain, renal/genitourinary | 1/5 (20%) | 0/0 (NaN) | ||
| Fatigue | 3/5 (60%) | 0/0 (NaN) | ||
| Weight loss | 1/5 (20%) | 0/0 (NaN) | ||
| Hepatobiliary disorders | ||||
| Pancreatitis | 1/5 (20%) | 0/0 (NaN) | ||
| Metabolism and nutrition disorders | ||||
| Transaminitis | 1/5 (20%) | 0/0 (NaN) | ||
| Musculoskeletal and connective tissue disorders | ||||
| pain, musculoskeletal, extremity-limb | 1/5 (20%) | 0/0 (NaN) | ||
| Nervous system disorders | ||||
| Tingling feet and scalp | 1/5 (20%) | 0/0 (NaN) | ||
| Renal and urinary disorders | ||||
| Urinary retention | 1/5 (20%) | 0/0 (NaN) | ||
| urination frequency and urgency | 1/5 (20%) | 0/0 (NaN) | ||
| Reproductive system and breast disorders | ||||
| Gynecomastia | 1/5 (20%) | 0/0 (NaN) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| voice changes/dysarthria | 4/5 (80%) | 0/0 (NaN) | ||
| Skin and subcutaneous tissue disorders | ||||
| Alopecia | 2/5 (40%) | 0/0 (NaN) | ||
| Dry skin | 1/5 (20%) | 0/0 (NaN) | ||
| Hand-foot syndrome | 2/5 (40%) | 0/0 (NaN) | ||
| Pruritis | 2/5 (40%) | 0/0 (NaN) | ||
| Rash | 2/5 (40%) | 0/0 (NaN) | ||
| Vascular disorders | ||||
| Hypertension | 4/5 (80%) | 0/0 (NaN) | ||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Evan Yu |
|---|---|
| Organization | University of Washington / Seattle Cancer Care Alliance |
| Phone | 206-288-1152 |
| evanyu@u.washington.edu |
- 6307
- NCI-2010-00604