Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as sirolimus, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. PURPOSE: This clinical trial is studying the best dose of sirolimus and to see how well it works before surgery in treating patients with advanced localized prostate cancer.

Detailed Description
-----------------
OBJECTIVES: Primary Determine the pharmacodynamically optimal dose (POD) of continuous daily oral sirolimus (rapamycin) in patients with advanced localized prostate cancer when given prior to radical prostatectomy, as measured by tumor S6 kinase inhibition by immunohistochemistry (IHC). Determine the proportion of men with downstream target inhibition in prostate tumor tissue at the POD using paired tumor biopsies from before and after rapamycin administration. Correlate tumor pharmacodynamic (PD) efficacy with a surrogate marker of tumor PD efficacy, peripheral blood mononuclear cell (PBMC) S6 kinase activity inhibition. Secondary Characterize the serum and prostate tissue pharmacokinetics of daily oral rapamycin at 2 dose levels. Determine the relationship of PD target inhibition of S6 kinase activity with pretreatment Akt activity and PTEN loss by IHC in prostate cancer. Describe the relationship between PD inhibition with the mTOR inhibitor rapamycin and pretreatment prostate biopsy Gleason sum, Ki-67 index of proliferation, Akt activity, p27 IHC, and PTEN. Correlate PD efficacy as measured by downstream S6 kinase activity inhibition with markers of increased apoptosis (activated caspase 3) and reduction in markers of proliferation (change in Ki-67) in prostate tumor specimens. Quantify and characterize the toxicity of daily continuous rapamycin at 2 dose levels in generally healthy men with prostate cancer prior to surgery. Evaluate the activity of rapamycin in prostate cancer as measured in prostate specific antigen response prior to surgery. OUTLINE: This is a multicenter, dose-escalation study. Patients receive oral sirolimus (rapamycin) once daily on days 1-14 in the absence of unacceptable toxicity. Cohorts of 12-21 patients receive escalating doses of rapamycin until the pharmacodynamically optimal dose is determined. Patients undergo radical prostatectomy on day 15. Patients undergo blood collection and tumor biopsies periodically during study for pharmacologic and correlative biomarker studies. After completion of study treatment, patients are followed at 30 and 90 days. PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Official Title
-----------------
A Pharmacodynamic Study of Pre-Prostatectomy Rapamycin in Men With Advanced Localized Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Rapamycin 3mg
* Drug: Rapamycin 6mg
* Procedure: Radical prostatectomy


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically determined adenocarcinoma of the prostate Stage T1c-T3b disease No evidence of disease that has spread beyond the prostate or seminal vesicles No metastatic prostate cancer, including bone, visceral, brain, and lymph node metastases Tumor Gleason score sum of 7-10 (4+3 and 3+4 allowed) with tumor involving at least 2 discrete core biopsy sections Scheduled to undergo radical prostatectomy No other subtypes of prostate cancer, including any of the following: Sarcoma Neuroendocrine tumors Small cell cancer Ductal cancer Lymphoma PATIENT CHARACTERISTICS: ECOG performance status 0-1 WBC > 3,500/mm^3 Absolute neutrophil count > 1,500/mm^3 Platelet count > 100,000/mm^3 Hemoglobin > 9 g/dL Creatinine < 2.0 mg/dL Bilirubin < 2 mg/dL ALT and AST < 2 times upper limit of normal (ULN) Alkaline phosphatase < 2 times ULN Triglycerides and total cholesterol < 2 times ULN No history of allergy to sirolimus (rapamycin) or its derivatives No uncontrolled medical condition that would increase risk or limit compliance with study requirements, including the following: Immunodeficiency Gastrointestinal disease that would limit ability to swallow, take oral medications, or absorb them No active infections No other concurrent malignancy PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy, biologic therapy, radiotherapy, or immunotherapy for prostate cancer No concurrent chronic treatment with immunosuppressants or medications that interfere with the metabolism of sirolimus (rapamycin) No concurrent medication or agents that would interfere with the metabolism or excretion of rapamycin or its derivatives, including any of the following: Phenytoin Carbamazepine Cyclosporine Clarithromycin Clotrimazole Erythromycin Amiodarone Protease inhibitors used to treated HIV infection Cisapride Grapefruit juice Diltiazem Tacrolimus Hypericum perforatum (St. John's wort) Barbiturates Rifampin Phenobarbital Rifabutin Efavirenz Nevirapine At least 7 days since prior herbal medicines and medications, including any of the following: Hydrastis canadensis (goldenseal) Uncaria tomentosa (cat's claw) Echinacea angustifolia roots Trifolium pretense (wild cherry) Chamomile Glycyrrhiza glabra (licorice) Dillapiol Naringenin Norfloxacin Atorvastatin Pravastatin Cimetidine Fluconazole

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control group<br>Men >18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy. Receive no intervention on Days 1-14. Surgery performed on Day 15. | Procedure: Radical prostatectomy<br>* Radical prostatectomy performed on Day 15<br>|
| Experimental: Low-dose Rapamycin (3mg)<br>Men >18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy. Must have adequate hepatic, renal and bone marrow function, no allergy to rapamycins, avoid medications interfering with rapamycin metabolism, no active infection, no prior therapies for prostate cancer. Will receive rapamycin 3mg (Wyeth Pharmaceuticals, 1mg tablets) oral (PO) once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15). | Drug: Rapamycin 3mg<br>* Rapamycin 3mg (Wyeth Pharmaceuticals, 1mg tablets) PO once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15).<br>* Other names: sirolimus;Procedure: Radical prostatectomy<br>* Radical prostatectomy performed on Day 15<br>|
| Experimental: High-dose Rapamycin (6mg)<br>Men >18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy. Must have adequate hepatic, renal and bone marrow function, no allergy to rapamycins, avoid medications interfering with rapamycin metabolism, no active infection, no prior therapies for prostate cancer. Will receive rapamycin 6mg (Wyeth Pharmaceuticals, 2mg tablets) oral (PO) once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15). | Drug: Rapamycin 6mg<br>* Rapamycin 6mg (Wyeth Pharmaceuticals, 2mg tablets) PO once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15).<br>* Other names: sirolimus;Procedure: Radical prostatectomy<br>* Radical prostatectomy performed on Day 15<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmocodynamically Optimal Dose (POD) of Rapamycin as Determined by Number of Participants With Greater Than or Equal to 60% Tumor S6 Kinase Inhibition by Immunohistochemistry (IHC). |  | Day 15 post-intervention | 
| Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD |  | Change from baseline to 15 days post-intervention | 
| Pharmacodynamic Response as Assessed by Median Post-treatment S6 Activity H-score | Pharmocodynamic response was taken as ≥60% decrease in the H-score for S6 phosphorylation in the radical prostatectomy tumor tissue compared with the pretreatment (baseline) biopsy tumor tissue. The H-score is a semiquantitative measure of the percentage of cells scoring positive (0-100) multiplied by the intensity of staining (0-3). | Change from baseline to 15 days post-intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis | Snap-frozen prostate tissue was evaluated for tissue rapamycin levels. | Change from baseline to 15 days post-intervention | 
| Pharmacokinetic Response of Rapamycin 6mg as Assessed by Whole Blood Analysis | Snap-frozen prostate tissue was evaluated for tissue rapamycin levels. | Change from baseline to 15 days post-intervention | 
| Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC) | Number of participants with change (increased, decreased or no change) in Akt phosphorylation as measured by immunohistochemistry (IHC) | Change from baseline to 15 days post-intervention | 
| PTEN Loss as Measured by Immunohistochemistry (IHC) | Determine the relationship of PD target inhibition of S6 kinase activity with pretreatment PTEN loss by IHC in prostate cancer. | Change from baseline to 15 days post-intervention | 
| p27 as Measured by Immunohistochemistry (IHC) | p27 by IHC in prostate cancer. | Change from baseline to 15 days post-intervention | 
| Change in Gleason Sum | pretreatment biopsy compared to post-treatment radical prostatectomy specimen | Change from baseline to 15 days post-intervention | 
| Increased Apoptosis as Measured by Activated Caspase 3 | Correlate PD efficacy as measured by downstream S6 kinase activity inhibition with markers of increased apoptosis (activated caspase 3) in prostate tumor specimens. | Baseline, 14 days post-intervention, 90-days post-operative | 
| Reduction in Proliferation as Measured by Decrease in Ki-67 | Correlate PD efficacy as measured by downstream S6 kinase activity inhibition with markers of reduction in markers of proliferation (change in Ki-67) in prostate tumor specimens. | Baseline, 14 days post-intervention, 90-days post-operative | 
| Toxicity as Per National Cancer Institute Common Toxicity Criteria v3.0 | Dose-limiting toxicity was defined as grade 3/4 neutropenia with fever lasting >7 days, platelets of <100,000/mm3 or associated with bleeding, grade ≥3 non-hematologic toxicity, or irreversible grade 2 toxicity related to rapamycine. | Baseline, 14 days post-intervention, 90-days post-operative | 
| Activity of Rapamycin as Measured by Prostate Specific Antigen (PSA) Response Prior to Surgery | PSA response to daily rapamycin | Change from baseline to Day 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage III prostate cancer, stage I prostate cancer, stage IIB prostate cancer, stage IIA prostate cancer, adenocarcinoma of the prostate