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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
32
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).
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).
Radical prostatectomy performed on Day 15
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, United States
Duke Comprehensive Cancer Center
Durham, North Carolina, United States
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).
Time frame: Day 15 post-intervention
Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD
Time frame: 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).
Time frame: Change from baseline to 15 days post-intervention
Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis
Snap-frozen prostate tissue was evaluated for tissue rapamycin levels.
Time frame: 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.
Time frame: 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)
Time frame: Change from baseline to 15 days post-intervention
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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.
Time frame: Change from baseline to 15 days post-intervention
p27 as Measured by Immunohistochemistry (IHC)
p27 by IHC in prostate cancer.
Time frame: Change from baseline to 15 days post-intervention
Change in Gleason Sum
pretreatment biopsy compared to post-treatment radical prostatectomy specimen
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: Change from baseline to Day 14