Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer
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.
Other: immunohistochemistry staining method
Procedure: neoadjuvant therapy
|Study Design:||Primary Purpose: Treatment|
|Official Title:||A Pharmacodynamic Study of Pre-Prostatectomy Rapamycin in Men With Advanced Localized Prostate Cancer|
|Study Start Date:||August 2006|
|Estimated Primary Completion Date:||January 2008 (Final data collection date for primary outcome measure)|
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00311623
|United States, Maryland|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins|
|Baltimore, Maryland, United States, 21231|
|United States, Michigan|
|University of Michigan Comprehensive Cancer Center|
|Ann Arbor, Michigan, United States, 48109-0942|
|Principal Investigator:||Michael A. Carducci, MD||Sidney Kimmel Comprehensive Cancer Center|