A Pharmacodynamic Study of Pre-Prostatectomy Rapamycin in Men With Advanced Localized Prostate Cancer
- 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
- 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
- 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
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.
Primary Purpose: Treatment
Michael A. Carducci, MD
Sidney Kimmel Comprehensive Cancer Center
United States: Federal Government
|University of Michigan Comprehensive Cancer Center||Ann Arbor, Michigan 48109-0752|
|Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins||Baltimore, Maryland 21231-2410|