NCT00311623

Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer

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

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 32 (actual)
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins · Academic / Other
• Sex: Male
• Age: 18 Years – 120 Years
• Healthy volunteers: Not accepted

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.

Conditions

• Prostate Cancer

Interventions

Type	Name	Description
DRUG	Rapamycin 3mg	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).
DRUG	Rapamycin 6mg	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).
PROCEDURE	Radical prostatectomy	Radical prostatectomy performed on Day 15

Timeline

• Start date: 2006-08-01
• Primary completion: 2008-01-01
• Completion: 2010-06-01
• First posted: 2006-04-06
• Last updated: 2019-02-22
• Results posted: 2019-02-22

Locations

3 sites across 1 country: United States

Regulatory

• FDA-regulated drug study