Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Rapamycin 3mg; Rapamycin 6mg; Radical prostatectomy
Intervention type(s): Drug; Drug; Procedure
Intervention description(s): 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
Other intervention name(s): sirolimus; sirolimus
Intervention MeSH terms: Sirolimus; Temsirolimus; MTOR Inhibitors
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: stage III prostate cancer; stage I prostate cancer; stage IIB prostate cancer; stage IIA prostate cancer; adenocarcinoma of the prostate