Clinical trial NCT00311623
Conditions: Prostate Cancer
Keywords: stage III prostate cancer stage I prostate cancer stage IIB prostate cancer stage IIA prostate cancer adenocarcinoma of the prostate
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2006-08-01; Completion date: 2010-06-01
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief 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.

Arms: arm 1: Men \>18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy.

Receive no intervention on Days 1-14. Surgery performed on Day 15. arm 2: Men \>18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy.

Must have adequate hepatic, renal and bone marrow function, no allergy to rapamycins, avoid medications interfering with rapamycin metabolism, no active infection, no prior therapies for prostate cancer.

Will receive rapamycin 3mg (Wyeth Pharmaceuticals, 1mg tablets) oral (PO) once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15). arm 3: Men \>18years old with prostate cancer clinical stages T1c to T3, no metastases, Gleason sum of 7-10, multiple positive diagnostic cores, Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, candidates for radical prostatectomy.

Must have adequate hepatic, renal and bone marrow function, no allergy to rapamycins, avoid medications interfering with rapamycin metabolism, no active infection, no prior therapies for prostate cancer.

Will receive rapamycin 6mg (Wyeth Pharmaceuticals, 2mg tablets) oral (PO) once daily on Days 1-14 with the last dose given on the morning before surgery (Day 15).
Interventions: intervention 1: Rapamycin 3mg intervention 2: Rapamycin 6mg intervention 3: Radical prostatectomy
Intervention descriptions: intervention 1: 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). intervention 2: 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). intervention 3: Radical prostatectomy performed on Day 15

Protocol documents: