A Pharmacodynamic Study of Pre-Prostatectomy Rapamycin in Men With Advanced Localized Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 3
- 主要终点
- Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Control group
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.
干预措施: Radical prostatectomy (Procedure)
Low-dose Rapamycin (3mg)
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).
干预措施: Rapamycin 3mg (Drug)
Low-dose Rapamycin (3mg)
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).
干预措施: Radical prostatectomy (Procedure)
High-dose Rapamycin (6mg)
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).
干预措施: Rapamycin 6mg (Drug)
High-dose Rapamycin (6mg)
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).
干预措施: Radical prostatectomy (Procedure)
结局指标
主要结局
Median S6 Kinase Inhibition in Prostate Tumor Tissue at the POD
时间窗: Change from baseline to 15 days post-intervention
Pharmocodynamically Optimal Dose (POD) of Rapamycin as Determined by Number of Participants With Greater Than or Equal to 60% Tumor S6 Kinase Inhibition by Immunohistochemistry (IHC).
时间窗: Day 15 post-intervention
Pharmacodynamic Response as Assessed by Median Post-treatment S6 Activity H-score
时间窗: Change from baseline to 15 days post-intervention
Pharmocodynamic response was taken as ≥60% decrease in the H-score for S6 phosphorylation in the radical prostatectomy tumor tissue compared with the pretreatment (baseline) biopsy tumor tissue. The H-score is a semiquantitative measure of the percentage of cells scoring positive (0-100) multiplied by the intensity of staining (0-3).
次要结局
- p27 as Measured by Immunohistochemistry (IHC)(Change from baseline to 15 days post-intervention)
- Pharmacokinetic Response of Rapamycin 6mg as Assessed by Whole Blood Analysis(Change from baseline to 15 days post-intervention)
- Number of Participants With Change in Akt Phosphorylation as Measured by Immunohistochemistry (IHC)(Change from baseline to 15 days post-intervention)
- Reduction in Proliferation as Measured by Decrease in Ki-67(Baseline, 14 days post-intervention, 90-days post-operative)
- Toxicity as Per National Cancer Institute Common Toxicity Criteria v3.0(Baseline, 14 days post-intervention, 90-days post-operative)
- Pharmacokinetic Response of Rapamycin 3mg as Assessed by Whole Blood Analysis(Change from baseline to 15 days post-intervention)
- PTEN Loss as Measured by Immunohistochemistry (IHC)(Change from baseline to 15 days post-intervention)
- Increased Apoptosis as Measured by Activated Caspase 3(Baseline, 14 days post-intervention, 90-days post-operative)
- Change in Gleason Sum(Change from baseline to 15 days post-intervention)
- Activity of Rapamycin as Measured by Prostate Specific Antigen (PSA) Response Prior to Surgery(Change from baseline to Day 14)