Neoadjuvant CCI-779 Followed By Radical Prostatectomy in Treating Patients With Newly Diagnosed Prostate Cancer Who Have a High Risk of Relapse

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as CCI-779, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving CCI-779 before surgery may shrink the tumor so that it can be removed. PURPOSE: This randomized phase II trial is studying how well CCI-779 works in treating patients who are undergoing radical prostatectomy for newly diagnosed prostate cancer at high risk of relapse.

Detailed Description
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OBJECTIVES: Primary Determine the effects of oral CCI-779 on changes in the phosphorylation state of proteins in the mammalian target of rapamycin (mTOR) signaling pathway in the tumor tissue of patients with newly diagnosed prostate cancer undergoing radical prostatectomy. Determine the effects of this drug on changes in p70S6 kinase activity, phosphorylation state of mTOR pathway proteins, and on global and targeted gene expression patterns in the peripheral blood mononuclear cells (PBMCs) of these patients. Secondary Determine the effects of this drug on global and targeted gene expression patterns in these patients. Identify pharmacodynamic/pharmacogenomic surrogate markers of this drug in both tumor tissue and PBMCs and determine if blood may be used as a surrogate tissue source for biomarkers of drug activity in the tumor in these patients. Determine, preliminarily, the potential antitumor effects of this drug in these patients. Determine the pharmacokinetics of this drug in these patients. Correlate phosphatase and tensin homolog (PTEN) gene status with the pharmacodynamic/pharmacogenomic effects of this drug in these patients. Determine the effects of this drug on changes in protein expression patterns in the plasma of these patients. OUTLINE: This is a randomized, open-label, multicenter study. Patients are randomized to 1 of 3 treatment arms. Patients randomized to arm III are stratified according to tumor expression of phosphatase and tensin homolog (PTEN) gene mutations (negative vs positive). Arm I: Patients receive oral CCI-779 once daily for a total of 8 weeks. Arm II: Patients receive a higher dose of CCI-779 as in arm I. Arm III: Patients receive a higher dose (higher than arm II) of CCI-779 as in arm I. Approximately 24-48 hours after the last dose of CCI-779, patients in all arms undergo radical prostatectomy. Patients are followed on day 7-10 and then at 4 weeks after study completion. PROJECTED ACCRUAL: A total of 40 patients (5 each for arms I and II and 30 for arm III) will be accrued for this study.

Official Title
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An Open-Label Study Of Exploratory Pharmacogenomics And Pharmacologic Effects Of Neoadjuvant Oral CCI-779 In Newly Diagnosed Prostate Cancer Patients Undergoing Radical Prostatectomy Who Have A High Risk Of Relapse

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: temsirolimus
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the prostate Diagnosis based on a minimum of 6 core biopsy samples Clinically confirmed organ-confined disease Candidate for radical prostatectomy No evidence of metastatic disease by CT scan and bone scan High risk of relapse based on either of the following criteria: Any one of the following: Stage T2C or higher Gleason score greater than 7 Prostate-specific antigen (PSA) greater than 20 ng/mL OR Any two of the following: Gleason score at least 7 PSA 10-20 ng/mL Greater than 50% of total biopsy cores with cancer involvement PATIENT CHARACTERISTICS: Age 18 and over Performance status ECOG 0-1 Life expectancy Not specified Hematopoietic No active bleeding Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin at least 10 g/dL Hepatic No acute or chronic hepatitis B Hepatitis B surface antigen negative No acute or chronic hepatitis C No antibodies to hepatitis C Bilirubin no greater than 1.5 times upper limit of normal (ULN) AST and ALT no greater than 2 times ULN Renal No ongoing urinary tract infection necessitating rapid or emergent surgical resection Creatinine no greater than 1.5 times ULN Cardiovascular No unstable angina No myocardial infarction within the past 6 months No life-threatening ventricular arrhythmia requiring ongoing maintenance therapy Pulmonary No known pulmonary hypertension No pneumonitis Other Fertile patients must use effective contraception during and for 12 weeks after study participation HIV negative No other severe immunocompromised states No active infection requiring antibiotic therapy No serious concurrent illness No other major illness that would substantially increase the risk associated with study participation No other malignancy within the past 5 years except basal cell or squamous cell skin cancer PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent immunotherapy Chemotherapy No prior chemotherapy No other concurrent chemotherapy Endocrine therapy More than 3 weeks since prior IV corticosteroids No concurrent systemic corticosteroids No prior or concurrent hormonal therapy for underlying malignancy Radiotherapy No prior or concurrent radiotherapy Surgery More than 3 months since prior major surgery Other More than 1 month since prior experimental drugs More than 3 weeks since prior immunosuppressive agents No concurrent immunosuppressive therapies No other concurrent investigational agents No concurrent enzyme-inducing anticonvulsants (e.g., phenobarbital, phenytoin, or carbamazepine) No concurrent ketoconazole, diltiazem, rifampin, terfenadine, cisapride, astemizole, pimozide, or Hypericum perforatum (St. John's wort) No concurrent grapefruit or grapefruit juice

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: temsirolimus|nan|
|Procedure: conventional surgery|nan|
|Procedure: neoadjuvant therapy|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phosphorylation state of proteins |  |  | 
| p70S6 kinase activity |  |  | 
| Phosphorylation state of mTOR pathway proteins |  |  | 
| Global and targeted gene expression patterns in peripheral blood mononuclear cells |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global and targeted gene expression patterns |  |  | 
| Pharmacodynamics and pharmacogenomic surrogate markers |  |  | 
| Antitumor effects |  |  | 
| Pharmacokinetics |  |  | 
| Correlation of phosphatase and tensin homolog gene status with pharmacodynamic and pharmacogenomic effects |  |  | 
| Protein expression patterns in the plasma |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the prostate, stage IIB prostate cancer, stage IIA prostate cancer, stage I prostate cancer