Everolimus in Treating Patients With Newly Diagnosed Localized Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving everolimus before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This randomized phase II trial is studying the side effects and how well everolimus works in treating patients with newly diagnosed localized prostate cancer.

Detailed Description
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OBJECTIVES: Primary To determine the clinical effects of everolimus, in terms of pathologic response (i.e., histologic P0, margin status, or capsular penetration) and surgical outcome, in patients with newly diagnosed localized prostate cancer treated with two different doses of everolimus prior to radical prostatectomy. To evaluate the safety and tolerability of this drug in these patients. Secondary To determine the effect of this drug on prostate-specific antigen (PSA) levels in these patients. To determine the effect of this drug on levels of expression of PTEN, Akt, phospho-mTOR (i.e., Se2448), phospho-p70 S6 kinase (i.e., Thre389), phospho-Smad3 (i.e., Ser433/435), phospho-Smads 1/5 (i.e., Ser463/465), AR, and TUNEL in these patients. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive low-dose oral everolimus once daily for up to 8 weeks in the absence of unacceptable toxicity. Arm II: Patients receive high-dose oral everolimus once daily for up to 8 weeks in the absence of unacceptable toxicity. Within 7 days after the last dose of everolimus, all patients undergo radical prostatectomy with bilateral pelvic lymphadenectomy. Tumor biopsy specimens acquired prior to treatment and prostate tumor tissue acquired at the time of radical prostatectomy are evaluated for biomarker correlative studies. Tissue samples are assessed by immunohistochemistry (IHC) and tissue microarray analysis for expression of cellular and molecular biomarkers (i.e., p-S6, p-4E-BP1, and p-Akt) that correlate with response. Prostatectomy specimens are also assessed by pathologic analysis for histopathologic response (i.e., pathologic stage, Gleason score, margin status, and tumor size). After completion of study therapy, patients are followed at 6 weeks.

Official Title
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Randomized Phase II Study of Two Different Doses of RAD-001 (Everolimus) as Neo-Adjuvant Therapy in Patients With Localized Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: Everolimus
* Procedure: conventional surgery


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed newly diagnosed, localized adenocarcinoma of the prostate, meeting any of the following criteria: Clinical stage T2a, T2b, T2c, or T3 disease (any grade or PSA) Gleason score 7 (4+3 only) or ≥ 8 (any stage or PSA) Serum PSA ≥ 10 ng/dL (any grade or stage) Any stage, PSA, or Gleason score AND ≥ 35% chance of biochemical failure at 5 years based on Kattan's nomogram Recommended for radical prostatectomy Normal testosterone level No pure neuroendocrine or small cell prostate cancer No metastatic disease by CT scan, MRI, bone scan, or X-ray No clinical evidence of CNS metastases PATIENT CHARACTERISTICS: Inclusion criteria: ECOG performance status (PS) 0-1 or Karnofsky PS 70-100% ANC ≥ 1,500/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 8 g/dL AST and ALT ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN Creatinine ≤ 1.5 times ULN PT/PTT normal (no anticoagulants) No active unresolved infection No known HIV positivity Fertile patients must use effective contraception during and for 6 months after completion of study therapy Exclusion criteria: Known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus or temsirolimus) or to its excipients Gastrointestinal (GI) disease, condition, or symptoms that may significantly impair GI function and alter the absorption of everolimus, including any of the following: Ulcerative disease Uncontrolled nausea Vomiting Diarrhea Malabsorption syndrome Other active malignancy or malignancy at ≥ 30% risk for relapse after completion of therapy, except nonmelanoma skin cancer Uncontrolled concurrent illness including, but not limited to, any of the following: Ongoing or active infection (e.g., bacterial, viral or fungal) Severely impaired lung function Uncontrolled diabetes (fasting serum glucose > 1.5 times ULN) Liver disease (e.g., cirrhosis, chronic active hepatitis, or chronic persistent hepatitis) Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness or social situation that would limit study compliance Any underlying medical condition which, in the principal investigator's opinion, will make the administration of everolimus hazardous OR obscure the interpretation of adverse events PRIOR CONCURRENT THERAPY: More than 4 weeks since major surgery More than 3 months since finasteride No prior or concurrent radiotherapy to the prostate gland or pelvis No prior hormones (e.g., luteinizing hormone-releasing hormone [LHRH] agonists, LHRH antagonists, or antiandrogens [e.g., bicalutamide, flutamide, or nilutamide]) and/or PC-SPES (or PC-x product) or estrogen-containing nutraceuticals No prior rapamycin mTOR inhibitor No prior small bowel resection that may significantly impair GI function and alter the absorption of everolimus No prior or concurrent immunotherapy, chemotherapy, or other investigational therapy for prostate cancer No other concurrent investigational or commercial agents No other concurrent anticancer agents No concurrent, chronic treatment with systemic steroids (except inhaled or topical steroids) or another immunosuppressive agent No concurrent live vaccines No concurrent strong inhibitors or inducers of the isoenzyme CYP3A administered as systemic therapy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose Everolimus Cohort<br>5mg Everolimus daily continuously for 8 weeks and conventional surgery | Drug: Everolimus<br>* Patients will receive arm-specific dosage of Everolimus daily continuously for 8 week<br>* Other names: RAD-001;Procedure: conventional surgery<br>* Radical prostatectomy with bilateral pelvic lymphadenectomy will be performed within 10 days of the completion of week 8 on RAD-001 (Everolimus).<br>|
| Active Comparator: High-dose Everolimus Cohort<br>10mg Everolimus daily continuously for 8 weeks and conventional surgery | Drug: Everolimus<br>* Patients will receive arm-specific dosage of Everolimus daily continuously for 8 week<br>* Other names: RAD-001;Procedure: conventional surgery<br>* Radical prostatectomy with bilateral pelvic lymphadenectomy will be performed within 10 days of the completion of week 8 on RAD-001 (Everolimus).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Who Are P0 (i.e., no Clinically Detectable Tumor in the Pathologic Specimen) at Surgery | Specimens are fixed in formalin for 24 hours.Specimens are the cut at 3 mm intervals perpendicular to the rectal surface and the sections are examined grossly and microscopically on routine Hematoxylin and Eosin stain (H&E) (pathologic complete response or P0) will be defined as responders. | After 8 weeks of therapy at the time of prostatectomy | 
| Toxicity Profile of Each Dose (Number of Patients With Worst Grade Toxicity) | Toxicity will be assessed using the NIH-NCI Common Terminology Criteria for Adverse Events, version 3.0 (CTCAEv3.0) | at daily dose for 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PSA | Time-to-event data, such as change in PSA will be summarized using the method of Kaplan and Meier. | Up to 16 weeks after start of study | 

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