Everolimus in Treating Patients With Newly Diagnosed Localized Prostate Cancer

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.

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