Sirolimus Before Surgery in Treating Patients With Advanced Localized Prostate Cancer

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.

DISEASE CHARACTERISTICS:

- Histologically determined adenocarcinoma of the prostate

- Stage T1c-T3b disease

- No evidence of disease that has spread beyond the prostate or seminal vesicles

- No metastatic prostate cancer, including bone, visceral, brain, and lymph node
metastases

- Tumor Gleason score sum of 7-10 (4+3 and 3+4 allowed) with tumor involving at least 2
discrete core biopsy sections

- Scheduled to undergo radical prostatectomy

- No other subtypes of prostate cancer, including any of the following:

- Sarcoma

- Neuroendocrine tumors

- Small cell cancer

- Ductal cancer

- Lymphoma

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- WBC > 3,500/mm^3

- Absolute neutrophil count > 1,500/mm^3

- Platelet count > 100,000/mm^3

- Hemoglobin > 9 g/dL

- Creatinine < 2.0 mg/dL

- Bilirubin < 2 mg/dL

- ALT and AST < 2 times upper limit of normal (ULN)

- Alkaline phosphatase < 2 times ULN

- Triglycerides and total cholesterol < 2 times ULN

- No history of allergy to sirolimus (rapamycin) or its derivatives

- No uncontrolled medical condition that would increase risk or limit compliance with
study requirements, including the following:

- Immunodeficiency

- Gastrointestinal disease that would limit ability to swallow, take oral
medications, or absorb them

- No active infections

- No other concurrent malignancy

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- No prior chemotherapy, biologic therapy, radiotherapy, or immunotherapy for prostate
cancer

- No concurrent chronic treatment with immunosuppressants or medications that interfere
with the metabolism of sirolimus (rapamycin)

- No concurrent medication or agents that would interfere with the metabolism or
excretion of rapamycin or its derivatives, including any of the following:

- Phenytoin

- Carbamazepine

- Cyclosporine

- Clarithromycin

- Clotrimazole

- Erythromycin

- Amiodarone

- Protease inhibitors used to treated HIV infection

- Cisapride

- Grapefruit juice

- Diltiazem

- Tacrolimus

- Hypericum perforatum (St. John's wort)

- Barbiturates

- Rifampin

- Phenobarbital

- Rifabutin

- Efavirenz

- Nevirapine

- At least 7 days since prior herbal medicines and medications, including any of the
following:

- Hydrastis canadensis (goldenseal)

- Uncaria tomentosa (cat's claw)

- Echinacea angustifolia roots

- Trifolium pretense (wild cherry)

- Chamomile

- Glycyrrhiza glabra (licorice)

- Dillapiol

- Naringenin

- Norfloxacin

- Atorvastatin

- Pravastatin

- Cimetidine

- Fluconazole