Phase II Study of RAD001 in a Neoadjuvant Setting in Men With Intermediate or High Risk Prostate Cancer

The mechanisms responsible for the development of hormonal refractory prostate cancer (HRPC) have been elusive. Genetic inactivation/loss of the PTEN tumor suppressor gene occurs in 30-60% of advanced prostate cancers and in 20% of the localized form. Researchers hypothesize that PTEN loss is a landmark genetic event in prostate cancer progression into the fatal HRPC form. One consequence of PTEN loss is activation of the oncogenic Akt and phosphorylation of downstream Akt targets including mTOR. mTOR controls many important cellular processes including cell cycle regulation. We propose to evaluate pharmacodynamic assessments of the mTOR inhibitor RAD001 in intermediate and high risk prostate cancer patients in the neoadjuvant setting. Patients will be admitted to 6 weeks treatment with RAD001 10 mg/day followed by either radical prostatectomy or radiotherapy combined with hormonal treatment. Immunohistochemistry with antibodies for phosphorylated p70S6K , pS6, Akt as well as antibodies for VEGF, BCL2 and PTEN in prostate cancer tissues before and after 6 weeks RAD001 treatment will be performed. Additionally, Patients will be evaluated by FDG-PET scan before (as baseline) and after RAD001 treatment. A link between mTOR signaling and glycolysis regulation was established and may provide a mechanism to assess drug-target interaction of RAD001 in prostate cancer. The secondary endpoint of the trial will be to determine the response proportion to RAD001 treatment by assessing time to biochemical failure followed by radiation therapy or radical prostatectomy. The data will be compared to a matched cohort of high and intermediate-risk prostate cancer patients admitted to the same treatments modalities without receiving RAD001.

Sex

Male

Minimum age

18 Years

Inclusion Criteria:

1. Histologic documentation of adenocarcinoma of prostate Gleason grade 7-10
2. No evidence for lymph node or distant disease
3. No prior RT to pelvis or other regions
4. Age \> 18 years
5. Performance status ECOG 0-1
6. ANC \>1500/l
7. Hemoglobin \> 9.0 g/dl
8. Platelets \>100,000/l
9. Total Bilirubin \<1.5 x upper limits of normal
10. AST or ALT \< 3 x upper limits of normal
11. Creatinine \< 1.5 x upper limits of normal
12. Electrolytes within 10% of normal Range
13. Cholesterol \< 300

Exclusion Criteria:

1. Prior hormonal therapy
2. Prior RT to the pelvis
3. Currently active second malignancy other than non-melanoma skin cancer
4. Patients who have any severe and/or uncontrolled medical conditions such as

   1. Unstable angina pectoris, symptomatic congestive heart failure (New York heart association grade 2 or greater failure), myocardial infarction ≤ 6 months prior to randomization, serious uncontrolled cardiac arrhythmia
   2. Active or uncontrolled severe infection
   3. Cirrhosis, chronic active hepatitis or chronic persistent hepatitis
   4. Severely impaired lung function
5. Evidence of bleeding diathesis or coagulopathy or need of administration of full-dose anti-coagulative(s)
6. Major surgical procedure, open biopsy or significant trauma within 28 days prior to day 1
7. Patients with active infection, including inflammation.
8. Prior therapy with mTOR inhibitors (sirolimus, temsirolimus, everolimus)
9. Uncontrolled diabetes mellitus as defined by fasting serum glucose \>1.5
10. Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent
11. Patients with a known history of HIV seropositivity