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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00657982
Recruitment Status : Unknown
Verified January 2009 by Sheba Medical Center.
Recruitment status was:  Recruiting
First Posted : April 14, 2008
Last Update Posted : January 21, 2009
Information provided by:
Sheba Medical Center

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Prostate Cancer Drug: RAD001 Phase 2

Detailed Description:

Newly diagnosed patients with prostate cancer, with localized untreated disease must be at intermediate or high risk for disease relapse based on their PSA, Gleason score, and clinical stage. Before starting treatment, a baseline radiographic evaluation with FDG-PET and magnetic resonance imaging (MRI) will be performed. Biopsies will also be performed to obtain fresh tissue for molecular and gene expression assays. In patients with a positive FDG-PET scan at baseline, Treatment Day 1-14 will be with RAD001 10 mg/day alone. After performing post-RAD001 FDG-PET evaluation, treatment Day 15 will be equivalent of Treatment Day 1 of the trial in patients with negative FDG-PET scan at baseline.

In patients with a negative FDG-PET scan at baseline, Treatment Day 1 is the beginning of the Phase II trial of RAD001 combined with androgen ablation treatment.

Patients will be treated with RAD001 10 mg per day combined with androgen ablation therapy for 8 weeks depending on their ability to tolerate the drug. Radiographic and biologic assays will be repeated after 8 weeks, at which time patients will undergo prostatectomy or external beam radiation therapy (ERT). Second biopsy will be performed in patients admitted to ERT They will receive RAD001 up to the day of surgery or ERT to ascertain better tissue concentration of the drug. Gene expression profiling will also be evaluated at that time. The primary endpoint of this study is pharmacodynamic assessments of the effects of RAD001 in prostate cancer. However, the secondary endpoints of this study will define its true success. Specifically, the study will evaluate pharmacodynamic assessments of the effects of RAD001 in prostate cancer using novel applications of radiology, molecular biology, and genomics. These novel endpoints will be correlated with more established pathologic measures, such as microvessel density, apoptotic indexes, PTEN, phospho-AKT and phospho-p70S6K. MRI and 3-dimensional. PSA effects will also be assessed. Prostate cancer tissues from high risk prostate cancer patients admitted to neoadjuvant androgen ablation without RAD001 will serve as controls.

An ambitious aspect of this project is to examine gene expression alterations that occur in these patients. It will be technically challenging to get enough tissue by needle biopsies for gene array analysis. However, clearly, obtaining this information might be very useful in describing the full effects of RAD001 therapy in this patient population.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of RAD001 in a Neoadjuvant Setting in Men With Intermediate or High Risk Prostate Cancer
Study Start Date : April 2008
Estimated Primary Completion Date : March 2010

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer
U.S. FDA Resources

Arm Intervention/treatment
Experimental: 1
RAD001 10 BID 6 weeks before definite treatment for localized prostate cancer
Drug: RAD001
10mg BID

Primary Outcome Measures :
  1. PET-CT [ Time Frame: 6 weeks ]

Secondary Outcome Measures :
  1. PSA failure [ Time Frame: 3-5 years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00657982

Sheba Medical Center Recruiting
Tel Hashomer, Israel, 52621
Contact: Raanan Berger, MD   
Sponsors and Collaborators
Sheba Medical Center

Responsible Party: Dr Raanan Berger, Sheba Medical Center Identifier: NCT00657982     History of Changes
Other Study ID Numbers: SHEBA-07-4616-RB-CTIL
First Posted: April 14, 2008    Key Record Dates
Last Update Posted: January 21, 2009
Last Verified: January 2009

Additional relevant MeSH terms:
Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Genital Diseases, Male
Prostatic Diseases
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents