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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

Phase 2
18 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

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



- 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.


- To determine the effect of this drug on prostate-specific antigen (PSA) levels in these

- 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.

Inclusion Criteria


- 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


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

- 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


- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of patients who are P0 (i.e., no clinically detectable tumor in the pathologic specimen) at surgery

Outcome Description:

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.

Outcome Time Frame:

After 8 weeks of therapy at the time of prostatectomy

Safety Issue:


Principal Investigator

Jorge A. Garcia, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

September 2007

Completion Date:

Related Keywords:

  • Prostate Cancer
  • adenocarcinoma of the prostate
  • stage I prostate cancer
  • stage II prostate cancer
  • stage III prostate cancer
  • Prostatic Neoplasms



Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center Cleveland, Ohio  44195