Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer
Condition: Cancer; Prostate Neoplasms
MeSH terms: Prostatic Neoplasms
Intervention: goserelin with dutasteride; goserelin with bicalutamide and dutasteride; goserelin with bicalutamide and dutasteride and ketoconazole
Intervention description: Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd; continue bicalutamide for one more week.; Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.; Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot), begin dutasteride 3.5 mg qd and ketoconazole 200 mg tid (with hydrocortisone 30 mg).
Intervention MeSH terms: Ketoconazole; Goserelin; Bicalutamide; Dutasteride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: Male
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No

Summary:

      Prostate cancer (CaP) is the most commonly diagnosed cancer among males in the U.S. and the
      second leading cause of cancer-related mortality. More than 230,000 men will be diagnosed
      with prostate cancer in the USA this year and more than 30,000 will die of this disease.

      Androgen deprivation, the elimination of testosterone and its active metabolites, remains the
      single most effective intervention available for the treatment of advanced prostate
      carcinoma. This is usually achieved by surgical removal of the testes (orchiectomy), by
      suppressing production of testosterone (LHRH agonists) and/or by blocking the androgens at
      receptor sites (antiandrogens). Unfortunately, androgen suppression does not cure the
      disease. Most patients progress within 0-5 years, and all patients ultimately progress if the
      cancer is not eliminated during initial therapy (usually prostatectomy or radiation).

      Hormone suppression treatment eliminates the detectable levels of testosterone in the blood.
      However, the testosterone levels in tissue remain high enough to stimulate androgen
      receptors. Overexpression of androgen receptors is present in all cell lines which
      demonstrate "androgen independence," i.e., are resistant to androgen-suppressive therapy.

      Approximately 95% of testosterone is supplied by the testes, with the remaining 5% supplied
      by the adrenal glands. The presumption that standard androgen deprivation achieves the
      optimal level of androgen suppression for patients is based on the levels of androgen which
      result from orchiectomy. However, because adrenal androgen levels are unaffected by standard
      modes of androgen deprivation, 5% of the body's testosterone remains despite hormone therapy.

      The hypothesis of this study is that more effective suppression of the androgen axis through
      elimination of adrenal androgens and more effective suppression of testosterone metabolites
      will lower intraprostatic androgen levels, minimizing activation of the androgen receptor and
      augmenting natural cell death (apoptosis). The investigators propose to test this hypothesis
      by administering neoadjuvant (pre-surgery) androgen deprivation therapy of different types
      before prostatectomy for patients with clinically localized prostate cancer. The
      investigators will assay serum and intraprostatic androgen levels, while assessing relative
      levels of apoptosis of normal and malignant tissue.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Men 18 years or older with a histologic diagnosis of clinically localized prostate
             cancer prior to radical prostatectomy as defined by:

               -  Clinical stage T1-T2b

               -  Prostate specific Antigen (PSA) less than 20

               -  Gleason score 7-10

          2. Patient's tumor must be considered surgically resectable .

          3. Eastern Cooperative Group (ECOG) performance status of 0-1.

          4. Life expectancy greater than 2 years.

          5. Able to understand and give informed consent.

          6. Laboratory values must be within specified limits.

        Exclusion Criteria:

          1. Patients with locally advanced or high risk disease not meeting the criteria defined
             above.

          2. Patients who have a total testosterone less than 280 ng/dL.

          3. Patients who are receiving any other investigational therapy.

          4. Patients with an active serious infection or other serious underlying medical
             condition.

          5. Dementia or significantly altered mental status that would prohibit the understanding
             and/or giving of informed consent.

          6. Histologic evidence of small cell carcinoma of the prostate.

          7. Patients who are currently receiving active therapy for other neoplastic disorders.

          8. Patients who are receiving any androgens, estrogens or progestational agents.

          9. Patients who are taking drugs or herbal supplements which affect androgen metabolism
             (e.g., spironolactone, aprepitant, bexarotene, clarithromycin, itraconazole,
             ketoconazole, St. John's wort).

         10. Patients who have chronic active hepatitis.

         11. Patients taking any of the following medications who cannot discontinue these
             medications for three months during administration of ketoconazole; statin cholesterol
             medications, cyclosporine, isoniazid, rifampin, terfenadine, triazolam or astemizole.

         12. Patients who have history of cerebrovascular accident, deep venous thrombosis,
             pulmonary emboli, unstable angina or clinical congestive heart failure.

         13. Medical conditions, which, in the opinion of the investigators would jeopardize either
             the patient or the integrity of the data obtained.

         14. Patients unwilling to use contraceptives while on study.

         15. Patients with a risk of nodal involvement of greater than 10% should have received a
             bone scan and CT of the pelvis prior to screening for the study as part of standard of
             care.