Antiandrogen Withdrawal in Treating Patients With Hormone-Refractory Prostate Cancer

Study Overview
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Brief Summary
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RATIONALE: Antiandrogen withdrawal may be an effective treatment for prostate cancer. PURPOSE: Randomized phase III trial to study the effectiveness of ketoconazole and hydrocortisone for antiandrogen withdrawal in treating men with prostate cancer that is refractory to hormone therapy.

Detailed Description
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OBJECTIVES: I. Compare the response rate and duration of response to antiandrogen withdrawal alone vs. antiandrogen withdrawal plus ketoconazole/hydrocortisone in patients with advanced hormone-refractory prostate cancer. II. Compare the response rate and duration of response to ketoconazole/hydrocortisone in patients treated with previous vs. simultaneous antiandrogen withdrawal. III. Evaluate the proportion of patients with circulating prostate cancer cells identified by reverse transcriptase-polymerase chain reaction (rt-PCR). IV. Determine whether rt-PCR positively correlates with response. V. Compare the likelihood of response to these regimens in patients whose prior hormonal therapy consisted of initial combined androgen blockage vs. initial monotherapy followed later by an antiandrogen. VI. Correlate adrenal androgen synthesis suppression, as measured by levels of various adrenal androgens, with response. OUTLINE: Randomized study. Patients who develop progressive disease on Arm I cross to Arm II. Arm I: Antiandrogen Withdrawal. Antiandrogen stopped. Arm II: Antiandrogen Withdrawal plus Adrenal Androgen Blockade. Antiandrogen stopped; plus Ketoconazole, KCZ; Hydrocortisone, HC, NSC-10483. PROJECTED ACCRUAL: Approximately 250 patients will be entered over 3 years to attain 238 eligible patients (including 25-40 minority patients).

Official Title
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A PHASE III TWO-ARM RANDOMIZED STUDY COMPARING ANTIANDROGEN WITHDRAWAL ALONE VERSUS ANTIANDROGEN WITHDRAWAL COMBINED WITH KETOCONAZOLE AND HYDROCORTISON IN PATIENTS WITH ADVANCED PROSTAGE CANCER

Conditions
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Prostate Cancer

Intervention / Treatment
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* Drug: ketoconazole
* Drug: therapeutic hydrocortisone
* Other: Withdrawal of antiandrogen therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically diagnosed adenocarcinoma of the prostate Progressive metastatic or regional nodal disease after at least 4 weeks on flutamide, bicalutamide, or nilutamide, i.e.: Greater than 25% increase in sum of products of perpendicular diameters of all measurable lesions not previously irradiated OR Prostate-specific antigen (PSA) at least 5 ng/mL and risen from baseline on at least 2 successive occasions at least 2 weeks apart PSA progression required for bone only disease or disease that responded to androgen deprivation and is negative on imaging scans at entry Primary testicular androgen suppression with a luteinizing hormone-releasing hormone (LHRH) analogue plus antiandrogen or by orchiectomy required Intermittent LHRH analog/antiandrogen therapy resumed at least 4 weeks prior to and continued at time of entry LHRH analogue continued throughout study in absence of orchiectomy PATIENT CHARACTERISTICS: Age: Any age Performance status: 0-2 Hematopoietic: Not specified Hepatic: Bilirubin no greater than 1.5 times normal AST no greater than 3 times normal Renal: Not specified Other: No active, uncontrolled condition including: Bacterial, viral, or fungal infection Hyperglycemia Gastric or duodenal ulcer No existing medical condition requiring systemic corticosteroids (inhaled and topical steroids allowed) No concurrent use of the following: Terfenadine Astemizole Cisapride PRIOR CONCURRENT THERAPY: No prior therapy with experimental agents for metastatic disease Biologic therapy: No prior immunotherapy for metastatic disease Chemotherapy: No prior estramustine or other chemotherapy for metastatic disease Endocrine therapy: See Disease Characteristics No prior hormonal therapy for metastatic disease No prior aminoglutethimide No prior ketoconazole No prior hydrocortisone or other corticosteroids Prior experimental hormonal therapy requires approval of study chair Radiotherapy: At least 4 weeks since radiotherapy (8 weeks since strontium therapy) Surgery: Orchiectomy allowed

Ages Eligible for Study
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Maximum Age: 120 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Antiandrogen withdrawal<br>antiandrogen therapy withdrawn; patient who progress will be crossed over to Arm 1A: 400 mg ketoconazole PO tid and hydrocortisone 30 mgs PO q am and 10 mgs PO qhs until treatment is no longer effective | Other: Withdrawal of antiandrogen therapy<br>* no drugs given<br>|
| Active Comparator: Antiandrogen withdrawal + therapy<br>Ketoconazole and hydrocortisone | Drug: ketoconazole<br>* 400 mg PO tid for as long as treatment is effective<br>Drug: therapeutic hydrocortisone<br>* hydrocortisone 30 mg PO q am and 10 mg PO qhs for as long as treatment is effective<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response: PSA |  | q 8 wks, at cross over (if applicable), at progression; q 6 mon in f/u | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating prostate cancer cells | Circulating prostate cancer cells as detected by rt-PCR will be correlated with outcomes | Pre treatment, 1 time | 
| Adrenal androgen synthesis suppression | Adrenal androgen synthesis suppression will be assessed vs response | pre tx, after 1 and 3 months tx, at progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the prostate, recurrent prostate cancer