Clinical trial NCT00002760: Antiandrogen Withdrawal in Treating Patients With Hormone-Refractory Prostate Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: adenocarcinoma of the prostate
recurrent prostate cancer
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-07-19
Enrollment: 260
Sex: MALE
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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).

Eligibility criteria: 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

Primary outcomes:
measure: Response: PSA
timeFrame: q 8 wks, at cross over (if applicable), at progression; q 6 mon in f/u
Secondary outcomes:
measure: Circulating prostate cancer cells
timeFrame: Pre treatment, 1 time
measure: Adrenal androgen synthesis suppression
timeFrame: pre tx, after 1 and 3 months tx, at progression
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF Cancer Center and Cancer Research Institute
state: California
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
Study officials:
affiliation: University of California, San Francisco
name: Eric Small, MD
role: STUDY_CHAIR
References:
citation: D'Amico AV, Halabi S, Vogelzang NJ, et al.: A reduction in the rate of PSA rise following chemotherapy in patients with metastatic hormone refractory prostate cancer (HRPC) predicts survival: results of a pooled analysis of CALGB HRPC trials. [Abstract] J Clin Oncol 22 (Suppl 14): A-4506, 383s, 2004.
citation: Halabi S, Small EJ, Kantoff PW, Kattan MW, Kaplan EB, Dawson NA, Levine EG, Blumenstein BA, Vogelzang NJ. Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol. 2003 Apr 1;21(7):1232-7. doi: 10.1200/JCO.2003.06.100.
citation: Gilligan TD, Halabi S, Kantoff PW, et al.: African-American race is associated with longer survival in patients with metastatic hormone-refractory prostate cancer (HRCaP) in four randomized phase III Cancer and Leukemia Group B (CALGB) trials. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-725, 2002.
citation: Ryan CJ, Halabi S, Ou SS, Vogelzang NJ, Kantoff P, Small EJ. Adrenal androgen levels as predictors of outcome in prostate cancer patients treated with ketoconazole plus antiandrogen withdrawal: results from a cancer and leukemia group B study. Clin Cancer Res. 2007 Apr 1;13(7):2030-7. doi: 10.1158/1078-0432.CCR-06-2344.
citation: Ryan CJ, Halabi S, Kaplan E, et al.: Use of adrenal androgen levels to predict response to ketoconazole in patients with androgen independent prostate cancer: results from CALGB 9583. [Abstract] J Clin Oncol 22 (Suppl 14): A-4558, 396s, 2004.
citation: Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol. 2004 Mar 15;22(6):1025-33. doi: 10.1200/JCO.2004.06.037.
citation: Halabi S, Small EJ, Hayes DF, Vogelzang NJ, Kantoff PW. Prognostic significance of reverse transcriptase polymerase chain reaction for prostate-specific antigen in metastatic prostate cancer: a nested study within CALGB 9583. J Clin Oncol. 2003 Feb 1;21(3):490-5. doi: 10.1200/JCO.2003.04.104.
citation: Halabi S, Small E, Farmer D, et al.: Reverse transcriptase polymerase chain reaction (RT-PCR) for prostate specific antigen (PSA) as a prognostic factor for survival among androgen independent prostate cancer patients (AICaP): a companion study to CALGB 9583. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-700, 2001.
citation: Vogelzang NV, Halabi S, Picus J, et al.: Prospective assessment of adrenal androgen levels as predictors of survival in androgen independent prostate cancer patients treated with ketoconazole: a correlative study to CALGB protocol 9583. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-749, 2001.