Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Antiandrogen Withdrawal in Treating Patients With Hormone-Refractory Prostate Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed any age NCI CLB-9583 NCT00002760, CALGB-9583

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.

Entry 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

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

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

Expected Enrollment

Approximately 250 patients will be entered over 3 years to attain 238 eligible 
patients (including 25-40 minority patients).

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.

Ryan CJ, Halabi S, Ou SS, et al.: 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 13 (7): 2030-7, 2007.[PUBMED Abstract]

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.

Small EJ, Halabi S, Dawson NA, et al.: Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 22 (6): 1025-33, 2004.[PUBMED Abstract]

Halabi S, Small EJ, Hayes DF, et al.: 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 21 (3): 490-5, 2003.[PUBMED Abstract]

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.

Small EJ, Halabi S, Picus J, et al.: A prospective randomized trial of antiandrogen withdrawal alone or antiandrogen withdrawal in combination with high-dose ketoconazole in androgen independent prostate cancer patients: results of CALGB 9583. [Abstract] Proceedings of the American Society of Clinical Oncology 20: A-695, 2001.

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.

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.

Halabi S, Small EJ, Kantoff PW, et al.: Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer. J Clin Oncol 21 (7): 1232-7, 2003.[PUBMED Abstract]

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.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Eric Small, MD, Protocol chair		Ph: 415-353-7095; 800-888-8664

Registry Information
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
Trial Start Date		1996-08-15
Registered in ClinicalTrials.gov		NCT00002760
Date Submitted to PDQ		1996-08-15
Information Last Verified		2007-05-08
NCI Grant/Contract Number		CA31946