TAPS: Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT00298155
• Collaborator: GlaxoSmithKline (Industry), AstraZeneca (Industry)
• Enrollment: 35
• Locations: 2
• Arms: 3
• Duration (Months): 90.1
• Patients Per Site: 17.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Cancer; Prostate Neoplasms	Drug: goserelin with dutasteride; Drug: goserelin with bicalutamide and dutasteride; Drug: goserelin with bicalutamide and dutasteride and ketoconazole	Phase 2

Detailed Description

Androgen deprivation has been the principal means of controlling advanced prostate cancer, but does not cure the disease and all patients ultimately progress if the tumor is not eliminated with definitive local therapy. It has been demonstrated that despite androgen deprivation with LHRH agonists or orchiectomy, prostate tissue and prostate cancer maintain levels of androgens which are more than adequate to stimulate the androgen receptor. These levels of androgen may continue to stimulate the receptor and allow both survival of tumor cells and induction of resistance by overexpression of the receptor. The presumption that standard androgen deprivation achieves the optimal level of androgen suppression for patients is based on the levels of androgen achieved with castration, which achieves relatively short term control of cancer in the majority of patients. The hypothesis of this study is that more effective suppression of the androgen axis through elimination of adrenal androgens and more effective suppression of conversion to dihydrotestosterone will lower intraprostatic androgen levels, minimizing activation of the androgen receptor and augmenting apoptosis. We propose to test this hypothesis in a prospective, randomized trial, administering neoadjuvant androgen deprivation therapy of different types prior to radical prostatectomy for patients with clinically localized prostate cancer for 3 months.

Plan of therapy

Patients with clinically localized (cT1-T2) prostate cancer, at intermediate-high risk for relapse who are candidates for radical prostatectomy will be treated with one of three regimens:

• Goserelin with dutasteride

• Goserelin with bicalutamide and dutasteride

• Goserelin with bicalutamide and dutasteride and ketoconazole

Patients will undergo radical prostatectomy 3 months after initiation of treatment.

Preoperative and intraoperative biopsies of the prostate gland will be utilized for analysis of prostatic hormones, gene expression and apoptosis.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Jun 1, 2010
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group 1 Goserelin + dutasteride	Drug: goserelin with dutasteride; 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.
Active Comparator: Group 2 Bicalutamide for one week, begin goserelin plus dutasteride, continue bicalutamide for the full 12 weeks	Drug: goserelin with bicalutamide and dutasteride; Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.
Active Comparator: Group 3 Begin bicalutamide for one week, goserelin injection; begin dutasteride, ketoconazole (and replacement hydrocortisone), continue bicalutamide for the full 12 weeks	Drug: goserelin with bicalutamide and dutasteride and ketoconazole; 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).

Outcome Measures

Primary Outcome Measures

1. Prostate Tissue DHT [After 12 weeks of neoadjuvant androgen deprivation]

   Tissue dihydrotesterone (DHT)

Secondary Outcome Measures

1. To Determine the Effects of Different Modes of Androgen Deprivation on Serum DHT [After 12 weeks of neoadjuvant androgen deprivation]

   Serum DHT

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 100 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

1. Patient's tumor must be considered surgically resectable .

2. Eastern Cooperative Group (ECOG) performance status of 0-1.

3. Life expectancy greater than 2 years.

4. Able to understand and give informed consent.

5. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Veterans' Administration Puget Sound Health Care System (VAPSHCS)	Seattle	Washington	United States	98108-1532
2	University of Washington	Seattle	Washington	United States	98195-6158

Sponsors and Collaborators

• University of Washington
• GlaxoSmithKline
• AstraZeneca

Investigators

• Principal Investigator: R. Bruce Montgomery, MD, University of Washington; Seattle Cancer Care Alliance; VA Puget Sound HCS
• Principal Investigator: Peter S. Nelson, MD, Fred Hutchinson Cancer Research Center; Seattle Cancer Care Alliance

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Bruce Montgomery, Professor, University of Washington
• ClinicalTrials.gov Identifier: NCT00298155
• Other Study ID Numbers: 28741; FHCRC-05026; 05-8538-V 01; 28741-A; 01253
• First Posted: Mar 1, 2006
• Last Update Posted: Aug 9, 2018
• Last Verified: Jul 1, 2018

• Additional relevant MeSH terms: Prostatic Neoplasms; Ketoconazole; Goserelin; Bicalutamide; Dutasteride

Study Results

Participant Flow

Arm/Group Title	Group 1	Group 2	Group 3
Arm/Group Description	Goserelin + dutasteride goserelin with dutasteride: 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 for one week, begin goserelin plus dutasteride, continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride: Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.	Begin bicalutamide for one week, goserelin injection; begin dutasteride, ketoconazole (and replacement hydrocortisone), continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride and ketoconazole: 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).
Period Title: Overall Study
STARTED	12	10	13
COMPLETED	12	10	13
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Group 1	Group 2	Group 3	Total
Arm/Group Description	Goserelin + dutasteride goserelin with dutasteride: 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 for one week, begin goserelin plus dutasteride, continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride: Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.	Begin bicalutamide for one week, goserelin injection; begin dutasteride, ketoconazole (and replacement hydrocortisone), continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride and ketoconazole: 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).	Total of all reporting groups
Overall Participants	12	10	13	35
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	66	60	64
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%
Male	12 100%	10 100%	13 100%	35 100%
Region of Enrollment (participants) [Number]
United States	12 100%	10 100%	13 100%	35 100%

Outcome Measures

1. Primary Outcome

Title	Prostate Tissue DHT
Description	Tissue dihydrotesterone (DHT)
Time Frame	After 12 weeks of neoadjuvant androgen deprivation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1	Group 2	Group 3
Arm/Group Description	Goserelin + dutasteride goserelin with dutasteride: 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 for one week, begin goserelin plus dutasteride, continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride: Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.	Begin bicalutamide for one week, goserelin injection; begin dutasteride, ketoconazole (and replacement hydrocortisone), continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride and ketoconazole: 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).
Measure Participants	12	10	13
Mean (Standard Deviation) [ng/g]	0.03 (0.01)	0.06 (0.06)	0.03 (0.02)

2. Secondary Outcome

Title	To Determine the Effects of Different Modes of Androgen Deprivation on Serum DHT
Description	Serum DHT
Time Frame	After 12 weeks of neoadjuvant androgen deprivation

Outcome Measure Data

Analysis Population Description

Patients with clinically localized prostate cancer treated for 3 months with the treatments in Groups 1-3

Arm/Group Title	Group 1	Group 2	Group 3
Arm/Group Description	Goserelin + dutasteride goserelin with dutasteride: 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 for one week, begin goserelin plus dutasteride, continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride: Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.	Begin bicalutamide for one week, goserelin injection; begin dutasteride, ketoconazole (and replacement hydrocortisone), continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride and ketoconazole: 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).
Measure Participants	12	10	13
Mean (Standard Deviation) [ng/dL]	4.2 (3.4)	3.6 (2.0)	5.7 (4.9)

Adverse Events

Arm/Group Title	Group 1		Group 2		Group 3
Arm/Group Description	Goserelin + dutasteride goserelin with dutasteride: 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 for one week, begin goserelin plus dutasteride, continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride: Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.		Begin bicalutamide for one week, goserelin injection; begin dutasteride, ketoconazole (and replacement hydrocortisone), continue bicalutamide for the full 12 weeks goserelin with bicalutamide and dutasteride and ketoconazole: 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).
All Cause Mortality
	Group 1		Group 2		Group 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Group 1		Group 2		Group 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/10 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Group 1		Group 2		Group 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/12 (100%)		10/10 (100%)		13/13 (100%)
General disorders
Fatigue	5/12 (41.7%)	5	6/10 (60%)	6	8/13 (61.5%)	8
Vascular disorders
hot flushes	12/12 (100%)	12	10/10 (100%)	10	13/13 (100%)	13

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.