Maximal Suppression of the Androgen Axis in Clinically Localized Prostate Cancer

NCT00298155 | Completed Phase 2 Results DMC

• 5 other identifiers: 28741FHCRC-0502605-8538-V 0128741-A01253
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 2

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.

Conditions

Cancer; Prostate Neoplasms

Outcome Measures

Primary Outcomes (1)

• Prostate Tissue DHT

  Tissue dihydrotesterone (DHT)

  After 12 weeks of neoadjuvant androgen deprivation

Secondary Outcomes (1)

• To Determine the Effects of Different Modes of Androgen Deprivation on Serum DHT

  After 12 weeks of neoadjuvant androgen deprivation

Study Arms (3)

Group 1

ACTIVE COMPARATOR

Goserelin + dutasteride

Drug: goserelin with dutasteride

Group 2

ACTIVE COMPARATOR

Bicalutamide for one week, begin goserelin plus dutasteride, continue bicalutamide for the full 12 weeks

Drug: goserelin with bicalutamide and dutasteride

Group 3

ACTIVE COMPARATOR

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

Interventions

goserelin with dutasteride DRUG

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.

Group 1

goserelin with bicalutamide and dutasteride DRUG

Bicalutamide 50 mg qd for one week, inject goserelin 10.8 mg (3-month depot) and begin dutasteride 3.5 mg qd.

Group 2

goserelin with bicalutamide and dutasteride and ketoconazole DRUG

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).

Group 3

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Patient's tumor must be considered surgically resectable .
• Eastern Cooperative Group (ECOG) performance status of 0-1.
• Life expectancy greater than 2 years.
• Able to understand and give informed consent.
• Laboratory values must be within specified limits.

You may not qualify if:

• Patients with locally advanced or high risk disease not meeting the criteria defined above.
• Patients who have a total testosterone less than 280 ng/dL.
• Patients who are receiving any other investigational therapy.
• Patients with an active serious infection or other serious underlying medical condition.
• Dementia or significantly altered mental status that would prohibit the understanding and/or giving of informed consent.
• Histologic evidence of small cell carcinoma of the prostate.
• Patients who are currently receiving active therapy for other neoplastic disorders.
• Patients who are receiving any androgens, estrogens or progestational agents.
• Patients who are taking drugs or herbal supplements which affect androgen metabolism (e.g., spironolactone, aprepitant, bexarotene, clarithromycin, itraconazole, ketoconazole, St. John's wort).
• Patients who have chronic active hepatitis.
• 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.
• Patients who have history of cerebrovascular accident, deep venous thrombosis, pulmonary emboli, unstable angina or clinical congestive heart failure.
• Medical conditions, which, in the opinion of the investigators would jeopardize either the patient or the integrity of the data obtained.
• Patients unwilling to use contraceptives while on study.
• 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.

Sponsors & Collaborators

• University of Washington: lead
• GlaxoSmithKline: collaborator
• AstraZeneca: collaborator

Study Sites (2)

Veterans' Administration Puget Sound Health Care System (VAPSHCS)

Seattle, Washington, 98108-1532, United States

Location

University of Washington

Seattle, Washington, 98195-6158, United States

Location

Related Publications (3)

• Mostaghel EA, Nelson PS, Lange P, Lin DW, Taplin ME, Balk S, Ellis W, Kantoff P, Marck B, Tamae D, Matsumoto AM, True LD, Vessella R, Penning T, Hunter Merrill R, Gulati R, Montgomery B. Targeted androgen pathway suppression in localized prostate cancer: a pilot study. J Clin Oncol. 2014 Jan 20;32(3):229-37. doi: 10.1200/JCO.2012.48.6431. Epub 2013 Dec 9.

  PMID: 24323034 RESULT

• Tamae D, Byrns M, Marck B, Mostaghel EA, Nelson PS, Lange P, Lin D, Taplin ME, Balk S, Ellis W, True L, Vessella R, Montgomery B, Blair IA, Penning TM. Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum. J Steroid Biochem Mol Biol. 2013 Nov;138:281-9. doi: 10.1016/j.jsbmb.2013.06.014. Epub 2013 Jul 10.

  PMID: 23851165 DERIVED

• Dean JP, Sprenger CC, Wan J, Haugk K, Ellis WJ, Lin DW, Corman JM, Dalkin BL, Mostaghel E, Nelson PS, Cohen P, Montgomery B, Plymate SR. Response of the insulin-like growth factor (IGF) system to IGF-IR inhibition and androgen deprivation in a neoadjuvant prostate cancer trial: effects of obesity and androgen deprivation. J Clin Endocrinol Metab. 2013 May;98(5):E820-8. doi: 10.1210/jc.2012-3856. Epub 2013 Mar 26.

  PMID: 23533230 DERIVED

MeSH Terms

Conditions

Neoplasms; Prostatic Neoplasms

Interventions

Goserelin; Dutasteride; bicalutamide; Ketoconazole

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Gonadotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Azasteroids; Steroids, Heterocyclic; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Bruce Montgomery
• Organization: University of Washington

rbmontgo@uw.edu

206-598-0860

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 27, 2006
• First Posted: March 1, 2006
• Study Start: July 1, 2006
• Primary Completion: June 1, 2010
• Study Completion: January 1, 2014
• Last Updated: August 9, 2018
• Results First Posted: May 8, 2017

Record last verified: 2018-07

Locations

US (2)