Clinical trial NCT00589472: Androgen Deprivation Therapy and Vorinostat Followed by Radical Prostatectomy in Treating Patients With Localized Prostate Cancer
Official title: Neoadjuvant Androgen Depletion in Combination With Vorinostat Followed by Radical Prostatectomy for Localized Prostate Cancer: Total Androgen-Receptor Gene Expression Targeted Therapy (TARGET)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Prostate Adenocarcinoma
Stage I Prostate Cancer
Stage IIA Prostate Cancer
Stage IIB Prostate Cancer
Stage III Prostate Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-01-09
Enrollment: 19
Sex: MALE
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase II trial studies how well androgen deprivation therapy and vorinostat followed by radical prostatectomy works in treating patients with prostate cancer that has not spread to other parts of the body. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as bicalutamide, goserelin acetate, and leuprolide acetate, may lessen the amount of androgens made by the body. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving androgen deprivation therapy and vorinostat before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the rate of pathologic complete response in patients with localized prostate cancer treated with androgen depletion therapy (ADT) and oral vorinostat administered for a minimum of 6 weeks and maximum of 8 weeks before radical prostatectomy.

SECONDARY OBJECTIVES:

I. To determine and evaluate pre- and post-treatment levels of prostate-specific antigen (PSA), testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone-dulfate (DHEA-S) in blood.

II. To determine and evaluate pre- and post-treatment levels of testosterone, androstenedione, androstenediol, DHT, DHEA, and DHEA-S in prostate.

III. To determine and evaluate gene and protein expression analysis including androgen receptor (AR) target genes, PSA and TMPRSS2 (transmembrane protease, serine 2), in pre-treatment biopsy and post-treatment radical prostatectomy.

IV. To determine and evaluate exploratory gene microarray analysis. V. To determine and evaluate the safety and tolerability of ADT in combination with vorinostat (SAHA) as assessed by physical examinations, adverse events, and laboratory assessments.

OUTLINE:

Patients receive bicalutamide orally (PO) once daily (QD) for 1 month and leuprolide acetate intramuscularly (IM) or goserelin acetate subcutaneously (SC) once a month until surgery. Patients also receive vorinostat PO QD beginning on the first day of androgen depletion therapy and continuing for up to 8 weeks or until the day of surgery. Patients then undergo an open or laparoscopic radical prostatectomy. Patients with positive surgical margins undergo immediate adjuvant external beam radiotherapy to the prostatic fossa, based on the judgment of the treating physician.

After completion of study treatment, patients are followed every 3 months for up to 1 year.

Eligibility criteria: Inclusion Criteria:

* Histologic documentation of prostatic adenocarcinoma in 3 or more biopsy cores, of which at least 1 core demonstrates \> 30% involvement with tumor; confirmation of localized disease by magnetic resonance imaging (MRI) with endorectal probe if available
* No evidence of distant disease on a:

  * Computed tomography (CT) or MRI of the abdomen and pelvis
  * Radionuclide bone scan (with plain film or MRI confirmation as clinically indicated)
* Appropriate candidate for radical prostatectomy

  * Adequate cardiac function (evidence of cardiac disease should be evaluated to determine appropriateness of patient as a surgical candidate)
  * Candidates may have a history of deep vein thrombosis, pulmonary embolism, and/or cerebrovascular accident, or require concomitant systemic anticoagulation, if otherwise deemed to be suitable for radical prostatectomy
* White blood cell (WBC) \> 3000/uL
* Platelets \> 150,000/uL
* Creatinine \< 2 mg/dL
* Serum PSA \< 100 ng/mL
* Bilirubin \< 1.5 X ULN (institutional upper limits of normal)
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) \< 2 X ULN
* Karnofsky performance status \> 70%
* Willingness to undergo pretreatment transrectal ultrasound-guided prostate needle biopsy (optional)
* Willingness to use adequate contraceptive methods during study therapy and for at least 3 months after completion of therapy
* Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

* Evidence of small-cell, transitional-cell, or neuroendocrine pathologic features
* Prior hormonal therapy with (e.g. 5-alpha-reductase inhibitors, gonadotropin hormone releasing analogs, steroids, megestrol acetate, or nonstudy-related antiandrogens), chemotherapy, or herbal medications administered with the intent to treat the patient's malignancy

  * Patients on valproic acid (a histone-deacetylase inhibitor) to treat prostate cancer are not eligible
* History of allergic reactions attributed to compounds of similar chemical or biological composition to vorinostat
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would compromise compliance with study requirements
* Currently active secondary malignancy (as determined by the treating physician) other than non-melanoma skin cancer

Primary outcomes:
measure: Pathologic Complete Response at the Time of Surgery
timeFrame: At 12 weeks
Secondary outcomes:
measure: Gleason Score
timeFrame: Baseline
measure: Levels of DHEA in Blood From Radical Prostatectomy Specimens
timeFrame: Up to 1 year
measure: Levels of DHEA-S in Blood From Radical Prostatectomy Specimens
timeFrame: Up to 1 year
measure: Levels of DHT in Blood From Radical Prostatectomy Specimens
timeFrame: Up to 1 year
measure: Levels of PSA in Blood From Radical Prostatectomy Specimens
timeFrame: Up to 1 year
measure: Levels of Testosterone in Blood From Radical Prostatectomy Specimens
timeFrame: Up to 1 year
Other outcomes:
measure: Protein Expression Analysis, Including AR Target Genes, PSA and TMPRSS2
timeFrame: Up to 1 year
measure: Safety and Tolerability of Androgen Depletion Therapy in Combination With Vorinostat as Assessed by Physical Examinations, Adverse Events, and Laboratory Assessments. Please See Adverse Events Section.
timeFrame: Up to 1 year
measure: Gene Expression Analysis, Including AR Target Genes, PSA and TMPRSS2
timeFrame: at 12 weeks
measure: Gene Microarray Analysis
timeFrame: Up to 1 year
measure: Levels of Testosterone in Prostate Tissue
timeFrame: Up to 1 year
measure: Levels of DHT in Prostate Tissue
timeFrame: Up to 1 year
measure: Levels of Androstenediol in Prostate Tissue
timeFrame: Up to 1 year
measure: Levels of Androstenedione in Prostate Tissue
timeFrame: Up to 1 year
measure: Levels of DHEA in Prostate Tissue
timeFrame: Up to 1 year
measure: Levels of DHEA-S in Prostate Tissue
timeFrame: Up to 1 year
Locations:
city: Los Angeles
country: United States
facility: UCLA / Jonsson Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Parnassus
state: California
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Newark
country: United States
facility: UMDNJ - New Jersey Medical School
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Susan Slovin
role: PRINCIPAL_INVESTIGATOR
References: