Androgen Deprivation Therapy and Vorinostat Followed by Radical Prostatectomy in Treating Patients With Localized Prostate Cancer

Phase 2

Completed

• Conditions: Stage III Prostate Cancer; Prostate Adenocarcinoma; Stage I Prostate Cancer; Stage IIA Prostate Cancer; Stage IIB Prostate Cancer
• Interventions: Drug: Bicalutamide; Drug: Goserelin Acetate; Other: Laboratory Biomarker Analysis; Drug: Leuprolide Acetate; Procedure: Therapeutic Conventional Surgery; Drug: Vorinostat

• Registration Number: NCT00589472
• Lead Sponsor: National Cancer Institute (NCI)

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.

Study Timeline

• Study Start: 2007-11
• Study First Submitted: 2007-12-20
• Study First Submitted QC: 2007-12-25
• Study First Posted: 2008-01-09
• Primary Completion: 2010-06
• Study Completion: 2010-06
• Results First Submitted: 2017-03-24
• Status Verified: 2017-09
• Results First Submitted QC: 2017-09-18
• Last Update Submitted: 2017-09-18
• Results First Posted: 2017-10-06
• Last Update Posted: 2017-10-06

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 19

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (Antihormone therapy and enzyme inhibitor therapy)	Goserelin Acetate	Patients receive bicalutamide PO QD for 1 month and leuprolide acetate IM or goserelin acetate 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.
Treatment (Antihormone therapy and enzyme inhibitor therapy)	Laboratory Biomarker Analysis	Patients receive bicalutamide PO QD for 1 month and leuprolide acetate IM or goserelin acetate 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.
Treatment (Antihormone therapy and enzyme inhibitor therapy)	Leuprolide Acetate	Patients receive bicalutamide PO QD for 1 month and leuprolide acetate IM or goserelin acetate 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.
Treatment (Antihormone therapy and enzyme inhibitor therapy)	Therapeutic Conventional Surgery	Patients receive bicalutamide PO QD for 1 month and leuprolide acetate IM or goserelin acetate 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.
Treatment (Antihormone therapy and enzyme inhibitor therapy)	Bicalutamide	Patients receive bicalutamide PO QD for 1 month and leuprolide acetate IM or goserelin acetate 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.
Treatment (Antihormone therapy and enzyme inhibitor therapy)	Vorinostat	Patients receive bicalutamide PO QD for 1 month and leuprolide acetate IM or goserelin acetate 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.

Primary Outcome Measures

Name	Time	Method
Pathologic Complete Response at the Time of Surgery	At 12 weeks	The primary endpoint will be pathologic complete response at the time of surgery. This represents the proportion of patients with no evidence of disease in the prostate (ie, the absence of tumor in the posttherapy pathology specimen) at the time of radical prostatectomy. Pathologic complete response at the time of surgery is the primary endpoint for this study. A Simon 2-stage optimal design that differentiates between response probabilities of 0.05 and 0.20 will be used in the analysis of the pathological complete response at 12 weeks (Type I error 10% and power 90%). A maximum of 38 pts were planned for accrual onto this study. If zero or one response was observed, then the trial was to be stopped. The design had power 0.90 for a population response proportion to 0.20 using a one-sided 0.10 size test. pT2 indicates that the cancer is confined to the prostate, while pT3 indicates that there is an extraprostatic extension of the cancer.

Secondary Outcome Measures

Name	Time	Method
Gleason Score	Baseline	A Gleason score is the sum of two numbers. Pathologist determines where the cancer is most prominent and assigns the primary grade, the secondary grade is assigned based on where the cancer is next most prominent. A score from one to five is assigned for each area based on how aggressive the tumor appears. A tumor with cell that appear close to normal is assigned a low Gleason score (six or below). A tumor with cells that appear clearly different from those of a normal prostate is assigned a high Gleason score (seven or above). A system of grading prostate cancer tissue based on how it looks under a microscope. Gleason scores range from 2 to 10 and indicate how likely it is that a tumor will spread. A low Gleason score means the cancer tissue is similar to normal prostate tissue and the tumor is less likely to spread; a high Gleason score means the cancer tissue is very different from normal and the tumor is more likely to spread.
Levels of DHEA in Blood From Radical Prostatectomy Specimens	Up to 1 year
Levels of DHEA-S in Blood From Radical Prostatectomy Specimens	Up to 1 year
Levels of DHT in Blood From Radical Prostatectomy Specimens	Up to 1 year
Levels of PSA in Blood From Radical Prostatectomy Specimens	Up to 1 year
Levels of Testosterone in Blood From Radical Prostatectomy Specimens	Up to 1 year

Trial Locations

Locations (15)

Memorial Sloan-Kettering Cancer Center; 🇺🇸 New York, New York, United States

UCLA / Jonsson Comprehensive Cancer Center; 🇺🇸 Los Angeles, California, United States

UCSF Medical Center-Parnassus; 🇺🇸 San Francisco, California, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Johns Hopkins University/Sidney Kimmel Cancer Center; 🇺🇸 Baltimore, Maryland, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

UMDNJ - New Jersey Medical School; 🇺🇸 Newark, New Jersey, United States

M D Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

University of Wisconsin Hospital and Clinics; 🇺🇸 Madison, Wisconsin, United States

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

University of Washington Medical Center; 🇺🇸 Seattle, Washington, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States