Prostate Adenocarcinoma, Stage IIA Prostate Cancer, Stage IIB Prostate Cancer, Stage III Prostate Cancer, Stage I Prostate Cancer
Conditions
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.
Interventions
DRUGBicalutamide
Given PO
DRUGGoserelin Acetate
Given SC
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLeuprolide Acetate
Given IM
PROCEDURETherapeutic Conventional Surgery
Undergo radical prostatectomy
DRUGVorinostat
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
19 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 PSA in Blood From Radical Prostatectomy Specimens | Up to 1 year | — |
| Levels of Testosterone in Blood From Radical Prostatectomy Specimens | Up to 1 year | — |
| Levels of DHT in Blood From Radical Prostatectomy Specimens | Up to 1 year | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Levels of Androstenedione in Prostate Tissue | Up to 1 year | — |
| Protein Expression Analysis, Including AR Target Genes, PSA and TMPRSS2 | Up to 1 year | — |
| Levels of DHEA-S in Prostate Tissue | Up to 1 year | — |
| Levels of DHEA in Prostate Tissue | Up to 1 year | — |
| 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. | Up to 1 year | Adverse events will be monitored at each scheduled visit and throughout the study. Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. |
| Gene Expression Analysis, Including AR Target Genes, PSA and TMPRSS2 | at 12 weeks | Estimates and 95% confidence intervals for the proportion of patients with nondetectable levels of PSA and TMPRSS2 will be computed. |
| Gene Microarray Analysis | Up to 1 year | — |
| Levels of Testosterone in Prostate Tissue | Up to 1 year | — |
| Levels of DHT in Prostate Tissue | Up to 1 year | — |
| Levels of Androstenediol in Prostate Tissue | Up to 1 year | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) 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.
Bicalutamide: Given PO
Goserelin Acetate: Given SC
Laboratory Biomarker Analysis: Correlative studies
Leuprolide Acetate: Given IM
Therapeutic Conventional Surgery: Undergo radical prostatectomy
Vorinostat: Given PO | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 17 / 19 |
| serious Total, serious adverse events | 2 / 19 |
Outcome results
Primary
Pathologic Complete Response at the Time of Surgery
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.
Time frame: At 12 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Pathologic Complete Response at the Time of Surgery | pT3 | 8 Participants |
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Pathologic Complete Response at the Time of Surgery | pT2 | 10 Participants |
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Pathologic Complete Response at the Time of Surgery | Complete Response | 0 Participants |
Secondary
Gleason Score
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.
Time frame: Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Gleason Score | 8 units on a scale |
Secondary
Levels of DHEA in Blood From Radical Prostatectomy Specimens
Time frame: Up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Levels of DHEA in Blood From Radical Prostatectomy Specimens | 256 ng/dL |
Secondary
Levels of DHEA-S in Blood From Radical Prostatectomy Specimens
Time frame: Up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Levels of DHEA-S in Blood From Radical Prostatectomy Specimens | 90 mcg/dL |
Secondary
Levels of DHT in Blood From Radical Prostatectomy Specimens
Time frame: Up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Levels of DHT in Blood From Radical Prostatectomy Specimens | 24 ng/dL |
Secondary
Levels of PSA in Blood From Radical Prostatectomy Specimens
Time frame: Up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Levels of PSA in Blood From Radical Prostatectomy Specimens | 9.44 ng/mL |
Secondary
Levels of Testosterone in Blood From Radical Prostatectomy Specimens
Time frame: Up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Antihormone Therapy and Enzyme Inhibitor Therapy) | Levels of Testosterone in Blood From Radical Prostatectomy Specimens | 319 ng/dL |
Other Pre-specified
Gene Expression Analysis, Including AR Target Genes, PSA and TMPRSS2
Estimates and 95% confidence intervals for the proportion of patients with nondetectable levels of PSA and TMPRSS2 will be computed.
Time frame: at 12 weeks
Other Pre-specified
Gene Microarray Analysis
Time frame: Up to 1 year
Other Pre-specified
Levels of Androstenediol in Prostate Tissue
Time frame: Up to 1 year
Other Pre-specified
Levels of Androstenedione in Prostate Tissue
Time frame: Up to 1 year
Other Pre-specified
Levels of DHEA in Prostate Tissue
Time frame: Up to 1 year
Other Pre-specified
Levels of DHEA-S in Prostate Tissue
Time frame: Up to 1 year
Other Pre-specified
Levels of DHT in Prostate Tissue
Time frame: Up to 1 year
Other Pre-specified
Levels of Testosterone in Prostate Tissue
Time frame: Up to 1 year
Other Pre-specified
Protein Expression Analysis, Including AR Target Genes, PSA and TMPRSS2
Time frame: Up to 1 year
Other Pre-specified
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.
Adverse events will be monitored at each scheduled visit and throughout the study. Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Time frame: Up to 1 year