| Eligibility |
Inclusion Criteria:
- Histologically or cytologically confirmed adenocarcinoma of the prostate without
neuroendocrine differentiation or small cell features
- Presence of metastatic disease that can be biopsied by any methodology applicable
- Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH)
analogue or orchiectomy (i.e., surgical or medical castration)
- Serum testosterone level =< 50 ng/dL at the screening visit
- Progressive disease defined as one or more of the following three criteria (NOTE:
Patients who received an antiandrogen must demonstrate disease progression following
discontinuation of antiandrogen):
- PSA progression defined by a minimum of two rising PSA levels with an interval of
>= 1 weeks between each determination. The PSA value at the screening visit
should be >= 2 ng/mL
- Soft tissue disease progression as defined by the Response Evaluation Criteria in
Solid Tumors (RECIST)
- Bone disease progression defined by two or more new lesions on bone scan
- Patients previously treated with chemotherapy must have no more than two prior
chemotherapy regimens for the treatment of metastatic prostate cancer
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Serum albumin >= 3.0 g/dL
- Serum potassium >= 3.5 mmol/L
- Estimated life expectancy of >= 6 months
- Able to swallow the study drug and comply with study requirements
- Willing and able to give informed consent
- Tumor specimen obtained prior to treatment initiation by interventional radiology
guided biopsy will be interrogated per immunohistochemistry (IHC) and features should
be as follows for a patient to be eligible
- Overexpression of androgen receptor (AR)-C terminal and AR-N terminal and PTEN
with lack of ARV7 expression along with and ki67 =<10%
- No combined RB loss and p53 mutation and
- No expression of neuroendocrine markers CD56 and chromogranin (all markers
assessed by standardized IHC protocols)
- Agrees to use a condom (even men with vasectomies) and another effective method of
birth control if he is having sex with a woman of childbearing potential or agrees to
use a condom if he is having sex with a woman who is pregnant while on study drug and
for 3 months following the last dose of study drug. Must also agree not to donate
sperm during the study and for 3 months after receiving the last dose of study drug
- The methods must consist of a condom and the use of another barrier method (such
as a diaphragm or cervical/vault caps) with a spermicidal agent. Your female
partner can choose to use an intrauterine device or system (intrauterine device
[IUD] or intrauterine system [IUS]) or use birth control pills, injections, or
implants instead of a barrier method
Exclusion Criteria:
- Known allergy to the study drugs or any of its components
- Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the
investigator, would make the patient inappropriate for enrollment or other medical
condition that would make prednisone/prednisolone (corticosteroid) use contraindicated
- Known metastases to the brain
- Absolute neutrophil count < 1000/uL at the screening visit
- Platelet count =< 100,000 x 10^9/uL at the screening visit
- Hemoglobin < 9 g/dL at the screening visit at the screening visit
- NOTE: patients may not have received any growth factors or blood transfusions within
seven days of the hematologic laboratory values obtained at the screening visit
- Total bilirubin (Tbili) > 1.5 times the upper limit of normal at the screening visit
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times the
upper limit of normal at the screening visit
- Creatinine (Cr) > 2 mg/dL at the screening visit
- History of another malignancy within the previous 2 years with > 30 % probability of
relapse other than curatively treated non-melanomatous skin cancer
- Treatment with androgen receptor antagonists (bicalutamide, flutamide, nilutamide),
5-alpha reductase inhibitors (finasteride, dutasteride), estrogens, chemotherapy, or
biologic therapy within 4 weeks of enrollment (day 1 visit)
- Radiation therapy within 3 weeks (if single fraction of radiotherapy within 2 weeks)
of enrollment (day 1 visit)
- Planned palliative procedures for alleviation of bone pain such as radiation therapy
or surgery
- Structurally unstable bone lesions suggesting impending fracture
- History of seizure or any condition that may increase the patient's seizure risk.
Also, history of loss of consciousness or transient ischemic attack within 12 months
of day 1
- Clinically significant cardiovascular disease including:
- Myocardial infarction within 6 months
- Uncontrolled angina within 6 months
- Congestive heart failure New York Heart Association (NYHA) class 3 or 4 in the
past, or history of anthracycline or anthracenedione (mitoxantrone) treatment,
unless a screening echocardiogram or multi-gated acquisition scan (MUGA)
performed within three months results in a left ventricular ejection fraction
that is >= 45%
- History of clinically significant ventricular arrhythmias (e.g., ventricular
tachycardia, ventricular fibrillation, torsades de pointes)
- Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on
the screening electrocardiogram (ECG) > 470 msec
- History of Mobitz II second degree or third degree heart block without a
permanent pacemaker in place
- Hypotension (systolic blood pressure < 86 millimeters of mercury or bradycardia
with a heart rate of < 50 beats per minute on any ECG taken at the screening
visit
- Bradycardia with a heat rate of < 50 beats per minutes in the screening ECG,
unless pharmaceutically induced and reversible
- Chronically uncontrolled hypertension as indicated by consistently elevated
resting blood pressure (systolic blood pressure > 170 mmHg or diastolic blood
pressure > 105 mmHg) during screening
- Have used or plan to use from 30 days prior to enrollment (day 1 visit) through the
end of the study the following medications known to lower the seizure threshold:
- Aminophylline/theophylline
- Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone)
- Bupropion
- Insulin
- Lithium
- Pethidine
- Phenothiazine antipsychotics (e.g., prochlorperazine [compazine], chlorpromazine,
mesoridazine, thioridazine)
- Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine,
doxepin, imipramine, maprotiline, mirtazapine)
- Prior use of ketoconazloe, enzalutamide, abiraterone or apalutamide or participation
in a previous clinical trial of ketoconazloe,enzalutamide, abiraterone or apalutamide
unless within the neoadjuvant setting
- Use of an investigational agent within 4 weeks of enrollment (day 1)
- Gastrointestinal disorder affecting absorption (e.g., gastrectomy)
- Major surgery within 4 weeks prior to enrollment (day 1)
- History of significant bleeding disorder unrelated to cancer, including:
- Diagnosed congenital bleeding disorders (e.g., von Willebrand's' disease)
- Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
VIII antibodies)
- History of gastrointestinal (GI) bleeding within one year
- Known active or symptomatic viral hepatitis or chronic liver disease
- Known history of pituitary or adrenal dysfunction
- Baseline moderate and severe hepatic impairment (Child Pugh class B & C)
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