Testing the Effects of Low Dose Apalutamide on Prostate-Specific Antigen (PSA) Levels in Men Scheduled for Removal of the Prostate Gland

Study Overview
=================
Brief Summary
-----------------
Apalutamide is an anti-androgen that blocks the effect of testosterone on prostate cancer growth. This phase IIa trial is designed to determine whether very low doses of apalutamide, given for 3 to 4 weeks before prostate surgery to men with prostate cancer confined to the prostate gland, reduces plasma levels of PSA (a biomarker of apalutamide's ability to block testosterone). If low dose apalutamide lowers PSA levels in this setting, further study of this agent in men with localized prostate cancer who wish to delay definitive therapy with surgery or radiation may be warranted.

Detailed Description
-----------------
PRIMARY OBJECTIVE: I. To determine the effects of low dose apalutamide on circulating levels of prostate specific antigen (PSA). SECONDARY OBJECTIVES: I. To determine the effect of low dose apalutamide on: Ia. Reversibility of testosterone levels 7-14 days post intervention; Ib. Post-intervention plasma trough apalutamide concentration; Ic. Health-related quality of life. EXPLORATORY OBJECTIVE: I. To determine the effects of apalutamide on intra-prostatic immune cell infiltration and Gleason score and the effects of tobacco/alcohol use on the study endpoints. OUTLINE: Patients receive apalutamide orally (PO) on study. Patients also undergo collection of blood samples throughout the study. After completion of the trial intervention, patients are followed up at 7-10 days, 60 days, and 3 months post-prostatectomy.

Official Title
-----------------
Clinical Study of Bioactivity of Low Dose Apalutamide in Prostate Cancer Patients Scheduled for Prostatectomy

Conditions
-----------------
Localized Prostate Carcinoma, Prostate Adenocarcinoma, Stage I Prostate Cancer AJCC v8, Stage II Prostate Cancer AJCC v8

Intervention / Treatment
-----------------
* Drug: Apalutamide
* Procedure: Biospecimen Collection
* Other: Quality-of-Life Assessment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed organ-confined adenocarcinoma of the prostate (PCa) suitable for prostatectomy Gleason score =< (4+4), however no Gleason pattern 5 Current serum PSA =< 20 ng/ml Age > 18 years Karnofsky >= 70% Leukocytes >= 3,000/uL Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (note: in subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject may be eligible) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) < 2.5 x institutional ULN Creatinine < 2 x institutional ULN Thyroid stimulating hormone (TSH) within the institutional normal range Willing to use adequate contraception (barrier method; abstinence; subject has had a vasectomy; or partner is using effective birth control or is postmenopausal) for the duration of study participation Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Prior or ongoing hormonal treatment for prostate cancer including, but not limited to orchiectomy, antiandrogens, abiraterone, ketoconazole, or estrogens, or luteinizing hormone-releasing hormone (LHRH) agonists/antagonists. Men on stable doses of 5-alpha reductase inhibitors (e.g., finasteride, dutasteride) are eligible as long as there is no planned dose change while on study Patients who have prostate cancer with distant metastases Presence of neuroendocrine differentiation in the prostate biopsies Serum testosterone (blood collected between 7-10 AM for men < 45 years of age and prior to 2 PM for men >= 45 years of age) < 200 ng/dL Have a history of prior malignancies other than prostate cancer within the past 2 years, excluding non-melanoma skin cancer Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to registration History of seizure or known condition that may pre-dispose to seizure (including but not limited to prior stroke, transient ischemic attack, loss of consciousness within 1 year prior to registration, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect) Use of drugs known to lower the seizure threshold, including: atypical antipsychotics (e.g. clozapine, olanzapine, risperidone, ziprasidone), bupropion, lithium, meperidine, pethidine, phenothiazine antipsychotics (e.g. chlorpromazine, mesoridazine, thioridazine), and tricyclic antidepressants (e.g. amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine) Concurrent use of drugs in category X drug interactions with apalutamide Participants may not be receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical composition of apalutamide Uncontrolled intermittent illnesses or medical conditions which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient. Such illnesses/conditions may include, but are not limited to, hypertension, ongoing or active infection, or psychiatric illness/social situations

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (apalutamide)<br>Patients receive apalutamide PO on study. Patients also undergo collection of blood samples throughout the study. | Drug: Apalutamide<br>* Given PO<br>* Other names: JNJ-56021927;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in prostate specific antigen (PSA) levels | The proportion of participants with >= 25% decline in PSA levels (from baseline to end-of-intervention) will be reported along with the 97.5% credible interval for the response rate based on the posterior distribution of the response rate derived from a non-informative prior for the response rate, which is consistent with the Bayesian approach. | Baseline up to end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reversibility of testosterone levels | The post-operative testosterone levels will be compared with the levels at baseline and end-of-intervention within each dose cohort. Paired t test will be performed on the changes in testosterone to evaluate the effects of low dose apalutamide for each dose group. A 95% CI will be reported for each of the two dose groups. | Baseline, and at 7-14 days post-intervention (post-operative) | 
| Post-intervention plasma trough apalutamide concentrations | Post-intervention plasma trough apalutamide concentrations will be quantified by a sensitive and specific liquid chromatography mass spectrometry assay. The correlation between plasma trough apalutamide and the change of PSA levels will be assessed. Pearson correlation coefficient will be derived to evaluate the correlation between the plasma trough apalutamide levels and the change of PSA levels. A 95% CI will be reported for each of the two dose groups. | Up to 7-14 days after prostate surgery | 
| Health-related quality of life (HRQOL) | HRQOL will be assessed by a validated questionnaire (Expanded Prostate Cancer Index Composite for Clinical Practice [EPIC-CP]) to allow for efficient and accurate measurement of urinary incontinence, urinary irritation, bowel, sexual, and hormonal HRQOL in prostate cancer patients. Changes (from baseline to end-of-intervention) in the overall score and subscore for each measure will be assessed for each dose group. Changes in EPIC-CP (from baseline to end-of-intervention) in the overall score and sub-score for each measure will be derived and paired t test will be performed to evaluate the change for each dose group. A 95% CI will be reported for each of the two dose groups. | Baseline, until end of intervention |