Genetic and Molecular Mechanisms in Assessing Response in Patients With Prostate Cancer Receiving Enzalutamide Therapy

PRIMARY OBJECTIVES:

I. To assess the correlations between baseline molecular features and pathways and
prostate-specific antigen (PSA) change (= 50% decline) at 12 weeks versus (vs.) baseline.

SECONDARY OBJECTIVES:

I. To measure PSA change at 12 weeks and at each study visit vs. baseline after enzalutamide
treatment.

II. To measure objective response after enzalutamide treatment. III. To assess the
correlations between the baseline molecular features and pathways and progression-free
survival, disease-specific survival, and overall survival.

IV. To assess the correlations between the baseline molecular features and pathways and time
to PSA progression.

V. To identify molecular features and cellular pathways present in tumors from men with
metastatic castrate-resistant prostate cancer (CRPC) that are progressing despite
enzalutamide treatment.

VI. To explore correlation between baseline molecular features and pathways and changes in
circulating tumor cells (CTCs) counts.

VII. To explore correlation between baseline molecular features and pathways and objective
response.

VIII. To assess the correlations between the baseline molecular features and pathways and
degree of PSA decline at 12 weeks and maximal PSA decline observed while on study.

IX. To assess the correlations between the baseline molecular features and time on treatment.

TERTIARY OBJECTIVES:

I. To assess correlations between cell-free deoxyribonucleic acid (DNA) (cfDNA) molecular
features from blood and molecular features and pathways from the biopsy samples.

II. To assess correlations between cfDNA molecular features and endpoints in the primary and
secondary objectives listed above.

III. To assess correlations between cell-free DNA and tumor molecular features and changes in
PSA after discontinuing enzalutamide.

IV. To explore correlations with baseline molecular features and tissue histology.

V. To explore correlations with baseline tissue histology and PSA change, time to PSA
progression, time on treatment, progression-free survival, and overall survival.

OUTLINE:

Patients receive enzalutamide orally (PO) once daily (QD) in the absence of disease
progression or unacceptable toxicity. Patients undergo a tumor biopsy of a metastatic site at
study entry (prior to initiation of enzalutamide) and after the time of progression. Patients
may continue treatment beyond progression at the investigator's discretion.

After completion of study treatment, patients are followed up at 2-3 or 6 weeks and then
every 12 weeks thereafter.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the prostate without pure
small cell carcinoma; patients without histologically confirmed adenocarcinoma may be
eligible if both the treating physician and the study principal investigator (PI)
agree that the patient?s history is unambiguously indicative of advanced
adenocarcinoma

- Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH)
analogue or orchiectomy (i.e., surgical or medical castration); patients who have not
had an orchiectomy must maintain effective GnRH-analogue therapy for the duration of
the trial

- Radiographic evidence of regional or distant metastases with suspected tumor in an
area that is safe to biopsy

- Willingness to undergo a tumor biopsy at baseline and at disease progression

- Serum testosterone level < 50 ng/dL at screening

- Progressive disease by PSA or imaging in the setting of medical or surgical
castration; disease progression for study entry is defined as one or more of the
following three criteria:

- PSA evidence for progressive prostate cancer which consists of a PSA level of at
least 2 ng/ml which has risen on at least 2 successive occasions, at least 1 week
apart; if the confirmatory PSA value is less than the screening value, then an
additional PSA value greater than #2 will be required to document progression of
>= 1 week

- PSA values to be obtained >= 1 week apart

- Soft tissue disease progression defined by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1

- Bone disease progression defined by two or more new lesions on bone scan

- Patient?s physician has already recommended enzalutamide for treatment of progression

- Eastern Cooperative Oncology Group (ECOG) performance status of 0?2

- Willing and able to give informed consent

- Estimated life expectancy >= 6 months

- Subjects who have partners of childbearing potential must be willing to use a method
of birth control with adequate barrier protection as determined to be acceptable by
the principal investigator and sponsor during the study and for 1 week after last
study drug administration

- A minimum of 4 weeks elapsed off of anti-androgen therapy prior to enrollment for
flutamide and 6 weeks for bicalutamide and nilutamide without evidence of an
anti-androgen withdrawal response; patients who NEVER HAD A PSA decline with the most
recent anti-androgen therapy or in whom the response to the most recent anti-androgen
was for < 3 months require only a 2 week washout period prior to first dose of study
drug

- A minimum of 4 weeks from prior systemic anti-cancer therapies or 3 weeks for
radiation treatment prior to enrollment is required

Exclusion Criteria:

- Severe, concurrent disease, infection, or co-morbidity that, in the judgment of the
investigator, would make the patient inappropriate for enrollment

- Previous treatment with docetaxel for metastatic prostate cancer

- Known metastases in the brain or active epidural disease (NOTE: patients with treated
epidural disease are allowed)

- Absolute neutrophil count < 1,000/uL

- Platelet count < 75,000/uL

- Hemoglobin < 9 g/dL at the screening visit; (NOTE: subject 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 (TBL) > 2.5 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

- Prothrombin time (PT) or international normalized ratio (INR) and a partial
thromboplastin time (PTT) > 1.5 times the upper limit of normal

- Previous treatment with an agent that blocks adrenal androgen synthesis (e.g.
abiraterone acetate, TAK-700, TOK-001, ketoconazole) or second generation androgen
receptor (AR) antagonists (e.g., BMS 641988, ARN-509,TOK-001)

- Systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day
within 4 weeks of study drug administration are prohibited

- Structurally unstable bone lesions suggesting impending fracture

- Previous treatment with enzalutamide (MDV3100)

- Medical contraindications to stopping aspirin, Coumadin or other anticoagulants prior
to image-guided tumor biopsies; follow institutional guidelines when determining drugs
to avoid and length of washout

- Plans to initiate treatment with an investigational agent during the study

- History of seizure or condition that may predispose to seizure; also, history of loss
of consciousness or transient ischemic attack within 12 months of (day 1 visit)

- Concomitant use of the strong CYP2C8 inhibitors gemfibrozil or trimethoprim (Bactrim)

- History of known malabsorption syndrome or prior surgery(ies) that may lead to
malabsorption

- Use of herbal products that may have hormonal anti-prostate cancer activity and/or are
known to decrease PSA levels (e.g., saw palmetto) within 4 weeks of study drug
administration (day 1)

- Use of the following drugs within 4 weeks of study drug administration: 5
alpha-reductase inhibitors (finasteride, dutasteride), estrogens, Cyproterone acetate,
biologic, or other agents with anti-tumor activity against prostate cancer, and
androgens (testosterone, dihydroepiandrosterone [DHEA], etc.)

- A second active malignancy except adequately treated non-melanoma skin cancer or other
non-invasive or in situ neoplasm