A Trial of Androgen Deprivation, Docetaxel, and Enzalutamide for Metastatic Prostate Cancer

This is a single center, single arm, phase II trial designed to evaluate the 12 month PSA
complete response rate in patients with metastatic hormone sensitive prostate cancer treated
with ADT, docetaxel and enzalutamide. The primary endpoint of this study will be 12-month PSA
complete response rate, which will be assessed against a contemporary historical control rate
for the combination of ADT and docetaxel alone in the metastatic hormone naive setting. The
study will be conducted at all participating sites across North and South Carolina within the
Levine Cancer Institute network. Enrollment is anticipated to be completed within 24 months.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the prostate without
evidence of small cell carcinoma or greater than 50% neuroendocrine differentiation..
Metastatic disease must be present including soft tissue and/or bone metastases prior
to study enrollment. Regional lymph node involvement must be accompanied by at least
one additional site of disease including visceral, non-regional nodal or skeletal
metastases.

- ADT with surgical castration with bilateral orchiectomy or medical castration with
LHRH agonist or LHRH antagonist therapy may have been initiated no greater than 84
days (12 weeks) prior to study consent and no greater than 112 days (16 weeks) prior
to enrollment date. However, patients are not eligible if PSA has risen >=25% and >= 2
ng/ml above nadir value since initiation of ADT prior to consent.

- PSA >= 5 ng/ml within 90 days prior to consent.

- Prior ADT for non-metastatic disease with LHRH agonist or LHRH antagonist therapy in
the neoadjuvant/adjuvant setting is permitted if total duration of therapy did not
exceed 36 months, 6 months have elapsed since completion of therapy prior to consent,
and serum testosterone > 50 ng/ml within 28 days prior to initiation of ADT.

- Age >= 18 years.

- ECOG performance status 0-2.

- Adequate liver function: AST and ALT <1.5x upper limit of normal, total bilirubin < 1x
upper limit of normal.

- Adequate bone marrow function: Platelets >100,000 cells/mm3, Hemoglobin > 8.0g/dL and
ANC > 1,500 cells/mm3.

- Adequate renal function with a creatinine clearance (based on Cockcroft-Gault formula)
greater than 30 mL/min.

- Ability to understand and the willingness to sign a written informed consent document.

- Able to swallow and retain oral medication.

Exclusion Criteria:

- Personal history of seizure.

- Personal history of conditions that may predispose to seizure activity including
cortical cerebrovascular accident or brain trauma.

- Central nervous system metastases, including involvement of brain parenchyma and
leptomeninges.

- Personal history of any condition that may impair absorption of enzalutamide.

- Prior or current therapy with ketoconazole, abiraterone, enzalutamide, ARN-509
(JNJ-56021927), ODM-201 (BAY1841788) or cytotoxic chemotherapy such as docetaxel,
cabazitaxel, cyclophosphamide.

- Prior therapy with bicalutamide, nilutamide or flutamide within 14 days of enrollment.

- Within 28 days of major surgery and/or lack of recovery from prior surgical procedure
or 14 days of palliative radiation prior to enrollment.

- Prior or current therapy with an investigational agent for metastatic prostate cancer.

- Known hypersensitivity to drugs formulated with polysorbate 80.

- Personal history of posterior reversible encephalopathy syndrome.

- CTCAE version 4.0 grade 2-4 peripheral sensory neuropathy.

- Human immunodeficiency virus infection or active hepatitis B or C infection.

- Uncontrolled and current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements in the opinion of the investigator.

- Presence of any of the following within the previous 3 months prior to enrollment:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, congestive heart failure, or cerebrovascular accident including transient
ischemic attack.

- History of an additional active malignancy within 12 months prior to the date of
consent (except non-melanoma skin cancer).

- Current use of strong CYP2C8 inhibitors, CYP3A4 inducers or CYP3A4, CYP2C9 or CYP2C19
substrates with a narrow therapeutic range as listed in Section 7.2.1.

- Any condition that requires the use of prednisone > 10mg daily, or equivalent daily
glucocorticoid dose, for greater than 14 days.