Enzalutamide and Decitabine in Treating Patients With Metastatic Castration Resistant Prostate Cancer

PRIMARY OBJECTIVES I. To determine the maximum tolerated dose (MTD) and recommended phase II
dose (RP2D) of decitabine in combination with enzalutamide in patients with refractory
metastatic castrate resistant prostate cancer (mCRPC). (Phase 1b) II. To determine the
12-month progression free survival rate of patients with enzalutamide-naive metastatic
castrate resistant prostate cancer (mCRPC) treated with decitabine plus enzalutamide. (Phase
2)

SECONDARY OBJECTIVES:

I. To determine the safety and tolerability of decitabine in combination with enzalutamide in
patients with refractory metastatic castrate resistant prostate cancer (mCRPC). (Phase 1b)
II. To determine the overall response rate, overall survival and prostate specific antigen
(PSA) changes in enzalutamide-naive mCRPC patients treated with decitabine plus enzalutamide.
(Phase 2) III. To determine the safety and tolerability of decitabine in combination with
enzalutamide in the study population. (Phase 2)

EXPLORATORY OBJECTIVES:

I. To determine the relationship between decitabine dose and plasma biomarkers (e.g., levels
of HbF, LINE-1 methylation, number of circulating tumor cell's [CTC?s] and, NY-ESO expression
in CTC?s). (Phase 1b) II. To explore plasma and tumor immune biomarkers associated with
efficacy to the study combination. (Phase 2) III. To determine if treatment emergent
neuroendocrine transformation is present as a result of the treatment combination of
enzalutamide plus decitabine. (Phase 2) IV. Evaluate changes in stem cell reprogramming
factors and deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) markers resulting from the
treatment combination. (Phase 2)

OUTLINE: This is a phase Ib, dose-escalation study of decitabine followed by a phase II
study.

Participants receive decitabine intravenously (IV) over 1 hour on days 1-5 and enzalutamide
orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 3 months for 24
months.

Inclusion Criteria:

- Histological or cytological documentation of diagnosis of prostate cancer, all
histological sub-types included.

- Documented progressive metastatic castrate resistant prostate cancer (mCRPC) based on
at least one of the following criteria:

- PSA progression defined as 25% increase over baseline value with an increase in
the absolute value of at least 2 ng/mL that is confirmed by another PSA level
with a minimum of a 1week interval and a minimum PSA of 2 ng/mL

- Soft-tissue progression defined as an increase >= 20% in the sum of the longest
diameter (LD) of all target lesions based on the smallest sum LD since treatment
started or the appearance of one or more new lesions

- Progression of bone disease (evaluable disease) or (new bone lesion[s]) by bone
scan

- If on an anti-androgen, must have documented progression 6 weeks after stopping
anti-androgen therapy

- Willing to undergo a biopsy, if readily available biopsy site present, i.e., nodal or
visceral metastasis (if adequate formalin-fixed, paraffin-embedded (FFPE) archival
mCRPC samples are not available (or biopsy was taken longer than 6 months from start
of study treatment), a fresh pre-treatment mCRPC biopsy needs to be obtained)

- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Have testosterone < 50 ng/dL. Note: Patients must continue primary androgen
deprivation with an luteinizing hormone-releasing hormone (LHRH) analogue (agonist or
antagonist) if they have not undergone orchiectomy

- White blood cells >= 1.5 x 10^9/L (obtained within 14 days prior to treatment start)

- Platelets (UNVPLT) >= 100 x 10^9/L (obtained within 14 days prior to treatment start)

- Hemoglobin (HGB) >= 9 g/dL (obtained within 14 days prior to treatment start)

- Potassium (K), total calcium (CA) (corrected for serum albumin), magnesium, sodium
(NA) and phosphorus within normal limits for the institution or corrected to within
normal limits with supplements before first dose of study medication (obtained within
14 days prior to treatment start)

- International normalized ratio (INR) =< 1.5 (obtained within 14 days prior to
treatment start)

- Serum creatinine (CREAT) =< 1.5 mg/dL or creatinine clearance > 50 mL/min (obtained
within 14 days prior to treatment start)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN. If
the patient has liver metastases, ALT and AST must still be =< 2.5 x ULN. Patients
with liver metastases and AST/ALT above this limit will not be enrolled (obtained
within 14 days prior to treatment start)

- Total serum bilirubin =< 1.5 x ULN; or total bilirubin (TBILI) =< 3.0 x ULN with
direct bilirubin within normal range in patients with well documented Gilbert?s
syndrome (obtained within 14 days prior to treatment start)

- Ability to swallow and retain oral medication (without crushing, dissolving or chewing
tablets)

- Phase Ib only: Prior enzalutamide treatment and/or other approved treatments for CRPC
are acceptable

- Phase II only: Participants MUST be treatment na?ve in the CRPC setting: i.e., no
prior exposure to abiraterone acetate other specific CYP-17 inhibitors; no prior
exposure to enzalutamide or investigational androgen receptor (AR) targeted agents;
and no prior exposure to chemotherapy and or RAD-223

- Sexually active males must agree to use a condom during intercourse while taking the
study drug and for at least 3 months after stopping study treatment. Sexually active
males should not father a child during this period. A condom is required to be used by
vasectomized men in order to prevent delivery of the drug via seminal fluid. Should a
woman become pregnant or suspect she is pregnant while her partner is participating in
this study, she should inform her treating physician immediately

- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

- Phase II only: Prior exposure to abiraterone acetate

- Phase II only: Prior exposure to hypomethylating agents like azacytidine or decitabine

- Phase II only: Prior chemotherapy for castration resistant disease. Chemotherapy given
in the castration-sensitive setting is permissible if stopped at least 4 weeks prior
to treatment start

- Phase II only: Prior isotope therapy with strontium-89, samarium or radium-223 within
12 weeks of treatment start

- Participants with known symptomatic brain metastases

- Participant has a concurrent malignancy or malignancy within 3 years of treatment
start, with the exception of adequately treated, basal or squamous cell carcinoma
ornon-melanomatous skin cancer

- Participant has a known history of human immunodeficiency virus (HIV) infection
(testing not mandatory)

- Participant has clinically significant, uncontrolled heart disease and/or recent
events including any of the following:

- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or
symptomatic pericarditis within 12 months prior to treatment start

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV)

- On screening 12 lead electrocardiography (ECG), any of the following cardiac
parameters: bradycardia (heart rate < 50 at rest), tachycardia (heart rate > 90
at rest), PR interval > 220 msec, QRS interval > 109 msec or, Fridericia's
correction formula (QTcF) > 450 msec. Congenital long QT syndrome or family
history of long QT syndrome

- Patient is currently receiving any of the following medications and cannot be
discontinued 7 days prior to treatment start:

- Known strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
hybrids and pummelos, star-fruit and, Seville oranges

- Medications that have a known risk to prolong the QT interval or induce Torsades
de Pointes

- Herbal preparations/medications, dietary supplements

- Patient who has received radiotherapy =< 4 weeks prior to start of treatment or
limited field radiation for palliation =< 2 weeks prior to treatment start and, who
has not recovered to grade 1 or better from related side effects of such therapy
(exceptions include alopecia) and/or in whom >= 30% of the bone marrow was irradiated

- Patients with central nervous system (CNS) involvement

- Patients with seizure disorder

- Patient has not recovered from all toxicities related to prior anticancer therapies to
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
version 4.03 grade < 1 (exception to this criterion: patients with any grade of
alopecia are allowed to enter the study)

- Participant has any other concurrent severe and/or uncontrolled medical condition that
would cause, in the investigator?s judgment, an unacceptable safety risk

- Unwilling or unable to follow protocol requirements

- Any condition which in the investigator?s opinion deems the participant an unsuitable
candidate to receive study drug