Enzalutamide and Cabazitaxel in Treating Patients With Metastatic, Castration-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of combination treatment with enzalutamide and
cabazitaxel (as determined by percent dose limiting toxicities [DLT], where DLT < 17% is
consistent with it being a tolerable combination).

II. To determine the efficacy of treatment with the hormonal agent enzalutamide and the
chemotherapy cabazitaxel in combination in men with metastatic castration-resistant prostate
cancer (CRPC) (as determined by percent of patients achieving >= 90% prostate specific
antigen [PSA] declines following initiation of treatment).

SECONDARY OBJECTIVES:

I. To further define the anticancer effect and safety profile of the combination of
enzalutamide and cabazitaxel.

II. Collect toxicity data (description of adverse events). III. Determine PSA response
(percent of patients who achieve >= 50% PSA decline and >= 30% PSA decline).

IV. Examine pharmacokinetic (PK) data of cabazitaxel to characterize enzalutamide and
cabazitaxel pharmacokinetic blood levels.

V. Determine tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for
measurable disease and Prostate Cancer Working Group 2 criteria for non-measurable (bone)
disease.

VI. Determine overall survival.

TERTIARY OBJECTIVES:

I. To determine baseline (and at progression) biological tumor characteristics to evaluate
for possible biomarkers indicative or predictive of response: apoptosis by cleaved caspase 3;
androgen signaling axis (including but not limited to: androgen receptor expression, androgen
receptor splice variants, and intratumoral androgen levels), and glucocorticoid receptor.

II. To collect circulating tumor cells (CTCs) and determine the degree to which tumor
characteristics (delineated above) are shared by the CTCs.

III. To collect plasma and serum pre-treatment and at progression for assessment of
circulating micro-ribonucleic acid (RNA)s and other circulating markers.

IV. To collect buffy coat to evaluate for steroid transporters.

OUTLINE: This is a dose de-escalation study of cabazitaxel.

Patients receive cabazitaxel intravenously (IV) over 1 hour on day 1 and enzalutamide orally
(PO) once daily (QD) on days 1-21 (days 2-21 of course 1). Patients also receive prednisone
PO twice daily (BID) as standard of care with cabazitaxel. Courses repeat every 21 days for
6-10 courses in the absence of disease progression or unacceptable toxicity. Patients may
continue enzalutamide PO QD on days 1-28 in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and then every 6
months for up to 5 years.

Inclusion Criteria:

- Metastatic CRPC

- Willing to provide a tumor sample via biopsy from a metastatic site of disease to be
collected at screening if safe and feasible per discretion of treating investigator;
adequate archival metastatic tissue can be used, if available, in lieu of baseline
biopsy if done when patient had CRPC; patients without a site amenable to biopsy and
lack of archival tissue may still join the study

- Evidence of prostate cancer progression by any of the following criteria: radiographic
or PSA criteria, or symptomatic progression related to prostate cancer

- Castrate testosterone levels (< 50 ng/dL) achieved by orchiectomy or maintenance on a
luteinizing hormone-releasing hormone (LHRH) agonist or antagonist

- Histologic confirmation of original prostate cancer diagnosis per institutional
standard; life expectancy of greater than 6 months

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

- Leukocytes >= 3,000/mm^3

- Absolute neutrophil count >= 1,500/mm^3

- Platelets >= 100,000/mm^3

- Total bilirubin within normal institutional limits (or < 2 X the upper limit of normal
in those with Gilbert?s disease)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 1.5 X institutional upper limit of normal

- Creatinine within less than the institutional upper limit of normal

- Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal

- Subject agrees to use a double barrier method of birth control during the course of
study treatment period with enzalutamide and/or cabazitaxel treatment and for at least
3 months after the study is discontinued

- A double-barrier method of contraception involves the use of a condom in
combination with 1 of the following: contraceptive sponge, diaphragm, or cervical
ring with spermicidal gel or foam

- Subject who has had a vasectomy at least 6 months prior to starting study
treatment period and those whose female sexual partner(s) are more than 55 years
of age and postmenopausal for at least 2 years or surgically sterile (tubal
ligation, hysterectomy, or bilateral oophorectomy) agree to use at least a condom

- Ability to understand, and the willingness to sign, a written informed consent
document, as well as comply with study requirements

- Must have appropriate wash out (> 6 half-lives) of androgen receptor antagonists, 5
alpha reductase inhibitors or ketoconazole prior to the start of cycle 1; if the agent
is not in the table below, the washout should be 2 weeks

- Bicalutamide; approximate half-life: 6 days; washout period required: 36 days

- Flutamide; approximate half-life: 6 hours; washout period required: 36 hours

- Nilutamide approximate half-life: 4 days; washout period required: 24 days

- Finasteride; approximate half-life: 8 hours; washout period required: 48 hours

- Aminoglutethimide; approximate half-life: 15 hours; washout period required: 4
days

- Ketoconazole; approximate half-life: 8 hours; washout period required: 48 hours

Exclusion Criteria:

- Prior chemotherapy for mCRPC prostate cancer; chemotherapy given neoadjuvantly,
adjuvantly, or for hormone sensitive metastatic disease is permitted as long as the
cancer did not progress on chemotherapy AND > 6 months have elapsed

- Patients may not have received any other investigational agents within the last 14
days at the time of treatment start

- Patients may not have received enzalutamide or ARN-509 (another androgen receptor
antagonist) in the past

- Patients may not have received cabazitaxel in the past

- Subject has clinical signs suggestive of high or imminent risks for pathological
fracture, spinal cord compression and/or cauda equina syndrome

- History of severe hypersensitivity reaction (>= grade 3) to docetaxel, polysorbate 80
containing drugs, or any of the capsule components of enzalutamide, including
Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene

- Concurrent or planned treatment with strong inhibitors or strong inducers of
cytochrome P450 family 3, subfamily A, polypeptide 4/5 (3A4/5); (a one-week wash-out
period is necessary for patients who are already on these treatments)

- Uncontrolled, intercurrent illness including, but not limited to, ongoing or active
infection, uncontrolled diabetes, symptomatic congestive heart failure, unstable
angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that
would limit compliance with study requirements

- Subject has a history of seizure or any condition that may predispose to seizure
including, but not limited to, underlying brain injury, stroke in the past 6 months,
primary brain tumors, brain metastases, prior seizures

- Subject has a history of unexplained loss of consciousness or transient ischemic
attack within 12 months of treatment start

- Subject is unwilling to stop using herbal supplements that can affect the PSA, such as
saw palmetto or prostate cancer (PC)-SPES

- Subject has another active malignancy other than non-melanomatous skin cancer (unless
it is metastatic) or superficial bladder cancer

- Must not have a gastrointestinal condition that would interfere with absorption

- Subjects may not be on other therapies that affect hormone levels, such as estrogens,
testosterones, ketoconazole during this study; however, megestrol for hot flashes is
permitted