Enzalutamide and Mifepristone in Treating Patients With Metastatic Hormone Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To establish the safe and pharmacologically active doses of mifepristone and enzalutamide
to use in combination. (Phase I) II. To determine if mifepristone in combination with
enzalutamide prolongs time to prostate-specific antigen (PSA) progression compared to
enzalutamide alone in patients with metastatic castration resistant prostate cancer. (Phase
II)

SECONDARY OBJECTIVES:

I. To evaluate the effect of mifepristone on endocrine biomarkers such as serum cortisol and
thyrotropin.

II. To determine the effect of mifepristone on enzalutamide clearance and steady state
enzalutamide exposure.

III. To determine if mifepristone affects PSA response rate when added to enzalutamide.

IV. To determine if mifepristone when added to mifepristone prolongs radiographic and
clinical progression free survival according to standard working group criteria.

V. To explore the role of glucocorticoid receptor (GR) and androgen receptor (AR) protein
expression within circulating tumor cells as a pharmacodynamic biomarker for mifepristone and
enzalutamide in castration resistant prostate cancer (CRPC).

VI. To explore the expression of GR and down-stream AR/GR targets in metastatic tumor
specimen prior to combination drug administration and at clinical progression.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

PHASE I: Patients receive enzalutamide orally (PO) on days 1-57 and mifepristone PO on days
29-57. Treatment continues in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive enzalutamide PO for 12 weeks per standard of care. Patients are
then randomized to 1 of 2 treatment arms.

ARM I: Patients receive enzalutamide PO per standard of care.

ARM II: Patients receive enzalutamide PO and mifepristone PO.

In both arms, treatment continues in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up for 1 year.

Inclusion Criteria:

- Histologically or cytologically confirmed prostate cancer

- Evidence of castrate testosterone level < 50 ng/dL (or surgical castration)

- For Phase I portion of the study: evidence of disease progression:

- 2 or more new lesions on bone scan or

- Progressive disease on computed tomography (CT)/magnetic resonance imaging (MRI)
according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
or

- Rising PSA: PSA evidence for progressive prostate cancer consists of a minimum
PSA level of at least 2 ng/ml, which has subsequently risen on at least 2
successive occasions, at least 2 weeks apart

- For Phase II portion of the study:

- Subjects must be on enzalutamide for metastatic CRPC and within the first 12
weeks of enzalutamide at 160mg/day

- Record of subject's enzalutamide start date and baseline PSA (within 28 days of
starting) before starting enzalutamide available

- Subjects must have documented clinically stable disease or better during the screening
period of the study as defined by all of the following:

- PSA =<1.25 times the PSA at start of enzalutamide

- Lack of radiographic progression as defined by Response Evaluation Criteria in
Solid Tumors (RECIST) 1.1 and Prostate Cancer Working Group Criteria

- Clinically stable as confirmed by treating physician

- Any prior therapy for castrate disease is acceptable except prior specific cytochrome
P450 family 17 (CYP17) antagonists (e.g. abiraterone acetate, orteronel) or prior
second generation AR antagonists (e.g. enzalutamide or ARN509) which are excluded
other than enzalutamide as specified for phase II portion; a minimum washout of 28
days for any other anticancer therapy prior to first dose of study drug is required
(only applicable for phase I)

- Any other radiotherapy or radionuclide require 28-day washout prior to first dose of
study drug

- Denosumab or zoledronic acid are allowed

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Total bilirubin =< 1.5 x the upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

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

Exclusion Criteria:

- Therapy with other hormonal therapy, including any dose of megestrol acetate (Megace),
finasteride (Proscar), dutasteride (Avodart), or any herbal product known to decrease
PSA levels (e.g., saw palmetto and PC-SPES), or any systemic corticosteroid within 2
weeks prior to first dose of study drug

- Inability to swallow capsules or known gastrointestinal malabsorption

- History of other malignancies, with the exception of: adequately treated non-melanoma
skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 solid tumor
malignancies who are without evidence of disease, or other solid tumors curatively
treated with no evidence of disease for >= 5 years from enrollment

- Blood pressure that is not controlled despite > 2 oral agents (systolic blood pressure
[SBP] > 160 and diastolic blood pressure [DBP] > 90 documented during the screening
period with no subsequent blood pressure readings < 160/100)

- History of seizure disorder or active use of anticonvulsants

- Corrected QT interval (QTc) on electrocardiogram (EKG) > 450 msec

- Serious intercurrent infections or non-malignant medical illnesses that are
uncontrolled

- Active psychiatric illness/social situations that would limit compliance with protocol
requirements

- New York Heart Association (NYHA) class II, NYHA class III, or IV congestive heart
failure (any symptomatic heart failure)

- Concurrent therapy with strong inhibitors or inducers of cytochrome P450 family 3,
subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450 family 2, subfamily C,
polypeptide 8 (CYP2C8) due to concerning possible drug-drug interactions