Open Label Phase Two Study of Enzalutamide With Concurrent Administration of Radium Ra 223 Dichloride in Castration-Resistant (Hormone-Refractory) Prostate Cancer Subjects With Symptomatic Bone Metastasis

This is an open label study designed to examine the effects of Enzalutamide with concurrent
administration of Radium Ra 223 dichloride in castrate resistant (hormone-refractory)
prostate cancer subjects with symptomatic bone metastasis, in both the pre- and post-
chemotherapy setting.

Radium Ra 223 dichloride is approved by the US Food and Drug Administration for this
indication. Enzalutamide is US Food and Drug Administration approved for this indication.

Approximately 40 subjects will be enrolled to obtain 30 evaluable subjects. All subjects will
receive Radium Ra 223 dichloride every 4 weeks for a total of 6 doses over 24 weeks and
concurrent Enzalutamide for a minimum duration of 24 weeks. The sponsor will provide
Enzalutamide after the End of Treatment visit until the last Long Term Follow Up visit has
been completed. Subjects will continue to receive Enzalutamide as long as a positive response
to therapy is demonstrated. Enzalutamide may be discontinued at any time per physician
discretion.

Subjects will be evaluated 30 days after the last dose of Radium Ra 223 dichloride. Including
screening, the total duration of the study is 32 weeks plus every 3 month follow up visits
while subjects are receiving Enzalutamide.

Inclusion Criteria:

Eligible subjects will conform to all of the inclusion criteria listed below:

1. Subject must be able to understand and be willing to sign the written Informed Consent
Form. A signed IRB approved Informed Consent Form must be appropriately obtained prior
to the conduct of any study-specific procedure.

2. Subject is willing and able to comply with the protocol, including all study visits
and procedures.

3. Subject is a male, greater than 18 years at time of enrollment.

4. Life expectancy of at least 9 months.

5. Subject has histologically documented prostate cancer confirmed by a pathology report
from a prostate biopsy or radical prostatectomy specimen.

6. Subject must:

1. have initiated a stable dose of daily Enzalutamide within 45 days of enrollment (Cycle
1/Week 1/ Day 1), or 2. plans to initiate a stable daily dose of Enzalutamide within 30
days of the first Radium Ra 223 dichloride treatment.

7. Subject must plan to receive all 6 Radium Ra 223 dichloride injections and daily oral
doses of Enzalutamide during the study, per protocol.

8. Subject has a history of bone metastasis from prostate cancer as evidenced by imaging
performed within 90 days of enrollment (Cycle 1/Week 1/Day 1) from one of the following:

1. Tc Bone Scan or 2. Sodium Fluoride PET/CT Scan

- If a bone scan is used, solitary lesions which could be contributed to causes other
than prostate cancer must be confirmed with a second modality (i.e.: plain films, CT
scan or MRI).

9. Subject has Castrate Resistant Prostate Cancer, defined as having a rising PSA
level and a testosterone level deprivation therapy (medical or surgical castration). Subject must also plan to
receive androgen deprivation therapy throughout the study.

- PSA progression is defined as having at least 2 rising PSA levels taken at least 7
days apart, with the 2nd PSA being 2.0 ng/dl or greater.

10. Subject has the presence of cancer related bone pain requiring treatment with
analgesic medications (including but not limited to acetaminophen, NSAIDS, Cox-2
inhibitors, and narcotic opioids).

11. Subject has an ECOG performance status of 0-2 at the screening and enrollment
visits.

12. Acceptable hematology and serum biochemistry screening values: White Blood Cell
(WBC) >/= 3,000/mm3 Absolute Neutrophil Count (ANC) >1500/mm3 Platelet (PLT) count
>100,000/mm3 Hemoglobin (HGB) > 10.0 g/dL (100g/L; 6.2 mmol/L Creatinine <1.5 ULN
Total bilirubin level <1.5 X ULN Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) <2.5 X ULN albumin >25 g/L Baseline electrolytes within normal
limits ( Sodium, potassium, chloride, calcium, phosphate, magnesium, LDH, γGT, urea,
total protein)

13. Normal Liver Function Tests (LFT) and normal Renal Function Tests (RFT) at the
screening visit. If the subject has LFT's or RFT's greater than 2.5 times the upper
limit of normal (ULN), Medical Monitor review, in conjunction with the subject's PI,
will be required.

14. Subjects receiving Anti-Resorptive medications, such as denosumab (XGEVA) and
Zolendronic Acid (Zometa), must be on a stable dose for at least 90 days prior to
enrollment (Cycle 1/Week 1/Day 1). Anti-resorptive medications may be not be added to
the subject's regimen during the study. Anti-resorptive discontinuation will be
allowed per Investigator discretion due to adverse events attributable to that
medication.

15. Subjects of childbearing potential must agree to use adequate contraception
beginning at the enrollment until at least 30 days after the last dose of the study
drugs. The definition of adequate contraception will be based on the judgment of the
principal investigator or a designated associate.

Exclusion Criteria:

Eligible subjects must not meet any of the exclusion criteria listed below:

1. Subject has known malignant pleural effusion, or known lung, liver or brain metastasis
(lymph node only metastasis <6 cm in short-axis diameter is allowed).

2. Subject has a history of seizure or any condition that may predispose him to seizures
(e.g. prior cortical stroke, significant brain trauma) at any time in the past, or a
history of loss of consciousness or transient ischemic attack within 12 months of
enrollment (Cycle 1/Week 1/Day 1).

3. Subject has received previous treatment with Enzalutamide for longer than 45 days
prior to enrollment (Cycle 1/Week 1/Day 1), or any prior treatment with Radium Ra 223
dichloride.

4. Subject has a known medical contraindication to Enzalutamide or Radium Ra 223
dichloride.

5. Subject is not willing to initiate a stable dose of daily Enzalutamide within 45 days
of enrollment (Cycle 1/Week1/Day 1), or does not plan to initiate a stable daily dose
of Enzalutamide within 30 days of the first Radium Ra 223 dichloride treatment (Cycle
1/Week 1/Day 1).

6. Subject does not plan to receive all 6 injections of Radium Ra 223 Dichloride and
daily Enzalutamide during the study, per protocol.

7. Subject has received previous strontium-89, samarium-153, rhenium-186, or rhenium-188
for the treatment of bone metastasis within 24 weeks prior to enrollment (Cycle 1/Week
1/Day 1).

8. Subject has received denosumab or Zolendronic Acid for less than 90 days prior to
enrollment (Cycle 1/Week 1/Day 1), or if the subject plans to discontinue an
anti-resorptive prior to the End of Treatment visit or the last Long Term Follow Up
visit.

9. Subject has received an investigational product or experimental therapy within 4 weeks
of enrollment (Cycle 1/Week 1/Day 1), or if initiation of either is planned prior to
the End of Treatment visit or the last Long Term Follow Up visit.

10. Subject has had treatment with cytotoxic chemotherapy within 4 weeks or enrollment
(Cycle 1/Week 1/Day 1), or planned prior to the End of Treatment visit or the last
Long Term Follow Up visit, or failure to recover from adverse events due to cytotoxic
chemotherapy administered more than 4 weeks prior to enrollment (Cycle 1/Week 1/Day
1), such as persistent myelosuppression, GI toxicity, or severe fatigue. Ongoing
neuropathy is not exclusionary.

11. Subject has a history of severe liver insufficiency (r Child-Pugh class B or C).

12. Subject has a history of a myocardial infarction or cardiac arrhythmia within 6 months
prior to enrollment (Cycle 1/Week 1/ Day 1).

13. Subject has a history of previous radiotherapy >25% of bone marrow, including hemibody
radiation.

14. Subject has a history of any other malignancy within the previous 5 years. A history
of squamous or basal cell carcinoma or low-grade superficial bladder cancer that has
been adequately treated at least 12 months prior to enrollment is not exclusionary.

15. Subject has undergone major surgery within 4 weeks prior to enrollment (Cycle 1/Week
1/Day 1).

16. Subject has had a blood transfusion or erythropoietin stimulation agents within 4
weeks of enrollment (Cycle 1/Week 1/Day 1).

17. Subject has known imminent or established spinal cord compression.

18. Subject has a serious concurrent medical condition or psychiatric illness.

19. Subject has a history of other serious illness of medical condition including, but not
limited to any uncontrolled infection, congestive heart failure New York Heart
Association (NYHA) class III or IV, Crohn's Disease or Ulcerative Colitis,
uncontrolled hypertension or Bone Marrow Dysplasia at screening.

20. Subject has a gastrointestinal disorder affecting absorption (e.g. gastrectomy, active
peptic ulcer disease within 90 days prior to enrollment (Cycle 1/Week 1/Day 1)

21. Subject is not able to swallow the study treatment capsules.

22. Subject has unmanageable fecal incontinence.

23. Subject has any condition that, in the opinion of the investigator, would impair the
patient's ability to comply with study procedures.