Androgen Deprivation Therapy +/- Radium-223 Dichloride in Metastatic Prostate Cancer With Bone Metastases

OUTLINE: This is a multi-center, randomized trial.

STRATIFICATION FACTORS:

Subjects will be stratified based on serum total alkaline phosphatase at baseline and extent
of disease (described below). Randomization will occur within stratification group.

- Extent of Disease: <6 skeletal metastases with no visceral metastases versus ≥6 skeletal
metastases or visceral metastases.

- Serum total alkaline phosphatase at baseline: normal vs abnormal. Abnormal alkaline
phosphatase is defined as > 130 IU/L.

Early Induction or Late Induction status will not be a stratification criterion.

TREATMENT SCHEDULE: CONTROL ARM A

All subjects will receive androgen deprivation therapy with a LHRH agonist (any LHRH agonist
such as leuprolide acetate or goserelin acetate is acceptable) or a LHRH antagonist
(degarelix) or bilateral orchiectomy, with dosage determined by the treating physician. Route
of administration and cycle days will be administered as per package insert. Androgen
deprivation therapy with LHRH agonist or LHRH antagonist will be given continuously.

All subjects will receive bicalutamide, 50 mg Oral (PO) Daily

TREATMENT SCHEDULE: EXPERIMENTAL ARM B

All subjects will receive androgen deprivation therapy with a LHRH agonist (any LHRH agonist
such as leuprolide acetate or goserelin acetate is acceptable) or a LHRH antagonist
(degarelix) or bilateral orchiectomy, with dosage determined by the treating physician. Route
of administration and cycle days will be administered as per package insert. Androgen
deprivation therapy with LHRH agonist or LHRH antagonist will be given continuously.

All subjects will receive bicalutamide, 50 mg oral (PO) daily

All subjects will receive Radium-223 dichloride, 50 kBq (1.35 microcurie) per kg body weight,
intravenous (IV bolus) every 28 days for 6 injections

The following laboratory values must be obtained within 28 days prior to registration for
protocol therapy:

Hematopoietic:

- Hemoglobin (Hgb) ≥ 8.0 g/dL (80 g/L) without packed RBC transfusion

- Platelets ≥ 100 K/mm3

- Absolute neutrophil count (ANC) ≥ 1.5 K/mm3

Hepatic:

- Total Bilirubin ≤ 2 x institutional upper limit of normal (ULN) except subjects with
Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL

- Aspartate aminotransferase (AST, SGOT) ≤ 2.5 x institutional ULN (≤ 5 x institutional
ULN in the presence of liver metastases).

- Alanine aminotransferase (ALT, SGPT) ≤ 2.5 x institutional ULN (≤ 5 × institutional ULN
in the presence of liver metastases).

Renal:

- Estimated Creatinine Clearance by Cockcroft-Gault formula ≥ 30 mL/min

Inclusion Criteria:

- All subjects or their legally authorized representative must be informed of the
investigational nature of the study and provide written informed consent and HIPAA
authorization for release of personal health information before performance of any
study related procedure not part of routine medical care. NOTE: HIPAA authorization
may be included in the informed consent or obtained separately.

- Men ≥ 18 years of age at the time of informed consent.

- Histological or cytological evidence of prostate adenocarcinoma.

- All subjects must have radiologic or pathologic evidence of ≥ 2 skeletal lesions with
or without pain at baseline on bone scan or axial imaging or 1 skeletal lesion and
bone pain within 28 days prior to the registration.

- All subjects must have a radiographic assessment (chest or abdominal/pelvic CT or MRI)
within 28 days prior to registration but do not need to have measurable disease.

- ECOG (Eastern Cooperative Oncology Group) Performance Status of 0-2 within 28 days
prior to registration. ECOG Performance Status of 3 will only be allowed if judged by
the treating investigator as attributable exclusively to bone pain.

- Subjects must fall into one of the two populations below:

- EARLY INDUCTION GROUP: Subjects who have started androgen deprivation therapy
(luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with or
without an anti-androgen agent) a maximum of 28 days before registration and who
otherwise meet all the eligibility criteria.

- LATE INDUCTION GROUP: Subjects who have NOT started any androgen deprivation therapy
(luteinizing hormone-releasing hormone (LHRH) agonist or antagonist therapy with or
without an antiandrogen agent).

- Anti-androgen receptor antagonist therapy must be bicalutamide. Subjects already
started on other anti-androgens must be willing to switch over to bicalutamide.

- Any prior androgen-deprivation therapy or finasteride as neoadjuvant or adjuvant
therapy or for biochemical recurrence must have been discontinued at least 6 months
prior to registration.

- Prior surgical treatment for prostate cancer is allowed but must have been completed
at least 14 days prior to registration and any toxicity from such therapy must have
recovered to ≤ grade 1 per CTCAE version 4 criteria by the time of registration.

- All subjects, including those who are surgically sterilized, must be willing to use an
effective method of contraception (barrier method of birth control or abstinence) from
the time informed consent is signed until 6 months after completion of protocol
therapy.

- Subjects must consent to bank whole blood, serum, plasma for future unspecified
studies.

Exclusion Criteria:

- Prior cytotoxic chemotherapy for metastatic prostate cancer. Prior cytotoxic
chemotherapy with curative intent in the neoadjuvant or adjuvant setting is allowed
but must have been completed at least 6 months prior to registration. No cytotoxic
chemotherapy is allowed during protocol specified therapy.

- Prior concomitant therapy with ketoconazole, aminoglutethimide or abiraterone acetate
or enzalutamide (MDV3100) or intent to treat with the above. Concurrent megestrol for
hot flashes is allowed.

- Prior or ongoing bisphosphonate (e.g,. zoledronic acid) or RANKL inhibitor (e.g.
denosumab) use is NOT allowed except when used solely for osteoporosis and strictly
per guidelines for that indication. Bisphosphonate or RANKL inhibitor cannot be
initiated for any indication during protocol specified therapy without consent of the
sponsor-investigator of the study.

- Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186 or
rhenium-188.

- Diagnosis of aplastic anemia, pure red cell aplasia, myelodysplasia or any of the
other bone marrow failure states.

- Any neuroendocrine differentiation including small cell carcinoma on histology or
cytology.

- No prior malignancy except for non-melanomatous skin cancer or non-muscle invasive
bladder cancer or adequately treated Stage I or II cancer (adequacy at discretion of
treating investigator) from which the subject is currently in complete remission, or
any other cancer from which the subject has been disease-free for at least 3 years.

- History of or active CNS metastasis (brain, leptomeningeal or cord compression). Brain
imaging studies are not required for eligibility if the subject has no neurologic
signs or symptoms suggestive of brain metastasis. Subjects with neurological symptoms
are recommended to undergo a head CT scan (with or without intravenous contrast) or
brain MRI (with or without intravenous contrast) to exclude brain metastasis. If brain
imaging studies are performed, they must be negative for CNS disease. Skull bone
involvement without neurological impact by prostate cancer is allowed.

- Treatment with any other investigational agent within 28 days prior to registration.
Subjects must not be treated with any other investigational agent while on protocol
specified therapy.

- Prior hemibody external radiation. Any external radiation therapy must have been
completed at least 14 days prior to registration. Any toxicity from such therapy must
have recovered to ≤ grade 1 per CTCAE version 4 criteria by the time of registration.

- Clinically significant infections as judged by the treating investigator. Subjects
must not have been diagnosed with human immunodeficiency virus (HIV) infection, active
chronic hepatitis B or C, life-threatening illness unrelated to cancer, or any serious
medical or psychiatric illness that could, in the investigator's opinion, potentially
interfere with participation in this study. Subjects should be tested for hepatitis B
or C or HIV infection during screening only if they are considered by the investigator
to be at high risk for these infections.

- Known hypersensitivity to bicalutamide.

- Known gastrointestinal (GI) disease or procedure that could interfere with the GI
absorption or tolerance of bicalutamide, including difficulty swallowing oral
medications.

- Grade III/IV cardiac disease as defined by the New York Heart Association Criteria
(i.e., subjects with cardiac disease resulting in marked limitation of physical
activity or resulting in inability to carry on any physical activity without
discomfort), symptomatic pulmonary embolism within 3 months, unstable angina pectoris,
myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia as
determined by the treating physician.