Trial of Ra-223 Dichloride in Combination With Hormonal Therapy and Denosumab in the Treatment of Patients With Hormone-Positive Bone-Dominant Metastatic Breast Cancer

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive Ra-223
dichloride by vein over no more than 1 minute on Day 1 of each 28-day study cycle.

You will also receive denosumab as an injection under the skin on Day 1 of Cycles 1- 6.

You will also receive hormone therapy while on study. Your doctor will discuss with you what
type of hormone therapy you will have, how it will be given, and its risks.

Study Visits:

On Day 1 of Cycle 1, blood (about 2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycles 2-5:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests.

On Day 1 of Cycle 6:

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

- Blood (about 3 tablespoons) will be drawn for biomarker testing, including genetic
biomarkers.

- Blood (about 5 teaspoons) will be drawn to test for CTCs, tumor markers, and genetic
testing.

- You will have a PET-CT scan and a bone scan to check the status of the disease. If the
doctor thinks it is needed, you will also have an MRI.

Length of Study Participation:

You may continue taking the study drugs for up to 6 cycles. You will no longer be able to
take the study drug if the disease gets worse, if intolerable side effects occur, or if you
are unable to follow study directions.

Your participation will be over after the end-of-study visit.

End-of-Study Visit:

After your last dose of study drug:

- You will have a physical exam.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

- Blood (about 3 tablespoons) will be drawn for biomarker testing, including genetic
biomarkers.

- Blood (about 5 teaspoons) will be drawn to test for CTCs, tumor markers, and genetic
testing.

- You will have a PET-CT scan and either a bone scan or a CT scan to check the status of
the disease. If the doctor thinks it is needed, you will also have an MRI.

- If the doctor thinks it is needed, you will have a bone marrow aspiration/biopsy to
check the status of the disease.

Inclusion Criteria:

1. Stage IV breast cancer with metastases to the bone and/or bone marrow.

2. Pathological or radiographically confirmation of metastases to the bone and/or bone
marrow. (The definition of radiologic diagnosis of bone metastasis is based on typical
and highly reliable imaging findings in studies such as bone scan (new or multiple
TC99m positive lesions), PET/CT (new or multiple FRG positive lesions), and MRI
(typical T1w replacement, T2w positive and T1 plus contrast media positive) for bone
metastasis with 2 or more lesions. If the bone metastasis is highly suspected or not
well defined by imaging, bone biopsy is necessary for confirmation.)

3. Visible uptake in at least one lesion on bone scanning prior to radium therapy.

4. No limit in number of prior hormonal agents in metastatic breast cancer; only one
prior chemotherapy is allowed in metastatic setting. Anti-HER2 targeting therapy,
CDK4/6 inhibitor, other targeted therapy (e.g., mTOR or PI3K inhibitor) in combination
with hormonal treatment will be counted as one hormonal agent. Any anti-HER2 targeting
therapy in combination with chemotherapy will not be counted as one additional
treatment.

5. Breast tumors with hormone receptor positive disease (ER+/PR+, ER+/PR- regardless of
HER2 status).

6. ECOG performance score of 0, 1.

7. Age =/> 18 years.

8. All acute toxic effects of any prior treatment have resolved to NCI-CTCAE v4.0 Grade 1
or less at the time of signing the Informed Consent Form (ICF).

9. Subjects (men and women) of childbearing potential must agree to use adequate
contraception beginning at the signing of the ICF until at least 6 months after the
last dose of study drug. The definition of adequate contraception will be based on the
judgment of the principal investigator or a designated associate.

10. Acceptable hematology and serum biochemistry screening values: White Blood Cell Count
(WBC) =/> 3,000/mm3 Absolute Neutrophil Count (ANC) =/> 1,500/mm3 Platelet (PLT) count
=/> 100,000/mm3 Hemoglobin (HGB) =/> 10 g/dl Total bilirubin level institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT)
11. Subjects must be able to understand and be willing to sign the written informed
consent form. A signed informed consent form must be appropriately obtained prior to
the conduct of any trial-specific procedure.

Exclusion Criteria:

1. Following breast cancer disease conditions are not eligible: A) Single Bone Lesion.
B)Two or more visceral metastasis C) Single visceral lesion < 2cm without any
laboratory changes or clinical symptoms due to the metastatic lesion is permitted.
D)Presence of brain metastases E) Imminent spinal cord compression based on clinical
findings and/or magnetic resonance imaging (MRI). T F) Impending fracture, spinal cord
compression, and/or potentially unstable compression fracture of vertebral body with
possibility of cord compression. G) Life expectancy severely limited by concomitant
illness (less than 12 months). H) Concurrent external beam radiation therapy to non
target lesion is permitted.

2. Following prior treatments are not eligible. A) Use of any investigational agent
within 30 days preceding enrollment. B) Treatment with cytotoxic chemotherapy within
previous 4 weeks C) Failure to achieve chemotherapy administered more than 4 weeks previous (however, ongoing neuropathy is
permitted). D) Received systemic therapy with radionuclides (e.g., strontium-89,
samarium-153, rhenium-186, or rhenium-188, or Ra-223 dichloride) for the treatment of
bony metastases.

3. Following medical conditions are not eligible. A) Other malignancy treated within the
last 3 years (except non melanoma skin cancer or low-grade superficial bladder cancer
or cervical dysplasia) B) Any other serious illness or medical condition, such as but
not limited to: Any infection =/> National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE) version 4.03 Grade 2. C) Cardiac failure New
York Heart Association (NYHA) III or IV. D) Crohn's disease or ulcerative colitis-Bone
marrow dysplasia or Myelodysplastic syndrome.

4. Women who are pregnant or breast-feeding. Women of childbearing potential must have a
negative serum pregnancy test performed within 7 days prior to the start of study
drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically
sterilized women are not required to undergo a pregnancy test.

5. Any condition which, in the investigator's opinion, makes the subject unsuitable for
trial participation.

6. Major surgery within 30 days prior to start of study drug.

7. Excluded therapies and medications, previous and concomitant: A) Concurrent
anti-cancer therapy (chemotherapy, surgery, immunotherapy, biologic therapy, anti-HER
2 targeting therapies, or tumor embolization) other than Ra 223 dichloride. Concurrent
external beam radiation therapy is permitted.B) Prior use of Ra-223 dichloride. C)
Concurrent use of another investigational drug or device therapy (i.e., outside of
study treatment) during, or within 4 weeks of trial entry (signing of the informed
consent form).