Radium Ra 223 Dichloride, Hormone Therapy, and Denosumab in Treating Patients with Hormone-Positive, Bone-Dominant Metastatic Breast Cancer

Inclusion Criteria

• Stage IV breast cancer with metastases to the bone and/or bone marrow
• 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/computed tomography [CT] [new or multiple FRG positive lesions], and magnetic resonance imaging [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)
• Visible uptake in at least one lesion on bone scanning prior to radium therapy
• 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
• Breast tumors with hormone receptor positive disease (estrogen receptor [ER]+/progesterone receptor [PR]+, ER+/PR- regardless of HER2 status)
• Eastern Cooperative Oncology Group (ECOG) performance score of 0, 1
• All acute toxic effects of any prior treatment have resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version (v)4.0 grade 1 or less at the time of signing the informed consent form (ICF)
• 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
• White blood cell count (WBC) >= 3,000/mm^3
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet (PLT) count >= 100,000/mm^3
• Hemoglobin (HGB) >= 10 g/dl
• Total bilirubin level =< 2.0 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN
• Creatinine =< 1.5 x ULN
• 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

• Following breast cancer disease conditions are not eligible: * Single bone lesion * Two or more visceral metastasis * Single visceral lesion < 2 cm without any laboratory changes or clinical symptoms due to the metastatic lesion is permitted * Presence of brain metastases * Imminent spinal cord compression based on clinical findings and/or MRI * Impending fracture, spinal cord compression, and/or potentially unstable compression fracture of vertebral body with possibility of cord compression * Life expectancy severely limited by concomitant illness (less than 12 months) * Concurrent external beam radiation therapy to non-target lesion is permitted
• Following prior treatments are not eligible: * Use of any investigational agent within 30 days preceding enrollment * Treatment with cytotoxic chemotherapy within previous 4 weeks * Failure to achieve =< grade 2 adverse events (AE) resolution from cytotoxic chemotherapy administered more than 4 weeks previous (however, ongoing neuropathy is permitted) * 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
• Following medical conditions are not eligible: * Other malignancy treated within the last 3 years (except non melanoma skin cancer or low-grade superficial bladder cancer or cervical dysplasia) * 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 ** Cardiac failure New York Heart Association (NYHA) III or IV ** Crohn’s disease or ulcerative colitis ** Bone marrow dysplasia or myelodysplastic syndrome
• 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
• Any condition which, in the investigator’s opinion, makes the subject unsuitable for trial participation
• Major surgery within 30 days prior to start of study drug
• Excluded therapies and medications, previous and concomitant: * Concurrent anti-cancer therapy (chemotherapy, surgery, immunotherapy, biologic therapy, anti-HER2 targeting therapies, or tumor embolization) other than Ra 223 dichloride; concurrent external beam radiation therapy is permitted * Prior use of Ra-223 dichloride * 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)