Testing the Addition of Radium Therapy (Radium-223 Dichloride) to the Usual Chemotherapy Treatment (Paclitaxel) for Advanced Breast Cancer That Has Spread to the Bones

Inclusion Criteria:

• Women or men with metastatic breast cancer with two or more bone metastasesidentified by technetium Tc-99m (99mTc) bone scintigraphy and/or CT, at least one ofthese bone lesions must not have been treated with prior radiation therapy

• A diagnosis of breast cancer must have been histologically or cytologicallyconfirmed at any time point

• Patients with non-bone metastases (in addition to bone metastases) are permitted if:

• Five or less visceral metastasis (=< 4 cm in size) and asymptomatic (notincluding lymph nodes)

• Enlarged lymph nodes =< 4 cm

• Patients with HER2 negative disease (HER2 negativity by immunohistochemistry [IHC]or fluorescent in situ hybridization [FISH] ratio according to the American Societyof Clinical Oncology-College of American Pathologists guideline criteria) (Hammondet al., 2010; Wolff et al., 2013). Hormone-receptor positive (estrogen receptor [ER]-positive and/or progesterone receptor [PR]-positive) as well as triple-negative (ER-negative, PR-negative and no overexpression of HER2) breast cancer may beenrolled. Hormone receptor status will be determined at the local institution. ERand PR negativity will be defined as < 1% tumor staining by IHC

• Patient must be eligible to receive therapy with paclitaxel for the treatment oftheir breast cancer. Patients with hormone-receptor positive disease should haveprogressed on at least one prior line of hormone therapy and a CDK4/6 inhibitor inthe metastatic setting to be eligible (except if patient had a contraindication orintolerable toxicity with the use of these agents). Previous radiation andchemotherapy for the treatment of metastatic breast cancer is allowed

• Age >= 18 years

• Because no dosing or AE data are currently available on the use of radium-223dichloride in combination with paclitaxel in patients < 18 years of age,children are excluded from this study, but will be eligible for futurepediatric trials

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Absolute neutrophil count (ANC) >= 1,500/mcL

• Platelets >= 100,000/mcL

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (with theexception of < 3 mg/dL for patients with Gilbert's disease)

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN (=< 5 ULN for patients with liver metastasis)

• Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 40mL/min/1.73 m^2

• Hemoglobin > 10 g/dL

• Human immunodeficiency virus (HIV)-infected patients on effective antiretroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, HBV viralload must be undetectable on suppressive therapy if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

• Patients with asymptomatic, treated brain metastases are permitted if there is noevidence of progression for at least 4 weeks after central nervous system (CNS)-directed treatment, as ascertained by clinical examination or brain imaging (magnetic resonance imaging [MRI] or CT scan) during the screening period

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial. History of other activemalignancy requiring treatment within the last 3 years or bone marrow dysplasia suchas myelodysplastic syndrome (MDS) is not allowed

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association functional classification. To beeligible for this study, patients should be class 2B or better

• Concomitant use of bisphosphonates or denosumab is required (except if medicalcontraindication such as hypocalcemia or concern for osteonecrosis of the jaw). Ifnot already on bone modifying agents, patient must initiate such therapy within onemonth before start of study treatment

• The effects of radium-223 dichloride on the developing human fetus are unknown. Forthis reason and because alpha particle-emitting radiopharmaceutical agents as wellas other therapeutic agents used in this trial are known to be teratogenic, women ofchild-bearing potential must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) prior to study entry, for the durationof study participation, and for at least 6 months after the last dose. Should awoman become pregnant or suspect she is pregnant while she or her partner isparticipating in this study, she should inform her treating physician immediately.Pre-menopausal subjects as well as subjects with ovarian radiation or concomitanttreatment with an luteinizing hormone-releasing hormone (LH-RH) agonist/antagonistmust have a negative pregnancy test and agree to use an adequate method ofcontraception as recommended by their treating physicians. Subjects of child-bearingpotential who are sexually active and their male partners must agree to utilize,during the treatment period and for 6 months after last dose of radium-223dichloride, 2 reliable and acceptable methods of contraception used simultaneously:a) barrier method such as a) condoms (male or female) with spermicidal agent or b)diaphragm or cervical cap with spermicide, combined with a highly effectivenon-hormonal birth control method such as an intra-uterine device. Men treated orenrolled on this protocol must also agree to use adequate contraception and notdonate sperm prior to the study, for the duration of study participation, and 6months after completion of radium-223 dichloride

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

• No prior paclitaxel in metastatic setting within 2 years prior to radium-223dichloride start. No prior paclitaxel in adjuvant or neoadjuvant setting within 6months prior to radium-223 dichloride start

Exclusion Criteria:

• Patients with peripheral neuropathy > grade 1

• Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e.,have residual toxicities > grade 1) with the exception of alopecia

• Patients who have had chemotherapy or immunotherapy with checkpoint inhibitor within 4 weeks prior to treatment. Patient who receives radiation therapy or hormonetherapy within 2 weeks prior to treatment are excluded. For patients on trialtherapy prior to study enrollment, washout period of 6 times the half-life ofpreviously administered investigational agents prior to starting radium-223dichloride is required

• Prior therapy with radionuclides (e.g., strontium, samarium, rhenium, radium)

• Patients who are receiving any other investigational agents. Vaccination for severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) is allowed as well as anytherapy as required for the treatment of active coronavirus disease 2019 (COVID-19)infection

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to radium-223 dichloride or other agents used in study

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because radium-223 dichloride is analpha particle-emitting radiopharmaceutical agent with the potential for teratogenicor abortifacient effects. Because there is an unknown but potential risk for AEs innursing infants secondary to treatment of the mother with radium-223 dichloride,breastfeeding should be discontinued if the mother is treated with radium-223dichloride. These potential risks may also apply to other agents used in this study

• Imminent/established spinal cord compression, pathological fracture in weightbearing bones or bone lesion with soft tissue component unless treated asappropriate with radiation and/or surgery before starting on trial

• Prior hemibody external radiotherapy

• Patients must not have an active infection requiring systemic treatment

• Patients must not use immunosuppressive medication =< 7 days of registration, EXCEPTfor the following:

• Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,intra-articular injection)

• Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone orequivalent

• Steroids as premedication for hypersensitivity reactions (e.g., CT scanpremedication) is allowed

• Patients with Crohn's disease or ulcerative colitis

• Patients with a marked baseline prolongation of QT/corrected QT interval (QTc)interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds [ms]) (CTCAE grade 1) using Fridericia's QT correction formula

• Patients with a history of additional risk factors for Torsades de Pointes (TdP) (e.g. heart failure, hypokalemia, family history of long QT syndrome)

• The use of concomitant medications that prolong the QT/QTc interval

• Life expectancy < 6 months