A Study of Abemaciclib and Radiation Therapy in People With Metastatic Breast Cancer

Inclusion Criteria:

• Aged ≥18 years at signing of informed consent.

• Both male and female patients are allowed

• Histologically confirmed metastatic breast cancer (mBC), current stage IV.

• Plan for ablative radiotherapy to a bone metastasis.

• Documented estrogen receptor (ER) positive and/or progesterone receptor (PgR)positive by immunohistochemistry. The threshold to qualify as ER or PgR positive is ≥1% per ASCO/CAP guidelines.

• HER2 negative tumor status confirmed by immunohistochemistry or FISH per ASCO/CAPguidelines.

• Any line of prior treatments (hormonal therapy and chemotherapy) is permittedincluding prior abemaciclib, palbociclib and ribociclib.

• At the time of enrollment, treating physician has intent to resume abemaciclib (atany dose) following radiotherapy.

• Patients who received chemotherapy must have recovered (Common Terminology Criteriafor Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy exceptfor residual alopecia or Grade 2 peripheral neuropathy prior to enrollment. Awashout period of at least 21 days is required between last chemotherapy dose andenrollment (provided the patient did not receive radiotherapy).

• Patients who received radiotherapy must have completed and fully recovered from theacute effects of radiotherapy. A washout period of at least 14 days is requiredbetween end of radiotherapy and enrollment. No prior radiotherapy to the currentintended target site is permitted (ie. reirradiation is excluded from this study).

• The patient must be able to swallow oral medications.

• The patient must have adequate organ function per the following criteria (as definedin Table 2):

Table 2: Laboratory Value Guidance to Establish Adequate Organ Function Hematologic ANC: ≥1.5 x 10^9/L Platelets: ≥100 x 10^9/L Hemoglobin: ≥8 g/dL Participants may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.

Hepatic Total bilirubin: ≤1.5 x ULN Patients with Gilbert's syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted ALT and AST: ≤3 x ULN

• Patient may remain on hormonal therapy and abemaciclib before enrollment.

• Patients must discontinue other CDK4/6 inhibitor (palbociclib or ribociclib) for atleast 7 days and recover from the acute effects of therapy (until the toxicityresolves to ≤Grade 1) except for residual alopecia and peripheral neuropathy.

• Measurable or non-measurable disease is permitted as defined by Response EvaluationCriteria in Solid Tumors version 1.1 (RECIST v1.1).

• Patients must have an Eastern Cooperative Oncology Group (ECOG) status of ≤2 orKarnofsky Performance Status (KPS) ≥60.

• Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal womenof reproductive capacity (those who are biologically capable of having children) andfor women less than 12 months after menopause.

• Women of childbearing potential must agree and commit to the use of a highlyeffective method of contraception as determined to be acceptable by theinvestigator, from the time of informed consent until 28 days after the last dose ofthe investigational product. Men must agree and commit to use a barrier method ofcontraception while on treatment and for 4 weeks after last dose of investigationalproducts.

• Patients (or their legally authorized representative) must provide written, informedconsent to participate in the study and follow the study procedures

• At the discretion of the treating radiation oncologist, radiation to a metastaticbone lesion is indicated inclusive of bone lesions in the spinal column.

Exclusion Criteria:

• Bone lesions in the calvarium are not eligible for the dose-finding or expansionportions of the study.

• Patients currently enrolled in a clinical trial involving an investigational productor non-approved use of a drug or device (other than the study drug/device used inthis study), or concurrently enrolled in any other type of medical research judgednot to be scientifically or medically compatible with this study.

• The patient has received an experimental treatment in a clinical trial within thelast 30 days or 5 half-lives, whichever is longer, prior to the start of studyintervention, or is currently enrolled in any other type of medical research (forexample: medical device) judged by the sponsor not to be scientifically or medicallycompatible with this study.

• Patients who received radiation therapy ≤14 days prior to initiation ofinvestigational agents are excluded.

• Patients are ineligible if they have serious and/or uncontrolled preexisting medicalcondition(s) that, in the judgment of the investigator, would preclude participationin this study (for example, interstitial lung disease, severe dyspnea at rest orrequiring oxygen therapy, severe renal impairment [e.g. estimated creatinineclearance <30ml/min], history of major surgical resection involving the stomach orsmall bowel, or preexisting Crohn's disease or ulcerative colitis or a preexistingchronic condition resulting in baseline Grade 2 or higher diarrhea).

• Females who are pregnant or lactating.

• The patient has active systemic bacterial infection (requiring intravenous [IV]antibiotics at time of initiating study treatment), fungal infection, or detectableviral infection (such as known human immunodeficiency virus positivity or with knownactive hepatitis B or C [for example, hepatitis B surface antigen positive].Screening is not required for enrollment.

• The patient has a personal history of any of the following conditions: syncope ofcardiovascular etiology, ventricular arrhythmia of pathological origin (including,but not limited to, ventricular tachycardia and ventricular fibrillation), or suddencardiac arrest.

• Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 diarrhea of any etiologyscreening).

• Malignant spinal cord compression (ESCC2 or above)

• Prior radiation therapy to the current target site.