Study of Abemaciclib and Elacestrant in Participants With Brain Metastasis Due to ER+/HER-2- Breast Cancer

Inclusion Criteria:

1. Participant has the signed informed consent form before any study-related activitiesaccording to local guidelines.

2. Women or men aged ≥18 years, at the time of informed consent signature.

• Female participants may be either postmenopausal or pre/perimenopausal.Postmenopausal status is defined by:

1. Age ≥60 years
2. Age <60 years and amenorrhea for 12 or more months without an alternativecause) and follicle stimulating hormone and estradiol in postmenopausalranges per local reference ranges
3. Documentation of prior bilateral oophorectomy, at least 1 month beforefirst dose of trial therapy).

• Pre-menopausal / peri-menopausal women and men must be concurrently receiving aluteinizing hormone-releasing hormone (LHRH) agonist starting at least 3-4weeks before the start of trial therapy and is planning to continue LHRH duringthe study.

3. Participant must have ER-positive, HER-2 negative tumor status as confirmed by locallaboratory testing in the following manner:

• Documentation of ER positive tumor with ≥ 1% staining by immunohistochemistry (IHC) as defined in the 2010 or 2020 American Society for Clinical Oncology (ASCO) recommendations for ER testing, with or without progesterone receptor (PGR) positivity

• HER-2 negative tumor with an IHC result of 0 or 1+ for cellular membraneprotein expression or an in situ hybridization negative result as defined inthe 2013 or 2018 ASCO recommendations for HER-2 testing

4. In Phase 2, participants must have at least one active and measurable brainmetastasis per RECIST version 1.1.

• Any of the following qualifies brain metastases as active:

1. Newly diagnosed brain metastasis in participants who never received priorcentral nervous system (CNS)-directed therapy.
2. Newly diagnosed brain metastasis outside any area that was previouslysubjected to CNS-directed therapy.
3. Brain metastases demonstrating unequivocal progression in the opinion ofthe treating investigator in an area that has previously been subjected toCNS-directed therapy.

• For lesions, including brain metastases, to qualify as measurable, and possiblybe selected as target lesions, per RECIST version 1.1, the longest diametermust be ≥10 millimeters [mm] by computed tomography [CT] or magnetic resonanceimaging [MRI]).

• In Phase 1b, the presence of brain metastases is allowed but not required foreligibility, in this case, at least 1 measurable lesion outside the brain isrequired.

5. Participants receiving concomitant corticosteroids must be on a stable or decreasingdose for at least 7 days prior to baseline and not receiving doses higher than 4 mgof dexamethasone per day or equivalent.

6. Participants have experienced no more than one seizure within 4 weeks prior tostarting trial therapy.

7. Participants' prior therapy received in the metastatic setting includes:

• At least one endocrine therapy

• Up to two chemotherapy regimens

• Up to two lines of prior cyclin-dependent kinase (CDK) 4/6 inhibitor, notincluding abemaciclib Note 1: Toxicity from prior therapy must be resolved to NCI CTCAE version 5.0 Grade ≤1, with the exception of alopecia and peripheral sensory neuropathy (Grade ≤2). Note 2: Chemotherapy refers to not targeted cytotoxic agents (for example,alkylating agents, taxanes, nucleotide analogs, platinum-based drugs, vincaalkaloids, etc) and antibody drug conjugates (ADCs). Targeted therapies (forexample, kinase inhibitors) are not considered chemotherapy for eligibilitypurposes. Not targeted cytotoxic agents administered for less than 1 cycle will notbe counted as a prior chemotherapy regimen.

8. Participant has documented intracranial and/or extracranial radiological progressionor recurrence while on or after the most recent therapy.

9. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2

10. Participant has a life expectancy ≥ 12 weeks.

11. Participant has adequate bone marrow and organ function, as defined by the followinglaboratory values:

12. Absolute neutrophil count (ANC) ≥1.5 × 10^9/liter (L)

13. Platelets ≥100 × 10^9/L

14. Hemoglobin ≥9.0 grams (g)/deciliter (dL)

15. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAEGrade ≤1 (if screening assessments are abnormal, these assessments may berepeated up to 2 times; participants may receive appropriate supplementation ortreatment prior to reassessment)

16. Creatinine clearance (per Cockcroft-Gault formula) ≥50 mL/minute

17. Serum albumin ≥3.0 g/dL (≥30 g/L)

18. Liver function tests:In absence of liver metastases, alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤3.0 × upper limit of normal (ULN). If the participanthas liver metastases, ALT and AST ≤5.0 × ULN.

19. Total serum bilirubin <1.5 × ULN except for participants with Gilbert'ssyndrome who may be included if the total serum bilirubin is ≤3.0 × ULN ordirect bilirubin ≤ 1.5 × ULN

20. The participant is willing and able to adhere to the study visit schedule and otherprotocol requirements.

Exclusion Criteria:

1. Immediate CNS-specific treatment is likely to be required, per the treatingphysician's assessment.

2. Participant has imminent organ failure and/or visceral crisis.

3. Participant has leptomeningeal metastases, defined as having positive cerebrospinalfluid (CSF) cytology or unequivocal radiologic and clinical evidence ofleptomeningeal involvement. Note: Discrete dural metastases are permitted.

4. Breast cancer treatment-naïve participants (that is, not having received anysystemic therapy) in the advanced/metastatic setting.

5. History of pulmonary embolism (PE), cardiovascular accident (CVA), myocardialinfarction (MI) in the past 6 months from screening visit.

6. Prior therapy with abemaciclib in the metastatic setting. Note: Use of abemaciclibin the adjuvant setting is allowed if the last treatment administration was morethan 12 months prior to first recurrence.

7. Prior therapy with elacestrant or other investigational selective estrogen receptordegraders (SERDs), or investigational alike agents such as selective estrogenreceptor modulators (SERMs), selective estrogen receptor covalent antagonists (SERCANs), complete estrogen receptor antagonists (CERANs), and proteolysistargetingchimeras (PROTACs) in the metastatic setting.

8. Participant has a concurrent malignancy or malignancy within 3 years of enrollment,with the exception of adequately treated basal or squamous cell skin cancer,superficial bladder cancer, carcinoma in situ of the cervix, or second primarybreast cancer; and any other malignancy that is considered in complete remission bythe Investigator(s) that is approved by the Medical Monitor.

9. Currently participating in another breast cancer intervention clinical study.Participants who are being followed for overall survival for another clinical trialwith no therapy and study intervention are allowed after the washout period for anyprior therapy.

10. Prior anti-cancer or investigational drug treatment within the following windows:

• Fulvestrant treatment (last injection) <42 days before first dose of study drug

• Any other endocrine therapy <14 days before first dose of study drug. Note:LHRH agonists should not be counted as endocrine therapy.

• Chemotherapy or other anti-cancer therapy <14 days before first dose of studydrug

• Any investigational anti-cancer drug therapy within <28 days or <5 half lives,whichever is shorter

• Bisphosphonates or receptor activator of nuclear factor-κB ligand (RANKL)inhibitors initiated, or dose changed <1 month prior to first dose of studydrug according to institutional guidelines.

11. Radiation therapy (including CNS directed) within 7 days before the first dose ofstudy drug or without a full recovery from radiotherapy acute effects.

12. Uncontrolled significant active infections

• Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV)infection must have undetectable viral load (or detected below the lower limitof quantification) during screening

• Participants known to be human immunodeficiency virus positive (HIV+) areallowed as long as they have undetectable viral load (viral suppression) atbaseline.

13. Major surgery within 4 weeks of starting trial therapy.

14. Inability to take oral medication, or history of malabsorption syndrome or any otheruncontrolled gastrointestinal condition that may significantly alter the absorptionof study drugs.

15. Females of childbearing potential who do not agree to use a highly effectivenon-hormonal method of contraception and to abstain from donating ova within 28 daysof the first dose of study treatment through 120 days after the last dose of studytreatment. Highly effective non-hormonal method of contraception includes any of thefollowing:

16. Intrauterine device (non-hormonal)

17. Sexual abstinence

18. Bilateral tubal occlusion/ligation

19. Have a vasectomized partner with confirmed azoospermia.

20. Male participants (including males after a vasectomy) with a pregnant ornon-pregnant female of childbearing potential partner who do not agree to use ahighly effective barrier contraception method (condoms) within 28 days of the firstdose of study treatment until 120 days of the last dose of study treatment. And maleparticipants who do not agree to abstain from freezing or donating sperm within thesame period. In addition, female partners of childbearing potential, of maleparticipants (who has not undergone vasectomy) must use highly effective methods ofcontraception.

21. Females who are pregnant or breastfeeding. Females should not get pregnant duringstudy treatment and for 120 days after last dose of study treatment. Females shouldnot breastfeed during administration of elacestrant and for 1 week after receivingthe last dose.

22. Known intolerance to either study drug or any of their excipients.

23. Participants currently receiving or received any of the following medications priorto first dose of trial therapy:

24. Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 (including foods and herbal preparations) within 14 days or <5 half-lives,whichever is shorter)

25. Herbal preparations/medications (which are not strong or moderate inducers orinhibitors of CYP3A4). These include, but are not limited to, kava, ephedra (mahuang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto,and ginseng within 7 days prior to initiating trial therapy

26. Vaccination, including but not limited to vaccination against coronavirusdisease-19 (COVID-19), during the 7 days prior to randomization.

27. Any severe medical or psychiatric condition that in the opinion of theinvestigator(s) would preclude the participant's participation in a clinical study.