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

Inclusion Criteria:

1. Patient 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 patients 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).

4. Patient 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, patients must have at least one active and measurable brain metastasisper RECIST version 1.1.

• Any of the following qualifies brain metastases as active:

1. Newly diagnosed brain metastasis in patients 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 that are clearly progressing in an area that haspreviously been subjected to CNS-directed therapy.

• For lesions, including brain metastases, to qualify as measurable, and possiblybe selected as target lesions, per RECIST version 1.1 (Appendix C), the longestdiameter must be ≥10 mm by CT or 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. Patients 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. Any neurological symptoms of brain metastases must be stable for at least 2 weeksbefore starting trial therapy. Fluctuations of the previously known symptoms deemedto be due to clinical intercurrent processes (e.g., electrolytes alterations, fever)are admissible if fully resolved before the first dose of study drugs.

7. Patient prior therapy received in the metastatic setting includes:

• At least one endocrine therapy

• Up to two chemotherapy regimens

• Up to two prior CDK 4/6 inhibitors, not including abemaciclib Note 1: Toxicityfrom prior therapy must be resolved to National Cancer Institute (NCI) CTCAEversion 5.0 Grade ≤1, with the exception of alopecia and peripheral sensoryneuropathy (Grade ≤2).

8. Patient has documented intra- and/or extra-cranial radiological progression orrecurrence while on or after the most recent therapy.

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

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

11. Absolute neutrophil count (ANC) ≥1.5 × 109/L

12. Platelets ≥100 × 109/L

13. Hemoglobin ≥9.0 g/dL

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

15. Creatinine clearance (per Cockcroft-Gault formula) ≥50 mL/min

16. Serum albumin ≥3.0 g/dL (≥30 g/L)

17. Liver function tests:In absence of liver metastases, alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤3.0 × upper limit of normal (ULN). If the patient hasliver metastases, ALT and AST ≤5 × ULN.

18. Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndromewho may be included if the total serum bilirubin is ≤3.0 × ULN or directbilirubin ≤ 1.5 × ULN

19. The patient 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. Patient has imminent organ failure and/or visceral crisis.

3. Patient has leptomeningeal metastases, defined as having positive CSF cytology orunequivocal radiologic and clinical evidence of leptomeningeal involvement.

4. Breast cancer treatment-naïve patients in the advanced/metastatic setting.

5. 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.

6. Prior therapy with elacestrant or other investigational SERDs, or investigationalalike agents such as SERMs, SERCANs, CERANs, and PROTACs in the metastatic setting.

7. Patient has a concurrent malignancy or malignancy within 3 years of enrollment, withthe exception of adequately treated basal or squamous cell skin cancer, superficialbladder cancer, carcinoma in situ of the cervix, or second primary breast cancer.

8. Currently participating in another breast cancer intervention clinical study.Patients who are being followed for overall survival for another clinical trial withno therapy and study intervention are allowed after the washout period for any priortherapy.

9. 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 RANKL inhibitors initiated, or dose changed <1 month priorto first dose of study drug.

10. Radiation therapy (other than CNS directed) within 14 days before the first dose ofstudy drug. CNS directed radiation therapy within 28 days before the first dose ofstudy drug.

11. Uncontrolled significant active infections

• Patients with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infectionmust have undetectable viral load during screening

• Patients known to be HIV+ are allowed as long as they have undetectable viralload at baseline.

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

13. Inability to take oral medication, or history of malabsorption syndrome or any otheruncontrolled gastrointestinal condition.

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

15. Intrauterine device (non-hormonal)

16. Sexual abstinence

17. Bilateral tubal occlusion/ligation

18. Have a vasectomized partner with confirmed azoospermia.

19. Male patients (including males with a vasectomy) with a pregnant or non-pregnantfemale of childbearing potential partner who do not agree to use a highly effectivebarrier contraception method (condoms) within 28 days ofthe first dose of studytreatment until 120 days of the last dose of study treatment. And male patients whodo not agree to abstain from donating sperm within the same period. In addition,female partners of childbearing potential, of male patients (who has not undergonevasectomy) must use highly effective methods of contraception.

20. 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.

21. Known intolerance to either study drug or any of the excipients.

22. Patients currently receiving or received any of the following medications prior tofirst dose of trial therapy:

23. 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)

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

25. Vaccination, including but not limited to vaccination against COVID-19, duringthe 7 days prior to randomization.

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