A Phase 1b/2, Open-Label Umbrella Study to Evaluate Safety and Efficacy of Elacestrant in Various Combinations in Patients with Metastatic Breast Cancer (ELEVATE)

• 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 alternative cause) and follicle stimulating hormone and estradiol in postmenopausal ranges per local reference ranges
3. Documentation of prior bilateral oophorectomy, at least 1 month before first dose of trial therapy).
• Pre-menopausal / peri-menopausal women and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist starting at least 3-4 weeks before the start of trial therapy and is planning to continue LHRH during the study.

• 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 membrane protein expression or an in situ hybridization negative result as defined in the 2013 or 2018 ASCO recommendations for HER-2 testing

• Any of the following qualifies brain metastases as active:
1. Newly diagnosed brain metastasis in participants who never received prior central nervous system (CNS)-directed therapy.
2. Newly diagnosed brain metastasis outside any area that was previously subjected to CNS-directed therapy.
3. Brain metastases demonstrating unequivocal progression in the opinion of the treating investigator in an area that has previously been subjected to CNS-directed therapy.
• For lesions, including brain metastases, to qualify as measurable, and possibly be selected as target lesions, per RECIST version 1.1, the longest diameter must be ≥10 millimeters [mm] by computed tomography [CT] or magnetic resonance imaging [MRI]).
• In Phase 1b, the presence of brain metastases is allowed but not required for eligibility, in this case, at least 1 measurable lesion outside the brain is required.

• At least one endocrine therapy
• Up to two chemotherapy regimens
• Up to two lines of prior cyclin-dependent kinase (CDK) 4/6 inhibitor, not including 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, vinca alkaloids, etc) and antibody drug conjugates (ADCs). Targeted therapies (for example, kinase inhibitors) are not considered chemotherapy for eligibility purposes. Not targeted cytotoxic agents administered for less than 1 cycle will not be counted as a prior chemotherapy regimen.

1. Absolute neutrophil count (ANC) ≥1.5 × 10^9/liter (L)
2. Platelets ≥100 × 10^9/L
3. Hemoglobin ≥9.0 grams (g)/deciliter (dL)
4. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE Grade ≤1 (if screening assessments are abnormal, these assessments may be repeated up to 2 times; participants may receive appropriate supplementation or treatment prior to reassessment)
5. Creatinine clearance (per Cockcroft-Gault formula) ≥50 mL/minute
6. Serum albumin ≥3.0 g/dL (≥30 g/L)
7. Liver function tests:

In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × upper limit of normal (ULN). If the participant has liver metastases, ALT and AST ≤5.0 × ULN.

8. Total serum bilirubin <1.5 × ULN except for participants with Gilbert's syndrome who may be included if the total serum bilirubin is ≤3.0 × ULN or direct bilirubin ≤ 1.5 × ULN

• 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 study drug
• 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 study drug according to institutional guidelines.

• Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection must have undetectable viral load (or detected below the lower limit of quantification) during screening
• Participants known to be human immunodeficiency virus positive (HIV+) are allowed as long as they have undetectable viral load (viral suppression) at baseline.

1. Intrauterine device (non-hormonal)
2. Sexual abstinence
3. Bilateral tubal occlusion/ligation
4. Have a vasectomized partner with confirmed azoospermia.

1. 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)
2. Herbal preparations/medications (which are not strong or moderate inducers or inhibitors of CYP3A4). These include, but are not limited to, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng within 7 days prior to initiating trial therapy
3. Vaccination, including but not limited to vaccination against coronavirus disease-19 (COVID-19), during the 7 days prior to randomization.