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 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 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).

• 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 patients 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 that are clearly progressing 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 (Appendix C), the longest diameter must be ≥10 mm by CT or 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 prior CDK 4/6 inhibitors, not including abemaciclib Note 1: Toxicity from prior therapy must be resolved to National Cancer Institute (NCI) CTCAE version 5.0 Grade ≤1, with the exception of alopecia and peripheral sensory neuropathy (Grade ≤2).

1. Absolute neutrophil count (ANC) ≥1.5 × 109/L
2. Platelets ≥100 × 109/L
3. Hemoglobin ≥9.0 g/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; subjects may receive appropriate supplementation or treatment prior to reassessment)
5. Creatinine clearance (per Cockcroft-Gault formula) ≥50 mL/min
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 patient has liver metastases, ALT and AST ≤5 × ULN.

8. Total serum bilirubin <1.5 × ULN except for patients 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 RANKL inhibitors initiated, or dose changed <1 month prior to first dose of study drug.

• Patients with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection must have undetectable viral load during screening
• Patients known to be HIV+ are allowed as long as they have undetectable viral load at baseline.

ion and to abstain from donating ova within 28 days of the first dose of study treatment through 120 days after the last dose of study treatment. Highly effective non-hormonal method of contraception includes any of the following:

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 COVID-19, during the 7 days prior to randomization.