Open-Label Umbrella Study To Evaluate Safety And Efficacy Of Elacestrant In Various Combination In Participants With Metastatic Breast Cancer

This is a multicenter, Phase 1b/2 trial in participants with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced/metastatic breast cancer. The phase 1b part of the trial will determine the recommended Phase 2 dose (RP2D) of elacestrant when administered in combination with alpelisib, everolimus, palbociclib, capivasertib, and ribociclib. The Phase 2 part of the trial will evaluate the efficacy and safety of the various combinations.

Inclusion Criteria: 1. Participant has signed the informed consent before all study specific activities are conducted. 2. Women or men aged ≥18 years (or the minimum age of consent in accordance with the local law), at the time of informed consent signature. Female participants may be of any menopausal status. * Postmenopausal status is defined as follows or in accordance with local regulations: 1. Age ≥60 years or 2. Age \ 1.5 x ULN, then creatinine clearance must be ≥50 milliliters/minute based on the Cockcroft-Gault formula. Note: C-G formula: * Creatinine clearance (male) = (\[140-age in years\] × weight in kilograms \[kg\])/ (\[serum creatinine in milligrams/deciliter (mg/dL)\] × 72) * Creatinine clearance (female) = (0.85 × \[140-age in years\] × weight in kg)/ (\[serum creatinine in mg/dL\] × 72) f. Serum albumin ≥3.0 g/dL (≥30 g/L) g. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN. If the participant has liver metastases, ALT and AST ≤ 5 × ULN h. Total serum bilirubin \140 mg/dL \[7.7 millimole (mmol)/L\], or glycosylated hemoglobin \[HbA1c\] level of \>6.4%). 3. Known intolerance to alpelisib or any of its excipients. 4. Participant is currently receiving or received drugs known to be a breast cancer resistant protein inhibitor (for example, curcumin, cyclosporine A, eltrombopag, febuxostat, fostamatinib, rolapitant, teriflunomide) within 14 days or 5 half-lives, whichever is shorter, prior to first dose of trial therapy (refer to Table 5.2 of https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers). 5. Participant has ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates or denosumab Additional Criteria for the Everolimus Combination (Phase 1b and Arm B): 1. Prior therapy with everolimus. 2. Known intolerance to everolimus or any of its excipients. Additional Criteria for the Abemaciclib Combination (Arm C): 1. Prior therapy with abemaciclib in the advanced or metastatic setting. Adjuvant therapy with abemaciclib is also exclusionary. 2. Known intolerance to abemaciclib or any of its excipients. 3. History of deep vein thrombosis or pulmonary embolism (unless on anticoagulation), cerebrovascular accident, or myocardial infarction, in the past 6 months. Participants on anticoagulation should have been on a stable dose for at least 3 months prior to enrollment. Additional Criteria for the Ribociclib Combination (Phase 1b and Arm C): 1. Prior therapy with ribociclib in the advanced or metastatic setting. Prior adjuvant therapy with ribociclib is also exclusionary. 2. Known intolerance to ribociclib or any of its excipients. 3. QTcF interval corrected by Fridericia formula (QTcF) values ≥450 milliseconds (msec). 4. Participants who already have or who are at significant risk of developing QTc prolongation, including participants with: * Long QT syndrome * Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias * Electrolyte abnormalities (K+, Ca++, Phos, Mg++) ≥Grade 1 5. Participant is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy. Additional Criteria for the Palbociclib Combination (Phase 1b): 1. Prior therapy with palbociclib in the advanced or metastatic setting. 2. Known intolerance to palbociclib or any of its excipients Additional Criteria for the Palbociclib Combination (Arm D): 1. Prior therapy with a CDK4/6i in the metastatic setting. 2. Known intolerance to palbociclib or any of its excipients. Additional Criteria for the Abemaciclib Combination (Arm D): 1. Prior therapy with any CDK4/6i. 2. Known intolerance to abemaciclib or any of its excipients. Additional Criteria for Ribociclib Combination (Arm D): 1. Prior therapy with a CDK4/6i in the advanced or metastatic setting. 2. Known intolerance to ribociclib or any of its excipients. 3. QTcF values ≥450 msec. 4. Participants who already have or who are at significant risk of developing QTc prolongation, including participants with: * Long QT syndrome * Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias * Electrolyte abnormalities (K+, Ca++, Phos, Mg++) ≥Grade 1 5. Participant is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy. Additional Criteria for Capivasertib Combination (Phase 1b and Arm E): Recruitment in this combination will occur only in countries where capivasertib is locally approved and available. 1. Prior treatment with any of the following: AKT, PI3K and mammalian target of rapamycin inhibitors and, for Arm E, fulvestrant. 2. Known intolerance to capivasertib or any of its excipients. 3. QTcF values ≥470 msec or factors that increase the risk of corrected QT interval (QTc) prolongation or risk of arrhythmic events such as heart failure, hypokalemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age, or any concomitant medication known to prolong the QT interval. 4. Clinically significant abnormalities of glucose metabolism as defined by any of the following: Participants with diabetes mellitus type 1; participants with diabetes mellitus type 2 requiring insulin treatment or participants with HbA1c level of \>8.0% (63.9 mmol/mol).