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

Inclusion Criteria:

1. Patient has signed the informed consent before all study specific activities areconducted.

2. Women or men aged ≥18 years (or the minimum age of consent in accordance with thelocal law), at the time of informed consent signature. Female patients may be of anymenopausal status.

• Postmenopausal status is defined by:

1. Age ≥60 years
2. Age <60 years and amenorrhea for 12 or more months (in the absence ofchemotherapy, tamoxifen, toremifene, or ovarian suppression) or afollicle-stimulating hormone (FSH) value >40 mIU/mL and an estradiolvalue<40 pg/mL (140 pmol/L) or in postmenopausal ranges per localreference ranges
3. Documentation of prior surgical sterilization (i.e., bilateral tuballigation, total hysterectomy, or bilateral oophorectomy, at least 1 monthbefore first dose of trial therapy).

• Premenopausal and perimenopausal women (who do not fit postmenopausal criteria)and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist initiated at least 4 weeks before the start of trial therapy andare planning to continue LHRH agonist treatment during the study treatment.

• For perimenopausal women to be considered of non-childbearing potential, FSHlevels must be >40 mIU/ml.

3. Histopathological or cytological confirmed ER+, HER2-, breast cancer, per locallaboratory, as per the American Society of Clinical Oncology (ASCO)/College ofAmerican Pathologists(CAP) guidelines (Allison et al, 2020, Wolff et al, 2018).Note: In the context of this trial, ER status will be considered positive if ≥10% oftumor cells demonstrate positive nuclear staining by immunohistochemistry, with orwithout PGR positivity. .

4. At least 1 not previously irradiated measurable lesion as per RECIST version 1.1and/or at least 1 lytic or mixed (lytic +sclerotic) bone lesion with identifiablesoft tissue components meeting the definition of measurability by RECIST version 1.1that can be evaluated by CT or MRI; patients with sclerotic/osteoblastic bonelesions only in the absence of measurable disease are not eligible.

5. ECOG performance status of 0 or 1.

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

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

8. Platelets ≥100 × 10^9/L

9. Hemoglobin ≥9.0 g/dL

10. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAEgrade ≤1

11. Creatinine is ≤ 1.5 x ULN or if creatinine is > 1.5 x ULN, then creatinineclearance must be ≥50 mL/min based on the Cockcroft-Gault formula. Note: C-Gformula:

• Creatinine clearance (male) = ([140-age in years] × weight in kg)/ ([serumcreatinine in mg/dL] × 72)
• Creatinine clearance (female) = (0.85 × [140-age in years] × weight inkg)/ ([serum creatinine in mg/dL] × 72)

6. Serum albumin ≥3.0 g/dL (≥30 g/L)

7. In absence of liver metastases, alanine aminotransferase (ALT) and aspartateaminotransferase (AST) ≤ 3.0 × ULN. If the patient has liver metastases, ALTand AST ≤ 5 × ULN

8. 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.

Exclusion Criteria:

1. Active or newly diagnosed CNS metastases, including meningeal carcinomatosis. Note:Patients with stable brain or subdural metastases are allowed if the patient hascompleted local therapy and was on a stable or decreasing dose of corticosteroids atbaseline for management of brain metastasis for at least 4 weeks before startingtreatment in this study. The dose must be ≤2.0 mg/day of dexamethasone orequivalent. Any signs (e.g., radiologic) or symptoms of brain metastases must bestable for at least 4 weeks before starting study treatment.

2. Patients with advanced, symptomatic visceral spread, that are at risk oflife-threatening complications in the short term, including massive uncontrolledeffusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or liverinvolvement >50%.

3. Prior chemotherapy or elacestrant in the advanced/metastatic setting.

4. Patients with known germline BRCA mutation without prior treatment with a PARPinhibitor before study entry.

5. Prior therapy with elacestrant or other investigational selective estrogen receptordegraders (SERDs), or investigational alike agents such as selective estrogenreceptor modulators (SERM), selective estrogen receptor covalent antagonists (SERCANs), complete estrogen receptor antagonists (CERANs), andproteolysis-targeting chimeras (PROTACs), in the metastatic setting. Prior treatmentwith fulvestrant is not exclusionary as it is an approved medication.

6. Patient has a concurrent malignancy or history of invasive malignancy within 3 yearsof enrollment, except basal or squamous cell skin cancer, superficial bladdercancer, or carcinoma in situ of the cervix that has completed curative therapy.Other malignancies with low risk of recurrence may be considered eligible withSponsor approval.

7. Uncontrolled significant active infections. • Patients with HBV and/or HCV infectionmust have undetectable viral load during screening.

• Patients known to be HIV+ are allowed if they have undetectable viral load atbaseline.

8. Documented pneumonitis/ILD prior to Cycle 1 Day 1.

9. Major surgery within 28 days before starting trial therapy.

10. Inability to take oral medications, refractory or chronic nausea, gastrointestinalconditions (including significant gastric or bowel resection), history ofmalabsorption syndrome, or any other uncontrolled gastrointestinal condition thatimpact the absorption of the study drug.

11. Known intolerance to elacestrant or any of its excipients.

12. Pregnant and breast-feeding women are excluded from the study. In addition, women ofchildbearing potential are excluded who:

• Within 28 days before starting trial therapy, did not use a highly effectivemethod of contraception.

• Do not agree to use a highly effective method of contraception (Appendix F) orabstain from heterosexual intercourse throughout the entire study period and for 120days after trial therapy discontinuation.

13. Men or women who do not agree to abstain from donating sperm or ova, or to use ahighly effective method of contraception, during the course of the treatment periodand for 120 days after the last dose of study treatment.

14. Patient is currently receiving or received any of the following medications prior tofirst dose of trial therapy:

• Anti-cancer therapy within 14 days (28 days for anticancer antibody basedtreatment) or 5 half-lives, whichever is shorter. Please note: Toxicity from prior therapy must be resolved to NCI CTCAE version 5.0Grade ≤1, except alopecia and peripheral sensory neuropathy (Grade ≤2).

• Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4within 14 days or 5 half-lives, whichever is shorter, (refer tohttp://medicine.iupui.edu/clinpharm/ddis/ orhttps://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers).

• Herbal preparations/medications within 7 days. These include, but are not limitedto, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng.

• Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization.

15. Evidence of ongoing alcohol or drug abuse as assessed by the investigator.

16. Any severe medical or psychiatric condition that, in the Investigator's opinion,would preclude the patient's participation in a clinical study.

Additional Eligibility for the Alpelisib Combination (Phase 1b and Arm A)

Inclusion:

In general, the SmPC of the respective combination drug should be consulted for instructions/restrictions with respect to interactions with concomitant medications.

1. PIK3CA mutation by local laboratory assessment.

2. One or up to two prior hormonal therapies in the advanced or metastatic setting, oneof which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with alpelisib or any other PI3K inhibitor.

2. Type 1 diabetes or uncontrolled type 2 diabetes (fasting plasma glucose level of >140 mg/dL [7.7 mmol/L], or glycosylated hemoglobin [HbA1c] level of >6.4%).

3. Known intolerance to alpelisib or any of its excipients.

4. Patient is currently receiving or received drugs known to be a BCRP inhibitor within 14 days or 5 half-lives, whichever is shorter, prior to first dose of trial therapy

5. Patient has ongoing osteonecrosis of the jaw from previous or concurrent treatmentwith bisphosphonates or denosumab

Additional Eligibility for the Everolimus Combination (Phase 1b and Arm B)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, oneof which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with everolimus.

2. Known intolerance to everolimus or any of its excipients.

Additional Eligibility for the Abemaciclib Combination (Arm C)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, oneof which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with abemaciclib in the advanced or metastatic setting. Adjuvanttherapy with abemaciclib is exclusionary if the patient relapsed within the past 12months.

2. Known intolerance to abemaciclib or any of its excipients.

Additional Eligibility for the Ribociclib Combination (Phase 1b and Arm C)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, oneof which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with ribociclib in the metastatic setting. Prior adjuvant therapy withribociclib is also exclusionary if the patient relapsed within the past 12 months.

2. Known intolerance to ribociclib or any of its excipients.

3. QTcF values ≥450 msec.

4. Patients who already have or who are at significant risk of developing QTcprolongation, including patients with:

• Long QT syndrome

• Uncontrolled or significant cardiac disease including recent (6 months)myocardial infarction, congestive heart failure, unstable angina, andbrady-arrhythmias

• Electrolyte abnormalities

5. Patient 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 trialtherapy.

Additional Eligibility for the Palbociclib Combination (Phase 1b)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, oneof which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with palbociclib in the metastatic setting.

2. Known intolerance to palbociclib or any of its excipients

Additional Eligibility for the Palbociclib Combination (Arm D)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting.

Exclusion:

1. Prior therapy with a CDK4/6i in the metastatic setting.

2. Known intolerance to palbociclib or any of its excipients.

Additional Eligibility for the Abemaciclib Combination (Arm D)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting.

Exclusion:

1. Prior therapy with any CDK4/6i in the metastatic setting.

2. Known intolerance to abemaciclib or any of its excipients.

Additional Eligibility for Ribociclib Combination (Arm D)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting.

Exclusion:

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. Patients who already have or who are at significant risk of developing QTcprolongation, including patients with:

• Long QT syndrome

• Uncontrolled or significant cardiac disease including recent (6 months)myocardial infarction, congestive heart failure, unstable angina, andbrady-arrhythmias

• Electrolyte abnormalities

5. Patient 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 trialtherapy.