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

This is a multicenter, Phase 1b/2 trial. The phase 1b part of the trial aims to determine the RP2D of elacestrant when administered in combination with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib. The Phase 2 part of the trial will evaluate the efficacy and safety of the various combinations in patients with ER+/HER2- advanced/metastatic breast cancer.

This is a multicenter, Phase 1b/2 trial. The Phase 1b aims at selecting the RP2D dose, defined as a dose that is associated with less than 33% of patients experiencing a DLT of elacestrant when administered in combination with alpelisib, everolimus, palbociclib, abemaciclib, and ribociclib, that is, ≤1 patient experiencing a DLT out of 6 DLT evaluable patients. For each combination, this phase will have between 1 and 3 cohorts of 6 DLT-evaluable patients each. The total number of DLT-evaluable patients in all the combinations will vary between 24 and 72.

The Phase 2 part of the trial will evaluate the efficacy and safety of the various combinations in patients with ER+/HER2- advanced/metastatic breast cancer.

The treatment arms will be:

* Arm A: 50 patients: elacestrant with alpelisib;
* Arm B: 50 patients: elacestrant with everolimus;
* Arm C: 60 patients (30 patients in each combination): elacestrant with either abemaciclib or ribociclib;
* Arm D: 90 patients (30 patients in each combination): elacestrant with either palbociclib, abemaciclib, or ribociclib
* Arm E: 60 patients: elacestrant with capivasertib

Phase 1b will have a total of 90 patients, while Phase 2 will have 310 patients for all treatment arm combinations.

Eligibility Criteria:
Inclusion Criteria:

1. Patient 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 patients may be of any menopausal status.

   * Postmenopausal status is defined by:

     1. Age ≥60 years
     2. Age \<60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) or a follicle-stimulating hormone (FSH) value \>40 mIU/mL and an estradiol value\<40 pg/mL (140 pmol/L) or in postmenopausal ranges per local reference ranges
     3. Documentation of prior surgical sterilization (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, at least 1 month before 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 and are planning to continue LHRH agonist treatment during the study treatment.
   * For perimenopausal women to be considered of non-childbearing potential, FSH levels must be \>40 mIU/ml.
3. Histopathological or cytological confirmed ER+, HER2-, breast cancer, per local laboratory, as per the American Society of Clinical Oncology (ASCO)/College of American 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% of tumor cells demonstrate positive nuclear staining by immunohistochemistry, with or without PGR positivity. .
4. At least 1 not previously irradiated measurable lesion as per RECIST version 1.1 and/or at least 1 lytic or mixed (lytic +sclerotic) bone lesion with identifiable soft tissue components meeting the definition of measurability by RECIST version 1.1 that can be evaluated by CT or MRI; patients with sclerotic/osteoblastic bone lesions 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 following laboratory values:

   1. Absolute neutrophil count (ANC) ≥1.5 × 10\^9/L
   2. Platelets ≥100 × 10\^9/L
   3. Hemoglobin ≥9.0 g/dL
   4. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE grade ≤1
   5. Creatinine is ≤ 1.5 x ULN or if creatinine is \> 1.5 x ULN, then creatinine clearance must be ≥50 mL/min based on the Cockcroft-Gault formula. Note: C-G formula:

      * Creatinine clearance (male) = (\[140-age in years\] × weight in kg)/ (\[serum creatinine in mg/dL\] × 72)
      * Creatinine clearance (female) = (0.85 × \[140-age in years\] × weight in kg)/ (\[serum creatinine in mg/dL\] × 72)
   6. Serum albumin ≥3.0 g/dL (≥30 g/L)
   7. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × 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.

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 has completed local therapy and was on a stable or decreasing dose of corticosteroids at baseline for management of brain metastasis for at least 4 weeks before starting treatment in this study. The dose must be ≤2.0 mg/day of dexamethasone or equivalent. Any signs (e.g., radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.
2. Patients with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term, including massive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or liver involvement \>50%.
3. Prior chemotherapy or elacestrant in the advanced/metastatic setting.
4. Patients with known germline BRCA mutation without prior treatment with a PARP inhibitor before study entry.
5. Prior therapy with elacestrant or other investigational selective estrogen receptor degraders (SERDs), or investigational alike agents such as selective estrogen receptor modulators (SERM), selective estrogen receptor covalent antagonists (SERCANs), complete estrogen receptor antagonists (CERANs), and proteolysis-targeting chimeras (PROTACs), in the metastatic setting. Prior treatment with fulvestrant is not exclusionary as it is an approved medication.
6. Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, except basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy. Other malignancies with low risk of recurrence may be considered eligible with Sponsor approval.
7. Uncontrolled significant active infections. • Patients with HBV and/or HCV infection must have undetectable viral load during screening.

   • Patients known to be HIV+ are allowed if they have undetectable viral load at baseline.
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, gastrointestinal conditions (including significant gastric or bowel resection), history of malabsorption syndrome, or any other uncontrolled gastrointestinal condition that impact 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 of childbearing potential are excluded who:

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

    • Do not agree to use a highly effective method of contraception (Appendix F) or abstain from heterosexual intercourse throughout the entire study period and for 120 days after trial therapy discontinuation.
13. Men or women who do not agree to abstain from donating sperm or ova, or to use a highly effective method of contraception, during the course of the treatment period and for 120 days after the last dose of study treatment.
14. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy:

    • Anti-cancer therapy within 14 days (28 days for anticancer antibody based treatment) or 5 half-lives, whichever is shorter.

    Please note: Toxicity from prior therapy must be resolved to NCI CTCAE version 5.0 Grade ≤1, except alopecia and peripheral sensory neuropathy (Grade ≤2).

    • Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 within 14 days or 5 half-lives, whichever is shorter, (refer to http://medicine.iupui.edu/clinpharm/ddis/ or https://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 limited to, 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, one of 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 treatment with 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, one of 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, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with abemaciclib in the advanced or metastatic setting. Adjuvant therapy with abemaciclib is exclusionary if the patient relapsed within the past 12 months.
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, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with ribociclib in the metastatic setting. Prior adjuvant therapy with ribociclib 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 QTc prolongation, including patients 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
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 trial therapy.

Additional Eligibility for the Palbociclib Combination (Phase 1b)

Inclusion:

1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of 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 QTc prolongation, including patients 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
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 trial therapy.