A Phase 1b/2, 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 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, 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

The total number of patients in Phase 2 for all treatment arm combinations will be 250 patients.

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 either postmenopausal, premenopausal, or perimenopausal.

   -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 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.
      • For perimenopausal women to be considered of non-childbearing potential, FSH levels must be >40 mIU/ml.
3. Histopathologically or cytologically 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.
4. At least one measurable lesion as per RECIST version 1.1 or a mainly lytic bone lesion. 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.
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 × 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
   5. Cockcroft-Gault based creatinine clearance ≥50 mL/min.

      Note:

      • 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.
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. Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, with the exception of basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy.
5. Uncontrolled significant active infections. • 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.

6. Documented pneumonitis/ILD prior to Cycle 1 Day 1.
7. Major surgery within 28 days before starting trial therapy.
8. 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.
9. Known intolerance to elacestrant or any of its excipients (see Table 18).
10. Females of childbearing potential 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 throughout the entire study period and for 28 days after trial therapy discontinuation
11. Men who do not agree to abstain from donating sperm, or to use a highly effective method of contraception, during the course of the treatment period and for 120 days thereafter.
12. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy:

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

    • 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/),
    • 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.
13. Evidence of ongoing alcohol or drug abuse as assessed by the investigator.

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

Inclusion:

1. PIK3CA mutation by local laboratory assessment.
2. One or two prior hormonal therapies in the 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 two prior hormonal therapies in the 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 two prior hormonal therapies in the metastatic setting, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with abemaciclib in the metastatic setting.
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 two prior hormonal therapies in the metastatic setting, one of which was in combination with a CDK4/6 inhibitor.

Exclusion:

1. Prior therapy with ribociclib in the metastatic setting.
2. Known intolerance to ribociclib or any of its excipients.
3. 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. None.

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 two prior hormonal therapies in the 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 two prior hormonal therapies in the metastatic setting.

Exclusion:

1. Prior therapy with a 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 two prior hormonal therapies in the metastatic setting.

Exclusion:

1. Prior therapy with a CDK4/6i in the metastatic setting.
2. Known intolerance to ribociclib or any of its excipients.
3. 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.