Sponsor decision to discontinue onapristone development.

This is a multicenter, Phase 1b-2 study of elacestrant in combination with onapristone in patients with advanced/metastatic ER+/PgR+/HER2- breast cancer.

This is a multicenter, phase 1b-2 trial. The phase 1b part of the trial is open label and aims to determine the recommended Phase 2 dose (RP2D) of onapristone and elacestrant when administered together. The Phase 2 part of the trial will evaluate the efficacy and safety of this combination in patients with ER+/PgR+/HER2- advanced/metastatic breast cancer after prior therapy with a CDK4/6 inhibitor.

Inclusion Criteria:

1. Women or men aged ≥18 years, at the time of informed consent signature. Note: Pre- and peri-menopausal women must receive goserelin for at least one month prior to initiating trial therapy, during the trial, and for at least one month after end of trial therapy. Men must receive triptorelin for at least one month prior to initiating trial therapy, during the trial and for at least one month after end of trial therapy.

2. Histopathologically or cytologically confirmed ER+, PgR+, 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). Note: In the context of this trial, ER and PgR status will be considered positive if ≥10% of tumor cells demonstrate positive nuclear staining by immunohistochemistry.

3. At least one measurable lesion as per RECIST version 1.1. Note: Patients with stable brain or subdural metastases are allowed if the patient has completed local therapy and has discontinued the use of corticosteroids for at least 4 weeks before starting treatment in this study. Any signs (e.g., radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment.

4. Prior therapy with an aromatase inhibitor or fulvestrant + a CDK4/6 inhibitor in the metastatic setting or in the adjuvant setting if within 12 months of last dose of adjuvant therapy. Note: Prior therapy with everolimus is allowed.

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. Breast cancer treatment-naïve patients in the metastatic setting.

3. Prior therapy with elacestrant, onapristone, or chemotherapy in the 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.

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

6. Major surgery within 4 weeks before starting trial therapy.

7. Inability to take oral medication, or history of malabsorption syndrome or any other uncontrolled gastrointestinal condition.

8. Females of childbearing potential who:

   1. Within 28 days before study entry, did not use a highly effective method of contraception.
   2. Do not agree to use a highly effective method of contraception throughout the entire study period and for 28 days after trial therapy discontinuation.

9. Males 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 28 days thereafter.

10. Known intolerance to either study drug or any of the excipients.

11. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy:

    1. 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/),
    2. 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.
    3. Investigational anti-cancer therapy with 21 days or 5 half-lives, whichever is shorter.
    4. Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization.

12. Evidence of ongoing alcohol or drug abuse.