18 Years and up
Accepting Healthy Volunteers?
1. Postmenopausal women defined as:
1. ≥ 60 years of age with no vaginal bleeding over the prior year, or
2. <60 years with "premature menopause" or "premature ovarian failure" manifest
itself with secondary amenorrhea for at least 1 year and follicle stimulating
hormone (FSH) and estradiol levels in the postmenopausal range according to
institutional standards, or
3. surgical menopause with bilateral oophorectomy.
2. If possible, a biopsy of metastatic breast cancer tissue will be obtained to provide
histological or cytological confirmation of ER+/HER2− disease as assessed by a local
laboratory, according to ASCO/CAP guidelines, using slides, paraffin blocks, or
paraffin samples. If a biopsy is not possible, the ER and HER2 status from the tissue
obtained at the time of the original diagnosis must confirm that the subject is ER+
3. Locally advanced or metastatic breast cancer with radiological or clinical evidence of
progression on an AI in combination with a CDK 4/6 inhibitor for advanced breast
cancer with demonstrated prior sensitivity to endocrine therapy (recurrence or
progression after at least 12 months of treatment in the metastatic setting).
4. Locally advanced or metastatic breast cancer with either measurable (according to
RECIST 1.1) or non-measurable lesions.
5. At least one or more of the following point ESR1 mutations as assessed in cell-free
circulating tumor DNA (ctDNA) obtained from a blood (plasma) or tissue sample: Y537S,
Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. The
ctDNA sample collection must be obtained within 30 days prior to randomization to
determine eligibility and baseline. A pre-study assessment, however, may be used to
determine eligibility if done within 30 days prior to Screening but a screening sample
will be collected to confirm eligibility.
6. Received one chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to
entry into the trial but must be free of all chemotherapy toxicity before study entry.
7. ECOG performance score of 0 or 1.
8. Adequate organ function as shown by:
1. absolute neutrophil count (ANC) >/=1,500 cells/mm3
2. platelet count ≤100,000 cells/mm3
3. hemoglobin >/=9.0 g/dl
4. ALT and AST levels ≤2.5 upper limit of normal (ULN) or ≤5 in the presence of
5. total serum bilirubin ≤1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert
6. alkaline phosphatase level ≤ 2.5 X ULN
7. creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault
8. International normalized ratio (INR), activated partial thromboplastin (aPTT), or
partial thromboplastin time (PTT) <2.0 X ULN.
9. Able to swallow tablets.
10. Able to understand and voluntarily sign a written informed consent before any
1. Prior use of any SERM (eg, tamoxifen, raloxifene, ospemifene, droloxifene, toremifene,
bazedoxifene, endoxifen, etc.) in the adjuvant or metastatic setting except for
subjects who completed adjuvant tamoxifen treatment and relapsed at least 1 year after
stopping tamoxifen and were then given an AI in combination with a CDK 4/6 inhibitor.
Prior use of raloxifene for osteoporosis, ospemifene for vulvo- vaginal atrophy, or
conjugated estrogens/bazedoxifene for hot flashes is allowed as long as the medication
had been stopped at the time of the subject being diagnosed with breast cancer.
2. Prior use of everolimus or phosphoinositide 3-kinase inhibitor (PI3K) inhibitors.
3. Presence of brain metastasis.
4. Lymphangitic carcinomatosis involving the lung.
5. Impending visceral crisis in need of cytotoxic chemotherapy as assessed by the
6. Radiotherapy within 30 days prior to randomization except in case of localized
radiotherapy for analgesic purposes or for lytic lesions at risk of fracture, which
can then be completed within 7 days prior to randomization. Subjects must have
recovered from radiotherapy toxicities prior to randomization.
7. History of long QTC syndrome or a QTC of >480 ms.
8. History of a pulmonary embolus (PE) or deep vein thrombosis (DVT) within the last 6
months or any known thrombophilia. Subjects stable on anti-coagulants for maintenance
are eligible as long as the DVT and/or PE occurred >6 months prior to enrollment and
there is no evidence for active thrombosis. The use of low dose ASA is permitted.
9. Any significant co-morbidity that would impact the study or the subject's safety.
10. History of a positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) or
hepatitis C virus (HCV) at Screening.
11. History of malignancy within the past 5 years (excluding breast cancer), except basal
cell or squamous cell carcinoma of the skin curatively treated by surgery, or early
stage cervical cancer.
12. History of vaginal bleeding over the last year.
13. Uncontrolled hypertension defined as sitting systolic pressure >160 mm Hg or diastolic
pressure >100 mm Hg at Screening.
14. History of non-compliance to medical regimens.
15. Unwilling or unable to comply with the protocol.
16. Current participation in any clinical research trial involving an investigational drug
or device within the last 30 days.