Evaluation of Lasofoxifene Combined With Abemaciclib in Advanced or Metastatic ER+/HER2- Breast Cancer With an ESR1 Mutation

Inclusion Criteria

• •1. Pre- or postmenopausal.
• •Postmenopausal women are 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. Note: Premenopausal women who meet all of the other entry criteria must be maintained on ovarian suppression (such as Lupron) during the study and subjects counseled to use appropriate contraception to prevent pregnancy.
• •2. If possible, a biopsy of metastatic breast cancer tissue should be obtained to provide histological or cytological confirmation of ER+/HER2- disease as assessed by a local laboratory, according to American Society of Clinical Oncology/College of American Pathologists 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+ and HER2-.
• •3. Locally advanced and/or metastatic breast cancer with radiological or clinical evidence of progression on the first or 2nd lines of hormonal therapy for metastatic disease. Progression may have occurred on no more than 2 of the following endocrine treatments for metastatic breast cancer: an aromatase inhibitor (AI) and/or fulvestrant either as monotherapy or in combination with any commercially approved CDKi; and/or the combination of fulvestrant and everolimus; and/or the combination of fulvestrant and alpelisib; and/or tamoxifen; and/or the combination of exemestane/everolimus. (Note: before starting study treatment, subjects should have stopped any CDKi for at least 21 days)
• •4. Subjects must have had no evidence of progression for at least 6 months during their first hormonal treatment for advanced breast cancer.
• •5. At least one or more of the following ESR1 point mutations as assessed in cell-free circulating tumor DNA (ctDNA) obtained from a blood or tissue sample: Y537S, Y537C, D538G, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, or Y537N. Note: the Sponsor's blood ctDNA assay must be used but tissue sequencing (if done) may be done by a validated commercial laboratory.
• •Note: A positive ESR1 mutation in tissue or ctDNA using a validated commercial assay if done prior or at the time of disease progression is acceptable to meet this entry criteria. However, blood for ctDNA must still be obtained for genomic analyses using the sponsor's ctDNA assay.
• •6. Locally advanced or metastatic breast cancer with either measurable (according to RECIST 1.1) or non-measurable lesions.
• •7. Subjects may have received one cytotoxic chemotherapy regimen for metastatic disease as well as those who received one cytotoxic chemotherapy regimen in the neo-adjuvant or adjuvant setting prior to entry into the trial can be enrolled but must be free of all chemotherapy acute toxicity excluding alopecia and Grade 2 peripheral neuropathy before study entry. A washout period of at least 21 days is required between last chemotherapy dose and entry into the study.
• •8. Stable breast cancer metastasis to the brain is allowed as long as the subject has received radiotherapy and not demonstrated any evidence of brain metastasis progression for at least 3 months after the completion of radiotherapy.
• •9. ECOG performance score of 0 or 1.
• •10. Adequate organ function as shown by:
• •1. absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
• •2. platelet count ≥ 100,000 cells/mm3
• •3. hemoglobin ≥ 8.0 g/dl
• •4. ALT and AST levels ≤ 3 upper limit of normal (ULN) or ≤ 5 in the presence of liver metastasis
• •5. total serum bilirubin ≤ 1.5 X ULN (≤ 3 X ULN for subjects known to have Gilbert Syndrome)
• •6. alkaline phosphatase level ≤ 3 ULN
• •7. creatinine clearance of 40 ml/min or greater as calculated by the Cockcroft-Gault formula
• •8. International normalized ratio (INR) and activated partial thromboplastin (aPTT) \< 2.0 X ULN
• •11. Able to swallow tablets.
• •12. Able to understand and voluntarily sign a written informed consent before any screening procedures.