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

1. Lymphangitic carcinomatosis involving the lung.

2. History of Grade 3 or Grade 4 interstitial lung disease (ILD) on previous therapy.

3. Visceral crisis in need of cytotoxic chemotherapy as assessed by the investigator.

4. Prior progression of disease on abemaciclib, fulvestrant, or other selective estrogen receptor degrader (SERD) therapy.

5. Subjects with a known hypersensitivity to fulvestrant or to any of the excipients

6. Radiotherapy within 30 days prior to Visit 0 (Day 1) 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 Visit 0 (Day 1). Subjects must have recovered from radiotherapy toxicities prior to Visit 0 (Day 1).

7. Known RB1 mutations or deletions that in the opinion of the investigator confer resistance to CDK4/6i. (Screening for RB1 mutation is not required for entry.)

8. History of long QTc (Q-T interval corrected for heart rate) syndrome or a QTc of \>480 msec.

9. History of a pulmonary embolus (PE), deep vein thrombosis (DVT), or any known thrombophilia, unless the event occurred greater than 6 months prior to screening and the subject is treated with chronic anticoagulant therapy such as apixaban (Eliquis) or rivaroxaban (Xarelto).

10. Lasofoxifene is not recommended for use in subjects with conditions that place them at increased risk for VTEs (such as severe congestive heart failure \[CHF\] or prolonged immobilization).

11. On concomitant strong CYP3A4 inhibitors.

12. On strong and moderate CYP3A4 inducers.

13. Any significant co-morbidity that would impact the study or the subject's safety, including subjects with significant malabsorption.

14. Active systemic bacterial or fungal infection (requiring intravenous \[IV\] antibiotics or antifungals at the time of initiating study treatment).

15. Known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).

16. 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.

17. Positive serum pregnancy test (only if premenopausal).

18. Sexually active premenopausal women and men unwilling to use double-barrier contraception.

19. Women who are breast feeding

20. History of non-compliance to medical regimens.

21. Unwilling or unable to comply with the protocol.

22. Current participation in any clinical research trial involving an investigational drug or device within the last 30 days.

23. Subjects with a history of familial hypertriglyceridemia or fasting triglyceride levels \>880 mg/dL at screening.

24. Fasting triglyceride level \>300 mg/dL and ≤880 mg/dL at screening. Subjects may be retested and enrolled if they have a repeat fasting triglyceride level less than or equal to 300 mg/dL prior to enrollment (e.g., after adjustment with diet and/or treatment).

25. Fasting cholesterol level \>400 mg/dL at screening. Subjects may be retested and enrolled if they have a repeat fasting cholesterol level less than or equal to 400 mg/dL prior to enrollment (e.g., after adjustment with diet and/or treatment).

What this study is about