Key Eligibility:
For Registration Step 1: Screening & Treatment
Inclusion criteria
1. Histologically or cytologically confirmed adenocarcinoma of the breast with unresectable or metastatic disease
2. Either: a. measurable disease with or without non-measurable disease, OR b. non-measurable disease only, but with bone metastases
3. CT or MRI of chest and abdomen AND whole-body bone scan within 28 days prior to registration
4. X-rays, scans, or other tests for non-measurable disease within 42 days prior to registration
5. HER-negative breast cancer
6. Most recent biopsy or surgical specimen must be ER+ or PgR+ or both by IHC ≥ 1%
7. Females: post-menopausal OR on ovarian ablation with GnRH agonist beginning at least 14 days prior to Cycle 1, Day 1, for duration of study
8. Males: on GnRH agonist beginning at least 14 days prior to Cycle 1, Day 1, for duration of study
9. Age 18 years or older
10. PS of 0 or 1
11. Complete medical history and physical within 28 days prior to registration
12. Adequate organ and bone marrow function within 28 days prior to registration
13. Calculated creatinine clearance ≥ 50 mL/min per Cockcroft-Gault formula within 28 days prior to registration
14. If of reproductive potential (female or male), agrees to use effective contraceptive method
15. Agrees to have blood submitted for ctDNA molecular response assessment
Exclusion criteria
1. No active CNS disease or leptomeningeal disease
2. No endocrine resistance (no breast cancer recurrence within 12 months of end of adjuvant endocrine therapy or adjuvant CDK4/6 inhibitor)
3. No initiated or planned NSAI + palbociclib or ribociclib
4. No prior systemic therapy (including chemo or hormone tx) for mets
5. Not on hormone replacement therapy
6. No prior fulvestrant or PI3K/AKT inhibitor
7. No strong inhibitors or potent inducers or substrates of CYP3A4 or CYP2D6 within 14 days prior to registration (21 days for St. John’s Wort)
8. No herbal or natural products meant as treatment or prophylaxis for cancer (participants must agree not to use)
9. No radiotherapy within 14 days prior to Step 1 registration
10. No major surgical procedure (except for placement of vascular access) or significant traumatic injury within 28 days prior to Step 1 registration
11. No anticipated need for major surgery during study
12. No unresolved toxicities from prior therapy >CTCAE grade 1 (except alopecia, lymphocyte decrease, grade 2 lymphopenia, or grade 2 chemo-induced neuropathy)
13. No uncontrolled diabetes mellitus or risk for hyperglycemia within 28 days prior to registration
14. If history of HIV infection, on effective anti-retroviral therapy at registration, with undetectable viral load on most recent test. 2
15. If history of HCV infection, must have been treated and cured or, if being currently treated, have undetectable HCV viral load on most recent test
16. No acute hepatitis B
17. If history of chronic HBV infection, on most recent tests must have both: a. negative HBsAg result (unless positive due to recent vaccination) and b. HBV DNA viral load < lower limit of quantification
18. No GI function impairment or GI disease that may significantly alter absorption of study drugs
19. If history of CNS mets or cord compression, clinically stable for at least 28 days since completing definitive treatment, and no systemic steroids
20. No prior or concurrent malignancy whose natural history or treatment may interfere with safety or efficacy assessment of study regimen (per treating physician)
21. No clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, as confirmed by triplicate ECG within 28 days prior to registration (see
