(Z)-Endoxifen for the Treatment of Premenopausal Women With ER+/HER2- Breast Cancer

Inclusion Criteria:

1. Female sex assigned at birth

2. Age 18 years or older

3. Not lactating, pregnant, or planning to become pregnant in the next year and agreesto take adequate steps to prevent becoming pregnant beginning at informed consent,during treatment and for 9 months after last dose and agree to not breast feedduring treatment and for 3 months after last dose.

4. Must agree to use at least one non-hormonal highly effective method of contraceptionfor the entire duration of study participation beginning at informed consent. Highlyeffective methods of birth control are defined as those, alone or in combination,that resulted in a low failure rate of <1% per year when used consistently andcorrectly such as intrauterine devices (IUDs, non-hormonal such as copper IUD),bilateral tubal occlusion, sexual abstinence or vasectomized partner

5. Premenopausal defined as any female who:

6. is menstruating or

7. is not menstruating (last menstrual period > 3 months prior to registration)but has a plasma estradiol in the premenopausal range as assessed locally

8. Pathologic confirmation of strongly estrogen receptor positive (ER+) (defined asestrogen receptor [ER] ≥ 67% or Allred Score 6-8) by local institution protocol

9. Treatment Cohort Part 2a, Randomized Treatment Cohort: Local pathology laboratoryfinding of Ki-67 > 10% in invasive breast cancer specimen obtained at or afterdiagnosis but prior to any anti-tumor treatment

10. Treatment Cohort Part 2b, Single Arm Treatment Cohort: Local pathology laboratoryfinding of Ki- ≤ 10% in invasive breast cancer specimen obtained at or afterdiagnosis but prior to any anti-tumor treatment

11. Eastern Cooperative Oncology Group ECOG Performance Status (ECOG PS) of 0 to 2

12. Nottingham (Elston-Ellis) Grade 1 or 2

13. HER2- breast cancer (histologically confirmed) using American Society of ClinicalOncology (ASCO)/College of American Pathologists (CAP) guidelines

14. Clinical T2 or T3 invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging)

15. Clinical N0 or N1 invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging)

16. MRI ≤ 35 days of registration

17. Mammogram performed ≤ 90 days of registration (Treatment Cohort Parts 2a and 2bonly)

18. Must have given written informed consent before any study-related activities arecarried out and must be able to understand the full nature and purpose of the trial,including possible risks and adverse effects

19. Willing to provide blood and breast tissue samples for research purposes atspecified timepoints for the duration of their participation in the trial.

Exclusion Criteria:

1. Bilateral invasive breast cancer; Inflammatory breast cancer defined as clinicallysignificant erythema of the breast and/or documented dermal lymphatic invasion orbilateral invasive breast cancer (patients with pre-malignant disease or DCIS/LCISin contralateral breast are eligible)

2. Prior diagnosis or treatment for breast cancer, including carcinoma in situ, orhistory of any other active malignancy within the past 2 years prior to study entrywith the exception of:

3. Adequately treated in situ carcinoma of the cervix uteri

4. Adequately treated basal cell carcinoma or localized squamous cell carcinoma ofthe skin

5. Any other malignancy with a life expectancy of less than 2 years

6. Any uncontrolled intercurrent illness including, but not limited to:

7. Ongoing or active infection requiring systemic treatment with stronginhibitors/inducers of CYP450 enzymes (including bacterial infection, fungalinfection, or detectable viral infection).

8. Symptomatic congestive heart failure,

9. Unstable angina pectoris,

10. Uncontrolled symptomatic cardiac arrhythmias

11. Uncontrolled hypertension

12. Uncontrolled diabetes (Hemoglobin A1c [HbA1c] >7%)

13. Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstrationof a QTc interval > 470 milliseconds [msec]) using Fridericia's QT correctionformula seen ≤ 28 days of registration

14. Any of the following co-morbid conditions:

15. Known cataracts or retinopathy

16. History of deep vein thrombosis (DVT)/pulmonary embolism (PE)

17. Known activated protein C (APC) resistance, an inherited coagulation disorder

18. End stage kidney disease requiring dialysis

19. Evidence of the following laboratory abnormalities ≤ 28 days prior to registration:

20. Total bilirubin ≥ 1.5 x upper limit of normal (ULN)

21. Aspartate aminotransferase (AST) or alanine amino transferase (ALT) ≥ 2.5 x ULN

22. Platelet count (PLT) ≤ 75,000/mm3

23. Hemoglobin (Hb) ≤ 10 g/dL

24. Hormonal therapies including birth control and hormone replacement therapy, or prioruse of androgen-based therapy during the study or within 1 week of registration. Ifsubject has a prior medical history of Depo-Provera®, it is recommended that thelast dose of 3-month contraceptive agents are > 2.5 months from registration.

25. Allergy to endoxifen, goserelin, or exemestane or any of their components

26. Participation in another investigational clinical trial ≤ 6 months of registration

27. Known metastatic disease

28. History of polycystic ovarian syndrome (Treatment Cohort Part 2b ONLY)