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

This open-label research study is studying (Z)-endoxifen as a possible treatment for pre-menopausal women with ER+/HER2- breast cancer. (Z)-endoxifen belongs to a group of drugs called selective estrogen receptor modulators or "SERM", which help block estrogen from attaching to cancer cells. This study has two parts: a pharmacokinetic part and a treatment part.

The PK part (how the body processes the drug) will enroll about 18 participants. All participants will take (Z)-endoxifen capsules daily. Twelve participants will be randomly assigned (50/50 chance) to take (Z)-endoxifen alone or (Z)-endoxifen with a monthly injection of goserelin a drug that temporarily stops the ovaries from making estrogen. This part will help determine the best dose of (Z)-endoxifen by measuring the drug levels in the blood and how long the body takes to remove it.

The treatment part has two parts:

* Part 2a will enroll 162 participants whose tumors have a high level of cell proliferation as indicated by the presence of a biomarker called Ki-67 (greater than 10%). Participants will be randomly assigned to one of two groups (50/50 chance):

  1. a group receiving (Z)-endoxifen daily with a monthly injection of goserelin
  2. a group receiving the current standard treatment of exemestane (an aromatase inhibitor that lowers estrogen) with a monthly injection of goserelin.
* The Part 2b will enroll about 30 participants whose tumors have low Ki-67 levels (10% or less). These participants will take daily (Z)-endoxifen alone without goserelin.

A key goal of the study is to see if (Z)-endoxifen can slow down or stop tumor growth as measured by a reduction in Ki-67 levels. Tumor tissue samples will be taken by breast biopsy after about 4 weeks of treatment to check levels of this biomarker. If the tumor shows signs of response, participants can continue treatment for up to 24 weeks or until they have surgery.

Study participation is up to 6 months (24 weeks of treatment) followed by surgery and a one-month follow up visit.


Eligibility Criteria:
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 agrees to 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 feed during treatment and for 3 months after last dose.
4. Must agree to use at least one non-hormonal highly effective method of contraception for the entire duration of study participation beginning at informed consent. Highly effective 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 and correctly 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:

   1. is menstruating or
   2. is not menstruating (last menstrual period \> 3 months prior to registration) but has a plasma estradiol in the premenopausal range as assessed locally
6. Pathologic confirmation of strongly estrogen receptor positive (ER+) (defined as estrogen receptor \[ER\] ≥ 67% or Allred Score 6-8) by local institution protocol
7. Treatment Cohort Part 2a, Randomized Treatment Cohort: Local pathology laboratory finding of Ki-67 \> 10% in invasive breast cancer specimen obtained at or after diagnosis but prior to any anti-tumor treatment
8. Treatment Cohort Part 2b, Single Arm Treatment Cohort: Local pathology laboratory finding of Ki- ≤ 10% in invasive breast cancer specimen obtained at or after diagnosis but prior to any anti-tumor treatment
9. Eastern Cooperative Oncology Group ECOG Performance Status (ECOG PS) of 0 to 2
10. Nottingham (Elston-Ellis) Grade 1 or 2
11. HER2- breast cancer (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
12. Clinical T2 or T3 invasive breast cancer (per American Joint Committee on Cancer \[AJCC\] 8th edition clinical staging)
13. Clinical N0 or N1 invasive breast cancer (per American Joint Committee on Cancer \[AJCC\] 8th edition clinical staging)
14. MRI ≤ 35 days of registration
15. Mammogram performed ≤ 90 days of registration (Treatment Cohort Parts 2a and 2b only)
16. Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects
17. Willing to provide blood and breast tissue samples for research purposes at specified timepoints for the duration of their participation in the trial.

Exclusion Criteria:

1. Bilateral invasive breast cancer; Inflammatory breast cancer defined as clinically significant erythema of the breast and/or documented dermal lymphatic invasion or bilateral invasive breast cancer (patients with pre-malignant disease or DCIS/LCIS in contralateral breast are eligible)
2. Prior diagnosis or treatment for breast cancer, including carcinoma in situ, or history of any other active malignancy within the past 2 years prior to study entry with the exception of:

   1. Adequately treated in situ carcinoma of the cervix uteri
   2. Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
   3. Any other malignancy with a life expectancy of less than 2 years
3. Any uncontrolled intercurrent illness including, but not limited to:

   1. Ongoing or active infection requiring systemic treatment with strong inhibitors/inducers of CYP450 enzymes (including bacterial infection, fungal infection, or detectable viral infection).
   2. Symptomatic congestive heart failure,
   3. Unstable angina pectoris,
   4. Uncontrolled symptomatic cardiac arrhythmias
   5. Uncontrolled hypertension
   6. Uncontrolled diabetes (Hemoglobin A1c \[HbA1c\] \>7%)
   7. Marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \> 470 milliseconds \[msec\]) using Fridericia's QT correction formula seen ≤ 28 days of registration
4. Any of the following co-morbid conditions:

   1. Known cataracts or retinopathy
   2. History of deep vein thrombosis (DVT)/pulmonary embolism (PE)
   3. Known activated protein C (APC) resistance, an inherited coagulation disorder
   4. End stage kidney disease requiring dialysis
5. Evidence of the following laboratory abnormalities ≤ 28 days prior to registration:

   1. Total bilirubin ≥ 1.5 x upper limit of normal (ULN)
   2. Aspartate aminotransferase (AST) or alanine amino transferase (ALT) ≥ 2.5 x ULN
   3. Platelet count (PLT) ≤ 75,000/mm3
   4. Hemoglobin (Hb) ≤ 10 g/dL
6. Hormonal therapies including birth control and hormone replacement therapy, or prior use of androgen-based therapy during the study or within 1 week of registration. If subject has a prior medical history of Depo-Provera®, it is recommended that the last dose of 3-month contraceptive agents are \> 2.5 months from registration.
7. Allergy to endoxifen, goserelin, or exemestane or any of their components
8. Participation in another investigational clinical trial ≤ 6 months of registration
9. Known metastatic disease
10. History of polycystic ovarian syndrome (Treatment Cohort Part 2b ONLY)