(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 (still having periods) women with ER+/HER2- breast cancer. This study includes a pharmacokinetic part (PK, how the drug works in your body) and a treatment part. The primary purpose of the study is to see how (Z)-endoxifen works on tumor cell growth by taking a biopsy after 4 weeks of treatment to measure Ki-67. Ki-67 is a cancer marker that indicates how well the treatments work to slow cancer cell growth. Overall, this study will help determine if (Z)-endoxifen can effectively treat premenopausal women with ER+/HER2- breast cancer without the need for monthly injections of goserelin which is a medication given to block the ovaries from making estrogen (also called ovarian suppression). Studies have shown harmful long-term effects of ovarian suppression in premenopausal women.The PK part of the study will be enrolled first, enrolling about 6 study participants who will all receive oral once daily (Z)-endoxifen treatment. This part of the study will help select the dose of (Z)-endoxifen to use in the treatment part by measuring the levels of (Z)-endoxifen in the blood stream and determine how long it takes for the body to remove it.About 160 study participants will be enrolled in the treatment part. The treatment part will help to determine how oral once daily (Z)-endoxifen, when taken by itself, compares to oral once daily exemestane (a medication that decreases the amount of estrogen in the body, also known as an aromatase inhibitor) and monthly injections of goserelin. Exemestane and goserelin taken together is a standard treatment regimen for premenopausal patients with ER+/HER2- breast cancer. Study participants are randomly assigned to treatment with an equal (50/50) chance to be assigned to (Z)-endoxifen or standard treatment.Study participation is up to 24 weeks of treatment followed by surgery.

Inclusion Criteria:Premenopausal women 18 years or olderNot lactating, pregnant, or planning to become pregnant in the next yearAgree to use one non-hormonal highly effective method of contraception for the entire duration of study participation. .ER+/HER2-: [ER] ≥ 67% or Allred Score 6-8) / HER2- (histologically confirmed) using American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelinesClinical Stage IIA or IIB invasive breast cancer (per American Joint Committee on Cancer [AJCC] 8th edition clinical staging)Nottingham Grade 1 or 2Largest tumor diameter > 2.0 cm either by imaging or clinical examinationECOG Performance Status (ECOG PS) of 0 to 2Exclusion Criteria:Inflammatory breast cancerPrior 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 entryUncontrolled intercurrent illness including, but not limited to:Ongoing or active infection requiring systemic treatment with strong inhibitors/inducers of CYP450 enzymes (including bacterial infection, fungal infection, or detectable viral infection).Symptomatic congestive heart failure, unstable angina pectoris, uncontrolled symptomatic cardiac arrhythmiasUncontrolled hypertension (defined as blood pressure > 160/90 mm Hg)Uncontrolled diabetes (Hemoglobin A1c [HbA1c] >50 mmol/mol)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 registrationKnown cataracts or retinopathyHistory of deep vein thrombosis (DVT)/pulmonary embolism (PE)Known activated protein C (APC) resistance, an inherited coagulation disorderCreatine clearance < 60 ml/hr by the Cockcroft-Gault equationTotal bilirubin ≥ 1.5 x upper limit of normal (ULN)Aspartate aminotransferase (AST) or alanine amino transferase (ALT) ≥ 2.5 x ULNPlatelet count (PLT) ≤ 75,000/mm3Hemoglobin (Hb) ≤ 10 g/dLHormonal therapies including birth control and hormone replacement therapy during the study or within 1 week of registrationAllergy to endoxifen, goserelin, or exemestane or any of their componentsParticipation in another investigational clinical trial ≤ 6 months of registration