Tamoxifen and Alpelisib Compared to Fulvestrant and Zotatifin for the Treatment of Newly Diagnosed or Recurrent Estrogen Receptor Positive, HER2 Negative Breast Cancer

Inclusion Criteria

• PRE-SCREENING: Biopsy proven ER positive, HER2 negative breast cancer. ER positivity is defined as >= 1% cells staining positive by immunohistochemistry. HER2 negativity is defined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), per American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) 2018 guidelines. Breast tumor must be intact and tumor size must be >= 1 cm as measured by ultrasound, mammogram, magnetic resonance imaging (MRI), or clinical exam. If tumor is locally recurrent, it must be in the breast (not skin, node, or chest wall recurrence). In the pre screening phase, Ki67 may or may not have been done locally. If done locally, Ki67 score must be >= 5%. Any nodal status is allowed, as is M0 or M1 disease
• PRE-SCREENING: Women or men, age >= 18 years old
• PRE-SCREENING: Performance status 0 to 1 (by Eastern Cooperative Oncology Group [ECOG] scale)
• PRE-SCREENING: Ability to understand and the willingness to sign a written informed consent document
• COHORT I: Integrative subtype tumor classification as integrative subtype 1 (IC1) per Dr. Christina Curtis’s laboratory
• COHORT I: Breast tumor Ki67 score >= 10% as assessed by central laboratory
• COHORT I: Able to swallow and retain oral medication
• COHORT I: Absolute neutrophil count >= 1.5 x 10^9/L
• COHORT I: Platelets >= 100 x 10^9/L
• COHORT I: Hemoglobin >= 9.0 g/dL
• COHORT I: Calcium (corrected for serum albumin) within normal limits or =< 11.5 mg/dL and judged clinically not significant by the investigator
• COHORT I: Magnesium within normal limits or =< 3.0 mg/dL
• COHORT I: International normalized ratio (INR) =< 1.5
• COHORT I: Creatinine clearance >= 35 mL/min by Cockcroft Gault
• COHORT I: Total bilirubin < 2 x upper limit of normal (ULN) except for subjects with Gilbert’s syndrome who may only be included if the total bilirubin is =< 3.0 x ULN or direct bilirubin =< 1.5 x ULN
• COHORT I: Potassium within normal limits, or corrected with supplements
• COHORT I: Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 3 x ULN
• COHORT I: Fasting serum amylase =< 2 x ULN
• COHORT I: Fasting serum lipase =< ULN
• COHORT I: Fasting plasma glucose =< 140 mg/dL
• COHORT I: Hemoglobin A1c (HbA1c) =< 6.4%
• COHORT I: Women who are of childbearing potential must agree to placement of an intrauterine device while taking study drug and for 6 months following their last dose of study drug, with the following exceptions: sole male partner has undergone a vasectomy at least 6 months prior to screening; OR total abstinence from male partners is in line with the preferred and usual lifestyle of the subject, and they agree to continue total abstinence Women are not of childbearing potential if: * >= 60 years of age * Amenorrhea >= 24 months * Amenorrhea >= 12 months with serum estradiol < 20 pg/mL * Prior bilateral oophorectomy (with follow up serum estradiol < 20 pg/mL) and/or hysterectomy Sexually active men must agree to use a condom during intercourse while taking drug and for 6 months after the last dose of the study drug and should not father a child during this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug via seminal fluid
• COHORT II: Integrative subtype tumor classification as integrative subtype 2 (IC2) or as integrative subtype 6 (IC6) per Dr. Christina Curtis’s laboratory
• COHORT III: Integrative subtype tumor classification as Typical Risk per Dr. Christina Curtis’s laboratory
• COHORT II & III: Breast tumor Ki67 score >= 10% as assessed by central laboratory
• COHORT II & III: Absolute neutrophil count >= 1.5 x 10^9/L
• COHORT II & III: Platelets >= 100 x 10^9/L
• COHORT II & III: Hemoglobin >= 9.0 g/dL
• COHORT II & III: Serum alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) (during screening)
• COHORT II & III: Serum aspartate aminotransferase (AST) =< 3 x ULN (during screening)
• COHORT II & III: Serum bilirubin =< 1.5 x ULN (unless due to Gilbert’s syndrome or hemolysis, in which case =< 3 x ULN is permitted) (during screening)
• COHORT II & III: Measured or estimated creatinine clearance (eClCR) > 50 mL/min (eClCR to be calculated by the Cockcroft Gault formula) (during screening)
• COHORT II & III: Serum potassium within normal limits (WNL) (within 72 hours before the start of study therapy)
• COHORT II & III: Serum calcium (adjusted for serum albumin concentration) WNL (within 72 hours before the start of study therapy)
• COHORT II & III: Serum magnesium WNL (within 72 hours before the start of study therapy) * Note: Oral or IV supplementation or medical therapy may be used to achieve normal values for serum potassium, calcium, and magnesium. Patients with abnormal serum chemistry values may still be considered for the trial if there is adequate assessment and documentation from the Principal Investigator that the patient is asymptomatic, and the values are not clinically significant. Patients who show clinical signs and symptoms related to their abnormal serum chemistry values as well as patients whose serum chemistry values are asymptomatic but clinically significant (e.g., hypokalemia or hyponatremia) should be excluded
• COHORT II & III: Prothrombin time (PT) =< 1.5 × ULN (grade =< 1) * Note: Does not apply if patient is stable and on therapeutic doses of an approved anticoagulant for deep vein thrombosis (DVT) or pulmonary embolism (PE)
• COHORT II & III: Activated partial thromboplastin time =< 1.5 × ULN (grade =< 1)
• COHORT II & III: Creatine phosphokinase (CPK) =< 1.5 x ULN
• COHORT II & III: For female patients of childbearing potential, a negative serum pregnancy test within 7 days prior to start of study therapy
• COHORT II & III: For female patients of childbearing potential, documented willingness to use a protocol recommended method of contraception from the start of the screening period until >= 30 days after the final dose of study therapy * Note: A female patient is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle stimulating hormone [FSH] levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin [beta HCG]); or is menopausal (age >= 55 years with amenorrhea for >= 6 months)
• COHORT II & III: For male patients who can father a child and are having intercourse with females of childbearing potential who are not using adequate contraception, documented willingness to use a protocol recommended method of contraception from the start of study therapy until >= 30 days after the final dose of study therapy and to refrain from sperm donation from the start of study therapy until >= 90 days after administration of the final dose of study therapy * Note: A male patient is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy

Exclusion Criteria

• PRE-SCREENING: Pregnant or nursing (lactating)
• PRE-SCREENING: Prior breast cancer directed therapy (surgery, radiation, chemotherapy, or endocrine therapy to treat breast cancer) is not allowed, with the exception of people with in breast recurrences. People with in-breast recurrences cannot have had breast cancer directed therapy (radiation, chemotherapy, or endocrine therapy; surgery is acceptable) within the 6 months prior to signing the pre-screening consent. Previous endocrine therapy for breast cancer risk reduction is allowed
• COHORT I: Known hypersensitivity to alpelisib or tamoxifen, or to any of the excipients of alpelisib or tamoxifen
• COHORT I: Established diagnosis of diabetes mellitus type I. (Type II diabetes is allowed if adequately controlled based on fasting plasma glucose and HbA1c, as described in inclusion criteria.)
• COHORT I: Currently-documented pneumonitis or interstitial lung disease
• COHORT I: Cirrhosis of the liver with Child Pugh score B or C
• COHORT I: Clinically significant or uncontrolled heart disease and/or recent cardiac events, including any of the following: * History of angina pectoris, coronary artery bypass graft, symptomatic pericarditis, or myocardial infarction within 6 months prior to the start of study treatment * History of documented congestive heart failure ( New York Heart Association [NYHA] functional classification III-IV) * History of documented left ventricular ejection fraction < 50% based on multigated acquisition (MUGA) scan or echocardiogram * Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high grade atrioventricular [AV] block (e.g., bifascicular block, Mobitz type 2, and third degree AV block without pacemaker in place) * Uncontrolled hypertension defined by a systolic blood pressure >= 160 mmHg and/or diastolic blood pressure >= 100 mmHg, with or without anti hypertensive medication. Initiation or adjustment of antihypertensive medication(s) is allowed prior to screening * Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome Bradycardia (heart rate < 50 at rest) by electrocardiography (ECG) or pulse * On screening ECG (done in triplicate with mean value taken), inability to determine the Fredericia QT correction formula (QTcF) interval (i.e., unreadable or not interpretable), or QTcF > 450 msec for males or > 460 msec for females
• COHORT I: Currently receiving strong inducers of CYP3A4 or inhibitors of breast cancer resistance protein (BCRP) that cannot be discontinued 7 days prior to start of treatment
• COHORT I: History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatitis
• COHORT I: Unresolved osteonecrosis of the jaw
• COHORT I: History of Stevens Johnson Syndrome (SJS), erythema multiforme, or toxic epidermal necrolysis (TEN)
• COHORT I: Currently receiving or has received systemic corticosteroids =< 2 weeks prior to starting study drug. (The following uses of corticosteroids are permitted: single doses, topical applications [e.g., for rash], inhaled sprays [eg, for asthma or chronic obstructive pulmonary disease [COPD)], eye drops, and local injections [e.g., intra articular])
• COHORT I: Known history of human immunodeficiency virus (HIV) infection
• COHORT I: Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate subject participation in the clinical study (e.g., chronic active hepatitis [testing not mandatory unless required by local regulations or requirements], severe hepatic impairment, etc.)
• COHORT II & III: Significant cardiovascular disease (e.g., myocardial infarction, arterial thromboembolism, cerebrovascular thromboembolism) within 6 months prior to start of study therapy; symptomatic dysrhythmias or unstable dysrhythmias requiring medical therapy; unstable angina; symptomatic peripheral vascular disease; New York Heart Association class 3 or 4 congestive heart failure; uncontrolled grade >= 3 hypertension (diastolic blood pressure >= 100 mmHg or systolic blood pressure >= 160 mmHg) despite antihypertensive therapy; or history of congenital prolonged QT syndrome
• COHORT II & III: Significant screening ECG abnormalities, including unstable cardiac arrhythmia requiring medication, left bundle branch block, 2nd degree atrioventricular (AV) block type II, 3rd degree AV block, grade >= 2 bradycardia, or corrected QT (QTcF) > 450 msec (based on the average of 3 measurements at 5 minute intervals)
• COHORT II & III: Evidence of an ongoing systemic bacterial, fungal, or viral infection (including upper respiratory tract infections) at the time of start of study therapy * Note: Patients with localized fungal infections of skin or nails are eligible
• COHORT II & III: Known active hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome related illness * Note: Patients with treated and inactive HBV, HCV, or HIV may enroll, following discussion with the sponsor
• COHORT II & III: Major surgery within 4 weeks before the start of study therapy or not fully recovered from major surgery
• COHORT II & III: Prior solid organ transplantation
• COHORT II & III: Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids * Note: At screening, patients may be using systemic corticosteroids (at doses of =< 10 mg of prednisone or equivalent) or topical or inhaled corticosteroids. During study therapy, patients may use systemic, enteric, topical or enteric corticosteroids as required for treatment emergent conditions
• COHORT II & III: Use of a strong or moderate inhibitor or inducer of cytochrome P450 (CYP) 3A4 within 7 days prior to the start of study therapy or expected requirement for use of a strong or moderate inhibitor or inducer of CYP3A4 during study therapy
• COHORT II & III: Any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate subject participation in the clinical study (e.g., chronic active hepatitis [testing not mandatory unless required by local regulations or requirements], severe hepatic impairment, etc)