Sapanisertib and Letrozole in Treating Patients with Estrogen Receptor Positive and HER2 Negative Stage I-IV Breast Cancer

Inclusion Criteria

• Post-menopausal women with clinical stage I-IV, ER positive/HER2 negative, breast cancer that will be managed by surgical resection; the subject is post-menopausal if: * She has had a prior bilateral oophorectomy * Age is 60 or greater * Age is under 60 but she has had at least 12 months or amenorrhea and with both follicle-stimulating hormone and estradiol levels in the post-menopausal range; treatment with a luteinizing hormone-releasing hormone is not allowed for induction of ovarian suppression on this trial * Patients with metastatic disease at diagnosis are eligible if clinically appropriate; the patient must have had a baseline magnetic resonance imaging (MRI) performed as standard-of-care that can be used to calculate the distance(s) of the longest dimension(s) of the primary tumor(s)
• Histologic documentation of breast cancer by core needle or incisional biopsy
• Tumor size must be >= 2 cm in the longest dimension
• Patients must be at high risk for recurrence, which will be defined during the pre-treatment screening period as meeting one of the following criteria: * A histologically positive nodal deposit >= 0.2 mm * Histologic grade 3 * Peritumoral lymphatic vessel or vascular invasion * Oncotype Dx score of 25 or greater
• The invasive cancer must be HER2-low, defined as immunohistochemistry (IHC) 0-1+, or with a fluorescence in situ hybridization (FISH) ratio of < 1.8 if IHC is 2+ or if IHC has not been performed
• The invasive cancer must be estrogen receptor alpha (ER)-positive, defined as having ER staining by IHC in >= 10% of malignant tumor cells
• The subject must be deemed appropriate for neoadjuvant endocrine therapy by the referring medical oncologist
• The subject must agree to 4 months (120 days) of neoadjuvant treatment with TAK-228 and letrozole, have blood draws and urine samples obtained, have research tumor biopsies performed at baseline and after 10 days of TAK-228 treatment, and have a repeat MRI performed prior to surgery (MRI is part of routine clinical care)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Life expectancy of 12 months or longer
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelet count >= 100 x 10^9/L
• Hemoglobin >= 9 g/dL
• Total bilirubin =< 1.5 x upper limit of normal (ULN)
• Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) =< 2.5 x ULN
• Creatinine clearance >= 50 mL/min based either on Cockcroft-Gault estimate from serum creatinine or based on urine collection (12 or 24 hour)
• Fasting serum glucose (=< 130 mg/dL)
• Fasting triglycerides =< 300 mg/dL
• Ability to swallow oral medications and maintain an empty stomach state for two hours prior to the TAK-228 dose and for one hour following administration
• Ability to give informed consent

Exclusion Criteria

• Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of treatment according to this protocol
• Any other presurgical therapy for breast cancer
• Prior anti-estrogen therapy within the last 5 years
• Prior treatment with an mTOR, AKT, or PI3K inhibitor
• Treatment within the past two years with a bisphosphonate or a Rank ligand inhibitor
• Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, subjects with enteric stomata are also excluded
• Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%; subjects with a history of transient glucose intolerance due to corticosteroid administration are allowed in this study if all other inclusion/exclusion criteria are met
• History of any of the following within the last 6 months prior to study entry: * Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures * Ischemic cerebrovascular event, including transient ischemic attack (TIA) and artery revascularization procedures * Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) * Placement of a pacemaker for control of rhythm * New York Heart Association (NYHA) class III or IV heart failure * Pulmonary embolism
• Significant active cardiovascular or pulmonary disease at the time of study entry, including: * Uncontrolled high blood pressure (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg) * Pulmonary hypertension * Uncontrolled asthma or oxygen (O2) saturation < 90% by ABG (arterial blood gas) analysis or pulse oximetry on room air * Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement * Medically significant (symptomatic) bradycardia * History of arrhythmia requiring an implantable cardiac defibrillator * Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsade de pointes)
• Treatment with strong CYP3A4 and CYP2C19 inhibitors and/or inducers must be discontinued at least 1 week before administration of the first dose of study drug
• Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either intravenous [IV] or oral steroids, excluding inhalers) within 1 week before administration of the first dose of study drug (patients already receiving erythropoietin on a chronic basis for >= 4 weeks are eligible)
• Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the patient in the study
• Central nervous system (CNS) metastasis
• Known human immunodeficiency virus infection
• Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection
• Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug
• Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days before receiving the first dose of study drug