TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer

Inclusion Criteria

• Female or male ≥ 18 years of age.
• Newly diagnosed ER-positive, HER2-negative breast cancer. ER-positive is defined as ≥ 1% immunohistochemical (IHC) staining of any intensity. HER2 test result is negative if a single test (or both tests) performed show:
• IHC 1+ or 0
• In situ hybridization negative based on:
• Single-probe average HER2 copy number 7%). Patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in the study if all other inclusion criteria and none of the other exclusion criteria are met.
• History of any of the following within the last 6 months before administration of the first dose of the study drugs:
• Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
• Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
• Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, and ventricular tachycardia)
• Placement of a pacemaker for control of rhythm
• New York Heart Association Class III or IV heart failure
• Pulmonary embolism
• Significant active cardiovascular or pulmonary disease including:
• Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic blood pressure > 95 mm Hg). Use of antihypertensive agents to control hypertension before week 1, day 1 is allowed.
• Pulmonary hypertension
• Uncontrolled asthma or O2 saturation 480 milliseconds or history of congenital long QT syndrome or torsades de pointes)
• Treatment with strong inhibitors and/or inducers of CYP3A4, CYP2C9, or CYP2C19 within 7 days preceding the first dose of the study drugs.
• 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 the study drugs.
• 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 the study drugs.
• Patients unwilling or unable to comply with the study protocol.
• Patients previously treated with hormonal therapy (tamoxifen, AI) or PI3K, AKT, dual PI3K/mTOR, TORC1/2, or mTORC1 inhibitors.
• Patients who are currently being treated with cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) other than the trial therapy.
• Patients with hypersensitivity to mTOR inhibitors or tamoxifen.