Alpelisib and Letrozole with or without Trastuzumab in Post-menopausal Patients with Hormone Receptor-Positive Metastatic Breast Cancer

Inclusion Criteria

• Patients must provide informed written consent
• Patients must be >= 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Clinical stage IV invasive mammary carcinoma, estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive by immunohistochemistry (IHC); patients with HER2 fluorescence in-situ hybridization (FISH) ratio < 2 (IHC 3+ is acceptable) will be enrolled in the ER+ / HER2-non-amplified cohort of patients; patients with HER2 FISH ratio >= 2 will be enrolled in the ER+ / HER2-amplified cohort of patients; patients may have either measurable or non-measurable disease, both are allowed
• A minimum of 10 patients in the trial (~50%) will need to have a PIK3CA mutation in their cancer
• Patients with ER and/or PR- positive/ HER2 non-amplified invasive mammary carcinoma must have had at least one line of endocrine therapy in the metastatic setting, or be diagnosed with metastatic breast cancer during or within 1 year of adjuvant endocrine therapy; there is no limit on lines of prior treatment in the metastatic setting
• Patients with ER and/or PR-positive/ HER2-amplified invasive mammary carcinoma must have had at least one line of HER2-targeted therapy in the metastatic setting, or be diagnosed with metastatic breast cancer during or within 1 year of adjuvant HER2-targeted therapy; there is no limit on lines of prior HER2-targeted treatments in the metastatic setting
• Patients must have available tissue (archived formalin-fixed paraffin embedded blocks [FFPB] or fresh frozen tissue from original diagnosis or metastatic setting) for correlative studies; tissue needs to be located and available at the time of registration (tissue needs to be submitted within 3 weeks of study initiation); patients will not be able to start study drugs without tissue availability
• Life expectancy >= 6 months
• Obtained within 2 weeks from study entry: Absolute neutrophil count (ANC) >= 1500/mm^3
• Obtained within 2 weeks from study entry: Platelet count >= 100,000/mm^3
• Obtained within 2 weeks from study entry: Hemoglobin (HgB) >= 9 g/dL
• Obtained within 2 weeks from study entry: Creatinine =< 1.5 X upper limits of normal
• Obtained within 2 weeks from study entry: International normalized ratio (INR) =< 2
• Obtained within 2 weeks from study entry: Fasting plasma glucose =< 140 mg/dL
• Obtained within 2 weeks from study entry: Hemoglobin A1c (HgBA1c) =< 8%
• Obtained within 2 weeks from study entry: Total bilirubin =< 1.5 x upper limit of normal (ULN) (patients with known Gilbert syndrome, a total bilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x ULN)
• Obtained within 2 weeks from study entry: Serum glutamic oxaloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) =< 3 x ULN if no liver metastasis present
• Obtained within 2 weeks from study entry: SGOT, SGPT =< 5 X ULN if liver metastasis present
• Patients must be able to swallow and retain oral medication
• Patients must be post-menopausal; post-menopausal female subjects should be defined prior to protocol enrollment by any of the following: * Subjects at least 55 years of age; OR * Subjects under 55 years of age and naturally (spontaneous) amenorrhea for at least 12 months or follicle-stimulating hormone (FSH) values >= 40 IU/L and estradiol levels =< 20 IU/L; OR * Prior bilateral oophorectomy; OR * Prior radiation castration with amenorrhea for at least 6 months * NOTE: Treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (such as goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression
• Patients must complete all screening assessments as outlined in the protocol

Exclusion Criteria

• Locally recurrent resectable breast cancer
• Any kind of malabsorption syndrome significantly affecting gastrointestinal function
• Patients with clinically manifest diabetes mellitus (treated and/or clinical signs or with fasting glucose >= 140 mg/dL / 7.8 mmol/L), history of gestational diabetes mellitus or documented steroid-induced diabetes mellitus
• Patients who have received radiation therapy =< 2 weeks prior to study entry; patients who have received prior radiotherapy must have recovered from toxicity (=< grade 1) induced by this treatment
• Patients who have received systemic anti-cancer therapy such as chemotherapy, or immunotherapy =< 4 weeks prior to study entry; concurrent anti-cancer therapy (chemotherapy, immunotherapy) other than the ones specified in the protocol is not permitted during study participation; patients must have discontinued the above cancer therapies for 4 weeks prior to the first dose of study medication, as well as recovered from toxicity (to =< than grade 1, except for alopecia) induced by previous treatments; any investigational drugs should be discontinued 4 weeks prior to the first dose of study medication.
• Prior hormonal/endocrine therapy =< 2 weeks prior to study entry (except for letrozole, which does not need to be interrupted); patients must have recovered from toxicity > grade 1, except for alopecia
• Prior HER2-targeted therapy < 3 weeks prior to study entry; patients must have recovered from toxicity > grade 1, except for alopecia
• Prior therapy with a PI3K inhibitor; prior use of Akt or mammalian target of rapamycin (mTOR) inhibitors are allowed
• Patients who have received herbal medications =< 2 weeks prior to study entry; herbal medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng
• Current use of any of the prohibited drugs
• Patients who are currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment
• Patients with a family history of congenital long QT syndrome
• Patients with abnormal calcium, potassium, or magnesium levels that is not or cannot be adequately corrected to =< grade 1 prior to initiation of study drugs
• Uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection requiring parenteral antibiotics * Impairment of lung function (chronic obstructive pulmonary disease [COPD] > grade 2, lung conditions requiring oxygen therapy) * Symptomatic congestive heart failure (class III or IV of the New York Heart Association classification for heart disease) * Known / previously documented left ventricular ejection fraction (LVEF) < 50% prior to trial enrollment * Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months * Uncontrolled hypertension within 2 weeks of study initiation (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg, found on two consecutive measurements separated by a 1 or 2-week period despite adequate medical support) * Clinically significant cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia that is symptomatic or requires treatment [National Cancer Institute -Common Terminology Criteria for Adverse Events, version 4.03, grade 3]) * QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 480 msec on screening electrocardiogram (EKG) * Known history of QT/corrected QT interval (QTc) prolongation or torsades de pointes (TdP) * ST depression or elevation of >= 1.5 mm in 2 or more leads * Diarrhea of any cause >= Common Terminology Criteria for Adverse Events (CTCAE) grade 2 * Psychiatric illness/social situations that would compromise patient safety or limit compliance with study requirements including maintenance of a compliance/pill diary * Patients with symptomatic brain metastases (patients with a history of brain metastases must be clinically stable for more than 4 weeks from completion of radiation treatment) * Patients with known history of chronic liver or renal failure * Patients with known history of chronic or acute pancreatitis