Background: Despite the considerable efficacy of trastuzumab, eventually all HER2-positive MBC patients develop resistance and disease progression. Upregulation of the PI3K pathway and oncogenic activating mutations of PIK3CA mutations have been implicated in trastuzumab resistance. Simultaneously targeting HER2 and PI3K pathways may allow for a more effective treatment option in this population. Methods: This investigator-initiated phase I, open-label, single arm study employs a dose-escalating 3+3 design to determine safety and efficacy of T-DM1 (an antibody-drug conjugate that incorporates the HER2-targeted properties of trastuzumab with a microtubule-inhibitory agent) in combination with an oral PI3K inhibitor BYL719 in patients with HER2-positive locally advanced or MBC whose disease has progressed on trastuzumab and taxane-based regimens in the metastatic setting or within 6 months in the adjuvant setting. Three to 6 patients are being enrolled in 3 successive cohorts with dose escalation of daily BYL719 (Cohort 1: 300 mg, Cohort 2: 350 mg, Cohort 3: 400 mg). T-DM1 is given at the FDA approved dose of 3.6 mg/kg every 3 weeks. At the maximum tolerated dose (MTD), an additional 10 patients will be enrolled to gain further knowledge on safety. The primary objectives are to determine safety, tolerability, feasibility, and MTD. The secondary objectives will evaluate pharmacokinetics of BYL719 and efficacy. Exploratory endpoints will examine alterations of the PIK3CA gene, decrease of PTEN expression and other Akt/mTOR downstream markers. This will be performed on archival metastatic tumor tissue or an optional baseline tissue biopsy and compared to optional tissue biopsy after 3 cycles of treatment. Clinical trial information: NCT02038010.