Background: Therapies directed at HER2 establish a successful treatment paradigm, but de novo and acquired resistance exist. Multiple large randomized clinical trials have demonstrated that dual HER2 targeted therapies are synergistic and result in improved efficacy. We hypothesize that dual targeted therapy with trastuzumab-emtansine and lapatinib will affect both PI3K and ERK1,2 MAPK pathways. This trial was designed to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of trastuzumab-emtansine (TE) and lapatinib (L), together with Nab paclitaxel (A). Methods: Eligible patients have stage IV HER2 positive breast cancer, normal LVEF, and Peripheral neuropathy < grade 2. Phase IB planned for up to 9 patients in a standard 3+3 dose de-escalation design. Starting dose level of TE 3.6mg/kg, Lapatinib 750mg and Abraxane(A) 80 mg/m2. DLTs were defined as ≥ grade 3 non hematological toxicity attributed to the study drugs. Currently, our lead cohort has three patients with manageable toxicities and we will start expansion cohort soon. The secondary endpoint includes the description of DLT and other toxicities, document anti-tumor activity as assessed by RECIST 1:1 criteria as well as plasma pharmacokinetics and pharmacodynamics of TE in combination of L and A as well as potential biomarkers of response including HER2 expression levels, PTEN, PI3K and others.