Background: Docetaxel, carboplatin (C) and trastuzumab (H) yields substantial pathologic complete response (pCR) in operable HER2+ breast cancer (BC). Eribulin mesylate (E) is a tubulin inhibitor shown to improve overall survival in pretreated advanced BC. This Phase I trial was designed to determine the maximum tolerated dose (MTD) of ECH as neoadjuvant therapy in HER2+ BC with a planned follow-on Phase II component with pCR as the primary endpoint. Methods: This was a multicenter open-label single arm trial. Eligible patients (pts) had operable stage IIA – IIIB HER2+ BC, ECOG 0-1, normal LVEF, QTc < 480 msec, < grade 1 neuropathy and no history of invasive cancer within 3 years. Phase I planned up to 18 pts to 1 of 3 E dose cohorts, with pts treated at the MTD also evaluable for the Phase II extension. Starting dose of E was 1.1 mg/m² with escalation to dose level +1 at 1.4 mg/m². ECH was given IV for six 3-week cycles with E d1 and d8; C AUC 6 d1; and H 8mg/kg loading dose d1c1 and 6mg/kg d1c2-c6. C1 dose limiting toxicities (DLTs) were defined as: grade 4 thrombocytopenia (TP), anemia, or neutropenia (N) lasting > 5 days; any grade 3-4 non-hematologic toxicity attributable to E, C, H, or the combination; or inability to deliver all three agents at assigned dose and schedule during cycle 1. Standard 3+3 dose escalation design was used. Results: 5/6 patients at 1.1 mg/m² and 4/6 at 1.4 mg/m² completed 6 cycles of ECH. The MTD of ECH was not determined. At 1.1 mg/m² E, Grade 3/4 hematologic toxicity: anemia 4 pts, TP in 2 pts, and N 4 pts, and at 1.4 mg/m² E, anemia 1 pt, TP in 2 pts and N in 5 pts. 8 of 12 (67%) pts required PRBC transfusions (range 2-12 units) and 2 pts required platelet transfusions (range, 4-12 units). 11 of 12 (92%) pts required dose reduction of E. At surgery, 10 pts (83.3%) achieved partial response and 2 (16.7%) had pCR. Conclusions: In this Phase I study, the ECH regimen was associated with levels of hematologic toxicities and transfusion requirements not observed in other eribulin-carboplatin studies. This combination is not planned to undergo further Phase II development in the HER2+ neoadjuvant setting. Clinical trial information: NCT01388647.