Background: ONT-380 is a selective small molecule inhibitor of HER2 kinase with nanomolar potency. Unlike dual HER2/EGFR agents, it does not inhibit EGFR at clinically relevant concentrations, decreasing the potential for EGFR-related toxicities. In preclinical studies, ONT-380 demonstrated greater than additive activity with trastuzumab, and was active in models of CNS metastases. In a single-agent phase 1 study in 50 patients (pts) with metastatic HER2+ cancer, the MTD was 600 mg BID, with DLT consisting of reversible gr 3 ALT/AST in 2/4 pts at 800 mg. In 22 HER2+ breast cancer pts treated at doses ≥ 600 mg BID, the clinical benefit rate (partial response [n = 3] plus stable disease for at least 6 months [n = 3]) was 27%. Based on data supporting dual blockade of HER2, as well as preclinical activity of ONT-380 in the CNS, ONT-380 is now being evaluated in combination with capecitabine and trastuzumab. Methods: The study objectives are to determine the MTD/Phase 2 dose and preliminary anti-tumor activity of ONT-380 given with capecitabine alone, trastuzumab alone, and both capecitabine and trastuzumab in pts with and without CNS metastases. The study population includes adult pts with HER2+ MBC who have received trastuzumab and ado-trastuzumab emtansine (T-DM1) but not capecitabine for metastatic disease. A 3+3 design will evaluate up to three dose levels of ONT-380 (starting at 300 mg PO BID) given in combination with either capecitabine (1000 mg/mg² PO BID for 14 days of a 21-day cycle) or trastuzumab (8 mg/kg IV loading dose; 6 mg/kg IV once every 21 days). If both combinations are tolerable, ONT-380 will be evaluated with both capecitabine and trastuzumab. Expanded cohorts of pts with and without CNS metastases may be enrolled for either doublet or triplet combinations. Tumor response will be evaluated using RECIST 1.1. CNS response will be also evaluated by modified RECIST 1.1 and volumetric criteria. Potential biomarkers of response, including p95 HER2 and HER2 mutations, will be assessed in archived tumor biopsies. Treatment will continue until unacceptable toxicity, disease progression, or withdrawal of consent. Clinical trial information: NCT02025192.