The MTD/RP2D of tucatinib (ONT-380) to be used in combination with either capecitabine alone (Combination 1) or trastuzumab alone (Combination 2) will be determined prior to evaluating tucatinib (ONT-380) in combination with both capecitabine and trastuzumab (Combination 3). If Combination 1 and Combination 2 are found to be tolerable, then tucatinib (ONT-380) will be evaluated in Combination 3, using the lowest MTD/RP2D or other SMC-recommended dose of tucatinib (ONT-380) determined for either of the two drug combinations. This will be followed by enrollment of an expansion cohort of patients treated at the MTD/RP2D for Combination 3. Additional expansion cohorts for either Combination 1 (tucatinib (ONT-380) and capecitabine) or Combination 2 (tucatinib (ONT-380) and trastuzumab) may also be enrolled.