A Study of Tucatinib (ONT-380) Combined With Capecitabine and/or Trastuzumab in Patients With HER2+ Metastatic Breast Cancer

Inclusion Criteria * Metastatic breast cancer, documented as HER2+ by fluorescence in situ hybridization (FISH) and/or 3+ staining by immunohistochemistry (IHC). * Progressive disease, with a history of prior treatment with both trastuzumab and T-DM1 (unless deemed intolerant to or ineligible for T-DM1 by the investigator) for metastatic disease. * If female and of child-bearing potential, has negative pregnancy test within 14 days prior to treatment. * If a sexually active male or a sexually active female of child-bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose of ONT-380, capecitabine, or trastuzumab, whichever is longest. * Must have target or non-target lesions as per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. * All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with the following exceptions: alopecia; neuropathy, which must have resolved to ≤ Grade 2; and congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence and must have resolved completely. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening. * In the opinion of the Investigator, life expectancy \> 6 months. * Adequate hematologic function as defined by: 1. Hemoglobin ≥ 9 g/dL 2. Absolute neutrophil count (ANC) ≥ 1000 cells/μL 3. Platelets ≥ 100,000/μL * Adequate hepatic function as defined by the following: 1. Total bilirubin ≤ 1.5 X upper limit of normal (ULN), unless a known history of Gilbert's disease 2. Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase \[AST/SGOT\] and alanine aminotransferase/serum glutamic pyruvic transaminase \[ALT/SGPT\]) ≤ 2.5 X ULN (\< 5 X ULN if liver metastases are present) * International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT. * Creatinine clearance ≥ 50 mL/min. * Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study drug. Exclusion Criteria * Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures. * Patient is breastfeeding. * Previous treatment with any experimental agent within 14 days or five half-lives of study treatment, whichever is greater. * Previous treatment with trastuzumab or other antibody-based therapy within three weeks of starting study treatment or with chemotherapy or hormonal cancer therapy within two weeks of starting study treatment. * Previous treatment with cumulative dose of doxorubicin \> 360 mg/m2 or previous treatment with another anthracycline with cumulative dose equivalent to \> 360 mg/m2 doxorubicin. * Previous treatment with: 1. Capecitabine for metastatic disease at any time, for patients assigned to cohorts using capecitabine plus ONT-380 (Combination 1) or capecitabine plus trastuzumab plus ONT-380 (Combination 3). However, patients who have previous treatment with capecitabine for metastatic disease are eligible for enrollment into cohorts using trastuzumab plus ONT-380 (Combination 2). Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible to enroll into all cohorts (Combination 1, 2, or 3). 2. Any small molecule HER2 inhibitors including (but not limited to) lapatinib, neratinib, or afatinib within the last 4 weeks prior to initiation of study therapy. * CNS disease: 1. Patients with leptomeningeal disease are excluded. 2. Dose escalation and expansion cohorts: Patients with symptomatic CNS metastases are excluded. Patients with treated CNS metastases or untreated asymptomatic CNS metastases not requiring immediate local therapy may be eligible. Enrollment of patients with metastases must be approved by the study medical monitor. 3. Optional CNS disease expansion cohorts: Patients with untreated asymptomatic CNS metastases not requiring immediate local therapy or patients with progressive CNS disease following local therapy may be eligible with medical monitor approval. * History of allergic reactions to compounds of similar chemical or biological composition to capecitabine (for patients assigned to Combination 1 or 3 only), trastuzumab (for patients assigned to Combination 2 or 3 only), or ONT-380, except for a history of Grade 1 or Grade 2 Infusion Related Reaction to trastuzumab, which has been successfully managed. * Patients with uncorrectable electrolyte abnormalities. * Known to be HIV positive. HIV testing is not required for those patients who are not known to be positive. * Known carrier of Hepatitis B and / or Hepatitis C (whether active disease or not). * Known liver disease, autoimmune hepatitis, or sclerosing cholangitis. * Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications. * Use of a strong CYP3A4 inhibitor or inducer within three elimination half-lives of the inhibitor or inducer prior to the start of study treatment. * Use of a strong CYP2C8 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment. (See Appendix F). * Radiotherapy within 14 days of first dose of ONT-380; patient must have recovered from acute effects of radiotherapy to baseline. * Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, congestive heart failure, and uncontrolled hypertension (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications). * Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug. * Patient with known dihydropyrimidine dehydrogenase deficiency (for patients assigned to Combination 1 or 3 only). * Patient requiring warfarin therapy with known history of difficulty in management of maintaining INR within therapeutic range. Patients on warfarin may be included if on a stable dose with a therapeutic INR.