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.