A Multicenter, Open-label, Treatment Protocol of Tucatinib in Combination With Capecitabine and Trastuzumab in Patients With Previously Treated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma

Inclusion Criteria: * Have histologically confirmed HER2+ breast carcinoma, with HER2+ defined by ISH or FISH or IHC methodology * For patients WITHOUT presence or history of brain metastases, have received previous treatment with trastuzumab, pertuzumab, and T-DM1 * For patients WITH presence or history of brain metastases, have received previous treatment with trastuzumab * Have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by treating physician), or be intolerant of last systemic therapy * Have measurable disease or non-measurable disease assessable by standard of care imaging methods * Have ECOG PS 0 or 1 * Have a life expectancy of at least 6 months, in the opinion of the treating physician Exclusion Criteria: * Eligible for a tucatinib clinical trial * Disease recurrence within 3 months of last capecitabine for metastatic disease * History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or biologically similar to tucatinib, except for Grade 1 or 2 infusion related reactions to trastuzumab that were successfully managed, or known allergy to one of the excipients in the protocol drugs * Have received treatment with any systemic anti-cancer therapy (excluding hormonal therapy), non-CNS radiation, or experimental agent ≤ 3 weeks of first dose of protocol treatment or are currently participating in an interventional clinical trial. Have received hormonal therapies \<1 week of the first dose of protocol treatment. * Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions: * Alopecia and neuropathy, which must have resolved to ≤ Grade 2 * CHF, which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely * Anemia, which must have resolved to ≤ Grade 2 * Have clinically significant cardiopulmonary disease * Have known myocardial infarction or unstable angina within 6 months prior to first dose of protocol treatment * Are known carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease with uncontrolled disease * Are known to be positive for HIV with uncontrolled disease * Are pregnant, breastfeeding, or planning a pregnancy * Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed) * Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications * Have used strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a CYP2C8 or CYP3A4 inducer within 5 day prior to start of tucatinib treatment. * Have known dihydropyrimidine dehydrogenase deficiency * Have evidence within 2 years of the start of protocol treatment of another malignancy that required systemic treatment. CNS Exclusion - patients must not have any of the following: * Any untreated brain lesions \> 2.0 cm in size, unless discussed with medical monitor and approval for enrollment is given * Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \> 2 mg of dexamethasone (or equivalent). However, patients on a chronic stable dose of ≤ 2 mg total daily of dexamethasone (or equivalent) may be eligible with discussion and approval by the medical monitor * Any brain lesion thought to require immediate local therapy, including (but not limited to) a lesion in an anatomic site where increase in size or possible treatment-related edema may pose risk to patient (e.g. brain stem lesions). * Known or suspected LMD as documented by the treating physician * Have poorly controlled (\> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy