Treatment Protocol of Tucatinib With Capecitabine and Trastuzumab in Patients With Unresectable Previously Treated HER2+ Breast Cancer

• 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