A Phase II Study of the Safety, Tolerability and Antitumor Activity of Tucatinib in Combination With Eribulin and Trastuzumab in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Cancer

Primary Outcome Measure:

• To assess the safety and tolerability of tucatinib in combination with eribulin and trastuzumab in patients with unresectable or recurrent metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, and trastuzumab deruxtecan.
• Evaluate the relative toxicity/tolerability of these therapeutic agents when used in combination in this patient cohort

Inclusion Criteria:

1. Histologically confirmed HER2+ breast carcinoma
2. Have received previous treatment with trastuzumab and a taxane in the metastatic setting or have recurred within 6 months of receiving a taxane in the adjuvant or neoadjuvant setting, or have a contraindication for their use.
3. Have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by site investigator), or be intolerant of last systemic therapy 
4. Have measurable or non-measurable disease assessable by RECIST 1.1 
5. Be at least 18 years of age at time of consent. 
6. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, 1 or 2 
7. Have a life expectancy of at least 6 months, in the opinion of the site investigator.
8. Have adequate hepatic function as defined by the following:
   1. Total bilirubin ≤1.5 X upper limit of normal (ULN)
   2. Transaminases ≤ 2.5 X ULN (≤ 5 X ULN if liver metastases are present)
9. Have adequate baseline hematologic parameters as defined by:
   1. Absolute neutrophil count (ANC) ≥ 1.5 x 103/µL
   2. Platelet count ≥ 100 x 103/µL
   3. Hemoglobin ≥ 9 g/dL
   4. In patients transfused before study entry, transfusion must be ≥ 14 days prior to start of therapy to establish adequate hematologic parameters independent from transfusion support
10. Have creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines. 
11. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT.
12. Have left ventricular ejection fraction (LVEF) ≥ 50%
13. If female of childbearing potential, must have a negative result of serum or urine pregnancy test performed within 7 days prior to first dose of study treatment. 
14. Women of childbearing potential and men with partners of childbearing potential must agree to use a highly effective birth control method, i.e., methods that achieve a failure rate of less than 1% per year when used consistently and correctly. Male patients with partners of childbearing potential must use barrier contraception.

CNS Inclusion - Based on screening contrast brain magnetic resonance imaging (MRI), patients must have one of the following:

1. No evidence of brain metastases
2. Untreated brain metastases not needing immediate local therapy
3. Previously treated brain metastases

Exclusion Criteria:

1. Have previously been treated with eribulin for metastatic disease
2. History of exposure to the following cumulative doses of anthracyclines:
   1. Doxorubicin > 360 mg/m2 b. Epirubicin > 720 mg/m2 c. Mitoxantrone > 120 mg/m2 d. Idarubicin > 90 mg/m2 e. Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) > 550 mg/m2 
3. History of allergic reactions to trastuzumab, eribulin, or compounds chemically or biologically similar to tucatinib, or known allergy to one of the excipients in the study drugs 
4. Have received treatment with any systemic anti-cancer therapy (including hormonal therapy), non-CNS radiation, or experimental agent ≤ 3 weeks of first dose of study treatment or are currently participating in another interventional clinical trial.
5. Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:
   1. alopecia and neuropathy, which must have resolved to ≤ Grade 2
   2. congestive heart failure (CHF), which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely.
   3. anemia, which must have resolved to ≤ Grade 2 
6. Have clinically significant cardiopulmonary disease
7. Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment.
8. Have chronic active Hepatitis B or Hepatitis C or have other known chronic liver disease
9. Are known to be positive for human immunodeficiency virus (HIV) 
10. Are pregnant, breastfeeding, or planning a pregnancy. 
11. Require therapy with warfarin or other coumarin derivatives
12. Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications.
13. Use of a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment
14. Unable for any reason to undergo contrast MRI of the brain. 
15. Have evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment.

CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:

1. Any untreated brain lesions > 2.0 cm in size
2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent).
3. 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).
4. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy

Other inclusion/exclusion criteria are present. Please contact the study team for a complete list.