Tucatinib+Trastuzumab+Eribulin in HER2+ MBC

Inclusion Criteria:

1. Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situhybridization (ISH) or fluorescence in situ hybridization (FISH) orimmunohistochemistry (IHC)

2. Have received previous treatment with trastuzumab, a taxane and trastuzumabderuxtecan in the metastatic setting or have recurred within 6 months of receivingthese treatments in the adjuvant or neoadjuvant setting. Prior capecitabine andT-DM1 is not required. Prior tucatinib therapy is allowed. Patients for whomTrastuzumab is contraindicated are not permitted. Have progression of unresectablelocally advanced or metastatic breast cancer after last systemic therapy (asconfirmed by site investigator),or be intolerant of last systemic therapy.

3. Have measurable or non-measurable disease assessable by RECIST 1.1

4. Be at least 18 years of age at time of consent.

5. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0,1 or 2

6. Have a life expectancy of at least 6 months, in the opinion of the siteinvestigator.

7. Have adequate hepatic function as defined by the following:

8. Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients withknown Gilbert's disease, who may enroll if the conjugated bilirubin is ≤1.5 XULN

9. Transaminases [aspartate aminotransferase/serum glutamic oxaloacetictransaminase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvictransaminase (ALT/SGPT)] ≤ 2.5 X ULN (≤ 5 X ULN if liver metastases arepresent)

10. Have adequate baseline hematologic parameters as defined by:

11. Absolute neutrophil count (ANC) ≥ 1.5 x 103/µL

12. Platelet count ≥ 100 x 103/µL; patients with stable platelet count from 75- 100x 103/µL may be included with approval from medical monitor,

13. Hemoglobin ≥ 9 g/dL

14. In patients transfused before study entry, transfusion must be ≥ 14 days priorto start of therapy to establish adequate hematologic parameters independentfrom transfusion support,

15. Have creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines or,in patients ≤ 45 kg in weight, a serum creatinine within institutional normallimits,

16. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN unless on medication known to alter INR and aPTT. (Note: Warfarinand other coumarin derivatives are prohibited.)

17. Have left ventricular ejection fraction (LVEF) ≥ 50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior tofirst dose of study treatment.

18. If female of childbearing potential, must have a negative result of serum or urinepregnancy test performed within 7 days prior to first dose of study treatment. Awoman is considered of childbearing potential, i.e. fertile, following menarche anduntil becoming post- menopausal unless permanently sterile. Permanent sterilizationmethods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Apostmenopausal state is defined as no menses for 12 months without an alternativemedical cause. NOTE: Postmenopausal patients with known β-HCG secreting tumors may be eligible when β-HCG-based urine or serum pregnancy tests yield false positive if they meet thedefinition of postmenopausal state and have a negative uterine ultrasound

19. Women of childbearing potential (as defined above) and men with partners ofchildbearing 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 usedconsistently and correctly. Such methods include: combined (estrogen and progestogencontaining) hormonal contraception associated with inhibition of ovulation (oral,intravaginal, or transdermal); progestogen- only hormonal contraception associatedwith inhibition of ovulation (oral, injectable, or implantable); intrauterinedevice; intrauterine hormone-releasing system; bilateral tubal occlusion/ligation;vasectomized partner; or sexual abstinence. Male patients with partners ofchildbearing potential must use barrier contraception. All study patients shouldpractice effective contraception, as described above, starting from the signing ofinformed consent until 7 months after the last dose of study medication orinvestigational medicinal product.

20. Patient must provide signed informed consent per a consent document that has beenapproved by an institutional review board or independent ethics committee (IRB/IEC)prior to initiation of any study-related tests or procedures that are not part ofstandard-of-care for the patient's disease.

21. Patients must be willing and able to comply with study procedures.

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. For patients withuntreated CNS lesions > 2.0 cm on screening contrast brain MRI, discussion with andapproval from the medical monitor is required prior to enrollment,

3. Previously treated brain metastases a. Brain metastases previously treated withlocal therapy may either be stable since treatment or may have progressed sinceprior local CNS therapy, provided that there is no clinical indication for immediatere-treatment with local therapy in the opinion of the site investigator, b. Patientstreated with CNS local therapy for newly identified lesions found on contrast brainMRI performed during screening for this study may be eligible to enroll if all ofthe following criteria are met: i. Time since whole brain radiation therapy (WBRT)is ≥ 21 days prior to first dose of study treatment, time since stereotacticradiosurgery (SRS) is ≥ 7 days prior to first dose of study treatment, or time sincesurgical resection is ≥ 28 days, ii. Other sites of disease assessable by RECIST 1.1are present, iii. Relevant records of any CNS treatment must be available to allowfor classification of target and non-target lesions

Exclusion Criteria:

1. Have previously been treated with eribulin for metastatic disease (except in caseswhere eribulin was given for ≤ 21 days and was discontinued for reasons other thandisease progression or severe toxicity)

2. History of exposure to the following cumulative doses of anthracyclines:

3. Doxorubicin > 360 mg/m2

4. Epirubicin > 720 mg/m2

5. Mitoxantrone > 120 mg/m2

6. Idarubicin > 90 mg/m2

7. Liposomal doxorubicin (e.g. Doxil, Caelyx, Myocet) > 550 mg/m2

8. History of allergic reactions to trastuzumab, eribulin, or compounds chemically orbiologically similar to tucatinib, except for Grade 1 or 2 infusion relatedreactions to trastuzumab that were successfully managed, or known allergy to one ofthe excipients in the study drugs

9. Have received treatment with any systemic anti-cancer therapy (including hormonaltherapy), non-CNS radiation, or experimental agent ≤ 3 weeks of first dose of studytreatment or are currently participating in another interventional clinical trial.An exception for the washout of hormonal therapies is gonadotropin releasing hormone (GnRH) agonists used for ovarian suppression in premenopausal women, which arepermitted concomitant medications.

10. Have any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:

11. alopecia and neuropathy, which must have resolved to ≤ Grade 2; and

12. congestive heart failure (CHF), which must have been ≤ Grade 1 in severity atthe time of occurrence, and must have resolved completely.

13. anemia, which must have resolved to ≤ Grade 2

14. Have clinically significant cardiopulmonary disease such as:

15. ventricular arrhythmia requiring therapy,

16. uncontrolled hypertension (defined as persistent systolic blood pressure > 150mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensivemedications)

17. any history of symptomatic CHF

18. severe dyspnea at rest (CTCAE Grade 3 or above) due to complications ofadvanced malignancy

19. hypoxia requiring supplementary oxygen therapy except when oxygen therapy isneeded only for obstructive sleep apnea.

20. Presence of Grade 2 or greater QTc prolongation on screening ECG.

21. conditions potentially resulting in drug-induced prolongation of the QTinterval or torsade de pointes: i. Congenital or acquired long QT syndrome. ii. Family history of sudden death iii.History of previous drug induced QT prolongation iv. Current use of medications withknown and accepted associated risk of QT prolongation

22. Have known myocardial infarction or unstable angina within 6 months prior to firstdose of study treatment.

23. Have chronic active Hepatitis B or Hepatitis C or have other known chronic liverdisease.

24. Are known to be positive for human immunodeficiency virus (HIV)

25. Are pregnant, breastfeeding, or planning a pregnancy.

26. Require therapy with warfarin or other coumarin derivatives (non-coumarinanticoagulants are allowed)

27. Have inability to swallow pills or significant gastrointestinal disease which wouldpreclude the adequate oral absorption of medications.

28. Use of a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, oruse of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of studytreatment

29. Unable for any reason to undergo contrast MRI of the brain.

30. Have any other medical, social, or psychosocial factors that, in the opinion of theinvestigator, could impact safety or compliance with study procedures.

31. Have evidence within 2 years of the start of study treatment of another malignancythat 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, unless discussed with medical monitorand approval for enrollment is given.

2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastasesat a total daily dose of > 2 mg of dexamethasone (or equivalent). However, patientson a chronic stable may be eligible with discussion and approval by the medicalmonitor.

3. Any brain lesion thought to require immediate local therapy, including (but notlimited to) a lesion in an anatomic site where increase in size or possibletreatment-related edema may pose risk to patient (e.g., brain stem lesions).Patients who undergo local treatment for such lesions identified by screeningcontrast brain MRI may still be eligible for the study based on criteria describedunder CNS inclusion criteria 19b.

4. Have poorly controlled (> 1/week) generalized or complex partial seizures, ormanifest neurologic progression due to brain metastases notwithstanding CNS-directedtherapy