Tucatinib With Brain and/or Spinal XRT in Patients With HER2+ Metastatic Breast Cancer and LMD

Inclusion Criteria: Phase 1

1. Men or women with HER2+* metastatic breast cancer. *HER2+ status will be defined inaccordance with ASCO-CAP 2018 guidelines, and can be diagnosed at any time prior toenrolment;

2. Evidence of LMD* in the brain and/or spine (either positive cerebral spinal fluidcytology and/or magnetic resonance imaging evidence of LMD). Measurable disease inthe central nervous system is not required. * The diagnosis of LMD can occur at anytime prior to enrolment;

3. Age 18+ at time of consent;

4. ECOG ≤ 2;

5. More than 14 days or 5 half-lives from the last dose of any experimental agent isrequired, whichever is greater;

6. All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1 priorto enrollment, except for alopecia; neuropathy, must have resolved to ≤ Grade 2.

Phase 2: Inclusion Criteria

1. Left ventricular ejection fraction (LVEF) must be within institutional limits ofnormal as assessed by ECHO or MUGA documented within 2 weeks prior to startingsystemic therapy on the study;

2. Adequate hematologic, liver, and renal function within 2 weeks prior to phase 2enrollment, as follows:

3. Hemoglobin ≥ 9 g/dL

4. ANC ≥ 1 x109/L

5. Platelets ≥ 100 x109/L

6. Total bilirubin ≤ 1.5 X upper limit of normal (ULN)

7. AST and ALT ≤ 2.5X ULN

8. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN

9. Creatinine clearance (CrCL) ≥ 50 mL/min

10. The last dose of prior therapy must have been completed 14 days prior to studyenrollment. Prior chemotherapy, immunotherapy, endocrine therapy, targeted therapyand experimental agents are allowed (including prior use of trastuzumab or otherantibody-based therapy). Prior use of capecitabine either alone or in combinationwith other HER2-targeted therapies (including other tyrosine kinase inhibitors) ispermitted;

Exclusion Criteria: Phase 1

1. Prior WBRT for brain metastases (prior stereotactic radiosurgery for parenchymal CNSmetastases received <7 days prior to consent );

2. Prior therapy specifically directed at LMD, including prior radiotherapy or systemictherapy;

3. Inability to comply with MRI-based surveillance of CNS disease;

4. Inability to swallow pills or any significant gastrointestinal diseases such asinflammatory bowel disease who suffer from uncontrolled diarrhea (based on theinvestigator's assessment),, which would preclude adequate absorption of oralmedications;

5. Diagnosed with Hereditary fructose intolerance;

6. Diagnosed with Gilbert's disease;

7. Prior history of other cancer (except non melanoma skin, cervical intraepithelialneoplasia) with evidence of disease within the last 5 years;

8. Prior use of tucatinib at any time prior to enrollment.

9. Hypersensitivity to any of the active substances in tucatinib, trastuzumab, orcapecitabine.

Phase 2:

1. Currently pregnant or breastfeeding;

2. Use of a strong cytochrome P450 (CYP)2C8 inhibitor within 5 half-lives of theinhibitor or use of a strong CYP3A4 or CYP2C8 inducer within 5 days prior to thefirst dose of systemic therapy (see Appendix C and D);

3. Myocardial infarction or unstable angina within 6 months prior to the first dose ofsystemic therapy.

4. Blood product transfusions in order to meet eligibility criteria