Tucatinib, Trastuzumab, and Capecitabine for the Treatment of HER2+ LMD

Inclusion Criteria: * Men and women, age ≥18 years at time of consent * Histologically proven metastatic infiltrating carcinoma of the breast that is HER2 positive - Immunohistochemistry (IHC) 3+ and/or Fluorescence in situ hybridization (FISH) ratio \>2.0, or average HER2 copy number \>6.0 signals per cell or per current ASCO-CAP (American Society of Clinical Oncology - College of American Pathologists) or NCCN (National Comprehensive Cancer Network) guidelines. (NOTE: HER2 testing may be performed on primary and/or metastatic site; Any estrogen and progesterone \[ER/PR\] status is allowed.) * Evidence of leptomeningeal disease (LMD) as diagnosed by a) presence of malignant cells in CSF (+CSF cytology) and/or b) Magnetic Resonance Imaging (MRI) evidence of LMD, plus clinical signs and/or symptoms. NOTE: Measurable extra-CNS disease is not required. Note: Patients who have MRI evidence of focal LMD with negative cytology and no symptoms are not eligible for enrollment. * Karnofsky Performance Status ≥ 50 or Eastern Cooperative Oncology Group (ECOG) ≤ 3 * Patient is able and willing to undergo study-required testing including: 1. Contrast-enhanced MRI Note: If patient has implants in place that are MRI incompatible, these must be removed prior to enrollment. 2. Placement of an Ommaya reservoir (ventricular access device). Note: This is mandatory for the first 15 patients enrolled onto the protocol (first stage). In the second stage, this is strongly recommended per protocol. If a patient cannot or chooses not to undergo Ommaya placement in the second stage, the patient will be allowed to enroll. 3. Evaluation by medical oncologist at baseline and at every cycle (required) 4. Evaluation by neurologist/neuro-oncologist at baseline and at every cycle (strongly recommended); if this is not possible at a site, a medical oncologist may per perform the protocol specified evaluations at each visit. * Patients who are on steroids due to CNS disease or LMD diagnosis should be on a stable dose for at least 5 days prior to registration. * Prior treatment allowances are as follows: 1. \>14 days since last dose of any previous endocrine therapy, chemotherapy, trastuzumab or other antibody-based therapy. NOTE: If patients have been previously receiving trastuzumab on a weekly basis (at a dose of 2mg/kg), only a 7 day washout will be required. 2. \>14 days or five half-lives since previous treatment with any experimental agent, whichever is greater 3. Cumulative dose of doxorubicin \>360 mg/m2 or previous treatment with another anthracycline with cumulative dose equivalent to \>360 mg/m2 doxorubicin is not allowed. 4. Patients must not have received any therapy specifically directed at LMD, including prior systemic or intrathecal therapy for LMD. 5. Radiotherapy: * Patients must not have received radiotherapy to the neuroaxis following diagnosis of LMD for the purpose of treating LMD, and may not receive * radiotherapy to the neuroaxis concurrently with the study drug; * Patients must not have received whole brain radiotherapy for parenchymal metastases within the last 2 weeks (14 days) or focal CNS radiotherapy within 1 week (7 days) prior to first dose of study drug. Note: Radiation for the purpose of palliation in the setting of a painful bone or dural metastasis can be allowed at the discretion of the treating physicians. * All toxicity related to prior cancer therapies must have resolved to ≤ Grade 1, with the following exceptions: alopecia; neuropathy, which must have resolved to ≤ Grade 2; and CHF, which must have been ≤ Grade 1 in severity at the time of occurrence, and must have resolved completely. Must be without significant systemic illness (e.g. infection unresponsive to treatment after 7 days) * Adequate hematologic, liver, and renal function, as follows: 1. Hemoglobin ≥ 9 g/dL 2. ANC ≥ 1000 cells/μL 3. Platelets ≥ 100,000/μ 4. Total bilirubin ≤ 1.5 X upper limit of normal (ULN), unless a known history of Gilbert's disease (≤ 3 X ULN) 5. Transaminases (AST/SGOT and ALT/SGPT) ≤ 2.5X ULN (\< 5 X ULN if liver metastases are present) 6. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 X ULN 7. Creatinine clearance (CrCL) ≥ 50 mL/min * Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by ECHO or MUGA documented within 4 weeks prior to enrollment on the study. * Able to understand the study requirements and document informed consent indicating his/her awareness of the investigational nature and the risks of this study. Exclusion Criteria: * Medical, social, or psychosocial factors that, in the opinion of the Investigator, could impact safety or compliance with study procedures. * Patient is pregnant or is breastfeeding. Note: If female and of child-bearing potential (females who are not surgically sterile or who have had a period in the last 12 months), has negative pregnancy test within 21 days prior to treatment. If a sexually active male or a sexually active female of child- bearing potential, agrees to use dual (two concurrent) forms of medically accepted contraception from the time of consent until 6 months after the last dose. * History of allergic reactions to compounds of similar chemical or biological composition to capecitabine (Group A only), trastuzumab or tucatinib, except for a history of Grade 1 or Grade 2 infusion related reaction to trastuzumab, that has been successfully managed. * Known to be HIV positive, or a carrier for Hepatitis B and/or Hepatitis C (whether active disease or not) * Known liver disease, autoimmune hepatitis, or sclerosing cholangitis * Inability to swallow pills or any significant gastrointestinal diseases, which would preclude adequate absorption of oral medications * Use of a strong CYP2C8/CYP3A4 inducer or inhibitor within three elimination half-lives of the inducer or inhibitor prior to the start of study treatment. * Known impaired cardiac function or clinically significant cardiac disease such as ventricular arrhythmia requiring therapy or congestive heart failure. Note: Patients with hypertension must have controlled disease defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg on antihypertensive medications. * Myocardial infarction or unstable angina within 6 months prior to the first dose of study drug. * Patient with known dihydropyrimidine dehydrogenase deficiency * Previous treatment with tucatinib * Previous treatment with capecitabine within 12 months prior to study registration * Prior history of other cancer (except non melanoma skin, cervical intraepithelial neoplasia) with evidence of disease within the last 5 years.