Abstract Background: Treatment options for patients with leptomeningeal disease (LMD) from HER2-positive breast cancer (HER2+ BC) are limited, and the prognosis is poor. Tucatinib is an oral, potent, HER2 specific tyrosine kinase inhibitor with good tolerability and notable early combinatory anti-tumor activity, including partial responses in heavily treated patients and those with parenchymal brain metastases (BM). Trial Design: This is a phase 2 single arm study to evaluate the efficacy of the combination of tucatinib plus trastuzumab (T) and capecitabine(C) in patients with HER2+ BC and newly diagnosed LMD. CNS disease will be evaluated at screening and every six weeks by MRI, CSF cytology, and neurological assessments according to RANO-LMD (adapted) and RANO-BM criteria. CT scans/PET-CT will evaluate extracranial disease according to RECIST criteria at screening and every 12 weeks. All patients will be followed for survival from the date of the last dose until death, lost to follow-up, or consent withdrawal. Symptom burden and quality of life assessments are conducted throughout the study. Blood and CSF sample collections occur at each cycle for the planned correlative analyses. Eligibility Criteria: Eligible patients are adults (>18 years old) with HER2+ BC, ECOG status<3/KPS>50, and newly diagnosed untreated LMD (defined as positive CSF cytology and/or radiographic evidence of LMD, plus clinical signs/symptoms. Patients with a history of treated BM or concurrent/new BM are allowed. Patients previously treated with tucatinib or capecitabine (within the last 12 months) are excluded. Specific Aims: The primary endpoint is OS. Secondary endpoints include safety, CNS PFS at 12 weeks, RR and CBR in CNS and extra-CNS disease, and symptom burden/quality of life. Statistical methods: This study has a Gehan-like design with an interim futility analysis and overall intent to estimate OS. For the interim analysis, we define success to be CNS PFS for 12 weeks. An event will be considered to be either CNS progression or death from any cause before 12 weeks.We will stop enrollment if there are fewer than two successes in the first 15 patients. If the trial continues to completion, the regimen will be considered worthy of future study if the median overall survival is > 4.4 months. Study Accrual: The target accrual is 30 patients. The study is currently active at UAB and MDACC. Other TBCRC sites throughout the country are to be activated this year. Citation Format: Rashmi K Murthy, Barbara J O'Brien, Ken R Hess, Nick Navin, Jason Johnson, Maria Gule-Monroe, Jose P Leone, Jennifer Specht, Michelle Melisko, Aki Morikawa, Anna M Storniolo, Adam Brufsky, Paula R Pohlmann, Deric M Park, Ben H Park, Ian Krop, Nancy U Lin, Antonio Wolff, Andres Forerro-Torres, Erica Stringer-Reasor. TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer TBCRC049: A phase II non-randomized study to assess the safety and efficacy of the combination of tucatinib and trastuzumab and capecitabine for treatment of leptomeningeal metastases in HER2 positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-01-02.