Background: We demonstrated that low doses of temozolomide (TMZ) administered in a prophylactic, metronomic fashion significantly prevented development of brain metastases in murine models of breast cancer. Based on these findings, we developed a secondary-prevention clinical trial. Methods: Phase I is a standard 3+3 design: T-DM1 3.6mg/kg IV every 21 days plus TMZ 30, 40 or 50 mg/m2 daily, to identify the maximum tolerated dose (MTD) of the combination, and is completing accrual, with 9 patients accrued, currently on the third and last dose level. Phase II will randomize patients to T-DM1 3.6mg/kg versus T-DM1 3.6mg/kg plus TMZ at recommended phase 2 dose (RP2D), to evaluate if addition of TMZ improves the recurrence-free incidence from distant new brain metastases at one year from 50% to 65%. Patients will undergo radiology guided lumbar puncture at baseline and after 6 weeks of treatment (C3D1) for correlative studies, brain MRI, systemic restaging CTs, and questionnaires for evaluation of symptoms and quality of life. Eligibility: HER2+ breast cancer with brain metastases (up to 10 lesions), treated with SRS and/or resection ≤12 weeks before enrollment, no leptomeningeal metastases, no previous WBRT, ECOG ≤2 and adequate organ and marrow function. Biomarkers, including cell free DNA from CSF, serum and tumor block, exosomal DNA, serum markers for neuroinflammation, and patient reported outcomes, will be analyzed in an exploratory fashion. Target accrual: up to 18 patients in phase I and 98 in phase II. Clinical trial information: NCT03190967.