Background: HER2⁺ breast cancer patients with leptomeningeal disease (LMD) represent a poor prognosis population with a high unmet clinical need. Although a multitude of treatment options are available for the management of systemic disease, once metastases travel to the leptomeninges, patients have a lack of treatment options aside from traditional local approaches. Data from a phase I/II study reveals intrathecal (IT) trastuzumab to be well tolerated with improved overall survival (OS) compared to historical controls in HER2⁺ breast LMD. Radiotherapy can improve the flow of IT therapy through the cerebrospinal fluid (CSF) and provide symptomatic relief. The monoclonal antibody pertuzumab is used in conjunction with trastuzumab in the management of metastatic and localized HER2⁺ breast cancer. Given the role of radiotherapy in the management of LMD along with the role of pertuzumab in the management of HER2⁺ breast cancer, there is a strong clinical rationale to combine radiotherapy with IT trastuzumab/pertuzumab in the management of HER2⁺ breast LMD. Methods: The study is designed as a prospective, single-arm, nonrandomized, open-label, phase I/II trial of radiation therapy followed by IT trastuzumab/pertuzumab in the management of HER2⁺ breast LMD. HER2⁺ LMD patients identified by magnetic resonance imaging (MRI) and/or CSF cytology, ≥ 18, with a life expectancy > 8 weeks are eligible. Treatment is initiated with radiotherapy, whole brain radiotherapy and/or focal brain/spine radiation followed by IT trastuzumab/pertuzumab. Safety and feasibility will be monitored by a modified toxicity probability interval-2 (mTPI-2) design. Dose reductions of IT trastuzumab will not be allowed. Once the maximum tolerated dose of IT pertuzumab is determined, the phase II portion of the study will commence to determine OS. Secondary objectives involve defining the CSF pharmacokinetics of IT trastuzumab/pertuzumab, evaluating the response rate (leptomeningeal and parenchymal), and progression free survival (leptomeningeal and parenchymal) following IT trastuzumab/pertuzumab. In the phase 2 portion, a single-arm two-stage trial is designed using the Restricted-Kwak-and-Jung’s Method. The primary endpoint is one-year OS. An interim analysis will be performed after 20 patients are enrolled. This study is open with 1 patient enrolled at the time of submission. Clinical trial information: NCT04588545.