INTRODUCTION: Trastuzimab is a humanized monoclonal antibody against Her2 whose limitation is central nervous system penetration that often leads to brain and leptomeningeal metastases (LM) in the setting to controlled systemic HER2 positive breast cancer. We performed a phase I clinical trial of intrathecal (IT) trastuzumab in patients with HER2 positive breast cancer and LM. METHODS: IRB consented patients were treated at defined dose levels; protocol was modified to accelerate dose escalation and increase IT dosage. Dose levels of IT treatment 10 mg, 20 mg, 40 mg, 60 mg and 80 mg were examined. Treatment was given twice a week x4 weeks, then once a week x4 weeks then every other week until progressive disease. MRI was done at 4 week intervals x2 then every 8 weeks. CSF was assessed every other week x2 then every 4 weeks. RESULTS: 13 women with HER2 positive breast cancer, 1 man with a glioblastoma, and one woman with anaplastic ependymoma were enrolled with a median age of 55 (42-67) and median KPS of 80 (60-90). Three patients were treated at the 10mg dose level, three at 20mg, one at 40mg, one at 60mg and 7 at 80mg. At the 80 mg dose level a patient was added as one patient was removed before complete evaluation and another patient had a grade 4 DLT of arachnoiditis. One patient had the Ommaya reservoir removed for infection unrelated to treatment. Data on CSF levels shows therapeutic levels in the patients treated with 10 mg, 20 mg and 40 mg; data analysis on CSF at 60 and 80 mg is pending. CONCLUSION: IT Trastuzumab is well tolerated up to 80 mg IT. Complete CSF PK data will be presented. A phase II study is underway at the 80 mg dose.