Background: Antiangiogenic agents targeting new blood vessel formation are approved to treat progressive glioblastoma (GBM), but limited data are available on the activity of vascular disrupting agents targeting established blood vessels in these tumors. Prostate specific membrane antigen (PSMA) is a transmembrane peptidase upregulated on endothelial cells of solid tumors including GBM, making it a potential therapeutic target. A PSMA-targeted monoclonal antibody conjugated with microtubule disrupting agent monomethyl auristatin E (MMAE) is undergoing evaluation in advanced prostate cancer (PSMA ADC, Progenics Pharmaceuticals). Unconjugated MMAE has demonstrated activity against GBM cell lines. Methods: We investigated the activity of PSMA ADC in a single arm Phase II study in progressive GBM patients following prior treatment with radiation, temozolomide and bevacizumab. 2.5 mg/kg PSMA ADC was administered intravenously every 3 weeks until disease progression, unacceptable toxicity or removal from study. Disease status was evaluated clinically and with contrast enhanced brain MRI every 3 cycles. Primary endpoint was objective response and secondary endpoints were progression-free survival (PFS), 6-month PFS and overall survival (OS). Results: 6 patients (4 males, 2 females, median age 63 years, KPS 70-90%) received PSMA ADC treatment. No objective responses were noted. 2/6 (33%) patients progressed after 1 cycle, 3/6 (50%) patients progressed after 2 cycles and 1/6 (17%) patient progressed after cycle 3. Median PFS was 6 weeks. Median OS was 2 months from study entry. Grade 3 and 4 adverse events included lymphopenia, dysphasia, syncope, neutropenia, leucopenia and fatigue. One patient had dose-limiting toxicity (sigmoid perforation possibly related to study drug) within 30 days of study treatment and off-study carboplatin resulting in death. Immunohistochemistry staining showed no PSMA expression in viable tumor samples of 2 patients and low expression (relative to that seen in prostate cancer trials) in 1. Conclusions: PSMA ADC had no demonstrable activity in these patients with progressive GBM likely due to minimal expression of the PSMA target and was associated with dose-limiting toxicity. Clinical trial information: NCT01856933