Background: Patients (pts) with recurrent GBM have few treatment options and a very poor prognosis. GBM tumors often exhibit aberrant epidermal growth factor receptor (EGFR) proliferative signaling. ABT-414 is an antibody drug conjugate consisting of a unique antibody targeting active EGFR or mutant EGFRvIII linked to a potent, toxic anti-microtubule agent monomethylauristatin F (MMAF). ABT-414 has demonstrated high antitumor activity in preclinical GBM tumor models harboring either wild type EGFR or EGFRvIII. Methods: Objectives were to evaluate the toxicities, pharmacokinetics (PK), and the recommended phase 2 dose of ABT-414 when administered every other week (QOW) in combination with TMZ in pts with recurrent or unresectable GBM. Assessments include adverse events (AEs, NCI-CTCAE), PK parameters, objective response (RANO criteria) and tumor tissue EGFR biomarkers. Results: As of Jan 1, 2014, safety data was compiled for 12 pts (6/6, Male/Female, median age 48). Common (≥ 3 pts) adverse events include blurred vision (n=5), corneal deposits (n=4), foreign body sensation in the eye, nausea, pyrexia, and headache (n=3 each). Grade 3/4 AEs include lymphopenia, corneal deposits, skin infection, and blood cholesterol increase (n=1 each). Three cohorts have been treated to date (0.5, 1.0, 1.5 mg/kg). One dose limiting toxicity of grade 3 corneal deposits was reported at 1.0 mg/kg with improvement of symptoms after a dose reduction. ABT-414 PK results in 7 pts appeared to be dose proportional from 0.5-1.0 mg/kg, with mild accumulation using QOW dosing, and a half-life of 7-8 days. As of Jan 9, best responses for 9 pts with measurable disease at baseline include 1 complete response (CR) and 2 partial responses (33%). Patient samples are being evaluated for EGFR amplification, EGFR VIII status and expression of EGFR mRNA to determine which marker best associates with clinical response. Conclusions: Preliminary safety data demonstrate a unique toxicity pattern related to MMAF-induced corneal epithelial microcysts. Preliminary responses in 3/9 pts with TMZ refractory GBM, including 1 CR, warrant further study. Phase 2 studies with ABT-414 in GBM are being planned. Clinical trial information: NCT01800695.