Background: VOR is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its single agent activity in recurrent disease (Galanis et al 2009) and radiosensitizing properties, this phase II trial was designed to test the addition of VOR to standard chemoradiation in newly diagnosed GBM patients (pts). Methods: Pts received vorinostat at 300 mg/day, days 1-5 weekly during RT in combination with temozolomide (75 mg/m²/day). Following a 4-6 week rest period, pts received up to 12 cycles of standard adjuvant TMZ in combination with VOR at a dose of 400 mg/day on days 1-7 and 15-21 of each cycle (Lee et al, 2012). Results: A total of 107 patients were accrued to this single arm trial. This preliminary report is based on mature outcome data in 73 patients. Final data analysis will be presented at the meeting. With a median follow up of 11.3 months (range 0.8-21.6 months), OS 15, (survival status at 15 mo, primary trial endpoint) was 39.1% with a median OS of 14.3 months and PFS of 8.1 months. MGMT methylation status is available in 52 pts; OS 15 and PFS were 44.4% vs 11.1% and 8.1 vs 6.4 mo in methylated and unmethylated pts respectively. Most common grade 3/4 toxicities were lymphopenia (32%), thrombocytopenia (28%), neutropenia (22%), fatigue (12.1%), anemia (8.4%) and anorexia (6.5%). There were no treatment related deaths. Conclusions: The HDAC inhibitor VOR in combination with TMZ and RT has tolerable toxicity in newly diagnosed GBM patients. Initial analysis based on mature outcome data in 70% of the evaluable patients does not indicate an improvement in outcome; final data will be presented at the meeting. Ongoing RNA sequencing analysis of baseline tumor tissue in 80 pts will assess if a 43 gene VOR responsive signature, identified in preclinical models, can define subgroups of patients deriving benefit from treatment. Clinical trial information: NCT00731731.