BACKGROUND: Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown 
radiosensitizing properties in preclinical studies. This open-label, single-arm 
trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase 
II) of vorinostat combined with standard chemoradiation in newly diagnosed 
glioblastoma.
METHODS: Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 
weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, 
patients received up to 12 cycles of standard adjuvant temozolomide and 
vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association 
between vorinostat response signatures and progression-free survival (PFS) and 
overall survival (OS) was assessed based on RNA sequencing of baseline tumor 
tissue.
RESULTS: Phase I and phase II enrolled 15 and 107 patients, respectively. The 
combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. 
Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 
3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound 
dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 
months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet 
its efficacy objective. Most common treatment-related grade 3/4 toxicities in 
the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and 
neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) 
demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) 
signatures had a reverse and positive association with OS/PFS, respectively.
CONCLUSIONS: Vorinostat combined with standard chemoradiation had acceptable 
tolerability in newly diagnosed glioblastoma. Although the primary efficacy 
endpoint was not met, vorinostat sensitivity and resistance signatures could 
facilitate patient selection in future trials.