Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown evidence of 
single-agent activity in glioblastoma (GBM), and in preclinical studies, we have 
demonstrated significant synergistic cytotoxicity between HDAC inhibitors and 
proteasome inhibitors in GBM cell lines. We therefore conducted a phase II trial 
to evaluate the efficacy of vorinostat in combination with the proteasome 
inhibitor bortezomib in patients with recurrent GBM. Vorinostat was administered 
at a dose of 400 mg daily for 14 days of a 21-day cycle, and bortezomib was 
administered at a dose of 1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of 
the cycle. A total of 37 patients were treated, and treatment was well 
tolerated: grade 3, 4 nonhematologic toxicity occurred in 30% of patients and 
consisted mainly of fatigue (14%) and neuropathy (5%); grade 3, 4 hematologic 
toxicity occurred in 37% of patients and consisted of thrombocytopenia (30%), 
lymphopenia (4%), and neutropenia (4%). The trial was closed at the 
predetermined interim analysis, with 0 of 34 patients being progression-free at 
6 months. One patient achieved a partial response according to the Macdonald 
criteria. The median time to progression for all patients was 1.5 months (range, 
0.5-5.6 months), and median overall survival (OS) was 3.2 months. Patients who 
had received prior bevacizumab therapy had a shorter time to progression and OS, 
compared with those who had not. On the basis of the results of this phase II 
study, further evaluation of the vorinostat-bortezomib combination in GBM 
patients in this dose and schedule is not recommended.