A phase I study was conducted to determine the dose-limiting toxicities (DLT) 
and maximum tolerated dose (MTD) for the combination of vorinostat with 
bevacizumab and CPT-11 in recurrent glioblastoma. Vorinostat was combined with 
bevacizumab and CPT-11 and was escalated using a standard 3 + 3 design. 
Vorinostat was escalated up to 2 actively investigated doses of this compound or 
until the MTD was identified on the basis of DLTs. Correlative science involving 
proteomic profiling of serial patient plasma samples was performed. Nineteen 
patients were treated. The MTD of vorinostat was established at 400 mg on days 
1-7 and 15-21 every 28 days when combined with bevacizumab and CPT-11. Common 
toxicities were fatigue and diarrhea. DLTs included fatigue, 
hypertension/hypotension, and central nervous system ischemia. Although the MTD 
was established, CPT-11 dose reductions were common early in therapy. High-dose 
vorinostat had an improved progression-free survival and overall survival when 
compared with low-dose vorinostat. Serum proteomic profiling identified IGFBP-5 
and PDGF-AA as markers for improved PFS and recurrence, respectively. A MTD for 
the combination of vorinostat with bevacizumab and CPT-11 has been established, 
although it has poor long-term tolerability. With the increased toxicities 
associated with CPT-11 coupled with its unclear clinical significance, 
investigating the efficacy of vorinostat combined with bevacizumab alone may 
represent a more promising strategy to evaluate in the context of a phase II 
clinical trial.