Abstract
Prognosis for recurrent glioblastoma remains poor with progression-free survival at six months (PFS6) of 9-15%, but with the addition of bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A (VEGF-A), studies have shown PFS6 improved to 40-50%. Vorinostat, a small molecule inhibitor of histone deactylase (HDAC), has anti-tumor activity directly through HDAC inhibition and indirectly by promoting anti-angiogenesis. Its good oral bioavailability and favorable toxicity profile make it a promising additive agent. We designed a clinical trial to examine the addition of vorinostat and bevacizumab (BEV) in recurrent GBM. This was a phase II open-label, single arm study. Primary endpoint was PFS6. Secondary endpoints were safety/tolerability, radiographic response, progression-free survival, and overall survival. Chief eligibility criteria included age ≥ 18 years, KPS ≥ 70, time interval ≥4 wks from last treatment, and ≤2 prior progressions. Dosing regimen was BEV 10 mg/kg iv q2wks, and vorinostat 400 mg po for 7 days on then 7 days off in a 28 day cycle. To date, 38 of 40 recurrent GBM patients have been enrolled. Most common treatment-related grade 2 and above toxicities were lymphopenia (50%), leukopenia (34%), neutropenia (26%), and hypertension (22%). There were two grade 4 toxicities (sinus bradycardia and pulmonary embolism) and no treatment-related grade 5 toxicities. With a median follow-up of 5.7 months (95% CI: 3.4, 8.8 months), PFS6 was 22.6% (95% CI: 8.9-40.1). Best radiographic responses included 4 partial responses, 30 stable responses, 1 radiographic progression, 2 too early to assess and 1 termination due to toxicity without follow-up imaging. In initial interim analysis, the combination of voriniostat and BEV did not improve PFS6 in comparison to historical controls on BEV alone, but median follow-up is only 5.7 months. Additional data will be presented with a longer follow-up time for analysis.
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