Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas.

Abstract

Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10mg/kg iv every 2weeks, TMZ 50mg/m2 po daily, and VOR 200 or 400mg po alternating 7days on then 7days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200mg and 6 receiving VOR 400mg. With no dose-limiting toxicities (DLTs) at 200mg and one DLT (thrombocytopenia, Grade 3) at 400mg, the MTD was 400mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2-67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group.