AT-33A PHASE II STUDY OF CONCURRENT RADIATION THERAPY, TEMOZOLOMIDE AND THE HISTONE DEACETYLASE INHIBITOR VALPROIC ACID FOR PATIENTS WITH GLIOBLASTOMA MULTIFORME

Abstract

BACKGROUND: Glioblastoma (GBM) remains an aggressive brain tumor with poor prognosis. Valproic acid (VPA) is an antiepileptic agent that has been shown to have HDACi activity and to radiosensitize GBM cells in preclinical models. This phase II study aimed to determine if the addition of VPA to standard radiation therapy and temozolomide would improve OS and PFS. METHODS: We prospectively assessed survival, radiological and clinical progression in 37 newly diagnosed glioblastoma patients with the administration of VPA at 25 mg/kg orally BID concurrent with radiation therapy (RT) and temozolomide (TMZ). The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently tapered up to 25 mg/kg/day over the week prior to radiation. RESULTS: 81% of patients took VPA according to protocol. Median OS was 29.6 months (21- 63.8), median PFS was 10.5 (6.8 - 51.2). OS at 6, 12, 24 months was 97%, 86%, 56% respectively. PFS at 6, 12, 24 months was 70%, 43%, 38% respectively. The most common grade 3 or 4 toxicities of VPA in conjunction with TMZ were blood/ bone marrow toxicity (32%), neurological (11%), metabolic/laboratory (8%). At the end of the study 26 (70%) patients were dead, 7 were live without disease, 4 alive with disease. Younger age (<= 50 years) compared to older age and class V RPA were significant for both OS and PFS. Using a landmark analysis, an early progression was related to a shorter interval between progression and death, whereas, a later progression was related to a longer interval between progression and death (p = 0.0002) HR 4.7. CONCLUSION: The addition of VPA to concurrent RT and TMZ in the treatment of newly diagnosed GBM may result in superior outcomes as compared to contemporary and historical data and merits further study.