Enzastaurin (ENZ) before and concomitant with radiation therapy (RTX) followed by ENZ maintenance therapy in patients with newly diagnosed glioblastoma (GBM) without hypermethylation of the O6-methylguanyl DNA-methyltransferase (MGMT) promoter: A multicenter, open-label, uncontrolled phase II study.

Abstract

2007 Background: There is an unmet need to improve efficacy outcome for GBM patients without hypermethylation of the MGMT promoter. Preclinical data indicate potential activity of ENZ, an oral PKC beta inhibitor, together with RTX (Tabatabai, Ann Neurol 2007, 61) in GBM. This single arm phase II study treated GBM patients with unmethylated MGMT promoter with ENZ and RTX. Methods: Patients (pts) with newly diagnosed supratentorial GBM without methylation of the MGMT promoter were eligible. ENZ 250 mg twice daily was given on 7 days before, concomitant with RTX (60 Gy; 5 times 2 Gy per week), and in the maintenance therapy until progression. The study’s primary endpoint was 6-months progression-free survival (PFS-6). The study needed to observe 43 events of progression or death to have 80% power to detect an improvement to 55% compared to 40% PFS-6 rate, observed in the EORTC trial (Hegi, NEJM 2005, 352). Results: Between 10/07 and 07/09 a total of 57 pts were enrolled (median age 57.6 years). ECOG scores were 0 (39 pts), 1 (16 pts) and 2 (2 pts). Complete resection was performed in 25 pts, partial resection in 23 pts, and biopsy in 9 pts. The 57 enrolled pts received 100% median ENZ dose intensity, the 53 pts continuing to RTX received 60 Gy median cumulative RTX dose. Two pts had grade 3/4 possibly drug-related lab adverse events. Eleven pts had grade 3 (5pts), 4 (3pts) and 5 (3pts) non lab toxicity. One pt died after CNS hemorrhage and 2 with infection. The PFS-6 rate was 51.8% (95% CI 38.1-63.9). Conclusions: This is the first trial performed in pts with GBM to publish data, limiting entrance to the molecularly defined unfavorable subgroup of pts with unmethylated MGMT status. Although showing some encouraging PFS-6 results, the study did not reach its primary endpoint. Side effects were manageable and the combination therapy was performed as planned. Further molecular data may identify subgroups of pts that warrant a controlled study to assess the role of ENZ for this pt population.