Phase I/II trial of vorinostat combined with temozolomide and radiation therapy for newly diagnosed glioblastoma: results of Alliance N0874/ABTC 02

Abstract

Background: Vorinostat, a histone deacetylase (HDAC) inhibitor, has shown radiosensitizing properties in preclinical studies. This open-label, single-arm trial evaluated the maximum tolerated dose (MTD; phase I) and efficacy (phase II) of vorinostat combined with standard chemoradiation in newly diagnosed glioblastoma.

Methods: Patients received oral vorinostat (300 or 400 mg/day) on days 1-5 weekly during temozolomide chemoradiation. Following a 4- to 6-week rest, patients received up to 12 cycles of standard adjuvant temozolomide and vorinostat (400 mg/day) on days 1-7 and 15-21 of each 28-day cycle. Association between vorinostat response signatures and progression-free survival (PFS) and overall survival (OS) was assessed based on RNA sequencing of baseline tumor tissue.

Results: Phase I and phase II enrolled 15 and 107 patients, respectively. The combination therapy MTD was vorinostat 300 mg/day and temozolomide 75 mg/m2/day. Dose-limiting toxicities were grade 4 neutropenia and thrombocytopenia and grade 3 aspartate aminotransferase elevation, hyperglycemia, fatigue, and wound dehiscence. The primary efficacy endpoint in the phase II cohort, OS rate at 15 months, was 55.1% (median OS 16.1 mo), and consequently, the study did not meet its efficacy objective. Most common treatment-related grade 3/4 toxicities in the phase II component were lymphopenia (32.7%), thrombocytopenia (28.0%), and neutropenia (21.5%). RNA expression profiling of baseline tumors (N = 76) demonstrated that vorinostat resistance (sig-79) and sensitivity (sig-139) signatures had a reverse and positive association with OS/PFS, respectively.

Conclusions: Vorinostat combined with standard chemoradiation had acceptable tolerability in newly diagnosed glioblastoma. Although the primary efficacy endpoint was not met, vorinostat sensitivity and resistance signatures could facilitate patient selection in future trials.

Fig. 1

Overall survival in the overall phase II cohort (A) and in patients with MGMT promoter methylated vs unmethylated tumors (B). Progression-free survival in the overall phase II cohort (C) and in patients with MGMT methylated vs unmethylated tumors (D). LCL, lower confidence limit; UCL, upper confidence limit.

Fig. 2

RNA sequencing analysis of baseline tissue obtained from 76 patients in the phase II trial: PFS in patients with tumors expressing the vorinostat sensitivity (A, sig-77; B, sig-80; C, sig-139) and vorinostat resistance (D, sig-79) molecular signatures. Overall survival in patients with tumors expressing the vorinostat sensitivity molecular signature sig-139 (E).

Fig. 3

Optimum RPART for OS and PFS subgroups using age, MGMT methylation status, and RNA sequencing analysis of baseline tissue obtained from 59 patients in the phase II trial: OS subgroups (A) and PFS subgroups (B). Overall survival subgroups: P1, patients with tumors that were MGMT methylated with medium values for sig-79; P2, patients with tumors that were MGMT methylated with low values for sig-79; P3, younger patients (age <46 y) with MGMT unmethylated tumors; P4, older patients (age ≥46 y) with MGMT unmethylated tumors; P5: patients with tumors with high values for sig-79. Progression-free survival subgroups: P1, patients with tumors with high values for sig-139; P2, patients with tumors that were MGMT methylated with low values for sig-139 and medium values for sig-79; P3, patients with tumors that were MGMT unmethylated with low values for sig-139 and medium values for sig-79; P4, patients with tumors with low values for sig-139 and low values for sig-79; P5, patients with tumors with high values for sig-79.