Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma

Abstract

Purpose: This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4).

Patients and methods: Patients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m(2), day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025.

Results: Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P < or = .001).

Conclusion: Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.

Fig 1.

CONSORT flowchart. *Includes protocol violation, entry criteria not met, lost to follow-up, physician or patient decision, or unknown.

Fig 2.

(A) Progression-free survival (PFS) by treatment arm for the intent-to-treat population (n = 266). PFS was defined as the time from the date of random assignment to the first date of progressive disease, which was identified by magnetic resonance imaging, evidence of neurologic progression, or death. (B) Median overall survival (OS) and 95% CI by treatment arm for the intent-to-treat population (n = 266). OS was defined as the time from the date of random assignment to death. Time-to-event estimates were calculated using the Kaplan-Meier method and were compared between regimens using the log-rank test. ENZ, enzastaurin; LOM, lomustine; HR, hazard ratio.