Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma

Abstract

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Fig. 1.

Kaplan-Meier analyses of overall and progression-free survival by study protocol. (A) Overall survival. For historical controls, 14 patients were censored with a median survival follow-up of 234 weeks (range: 129–279 weeks). For ETRT, 19 patients were censored with median survival follow-up of 103 weeks (range: 70–175 weeks). (B) Progression-free survival. For historical controls (n = 193), 9 patients were censored with median survival follow-up of 207 weeks (range: 129–254 weeks). For ETRT, 11 patients were censored with median survival follow-up of 120 weeks (range: 70–177 weeks). ETRT — Current trial. TTRT — Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme. RTRT — A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma. OTRT — Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Abbreviation: n, number of patients.

Fig. 2.

Clinical outcomes by MGMT methylation status. (A) Overall survival. Based on Cox models, unmethylated MGMT was associated with increased hazard of earlier death, adjusting for the effect of age and KPS (HR = 5.19, 95% CI: 1.88–14.31, P = .001). (B) Progression-free survival. Similarly, unmethylated MGMT was associated with increased hazard of earlier progression, adjusting for the effect of age and KPS (HR = 3.07, 95% CI: 1.31–7.23, P = .01). Abbreviations: CI, confidence interval; HR, hazard ratio; MGMT, O-6-methylguanine-DNA methyltransferase.