Dose-intensified rechallenge with temozolomide: One week on/one week off versus 3 weeks on/one week off in patients with progressive or recurrent glioblastoma.

Abstract

TPS154 Background: No standard of care has been defined for patients with glioblastoma who relapse or progress on or after standard temozolomide (TMZ)-based radiochemotherapy. Rechallenge with TMZ using various dose-intensified regimens is a common approach for recurrent glioblastoma. O6-methylguanylmethyltransferase (MGMT) promoter methylation is a strong prognostic marker in newly diagnosed glioblastoma. However, in recurrent glioblastoma, the prognostic value of the MGMT status has remained unclear. Methods: The DIRECTOR trial will investigate whether dose-intensified regimens of TMZ can overcome MGMT-mediated chemoresistance and which TMZ rechallenge regimen is most effective and tolerable in recurrent glioblastoma. Results: DIRECTOR is a prospective, randomized, open-label phase II trial which assesses the efficacy of 2 regimens of dose-intensified TMZ, 1 week on/1 week off (120 mg/m2) versus 3 weeks on/1 week off (80 mg/m2), in patients with glioblastoma who progress or relapse after standard first-line TMZ radiochemotherapy and at least 2 cycles of TMZ maintenance. To assess the MGMT promoter methylation status at recurrence, patients will have to undergo resection or biopsy at relapse. The primary endpoint is time-to-treatment failure (TTF) defined as progression, intolerability of study treatment, or death from any cause. Secondary endpoints are progression-free survival (PFS), overall survival (OS), response and MGMT correlations. 166 patients are needed to show a statistically significant difference in median TTF between arm A and B (HR 0.63) with 80% power. Efficacy is assessed every 2 months by MRI using MacDonald criteria. Quality-of-life will be evaluated utilizing QLQ-C30 and QLQ-BN20 EORTC scores. Dose adjustments for TMZ will be implemented according to protocol. Patients will be followed up until treatment failure (last study visit) and the centers are encouraged to further document the course of disease in 3-monthly intervals. Conclusions: The trial is performed in 13 sites in Austria, Germany, and Switzerland. Six of 166 patients have been enrolled. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck, Merck Serono, Roche, Schering-Plough Merck, Merck Serono, Roche, Schering-Plough, Wyeth Lilly, Merck Serono, Schering-Plough