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 is an open-label prospectively randomized phase II trial investigating 2 different TMZ rechallenge regimens, i.e. 1 week on/1 week off (Arm A, 120-150 mg/m² per day for 7 days) versus 3 weeks on/1 week off (Arm B, 80-100 mg/m² per day for 21 days) in recurrent glioblastoma. Patients were enrolled at first progression after having completed the first-line TMZ radiochemotherapy and at least 2 adjuvant TMZ cycles. At randomization, MGMT gene promoter methylation status from the primary or recurrent tumor was mandatory. The study treatment was monitored every 2 months by MRI using MacDonald criteria. Translational studies included blood biomarker (e.g. regulatory T cell counts, MGMT activity in peripheral blood). In addition, quality-of-life was evaluated by QLQ-C30 and QLQ-BN20 EORTC scores. Neurocognitive testing using the NeuroCogFx was optional. The primary endpoint is median time-to-treatment failure that was defined as progression, toxicity or death from any cause. Secondary endpoints are progression-free survival, overall survival, response and MGMT correlations. The trial was performed in 16 sites in Austria, Germany, and Switzerland. 105 of 166 patients have been enrolled (53 patients in Arm A and 52 patients in Arm B) before the enrollment was prematurely stopped on 30 June 2012. The database will be closed on 30 June 2013. Clinical trial information: NCT00941460.