Most glioblastoma tumours exhibit intrinsic phosphatidylinositol 3-kinase (PI3K) pathway activation. Preclinical in vitro and in vivo models suggest that buparlisib (an oral pan-PI3K inhibitor) can have an effect on glioblastoma directly and by enhancing the activity of radiation and of temozolomide. This was a phase I, two-stage, multicentre, open-label, dose-escalation study of buparlisib in combination with temozolomide and radiotherapy in patients with newly diagnosed glioblastoma. In stage I, patients who completed the concomitant phase of combination of temozolomide and radiation prior to study entry received buparlisib in combination with temozolomide. In stage II, patients received buparlisib in combination with temozolomide and radiotherapy in the concomitant phase and temozolomide in the adjuvant treatment phase. The primary objective was to estimate the maximum tolerated dose (MTD) of buparlisib when combined with the approved first-line treatment of temozolomide and radiotherapy. The MTD of buparlisib in combination with temozolomide at stage I (adjuvant phase only) was 80 mg/day, which was used as the starting dose in stage II. The MTD of buparlisib in combination with temozolomide and radiotherapy in stage II (concomitant + adjuvant phase) was not determined due to the observed dose-limiting toxicities and treatment discontinuations due to adverse events (AEs). In stage I, the most commonly reported AEs were nausea (72.7%) and fatigue (59.1%). In stage II, the most commonly reported AEs were fatigue and nausea (56.3% each). No on-treatment deaths were reported during the study. Considering that the primary objective of estimating the MTD was not achieved in addition to the observed challenging safety profile of buparlisib in combination with radiotherapy and temozolomide, Novartis decided not to pursue the development of buparlisib in newly diagnosed glioblastoma.Trial registration numberClinicalTrials.gov identifier: NCT01473901.