Background: CTO is an oral inhibitor of non-voltage-dependent calcium signaling that results in simultaneous modulation of several receptor-mediated signaling pathways. A single-agent phase I trial determined the maximum tolerated dose (MTD) at 427 mg/m2, with a safe toxicity profile. A phase IB in combination with TMZ for recurrent malignant glioma found therapeutic brain tissue concentrations and early evidence of activity, with radiographic responses and median survival of 15 months, prompting this newly diagnosed disease study. Methods: Following a 3+3 design, pts were enrolled to receive escalating doses of daily CTO (219-481mg/m2) added to the standard GBM RT regimen (60 Gy concurrent with TMZ 75 mg/m² daily, followed by adjuvant TMZ 150-200 mg/m2 X5/28 days). Results: All enrolled pts (N = 15) had GBM (methylated MGMT: 33%; unmethylated: 67%). Next generation sequencing (N = 9) showed mutations involving TERT (56%), EGFR (33%), IDH-1 (22%) and TP53 (44%), among others. ChemoRT was well tolerated at CTO doses of 219-481 mg/m², with no dose-limiting toxicities (DLT) observed during the DLT period; adverse events included fatigue, nausea, constipation and headache. DLTs were however observed beyond the DLT observation period, and after RT: Gr 3 febrile neutropenia (N = 2), gr 4 neutropenia (N = 1), gr 4 platelets (N = 1) and gr 3 ALT/AST (N = 1). This prompted a halt in dose escalation at 481 mg/m² (declared the maximum administered dose, MAD) and expansion of a lower dose level (370 mg/m²). Efficacy evaluation is ongoing, with one confirmed partial response and stable diseases for 7+ cycles. PK data confirmed therapeutic levels starting at 219 mg/m². Tissue and DCE-perfusion MRI correlates are ongoing. Conclusions: CTO in combination with RT and TMZ is safe and well tolerated. The MAD dose was 481 mg/m2 and recommended phase II dose is 370 mg/m2, although further evaluation of this dose level and longer follow up may be warranted. Further phase IB studies of CTO should consider designs such as continuous reassessment method, which better address late toxicities in comparison to a 3+3 design. Given encouraging signals of activity, a randomized study is warranted. Clinical trial information: NCT01107522