Background: A possible mechanism of resistance to targeted therapeutics is the existence of redundant signaling pathways. CTO is an oral inhibitor of non-voltage-dependent calcium signaling resulting in simultaneous modulation of several receptor-mediated, calcium-dependent signal transduction pathways, including EGFR, MEK, RAS, HDAC, HSP90, WNT/β-catenin and VEGF. A phase I single-agent study in solid tumors found a safe toxicity profile and predictable pharmacokinetics at doses of 75-427 mg/m²/day, with responses seen in refractory tumors with different mutations. CTO crosses the blood-brain barrier, and pre-clinical studies have shown single-agent activity in glioblastoma xenografts and robust synergism with temozolomide (TMZ), prompting this phase IB study. Methods: Patients with recurrent glioblastoma or MG were eligible regardless of number of recurrences and previous bevacizumab exposure. The primary objective was to establish the maximum tolerated dose (MTD) of daily oral CTO combined with TMZ 150 mg/m²x5 every 28 days, using a standard 3+3 design. Results: The combination was well tolerated, with no dose-limiting toxicities observed at the 4 dose levels examined (N=15), ranging from 219mg to 481mg/m²/day. The most frequent adverse events were fatigue, nausea, vomiting, and dizziness, all of which grades 1 or 2; no QTc prolongation was seen. PK data demonstrated therapeutically relevant metabolite (CAI) levels starting at 219mg/m²doses, with no significant interactions with TMZ. Preliminary evidence of activity was observed: three radiographic responses among 11 evaluable patients; 7 patients continuing treatment beyond 2 cycles; stable disease as durable as 9+ cycles. Tissue correlates and analysis of DCE-perfusion MRI are ongoing. Conclusions: CTO at doses as high as 481mg/m²/day is safe and well tolerated in combination with TMZ, with no MTD defined after examination of all pre-established dose-escalation levels; further escalation to increase CNS exposure may be warranted. The early signals of activity in this heavily pre-treated population are encouraging and deserve further investigation. Clinical trial information: NCT01107522.