Background: BEV is approved for the treatment of recurrent glioblastoma pts, but there is a lack of effective therapies once a tumor recurs on BEV. CTO, an oral inhibitor of non-voltage-dependent calcium signaling, modulates several pathways (EGFR, MEK, RAS, HDAC, HSP90, WNT/B-catenin, Akt, ERK, VEGF, Bcr-Abl). We postulated that combining CTO with BEV may result in greater VEGF inhibition and might allow salvage post-BEV failure. We are reporting on phase 1 of the study. Methods: Study objectives are to assess the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and activity of CTO when combined with BEV among pts with recurrent WHO grade III or IV MG post-BEV failure. CTO dose escalation has followed a classical 3+3 design at a dose ranging from 225-642mg/m²/day. BEV has been administered intravenously at 10mg/kg every 2 weeks. Pharmacokinetic (PK) sampling is performed during cycle 1 at each dose level. MRI of the brain is evaluated at baseline and every 8 weeks using RANO criteria. Results: To date, 15 pts have been enrolled on study. All pts have WHO grade IV MG. Median age at enrollment is 54 (32-66) years in eight females and seven males. Of the five pts treated at dose level 1 of CTO (225mg/m²/day), three remained stable for 4 cycles and demonstrated CAI (the active moiety of CTO in plasma) levels of 2317 and 361 ng/ml. Of the six pts treated at dose level 2 (293mg/m²/day), one pt remained stable for 7 cycles and one pt experienced a DLT, grade 3 hypertension and fatigue. Four pts were treated on dose level 3 (380 mg/m²/day), but two pts were not eligible for MTD determination, as they discontinued CTO before the end of cycle 1 without experiencing a DLT. Grade 3 study-related adverse events included: fatigue (n = 1), soft tissue infection (n = 1), proteinuria (n = 2) and hypertension (n = 2). No grade 4 or 5 study-related adverse events have been observed. Conclusions: CTO, at a dose of 380mg/m²/day, given in combination with BEV is safe thus far and tolerable. Non-evaluable pts for MTD are being replaced. Some pts having previously failed BEV have remained stable for a period of time on the combination. Further dose escalation is continuing to determine the Phase II dose. Clinical trial information: NCT01954030