ID #651 A phase 1/2 and surgical Pediatric Brain Tumor Consortium (PBTC) study evaluating the casein kinase 2 (CK2) inhibitor CX-4945 (silmitasertib sodium) in children and adults with recurrent sonic hedgehog (SHH) medulloblastoma (MB): PBTC-053

Background Phosphoproteomics studies have identified a critical role for the protein kinase CK2 in SHH MB growth by affecting the terminal-most components of the pathway. CX-4945 is an oral selective inhibitor of CK2 with promising preclinical data in medulloblastoma models. Methods PBTC conducted the first multicenter prospective clinical trial of CX-4945 in children and adults with recurrent SHH MB. There were 3 components: phase 1 for skeletally immature patients; phase 2 for skeletally mature patients/adults; and a surgical arm for patients undergoing tumor resection. Stratification by skeletal maturity addressed potential growth plate toxicities with SHH pathway inhibition. SHH subgroup was confirmed by methylation profiling. The phase 1 component followed the rolling-6 design, phase 2 used a Simon two-stage minimax design to assess objective response rate. Results Six subjects (median age: 10.8 years, range 8.3-13.9) were enrolled to the phase 1 component. No dose-limiting toxicities occurred at dose level 2 (800 mg/m2 twice a day given continuously); growth plate toxicities were not observed. Twelve participants (of 16 planned for interim efficacy analysis, median age 24.7 years [range 13.3-42]) enrolled in the phase 2 arm, with no objective responses observed. Three of the planned 6 surgical arm subjects had tumors analyzed for CX-4945 brain tissue concentrations, and 2/3 had measurable concentrations (54 and ∼131 ng/ml). Grade 3/4 adverse related events were limited to hypokalemia and nausea experienced by one subject. Two participants achieved sustained stable disease and remained on treatment for 6 and 9 cycles. Trial enrollment was terminated early due to discontinuation of consortium funding. Conclusions CX-4945 was well tolerated in patients with recurrent SHH MB at doses reaching 800 mg/m2 twice daily, a final maximum tolerated dose was not determined. Early study closure restricts definitive conclusions; however the lack of an efficacy signal suggests limited activity in this patient population.