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
Ralph Salloum, Tersa Purzner, Clinton Stewart, Yu Wang, Daniel Leino, Catherine Cottrell, Benhamida Jamal, Zied Abdullaev, Tina Poussaint, Gordon Li, Richard Lu, Jennifer Young, Priya Vaidyanathan, Giles Robinson, Daniel Moreira, James Felker, Natahn Robison, Eugene Hwang, Sonia Partap, Natasha Pillay Smiley, Sameer Farouk, Patricia Baxter, Franklin Chien, Yoon Cho, Paul Fisher, Jason Fangusaro, Maryam Fouladi, Arzu Onar, Ira DunkelAbstract
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.