PURPOSE: This phase I trial was undertaken to determine the maximum tolerated 
dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, 
pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the 
novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog 
signaling, in patients with advanced solid tumors.
EXPERIMENTAL DESIGN: Oral sonidegib was administered to 103 patients with 
advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), 
at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, 
continuously, with a single-dose pharmacokinetics run-in period. Dose 
escalations were guided by a Bayesian logistic regression model. Safety, 
tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor 
biopsies were assessed.
RESULTS: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The 
main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of 
patients) was observed at doses ≥ the MTD in an exposure-dependent manner. 
Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal 
toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib 
exposure increased dose proportionally up to 400 mg daily, and displayed 
nonlinear pharmacokinetics at higher doses. Sonidegib exhibited 
exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed 
in patients with medulloblastoma and BCC were associated with evidence of 
hedgehog pathway activation.
CONCLUSIONS: Sonidegib has an acceptable safety profile in patients with 
advanced solid tumors and exhibits antitumor activity in advanced BCC and 
relapsed medulloblastoma, both of which are strongly associated with activated 
hedgehog pathway, as determined by gene expression.