A Phase I, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Smoothened Inhibitor Sonidegib (LDE225) in Patients with Advanced Solid Tumors

• DOI: 10.1158/1078-0432.ccr-13-1710
• Publication Date: 2014-02-13T02:34:10Z
• Authors: Jordi Rodon; Hussein A. Tawbi; Anne L. Thomas; Ronald G. Stoller; Christian P. Turt...; Jose Baselga; John Sarantopoulos; Devalingam Mahali...; Yaping Shou; Melissa A. Moles; Lin Yang; Camille Granvil; Eunju Hurh; Kristine L. Rose; Dereck D. Amakye; Reinhard Dummer; Alain C. Mita
• Keywords: Smoothened; Tolerability; Dysgeusia; Pharmacodynamics

Abstract 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 novel smoothened inhibitor sonidegib (LDE225), a potent hedgehog signaling, in patients with advanced solid tumors. Experimental Design: Oral administered 103 tumors, including medulloblastoma basal cell carcinoma (BCC), at doses ranging from 100 3,000 mg daily 250 750 twice daily, continuously, single-dose pharmacokinetics run-in period. Dose escalations were guided by Bayesian logistic regression model. Safety, efficacy, biomarkers skin tumor biopsies assessed. Results: The MTDs 800 daily. main DLT reversible grade 3/4 elevated serum creatine kinase (18% patients) observed ≥ MTD an exposure-dependent manner. Common 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, alopecia. Sonidegib exposure proportionally up 400 displayed nonlinear higher doses. exhibited reduction GLI1 mRNA expression. Tumor responses BCC associated evidence pathway activation. Conclusions: has acceptable safety profile tumors exhibits relapsed medulloblastoma, both which are strongly activated pathway, as determined gene Clin Cancer Res; 20(7); 1900–9. ©2014 AACR.