University of Leicester
Sonidegib Ph I manuscript_CCR_resubmission_31Oct2013.pdf (1.18 MB)

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

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journal contribution
posted on 2019-02-28, 12:22 authored by J Rodon, HA Tawbi, AL Thomas, RG Stoller, CP Turtschi, J Baselga, J Sarantopoulos, D Mahalingam, Y Shou, MA Moles, L Yang, C Granvil, E Hurh, KL Rose, DD Amakye, R Dummer, AC Mita
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.


Financial support for editorial assistance was provided by Novartis Pharmaceuticals Corporation. The Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas, is also funded by the Cancer Center Support grant P30CA054174. The University of Pittsburgh Cancer Institute shared resources that are supported in part by award P30CA047904 were used for this project. The UPCI-Clinical Translational Research Center supported by the Clinical Translational Science Institute under the award NIH/NCRR/CTSA Grant UL1 RR024153 was used for this project.



Clin Cancer Res, 2014, 20 (7), pp. 1900-1909

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