Abstract
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. 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. 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. 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.
Highlights
The hedgehog signaling pathway plays a key role during embryo-fetal development of the brain, bones, and Authors' Affiliations: 1Vall d'Hebron Institut d'Oncologia and Universitat Autonoma of Barcelona, Barcelona, Spain; 2University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 3University of Leicester, Leicester, United Kingdom; 4University Hospital of Zu€rich, Zu€rich, Switzerland; 5Memorial Sloan-Kettering Cancer Center, New York, New York; 6Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas; 7Novartis Institutes for BioMedical Research, Cambridge, Massachusetts; and 8Novartis Pharmaceuticals Corporation, East Hanover, New JerseyNote: Supplementary data for this article are available at Clinical Cancer Research Online.Y
The main doselimiting toxicities (DLT) of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ! the maximum tolerated dose (MTD) in an exposuredependent manner
Tumor responses observed in patients with medulloblastoma and basal cell carcinoma (BCC) were associated with evidence of hedgehog pathway activation
Summary
The hedgehog signaling pathway plays a key role during embryo-fetal development of the brain, bones, and Authors' Affiliations: 1Vall d'Hebron Institut d'Oncologia and Universitat Autonoma of Barcelona, Barcelona, Spain; 2University of Pittsburgh Cancer Institute and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; 3University of Leicester, Leicester, United Kingdom; 4University Hospital of Zu€rich, Zu€rich, Switzerland; 5Memorial Sloan-Kettering Cancer Center, New York, New York; 6Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas; 7Novartis Institutes for BioMedical Research, Cambridge, Massachusetts; and 8Novartis Pharmaceuticals Corporation, East Hanover, New Jersey. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Y. Shou and D.D. Amakye are no longer associated with Novartis. H.A. Tawbi, and A.C. Mita contributed to this article
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