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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

Rodon, J and Tawbi, HA and Thomas, AL and Stoller, RG and Turtschi, CP and Baselga, J and Sarantopoulos, J and Mahalingam, D and Shou, Y and Moles, MA and Yang, L and Granvil, C and Hurh, E and Rose, KL and Amakye, DD and Dummer, R and Mita, AC (2014) 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. CLINICAL CANCER RESEARCH. pp. 1900-1909.

Abstract

Purpose: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), doselimiting 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. (C) 2014 AACR

Item Type: Article
Additional Information: NIBR author: Shou, Y institute: NIBR contributor address: Vall Hebron Inst Oncol, Barcelona, Spain, Univ Autonoma Barcelona, E-08193 Barcelona, Spain ; Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA, Univ Pittsburgh, Sch Med, Pittsburgh, PA 15232 USA tawbih@upmc.edu; Univ Leicester, Leicester, Leics, England ; Univ Zurich Hosp, CH-8091 Zurich, Switzerland ; Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA ; Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, Inst Drug Dev, San Antonio, TX 78229 USA ; Novartis Inst BioMed Res, Cambridge, MA USA ; Nova Pharmaceut Corp, E Hanover, NJ USA ; Vall Hebron Inst Oncol, Barcelona, Spain; Univ Autonoma Barcelona, E-08193 Barcelona, Spain; Tawbi, HA; Univ Pittsburgh, Inst Canc, Div Hematol Oncol, 5150 Ctr Ave, Pittsburgh, PA 15232 USA
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12
URI: https://oak.novartis.com/id/eprint/22591

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