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 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. Clin Cancer Res; 20(7); 1900–9. ©2014 AACR.

Smoothened

Tolerability

Dysgeusia

Pharmacodynamics

10.1158/1078-0432.ccr-13-1710

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Citations (219)

A PHASE 3, MULTICENTER, OPEN-LABEL, RANDOMIZED, CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF ORAL SONIDEGIB (LDE225) VERSUS TEMOZOLOMIDE IN PATIENTS WITH HEDGEHOG PATHWAY-ACTIVATED RELAPSED MEDULLOBLASTOMA

Mark W. Kieran Darren Hargrave P.Y. Wen Stewart Goldman Dereck D. Amakye

Temozolomide

Open label

Off-label use

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The controversial role of the Hedgehog pathway in normal and malignant hematopoiesis

Leukemia (2011)

Brenton G. Mar Dereck D. Amakye Iannis Aifantis Silvia Buonamici

Smoothened

Patched

Hematopoietic stem cell

10.1038/leu.2011.143

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Citations (63)

COO5. Phase I study of the smoothened inhibitor LDE225 in patients with advanced solid tumours

Melanoma Research (2011)

Reinhard Dummer Jordi Rodón Hussein A. Tawbi Dereck D. Amakye Yaping Shou

Dummer, R.a; Rodon, J.b; Tawbi, H.c; Amakye, D.d; Shou, Y.d; Granvil, C.d; Feng, W.d; Gobbi, S.a; Thomas, A.e; Garcia-Patos, V.b; Mita, A.C.f Author Information

Smoothened

10.1097/01.cmr.0000399439.50622.b5

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Abstracts

Neuro-Oncology (2013)

Li Bie Yo‐El S. Ju Jin Zhang Loretta Donovan S. Birks

INTRODUCTION: Ginsenoside Rg3 is a natural active ingredient that is extracted from Korean red ginseng root.It elevates therapeutic effect of radiotherapy and chemotherapy, but the study found that the application of Rg3 is heavily limited by its low bioavailability and poor absorption via oral administration.METHOD: Rg3-loaded PEG-PLGA-NPs (Rg3-NPs) were prepared by the modified spontaneous emulsification solvent diffusion (SESD) method, and the physicochemical characteristics of Rg3-NPs were investigated in our study.We treated primary glioblastoma with 50 mM Rg3-NPs for 48h.We then used gene expression arrays (Illumina) for genome-wide expression analysis and validated the results for genes of interest by means of Real-Time PCR.Functional annotations were then performed using the DAVID and KEGG online tools.RESULTS: MTT shows that the growth of cells can be significantly inhibited by Rg3-NPs in a dose-dependence manner.FCM test shows Rg3-NPs can be released from the conjugate nanoparticle and react with the genes in the cell nuclei causing changes in the gene molecules.We also found that cancer cells treated with Rg3-NPs undergo cell-cycle arrest at different checkpoints.This arrest was associated with a decrease in the mRNA levels of core regulatory genes as determined by microarray-analysis and verified by Real-Time PCR.Furthermore, Rg3-NPs induced the expression of apoptotic and anti-migratory proteins p53 in cell lines.CONCLUSIONS: The results of the present study, together with the results of earlier studies show that Rg3-NPs targets genes involved in the progression of the M-phase of the cell cycle.It is associated with several important pathways, which include apoptosis (p53).Rg3-NPs may be a potent cell-cycle regulation drug targeting the M-phase in glioblastoma cell lines. 0004.

10.1093/neuonc/not047

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Citations (1)

Phase I study of LDE225 in advanced solid tumors: Updated analysis of safety, preliminary efficacy, and pharmacokinetic-pharmacodynamic correlation.

Journal of Clinical Oncology (2011)

Hussein A. Tawbi Jordi Rodón Reinhard Dummer A. Thomas Camille Granvil

3062 Background: LDE225 is a potent and selective inhibitor of Smo, a key regulatory protein in the Hedgehog (Hh) signaling pathway, which is linked to the pathogenesis of many human cancers. This open-label, dose-escalation study aims to evaluate the tolerability, safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of LDE225. Methods: Patients (pts) with advanced cancer (n=76) received oral doses of LDE225, ranging from 100 to 3,000 mg QD and 400 and 750 mg BID, on a continuous 28-day dosing schedule, with a single dose PK run-in period. Dose escalations were guided by a Bayesian logistic regression model. Clinical assessments for safety and antitumor activity were performed. Blood was sampled for PK, as were skin and tumor biopsies for PD analysis. Results: LDE225 was well tolerated up to 800 mg QD. At QD doses ≥ 1,000 mg and BID doses ≥ 400 mg, dose-limiting CTCAE G3/4 increases in plasma creatine phosphokinase (CK) associated with myalgia were observed. Treatment-related G1/2 AEs in > 10% of pts include nausea, vomiting, dysgeusia, decreased appetite, myalgia, muscle spasms and fatigue. Systemic exposure of LDE225 increased with increasing dose but was less than dose-proportional. Steady-state concentrations were achieved after 28 days, with a mean effective half-life of approximately 6 days (range: 1–14 days). An association between high systemic drug exposure and dose-limiting CK elevation was identified. Exposure-dependent reduction in Gli-1 mRNA expression was observed in skin and tumor biopsies (up to 95% and 99%, respectively). A link between Hh target gene expression and antitumor activity was demonstrated in pts with medulloblastoma (1 PR and 1 metabolic PR) and advanced basal cell carcinoma (BCC; 1 CR with histologic clearance and 4 PRs). Disease stabilization (> 4 months) in 5 pts (lung adenocarcinoma, spindle cell sarcoma, breast cancer, and BCC [x2]) was also observed. Conclusions: The MTD of LDE225 is 800 mg QD. LDE225 exhibits exposure-dependent target inhibition, a promising antitumor activity that is linked with Hh pathway inhibition, and evidence of histologic clearance in BCC.

Dysgeusia

Pharmacodynamics

myalgia

Tolerability

10.1200/jco.2011.29.15_suppl.3062

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A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers

Cancer Chemotherapy and Pharmacology (2006)

D. Ross Camidge M. N. Pemberton Jim Growcott Dereck D. Amakye David M. Wilson

Pharmacodynamics

10.1007/s00280-006-0387-2

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Citations (24)