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A Phase 1, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Hedgehog Inhibitor Sonidegib (LDE225) in Patients With Advanced Solid Tumors


Rodon, Jordi; Tawbi, Hussein A; Thomas, Anne L; Stoller, Ronald; Turtschi, Christian P; Baselga, Jose; Sarantopoulos, John; Mahalingam, Devalingam; Shou, Yaping; Moles, Melissa A; Yang, Lin; Granvil, Camille; Hurh, Eunju; Rose, Kristine L; Amakye, Dereck D; Dummer, Reinhard; Mita, Alain C (2014). A Phase 1, Multicenter, Open-Label, First-in-Human, Dose-Escalation Study of the Oral Hedgehog Inhibitor Sonidegib (LDE225) in Patients With Advanced Solid Tumors. Clinical Cancer Research, 20(7):1900-1909.

Abstract

PURPOSE: This phase 1 trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog (Hh) signaling, in patients with advanced solid tumors.

EXPERIMENTAL DESIGN: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma (MB) and basal cell carcinoma (BCC), at doses ranging from 100 to 3000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose PK run-in period. Dose-escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, PK, 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 PK at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with MB and BCC were associated with evidence of Hh pathway activation.

CONCLUSIONS: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed MB, which is strongly associated with activated Hh pathway, as determined by gene expression.

Abstract

PURPOSE: This phase 1 trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog (Hh) signaling, in patients with advanced solid tumors.

EXPERIMENTAL DESIGN: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma (MB) and basal cell carcinoma (BCC), at doses ranging from 100 to 3000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose PK run-in period. Dose-escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, PK, 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 PK at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with MB and BCC were associated with evidence of Hh pathway activation.

CONCLUSIONS: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed MB, which is strongly associated with activated Hh pathway, as determined by gene expression.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Date:2014
Deposited On:07 Mar 2014 16:41
Last Modified:08 Dec 2017 04:23
Publisher:American Association for Cancer Research
ISSN:1078-0432
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/1078-0432.CCR-13-1710
PubMed ID:24523439

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