Abstract 1288: A Phase I evaluation of safety, pharmacokinetics (PK) and pharmacodynamics (PD) of LDE225, a smoothened (Smo) antagonist, in patients with advanced solid tumors
Authors: Mita Alain , Rodon Jordi , Dummer Reinhard , Baselga Jose , Shou Yaping , Feng Wentao , Mahalingam Devalingam , Thomas Anne , Granvil Camille , Amakye Dereck , Tawbi Hussein 
Published: June 2012

Abstract
Dysregulation of the Hedgehog (Hh) signaling pathway is implicated in the pathogenesis of multiple human cancers. LDE225 is a potent selective and orally bioavailable inhibitor of Smo-dependent Hh signaling. This first-in-human study aims to determine the MTD and recommended phase II dose (RP2D) of LDE225, with secondary objectives assessing safety, PK, PD and efficacy.
Patients (N=71) with advanced solid tumors were treated with oral LDE225 100 to 3000 mg once daily (QD) or 400 and 750 mg twice daily (BID) on a continuous 28-day dosing schedule, with a single dose 7-day PK run-in prior to the first treatment cycle. A minimum of 3 patients were enrolled at each dose level, with dose escalations guided by a Bayesian logistic regression model. Clinical assessments for safety and antitumor activity were performed and blood was sampled for PK assessments. Skin and tumor biopsies were collected for PD analysis.
Once daily dosing of LDE225, up to 800 mg/day, is well tolerated with no reports of DLTs. At QD doses ≥1500 mg and BID doses ≥400 mg, dose-limiting CTCAE G3/4 increases in plasma creatine phosphokinase (CK) associated with muscle pain have been observed. Common (&gt;5%) treatment-related G1/2 AEs reported include nausea, vomiting, dysgeusia, decreased appetite, diarrhea, myalgia, asthenia, headache, muscle cramps, fatigue, and increased plasma CK. Preliminary PK data demonstrates less than dose-proportional increases in Cmax and AUC. Increases in Cmax and AUC0-24h of 3- and 6-fold, respectively, were observed on day 15 compared with day 1, with an effective half-life &gt;4 days (range: 1-14 days). Predicted target LDE225 exposures were achieved between days 15 and 28 at doses ≥400mg/day. Dose- and plasma exposure-dependent inhibition of Hh, indicated by reduction in Gli-1 mRNA expression, were observed, with up to 95% mean reduction in skin compared with baseline values suggesting that PD effect in the skin is a good surrogate for the effect in tumor. Using a logistic regression analysis, a relationship between LDE225 plasma exposure and G3/4 CPK elevation was identified. As predicted, evidence of antitumor activity has been demonstrated in patients with medulloblastoma (1 PR and 1 partial metabolic response) and advanced basal cell carcinoma (1 CR, 2 PRs and 1 SD). Disease stabilization (&gt;4 months) in 4 patients with other cancers (lung adenocarcinoma, spindle cell, sarcoma, breast cancer) were also observed. Updated safety, PK/PD and preliminary efficacy will be presented.
LDE225 is well tolerated following once daily administration at doses up to 800 mg. Exposure-dependent target inhibition in surrogate tissues has been demonstrated and tumor responses have been observed, particularly in tumors with evidence of Hh pathway activation, at tolerable systemic exposures. Further clinical development of LDE225 is supported by the encouraging emerging data.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1288. doi:10.1158/1538-7445.AM2011-1288