A phase I dose-escalation study of LDE225, a smoothened (Smo) antagonist, in patients with advanced solid tumors.

Abstract

2500 Background: LDE225 is a potent and selective inhibitor of Smo, a key signaling protein in the hedgehog (Hh) pathway. Activation of the Hh pathway is implicated in the pathogenesis of a wide range of malignancies. This first-in-human study aims to determine the maximum tolerated dose of LDE225, with additional assessments of its pharmacokinetics (PK), pharmacodynamics (PD), and potential efficacy. Methods: Patients (pts) age ≥18 with advanced solid tumors are treated with LDE225 orally once daily on a continuous 28-day dosing schedule. A single-dose 7-day PK run-in is performed prior to the first treatment cycle. A minimum of 3 patients is enrolled at each dose level, and dose escalation decisions are guided by a Bayesian logistic regression model. Hair follicles and skin biopsies are collected for PD analysis. Results: To date 25 pts have been treated across dose levels of 100, 200, 400, and 800 mg. LDE225 has been well tolerated and no DLTs have been observed. CTC grade 1–2 adverse events considered possibly treatment-related have included fatigue, nausea, vomiting, anorexia, muscle cramps, and dysgeusia. The PK of LDE225 has been dose-proportional, with a mean half-life of 60 hours. There is a 2-fold increase in Cmax and a 4-fold increase in AUC0–24h at steady-state on day 15 compared with day 1. Dose-dependent reductions in Gli1 mRNA expression in skin have been detected on day 28, with mean (95% CI) fold changes from baseline of 1.13 (−6.38, 4.91), −3.17 (−11.41, 1.14), and −7.36 (−53.45, −1.01) at 100, 200, and 400 mg/day, respectively. One pt (medulloblastoma, 200 mg/day) achieved an objective partial response (PR) that was maintained for ∼f4 months and five patients (lung adenocarcinoma, basal cell carcinoma, spindle cell sarcoma, osteosarcoma and breast cancer) have received LDE225 for more than 4 months. Conclusions: LDE225 is well tolerated and has a favorable PK profile. Continued clinical development of LDE225 is supported by the early evidence for its activity, including decreases in Gli-1 mRNA expression in skin and an objective response observed in medulloblastoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Institutes for Biomedical Research Novartis Novartis Novartis