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

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 exposuredependent 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.

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

“…Patients were randomized 1 : 2 to 200 or 800 mg based on previous data suggesting that 800 mg would show better efficacy 7. Randomization was performed using the central Interactive Response Technology system (Cenduit, Allentown, PA).…”

“…Surgery, the primary course of treatment for most BCCs, and radiotherapy are often not viable options in advanced BCC 1, 2, 3. In recent years, hedgehog (Hh) pathway inhibitors (HPIs) were developed to block aberrant Hh signalling that is found in most sporadic BCCs; HPIs have demonstrated efficacy in patients with laBCC and those with mBCC 4, 5, 6, 7, 8, 9, 10, 11, 12, 13…”

Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration

“…Replacement of such lost TRCs following nerve injury can occur but depends on reestablishment of the innervation (6,7). Although the molecular mechanisms by which neurons induce TRC maintenance and regeneration remain unknown, a potential involvement of the Hedgehog protein signal is suggested by loss or alteration of taste sensation in cancer patients systemically treated with any of several drugs that block response to the Hedgehog signal (8)(9)(10)(11).…”

Malignant rhabdoid tumors of soft tissues in children. Literature review

“…Повторное включение гена SMARCB1 приводит к сни-жению уровня экспрессии GLI1 в образцах тканей, что указывает на участие данного пути в формиро-вании ЗРО. SHH-ингибиторы (такие, как висмоде-гиб) находятся в I-II фазах клинических исследова-ний при медуллобластоме, триоксид мышьяка вошел в клиническую практику как средство борьбы с острым промиелоцитарным лейкозом [102][103][104].…”