A phase I/II study of LDE225, a smoothened (Smo) antagonist, in pediatric patients with recurrent medulloblastoma (MB) or other solid tumors.

• DOI: 10.1200/jco.2012.30.15_suppl.9519
• Publication Date: 2020-03-11T19:25:38Z
• Authors: Birgit Geoerger; Isabelle Aerts; Michela Casanova; Julia C. Chisholm; Darren R Hargrave; Sarah Leary; David M Ashley; Eric Bouffet; Tobey MacDonald; Eunju Hurh; Jyotirmoy Dey; Stacey Kalambakas; Dereck Dokyi Amakye; Mark W. Kieran
• Keywords: Smoothened; Vismodegib

9519 Background: Hedgehog (Hh) signaling is crucial in the development and homeostasis of many human organs tissues. Aberrant Hh involved tumorigenesis through promotion cell proliferation, survival, differentiation wide range cancers, including approximately 30% MBs. LDE225 a potent selective inhibitor Smo, key positive regulator signaling. The phase I exploring safety pharmacokinetics pediatric patients with advanced solid tumors that are potentially dependent on Preliminary data from ongoing presented. Methods: Dose-escalation was performed according to Bayesian design starting at 372 mg/m 2 continuous once daily oral LDE225. Safety preliminary efficacy maximum tolerated dose will be assessed adult recurrent MB II expansion part. Pharmacokinetic profiles were Day 1 21. Tumor samples analyzed for pathway activation status using 5-gene signature assay. Results: Thirty-three (24 MB, 3 rhabdomyoscarcoma [RMS], osteosarcoma, each neuroblastoma, gliomatosis oligoastrocytoma) median age 13 years (range, 4–17 y) have enrolled. Dose-limiting toxicity Grade 4 creatine phosphokinase elevation occurred RMS patient out 7 treated . No dose-limiting observed 233 425 mg /m absorbed T max h 1–24 h). Systemic exposures comparable adults. Two achieved confirmed complete response (CR) doses Analysis 14 available tumor assay showed CR Hh‑activated tumor. remaining 12 who did not achieve determined non-activated. Conclusions: well malignancies. show promising medulloblastoma support use as pre-selection tool future trials.