title: Phase I, multicenter, open-label, dose-escalation study of sonidegib in Asian patients with advanced solid tumors.
abstract: Sonidegib is a selective inhibitor of Smoothened receptor, which is a key regulator of the Hedgehog signaling pathway. The purpose of this study was to determine the maximum tolerated dose based on dose-limiting toxicity (DLT) and the recommended dose (RD) of sonidegib in Asian patients with advanced solid tumors. This was an open-label, single-arm, multicenter, two-group, parallel, dose-escalation, phase I study undertaken in Asian patients; group 1 included patients from Japan and group 2 included patients from Hong Kong and Taiwan. Dose escalation was guided by a Bayesian logistic regression model dependent on DLTs in cycle 1 and other safety findings. A total of 45 adult Asian patients with confirmed advanced solid tumors were enrolled. Group 1 included 21 patients (12 treated with 400 mg q.d. [once daily] and 9 treated with 600 mg q.d.) and group 2 included 24 patients (12 treated with 400 mg q.d., 8 treated with 600 mg q.d., and 4 treated with 800 mg q.d.). Elevation in creatine kinase was the DLT in both groups. The most common adverse events suspected to be related to sonidegib in both patient groups were increase in creatine kinase levels, myalgia, fatigue, and abnormal hepatic function. The RD of 400 mg q.d. was defined in both groups. Difference in tolerability was noted between the East Asian patients and Western population. The RD in East Asian patients (400 mg q.d.) was lower than in patients from Europe and the USA (800 mg q.d. and 250 mg twice daily). (Registered with Clinicaltrials.gov: NCT01208831.).
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan. hminami@med.kobe-u.ac.jp.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Minami
authors.affiliation: Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ando
authors.affiliation: Department of Clinical Oncology, Phase I Clinical Trial Centre, Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Brigette Buig Yue
authors.initials: BB
authors.lastname: Ma
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Jih-
authors.initials: J
authors.lastname: Hsiang Lee
authors.affiliation: Department of Neurosurgery, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Momota
authors.affiliation: Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.|Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Clinical Oncology, Prince of Wales Hospital, Shatin, Hong Kong.
authors.forename: Leung
authors.initials: L
authors.lastname: Li
authors.affiliation: Novartis Pharma, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukino
authors.affiliation: Translational Clinical Oncology Department, Biomarkers and Support Group, Novartis Pharma, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ito
authors.affiliation: Oncology Clinical Development Department, Oncology Clinical Pharmacology Group, Novartis Pharma, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tajima
authors.affiliation: Novartis Pharma, Tokyo, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Mori
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.|Department of Urology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D015415:Biomarkers; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D001713:Biphenyl Compounds; D011725:Pyridines; C561435:sonidegib
keywords: Creatine kinase; hedgehog; phase I study