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.)

Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas

“…CK elevation was the most common grade 3/4 event, occurring in 6% of patients taking the 200 mg dose; women show a lower risk of CK abnormality than men 52. Furthermore, CK elevations were observed at low doses in Japanese patients, which resulted in their lower MTD of sonidegib 48,49. Serious adverse events, including rhabdomyolysis and very high CK, were very rarely associated with sonidegib.…”

GLI1 activation is a key mechanism of erlotinib resistance in human non‑small cell lung cancer

“…For example, the SMO inhibitor, vismodegib, was approved by the Food and Drug Administration for the treatment of advanced and metastatic basal cell carcinoma (BCC) ( 33 , 34 ). Vismodegib and numerous other SMO inhibitors, such as sonidegib ( 35 – 38 ) and saridegib ( 39 , 40 ), are currently undergoing clinical trials in the treatment of BCC and many types of solid tumors ( 25 ).…”

The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

“…The safety, efficacy and tolerability of sonidegib have been investigated as monotherapy or in combined therapies in human trials for the clinical management of several advanced solid tumors. For MB patients, the treatment with sonidegib has been reported in four clinical trials Table 1 [31,32]. A phase I trial on patients with recurrent or refractory MB (NCT01125800) showed that oral once daily sonidegib administration (680 mg/m 2 related to the Body Surface Area, BSA) was well tolerated in children and had antitumor activity in both pediatric and adult patients with relapsed SHH-MB (Table I) [31].…”

“…Clinical trials are being conducted to evaluate the efficacy of vismodegib and sonidegib in MB. These two drugs are known to be targeting the upstream receptor SMO and have already been approved by the Food and Drug Administration (FDA) for treating metastatic or locally advanced BCC [30][31][32]. However, the responses to SMO inhibitors have been variable, likely due to SMO drug-resistance mutations.…”