Phase I Study for Ceritinib (Ldk378) in Japanese Patients with Alk Genetic Alterations

Aim: ALK rearranged (ALK+) NSCLC is sensitive to tyrosine kinase inhibitors (TKI) such as crizotinib and alectinib, but resistance develops. A global Phase I trial (Shaw et al, NEJM 2014) of ceritinib, a novel ALK TKI, established 750 mg daily as MTD, with an ORR of 59%. The primary objective of the present study was to estimate MTD in Japanese pts. Methods: The study enrolled Japanese pts with ALK+ advanced tumors. Adaptive dose escalations were guided by a Bayesian model. Results: 19 pts (18 NSCLC) received ceritinib 300-750 mg QD. The most common AEs were gastrointestinal toxicities (nausea 95%, diarrhea, vomiting 74%). Two DLTs occurred; Grade 3 lipase increase at 600 mg and Grade 3 drug-induced liver injury at 750 mg. ORR was 58% (11/19). In 9 crizotinib- and 3 alectinib-pretreated pts, partial responses were achieved by 5 and 2 pts. One alectinib/crizotinib-pretreated pt with disease progression in the brain had a 43% reduction in target tumor lesions. Conclusions: Ceritinib MTD was 750 mg QD in Japanese pts, with a safety profile comparable to that in the global trial. Antitumor activity was observed in ALK TKI-resistant pts. The dose expansion part to further examine the activity of ceretinib in alectinib resistant pts is ongoing, and preliminary results of this part will be presented. Disclosure: T. Seto: I have received research funding and honoraria from Novartis Pharma K.K; N. Suenaga: Naoko Suenaga is an employee of Novartis Pharma K.K; T. Tajima: Takeshi Tajima is an employee of Novartis Pharma K.K; K. Tokushige: Kota Tokushige is an employee of Novartis Pharma K.K; A.L. Boral: Anthony Boral is a full time employee of Novartis Pharmaceuticals; M. Robson: Matthew Robson is an employee of Novartis Pharma K.K. All other authors have declared no conflicts of interest.