A Phase I/Randomized Phase II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nintedanib versus Sorafenib in Asian Patients with Advanced Hepatocellular Carcinoma.

Autor:	Yen CJ; Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan., Kim TY; Seoul National University Hospital, Seoul, Republic of Korea., Feng YH; Chi Mei Medical Center, Yongkang, Tainan, Taiwan., Chao Y; Taipei Veterans General Hospital, Taipei, Taiwan., Lin DY; Chang Gung Memorial Hospital & Chang Gung University, College of Medicine, Taoyuan, Taiwan., Ryoo BY; Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea., Huang DC; Boehringer Ingelheim Taiwan Limited, Taipei, Taiwan., Schnell D; Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany., Hocke J; Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany., Loembé AB; Boehringer Ingelheim B.V., Alkmaar, the Netherlands., Cheng AL; National Taiwan University Hospital, Taipei, Taiwan.; National Taiwan University Cancer Center, Taipei, Taiwan.
Jazyk:	angličtina
Zdroj:	Liver cancer [Liver Cancer] 2018 May; Vol. 7 (2), pp. 165-178. Date of Electronic Publication: 2018 Mar 15.
DOI:	10.1159/000486460
Abstrakt:	Background: Nintedanib is an oral, triple angiokinase inhibitor of vascular endothelial growth factor/platelet-derived growth factor/fibroblast growth factor receptors. This randomized, multicenter, open-label, phase I/II study evaluated the safety, pharmacokinetics, maximum tolerated dose (MTD) in terms of dose-limiting toxicities (DLTs), and efficacy of nintedanib versus sorafenib in Asian patients with unresectable advanced hepatocellular carcinoma (HCC). Patients and Methods: For the phase I portion, patients were stratified into two groups according to their alanine aminotransferase/aspartate aminotransferase (ALT/AST) and Child-Pugh score at baseline. For phase I, the primary endpoint was determination of the MTD in terms of DLTs. For phase II, patients with a Child-Pugh score of 5-6, an Eastern Cooperative Oncology Group performance score ≤2, and an ALT/AST ≤2× the upper limit of normal were enrolled and randomized 2: 1 to nintedanib 200 mg twice daily (b.i.d.) (the MTD determined in phase I) or sorafenib 400 mg b.i.d. continuously in 28-day cycles until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint for phase II was time to progression (TTP) by central independent review (CIR; by Response Evaluation Criteria in Solid Tumors v1.0); the secondary endpoints included overall survival (OS). All analyses were exploratory. Results: The MTD was 200 mg in both groups. For phase II, 95 patients were randomized to nintedanib ( n = 63) or sorafenib ( n = 32). For nintedanib and sorafenib, respectively, the median CIR TTP was 2.8 vs. 3.7 months (hazard ratio [HR] = 1.21, 95% confidence interval [CI] 0.73-2.01) and the median OS 10.2 vs. 10.7 months (HR = 0.94, 95% CI 0.59-1.49). Nintedanib-treated patients had fewer grade 3 or higher AEs (56 vs. 84%), serious AEs (46 vs. 56%), and AEs leading to dose reduction (19 vs. 59%) and drug discontinuation (24 vs. 34%). AEs associated more frequently with nintedanib were vomiting and nausea, whereas those associated more frequently with sorafenib were ALT/AST increases, diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome. Conclusions: Nintedanib showed numerically similar efficacy to sorafenib for CIR TTP and OS in Asian patients with advanced HCC and adequate liver function. AEs were generally manageable.
Databáze:	MEDLINE
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