Background: Resminostat is an oral hydroxamate-type inhibitor of class I, IIB, and IV histone deacetylases. A European Phase II study of second-line combination therapy with resminostat and sorafenib for hepatocellular carcinoma (HCC) in patients (pts) revealed a promising improvement in overall survival (OS). Here we report the findings on safety and efficacy of an Asian Phase I/II study on first-line combination therapy with sorafenib and resminostat in HCC pts. Methods: Pts with advanced or metastatic HCC considered Child-Pugh A and ECOG 0/1 were enrolled in Japan and Korea. Sorafenib was administered at 400 mg (bid) in both Phase I and II. Resminostat was administered on days 1 to 5 every 14 days. In Phase I, the dose of resminostat was escalated from 400 mg/day (DL1) to 600 mg/day (DL2). In Phase II, pts were randomly assigned to sorafenib monotherapy or sorafenib/resminostat combination therapy at a ratio of 1:1. The primary endpoint was time to progression (TTP). Tumor response was assessed according to RECIST version 1.1 every 6 weeks. Results: A total of 9 pts were enrolled in Phase I (DL1, 3 pts; DL2, 6 pts). Higher incidences of G3-4 toxicities, including one DLT (G4 thrombocytopenia), were observed at DL2. Therefore, DL1 was determined as the recommended dose for Phase II. A total of 170 pts were enrolled in Phase II. The median TTP was 2.8 months in the combination and control arm, respectively (HR: 0.984). No significant difference was observed in the median OS. Retrospective analysis revealed favorable results for the combination option in certain subgroups: for example, HBV+ (TTP: HR, 0.630; OS: HR, 0.846); no prior therapy (TTP: HR, 0.629; OS: HR, 0.590); and platelet count > = 151.000 (TTP: HR, 0.646; OS: HR, 0.509). Conclusions: Although the primary endpoint was not reached in this Phase II all-comer HCC study, the results of the subgroup analysis suggest a population-specific effect for the combination therapy, especially in one which is HBV+. This warrants the further development of this combination as first-line therapy in a well-defined subset of pts with advanced HCC. Clinical trial information: NCT02400788