Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients

Purpose: Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib versus sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). Experimental design: In phase I, resminostat (400mg or 600mg/day on days 1 to 5 every 14days) was administered with sorafenib (800mg/day for 14days) to determine the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Results: Nine patients (3: 400mg, 6: 600mg) were enrolled in phase I, and the recommended dose of resminostat was determined to be 400mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1months with monotherapy versus 2.8/11.8months with combination therapy (Hazard Ratio [HR]: 0.984, p=0.925/HR: 1.046, p=0.824). The overall incidence of adverse events was similar in both groups (98.8% versus 100.0%). However, thrombocytopenia Grade 3 was significantly more frequent in the combination therapy group (34.5% versus 2.4%, p<0.001). Subgroup analysis revealed that median TTP/OS was 1.5/6.9months for monotherapy versus 2.8/13.1months for combination therapy (HR: 0.795, p=0.392/HR: 0.567, p=0.065) among patients with a normal-to-high baseline platelet count ( 150x10(3)/mm(3)). Conclusions: In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.