AT7867 AT-7867 against both the VEGF receptor and platelet

derived growth factor receptor families. Recently, Toh and colleagues reported the results of an open label, multicenter phase II trial of linifanib, which evaluated the agent in 44 patients with advanced HCC.9 The proportion of patients who AT7867 AT-7867 remained progression free at 16 weeks was 31.8 , this rate was higher in patients with Child Pugh A versus Child Pugh B disease. Similarly, the median OS was 9.7 months, this rate was higher in patients with Child Pugh A disease. The most common grade 3 4 adverse events reported with linifanib were hypertension and fatigue. Based on these successful results, linifanib is currently in phase III clinical development for HCC.10Brivanib is a dual selective inhibitor of both the fibroblast growth factor receptor and the VEGF receptor.
11 Preclinical studies with brivanib suggested it inhibited tumor growth in an animal model of HCC.12 This finding led to a phase II trial, the analysis of which was recently reported by Finn and colleagues.13 In 101 patients with advanced BIBR 1532 HCC, brivanib induced both tumor responses and disease stabilization. Based on these promising data, brivanib is now being evaluated in a number of phase III clinical studies in the first line and second line settings.14,15 Sunitinib is an orally available inhibitor of the VEGF and platelet derived growth factor receptor as well as of c Kit. Recently, a randomized phase III trial comparing the superiority of sunitinib against sorafenib was discontinued, following an independent review by the Data Monitoring Committee.
16 This review found that there was a higher incidence of serious adverse events in the sunitinib arm compared with the sorafenib arm, and it also showed that sunitinib did not meet the criteria to demonstrate either superiority or noninferiority in OS compared with sorafenib. In a randomized, phase II clinical trial, sorafenib in combination with doxorubicin was evaluated against doxorubicin plus placebo.17 The primary endpoint of median time to progression was 9 months for the doxorubicin plus sorafenib arm and 5 months for the doxorubicin plus placebo arm. An exploratory comparison of OS between the 2 arms showed a significant difference of 13.8 months in favor of doxorubicin plus sorafenib versus 6.5 months for doxorubicin plus placebo. Grade 3 4 toxicities included fatigue and neutropenia.
Sorafenib related toxicities included grade 3 4 diarrhea and grade 3 4 hand foot syndrome. The most concerning toxicity was an increased incidence of left ventricular dysfunction in the doxorubicin plus sorafenib arm. These data suggest that a potential synergistic effect between doxorubicin and sorafenib leading to worsening cardiac function may exist. Anthracyclines such as doxorubicin depend on Ask 1 to exert their cell death effect. In liver cancer cells, a bFGFmediated activation of Raf 1, one of the targets of sorafenib, may promote a complex between Raf 1 and Ask 1 at the mitochondrial level, le