OSU 08173 – A Randomized, Double-Blind, Multi-Center, Phase III Study of Brivanib Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Subjects with Advanced Hepatocellular Carcinoma (HCC) Who Have Failed or Are Intolerant to Sorafenib: The BRISK PS Study
HYPOTHESIS: The overall survival of patients with advanced HCC who have progressed following sorafenib therapy, or who are intolerant to it, will be superior for those randomized to receive brivanib plus best supportive care as compared with patients who receive placebo plus best supportive care.
STUDY DESIGN: Double-blind, placebo controlled, randomized phase III clinical trial.
RATIONALE: HCC is diagnosed at an advanced stage in more than 80 percent of patients, precluding potentially curative therapy. The prognosis of advanced HCC largely depends on tumor characteristics, the severity of underlying chronic hepatic disease and the patient’s general condition.
Systemic chemotherapy, immunotherapy and hormonal therapy have been tested in HCC with little benefit. The use of more aggressive systemic chemotherapy regimens is limited by liver cirrhosis and compromised liver function in these patients, whom clinical studies show have a median overall survival of three to seven months.
Overwhelming evidence indicates that angiogenesis is fundamentally important for the progression and dissemination of HCC. Key drivers of this process are the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) pathways.
The recent regulatory approval of sorafenib demonstrates that VEGF-receptor inhibition is an effective therapeutic strategy in HCC in patients with advanced disease. However, recent findings indicate that the efficacy of sorafenib, and antibodies such as bevacizumab, is limited by activation of the FGF pathway, an angiogenic rescue mechanism that overcomes VEGF-receptor-mediated angiogenesis inhibition.
Brivanib (BMS-582664) is an oral, investigational, small-molecule inhibitor of both VEGF receptors and FGF receptors.
Preliminary results of the brivanib phase I/II development program indicate potential clinical activity in patients with advanced tumors who have received prior antiangiogenic treatments. Phase II data in advanced HCC support use of brivanib either in the frontline setting or after one prior anti-angiogenic therapy. By exerting a continuous VEGF-receptor inhibition combined with FGF-receptor pathway blockade, brivanib may prolong overall survival in HCC patients with progressive disease or intolerance to sorafenib treatment.
AT A GLANCE
Clinical trial OSU 08173
PI: Tanios Bekaii-Saab, MD,
assistant professor of Internal
Medicine, Division of Hematology and Oncology
Eligibility: Histologically/cytologically confirmed HCC; Advanced disease not eligible for surgery or loco-regional therapy or progression after surgery or loco-regional therapy; Cirrhosis Child-Pugh A or B score of 7; ECOG 0-2; Life expectancy of at least 8 weeks; Cannot have brain metastases or evidence of leptomeningeal disease; No prior immunotherapy for HCC; No prior use of any systemic anticancer chemotherapy or targeted agents for HCC (except sorafenib).