ArQule, Inc.'s partner Kyowa Hakko Kirin Co. has initiated a phase III clinical trial evaluating tivantinib (ARQ 197) in Japanese patients with c-Met diagnostic-high inoperable hepatocellular carcinoma treated with one prior sorafenib therapy.

The phase III trial is a randomized, double-blind placebo-controlled study to compare progression-free survival (PFS) in patients treated with tivantinib with those treated with placebo. Kyowa Hakko Kirin plans to enroll approximately 160 patients in this study.

"With the commencement of this study, two phase III trials are now ongoing worldwide to evaluate the impact of tivantinib therapy in second line HCC," said Brian Schwartz, MD, chief medical officer of ArQule. "We are also enrolling patients in the ongoing pivotal, randomized, double-blind METIV-HCC trial, being conducted in the West by ArQule and our partner, Daiichi Sankyo Co., Ltd., under a Special Protocol Assessment (SPA) agreement."

Tivantinib is an orally administered, selective inhibitor of MET, a receptor tyrosine kinase, which is currently in phase II and III clinical trials. In certain healthy adult cells, MET is present in low to normal levels to support natural cellular function, but in some cancer cells, MET is inappropriately and continuously activated. When abnormally activated, c-Met plays multiple roles in aspects of human cancer, including cancer cell growth, survival, angiogenesis, invasion and metastasis. The activation of certain cell signalling pathways, including MET, has also been associated with the development of resistance to EGFR inhibitors such as cetuximab.

Pre-clinical data have demonstrated that tivantinib inhibits MET activation in a range of human tumour cell lines and shows anti-tumour activity against several human tumour xenografts. In clinical trials to date, treatment with tivantinib has been generally well tolerated and has shown clinical activity in the tumours studied. Tivantinib has not yet been approved for any indication in any country.

On December 19, 2008, ArQule and Daiichi Sankyo Co., Ltd. signed a license, co-development and co-commercialization agreement to co-develop tivantinib in the US, Europe, South America and the rest of the world, excluding Japan, China (including Hong Kong), South Korea and Taiwan, areas for which Kyowa Hakko Kirin has exclusive rights for development and commercialization under an exclusive license agreement signed with ArQule in 2007.

ArQule is a biotechnology company engaged in the research and development of next-generation, small-molecule cancer therapeutics.