Phase Ib, Single-arm Study of AZD6094 (Volitinib) in Combination With Docetaxel, in Any Solid Cancer and Sequential Phase II, Single-arm Study of AZD6094 (Volitinib) in Combination With Docetaxel in Advanced Gastric Adenocarcinoma Patients With MET Amplification as a Second Line Treatment

Phase Ib/II, single-arm study of AZD6094 (Volitinib) in combination with docetaxel, in advanced gastric adenocarcinoma patients with MET amplification as a second-line treatment. Phase Ib:Investigational product, dosage and mode of administration Volitinib is an orally available, potent, selective, small molecule c-MET inhibitor. Volitinib should be administered at least 200mg orally once a day in 21 days for achieving appropriate antitumor activity. Docetaxel 60 mg/m2 will be administered via intravenous access once every 3 weeks Phase II: Investigational product, dosage and mode of administration Volitinib is an orally available, potent, selective, small molecule c-MET inhibitor. Subjects will receive Volitinib once daily ( at the MTD determined from Phase Ib) for 21 days as one cycle. Docetaxel 60 mg/m2 will be administered via intravenous access once every 3 weeks.

Volitinib is a potent and selective small molecule c-Met kinase inhibitor. Volitinib was found to inhibit c-Met kinase at the enzyme and cell levels with IC50s of 4 nM for both enzyme and Met phosphorylation in the cell. Consistent with its potent enzyme and cell activity, volitinib was found to inhibit cell growth in vitro against tumors with c-Met gene amplification in the absence of HGF stimulation with IC50s generally below 10 nM. It also potently inhibited HGF-stimulated cell proliferation against tumors with c-Met overexpression or carrying a HGF/c-Met autocrine loop. In a xenograft model Hs746T with c-Met gene amplification, suboptimal doses 0.6 mg/kg volitinib and 3 mg/kg docetaxel induced TGI(expand) of 55.8% and 80.8%, respectively, whereas combination resulted in a TGI by 101.1%, and statistical significance was seen between combination group and either of mono-therapy group. Plasma exposures of volitinib and docetaxel were determined after last dose at the end of study, and there was no significant difference between combination and single agent on exposures of either volitinib or docetaxel. More importantly, combination was well tolerant and no body weight loss was found in the animals. These results suggested that it would be worthwhile to study the combination use of volitinib and docetaxel in clinic.