A phase I study of ARQ 197 in combination with temsirolimus in patients (Pts) with advanced solid tumors.

2555 Background: Disregulated c-Met activity is implicated in tumor progression and metastasis. Phosporylation of c-Met leads to activation of the PI3K/AKT/mTOR pathway. Preclinical studies demonstrate that combined inhibition of c-Met and mTOR is effective. ARQ 197 (tivantinib) is an inhibitor of c-Met and Temsirolimus selectively inhibits mTOR. This study is designed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), adverse events (AEs), clinical activity, and pharmacokinetic (PK) parameters of this combination. Methods: This open label phase I study utilizes a 3+3 dose escalation of ARQ 197 (120mg-480mg bid) and Temsirolimus (20-25mg IV weekly) followed by dose expansion at MTD. ARQ 197 is primarily metabolized by CYP2C19. Separate cohorts for dose escalation are incorporated for poor and extensive metabolizers. Cycles are 28 days, except cycle 1 which is 35 days, to evaluate PK interactions. Results: 14 pts (median age 60.5 [range 29-71]; 8 male:6 female) were enrolled. T...