Background: A wide variety of human cancers exhibit dysregulated c-Met activity that has implications in oncogenesis. Phosphorylation of c-Met results in activation of the PI3K/AKT/mTOR pathway. Combined blockade of c-Met and mTOR pathways has shown efficacy in preclinical studies. ARQ 197 (tivantinib) is a c-Met inhibitor and temsirolimus is a selective mTOR inhibitor. We aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the above combination. Methods: This open-label phase I study used a 3 + 3 dose escalation design. Patients (pts) in cohorts of 3 were treated with escalating doses of ARQ 197 (120-360 mg tablets orally twice daily) and temsirolimus (20 mg IV weekly) followed by dose expansion at MTD. Separate cohorts were planned for poor and extensive ARQ 197 metabolizers based on CYP2C19 genotypes. Cycles were 28 days besides cycle 1 that was 35 days to allow for PK analysis. Results: 21 pts (median age 57 [range 29-71]) were enrolled for dose escalation. All were extensive CYP2C19 metabolizers. The most common types of cancer were colorectal (6 pts), ovarian (4 pts), renal (2 pts) and pancreatic (2 pts). In the dose escalation cohort, 16/21 pts were evaluable per protocol. They remained on study for a median of 73.6 days (range 15-296). The MTD was ARQ 197 240 mg bid and temsirolimus 20 mg once weekly. DLTs included grade (gr) 4 neutropenia (2 pts; 1 with gr 3 febrile neutropenia) and gr 3 abdominal pain (1 pt). The most common AEs at least possibly related to therapy included: fatigue (62%; gr 1-2 in 12 pts, gr 3 in 1 pt), anemia (48%; gr 2 in 9 pts, gr 3 in 1 pt), nausea (48%; gr 1-2 in 9 pts, gr 3 in 1 pt), vomiting (48%; gr 1-2 in 9 pts, gr 3 in 1 pt) and diarrhea (48%; gr 1-2 in 9 pts, gr 3 in 1 pt). 1 pt with ovarian cancer had a confirmed partial response and remained on study for 9 months. A second pt with ovarian cancer has stable disease and remains on study at 5 months. 4 of 6 pts have been enrolled to the dose expansion cohort and are in cycle 1. Data from the dose expansion will be presented. Conclusions: The combination of ARQ 197 with temsirolimus appears to be well tolerated with evidence of clinical activity. The MTD expansion and PK analysis are ongoing. Clinical trial information: NCT01625156