Background: Volitinib is a selective oral small molecule inhibitor of cMet kinase with potent in vivo inhibitory effects on a variety of human tumor xenografts. Methods: This phase I, first-in-human dose-escalation study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) profile, and preliminary antitumor activity of volitinib. Results: By Dec 31, 2013, 32 patients (pts) had been enrolled and treated with volitinib at doses of 100-1000mg QD or 300-400mg BID. Pts had a median age of 61 (27-78) yrs, 66% were male. The most common tumor types were papillary renal cell carcinoma (PRCC, 6) and CRC (5). The most common adverse events were constipation, diarrhea, fatigue, nausea, vomiting, dizziness and peripheral edema, mostly grade (G) 1/2. Four pts reported 5 DLTs: 1 G3 elevated ALT (600mg QD), 1 G3 fatigue (800mg QD), and 2 G3 fatigues and 1 G3 headache (1000mg QD). 800mg was identified as MTD of the QD regimen. Dose-escalation in the BID cohort is currently ongoing at 400mg BID. PK analysis showed volitinib was rapidly absorbed with Tmax around 2 hours and half-life around 5 hours. Both Cmax and AUC displayed dose-proportional increase and no obvious accumulation occurred. Two PRCC pts in the 600mg QD cohort (one with ongoing treatment at 1 year) and 1 PRCC pt in the 300mg BID cohort achieved partial response. A CRC pt in the 600mg QD cohort achieved 29% tumor reduction. A PRCC pt in the 1000mg QD cohort achieved 27% tumor reduction and remains on study. Analysis of pre-treatment tumor sample showed that the responders had either gene copy number increase (Chromosome7 gains or MET gene amplification) or high MET protein expression. Conclusions: Volitinib was well tolerated at doses up to 800 mg QD and demonstrated promising anti-tumor activity in pts with evidence of dysregulated MET signaling. It demonstrated linear PK without marked drug accumulation. Further clinical studies are warranted. Clinical trial information: NCT01773018.