Background: Second line treatment options in advanced HCC are limited. Axitinib, a selective tyrosine kinase inhibitor (TKI) of VEGFRs 1, 2, 3, merits exploration in HCC. Methods: This was a single arm, phase II trial of axitinib in advanced HCC. Eligible patients (pts) were Child-Pugh (CP) A/B7, with measurable progressive disease (PD) after TKIs/antiangiogenic drugs. Axitinib started at 5 mg bid orally, titrated from 2-10 mg bid as tolerated; 28 days=1 cycle. Treatment continued to PD or intolerable toxicity. Primary endpoint was tumor control; PR, CR or SD at 16 wks by RECIST 1.1 (P₀=5%, P₁=20%), secondary endpoints; compare response by RECIST 1.1 to Choi and modified RECIST, explore dynamic contrast enhanced imaging models, safety, PFS and OS. Results: Thirty pts were enrolled from 01/11-10/13. Median age; 64y (range 18-78), 21 males (70%) with ECOG PS 0/1 (9/21 pts), CP A (73%), BCLC staging C (100%), etiology hepatitis B/C (30%/30%), alcohol (17%) with prior therapy; Temsirolimus/Bevacizumab (2pts), sorafenib/doxorubicin (2pts) and sorafenib alone (26pts). Med duration of treatment; 4 cycles (range 1-17). Out of 26pts evaluable for response, there were 2 confirmed PRs per RECIST 1.1; 10 PR by Choi, 8 PR and 1 CR by modified RECIST. Tumor control rate at 16 wks; 42% (95%CI 22.3-63.1), 7 pts had SD >28 wks. 2 week perfusion changes were noted on functional imaging. Of 22 pts with evaluable AFP response, 8 (36%) had >50% decrease from baseline. Most common axitinib related grade 3 (G3) AEs were hypertension (HTN) (17%) and diarrhea (10%), 2 had G4 thrombocytopenia. Only 20% of pts tolerated dose escalation above 5 mg bid. Of 11 pts with any grade HTN, 7 had disease control >28 wks. Dose interruptions due to AEs were common (40%); included anorexia (13%), fatigue (10%), HTN (7%). 4 pts discontinued treatment due to related AEs. PFS + OS data are maturing. Current 3 mo PFS rate; 59%. 80% have progressed at this time, 4 pts remain on treatment. Conclusions: With 42% tumor control at 16 wks, primary endpoint was met.Axitinib has shown encouraging tolerable clinical activity in this VEGF pretreated HCC pt population and warrants further study incorporating potential biomarkers of response. Clinical trial information: NCT 01334112.