Background: The oral MKI sorafenib has been shown to significantly increase PFS, OS and DCR in treatment-naïve HCC in randomized Ph 3 trials. Despite these landmark studies OS benefit is modest, particularly for those with C-P cirrhosis grades B/C and toxicity is a major management problem. We report results of second-line treatment with palbociclib, PD-0332991, an orally available selective inhibitor of cyclin dependent kinases 4 and 6, which has potent anti-proliferative activity in pre-clinical studies. Methods: This is an open-label, nonrandomized single institution trial for pts with inoperable, advanced HCC, who have failed or are intolerant of first line therapy with sorafenib. Eligible subjects were treated with 125 mg PD-0332991 orally/day, 1-21 of a 28-day cycle, until disease progression, unacceptable toxicity, withdrawal from study or death. Tumor response by CT or MRI was assessed using mRECIST v1.1. Toxicity assessments were per NCI CTCAE v4.0. The primary endpoint is TTP. Secondary endpoints are safety/tolerability, OS & RR. Results: 21 pts (18 M, 3 F) have been enrolled. Median age: 62 (32-78) yrs. 47% Cauc, 19% AA and 33% Asian. 17 C-P A, 4 C-P B. ETOH 19%, HCV 48%, HBV 24%, NASH 5%, unknown 10%. 71% had >1 metastatic site. All had pathologically confirmed Retinoblastoma-positive HCC. Median duration of therapy was 17 (8-69) wks and (4.25 (2-17) cycles. Most common grade 3/4 AEs were neutropenia and thrombocytopenia. Non-serious AEs were anemia, pain, ascites and fatigue. 4 pts were non-evaluable, median OS = 10.5 (5.5-14) wks. In evaluable pts, there was 1 PR and 0 CRs. 6 pts died of ESLD without observable disease progression by RECIST, median OS = 19 (4 - 43) wks. Nine pts had disease control (PR or SD) followed by disease progression, median TTP was 24 (4-64) wks. Prolonged stability was seen in 3 pts. OS was 40 (24-96) wks, excluding 2 pts who are alive at 120 and 59 wks. 2 pts remain on trial. Conclusions: Palbociclib demonstrates activity in patients with advanced HCC after failure of first-line sorafenib. This trial will meet its primary endpoint. Consistent with a cytostatic MOA, some pts experienced HCC stabilization and OS was determined by ESLD. Palbociclib is well tolerated in cirrhotic patients with advanced HCC. Clinical trial information: NCT01356628