Background: SD may synergistically improve outcome after PD on S by promoting ASK-1 mediated apoptosis through RAF-1 inhibition. In a prior retrospective analysis of 14 pts who in the lack of other choices of therapy received SD after PD on S, progression free survival (PFS) and overall survival (OS) were 3.4 and 10.1 months (m) respectively Methods: A non-randomized, open label, single institution, single arm phase II study of SD in pts with histologically confirmed advanced HCC. Eligibility: RECIST 1.1 radiologic PD on S, ECOG 0-1, Child-Pugh A, and adequate major organ function. Therapy: S 400mg twice a day (once a day if bilirubin (B) ≥1.3mg/dl ≤3mg/dl) and D 60mg/m2 (30mg/m2 if B ≥1.3 mg/dl ≤3mg/dl) on day 1 of 3-week cycle. Cross-sectional imaging was performed every 3 cycles. The primary endpoint was OS at 6m (OS6), based on Simon two-stage design, unacceptable OS6 50%, acceptable OS6 72%, type I and II errors 5 and 15% respectively. Secondary endpoints included PFS, OS, response rate by RECIST 1.1, and associations between duration of prior S and OS and PFS. Baseline and on-treatment biopsies evaluated ASK-1 and p-ERK expression levels (separate report) Results: N = 30 pts enrolled. The majority were male (86%), median age 64 years (range 24-82), 16 pts had hepatitis (53%). OS6 was 76.6% [95%CI: 57.2-88.1%]. Median doses of D and S were 94mg and 380mg respectively. OS was 8.6 [95%CI: 7.3-12] m, and PFS was 3.6 [95%CI: 2.4-4.4] m. There were 3 (10.7%) partial responses and 17 (60.7%) stable disease. Median duration of prior S treatment was 3.3 [range: 0.9-27] m. Neither OS nor PFS were associated with previous S duration (p value 0.11 and 0.15 respectively). Grade 3-4 adverse events occurring in ≥ 10% of pts: neutropenia (16%), febrile neutropenia (10%), lymphopenia (43%), anemia (10%), thrombocytopenia (10%), elevated AST (23%) and ALT (10%), hypophosphatemia (10%), and fatigue (10%). There was no treatment related death. Conclusions: Despite the study meeting its primary endpoint, SD resulted in significant toxicity and a median OS of 8.6 m. Based on front-line evaluation of SD and the results reported herein, further development of SD in HCC is not warranted Clinical trial information: NCT01840592