Background: Fostrox is an orally administered troxacitabine-based nucleotide prodrug in clinical development in combination with lenvatinib (NCT03781934). Fostrox is rapidly metabolized by human hepatocytes, directing high levels of the active metabolite to the liver. Phase I fostrox monotherapy demonstrated selective intra-tumoral activity in on-treatment liver biopsies. The anti-angiogenic activity of lenvatinib has the potential to synergize with fostrox by hypoxia-induced increase in the enzymatic generation of the active metabolite of fostrox in the tumor. Methods: In a phase Ib/IIa study with an inter-patient dose escalation 3+3 cohort design followed by a dose expansion phase, fostrox was administered orally QD for 5 days in 21-day cycles in combination with lenvatinib according to local prescription information. Patients (pts) with <2 prior lines systemic treatment for advanced, unresectable HCC were recruited at 10 sites in Spain, South Korea and UK. Pts with histologically, radiologically, or cytologically confirmed HCC, Child-Pugh A, ≥18 years, ECOG PS ≤ 1 and adequate organ function were eligible. The primary objective was to assess safety and tolerability. Key secondary endpoints were ORR based on RECIST 1.1 and mRECIST. Exploratory endpoints included pharmacokinetics (PK) and pharmacodynamic effects of fostrox in combination with lenvatinib. Results: At interim data cut-off 18 pts (6 pts in Ib and 12 pts in IIa) were enrolled at fostrox QD doses of 20mg (3 pts) and 30mg (15 pts) in combination with lenvatinib. Median age was 63 years (range: 42-82). No DLTs and only 1 discontinuation of fostrox due to AEs with a median FU of 3.8 months, were observed. Most common grade 3/4 AEs were transient neutrophil count decrease, platelet count decrease and hypertension. No febrile neutropenia, bleeding events or proteinuria were reported. The safety profile was consistent with each individual agent. In phase Ib, central independent review based on RECIST 1.1 showed SD in 5/6 pts, while mRECIST showed CR in 1 pt, PR in 2 pts and SD in 2 pts. Updated phase Ib data and efficacy data from phase IIa by central independent review, together with PK for fostrox and lenvatinib, and liver biopsy biomarker data, will be presented. Conclusions: Fostrox in combination with lenvatinib, in pts with HCC who progressed on previous systemic treatment, had an acceptable safety and tolerability profile with promising interim efficacy results from the completely enrolled phase Ib/IIa study. Clinical trial information: NCT03781934.