Background: Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. DX1002 is a novel, specific, small-molecule, tubulin inhibitors, that targets the beta subunit of tubulin in tumor vascular endothelial cells. It has been designed to destroy tumor blood vessels which has been demonstrated in preclinical efficacy models. The objectives of this trial were to assess safety, tolerability and preliminary efficacy of DX1002 in patients (pts) with pre-treated advanced HCC or gastric cancer. Here, we present the results from the HCC subpart. Methods: This is a prospective, single-arm open-label multi-center phase Ib/IIa trial (CTR2400080296) to investigate DX1002 in patients with pre-treated advanced HCC or gastric cancer. Patients received DX1002 600 mg orally once daily, continuously in 28-day cycles until progressive disease or intolerable toxicity. Primary endpoints were safety and objective response rate (ORR); other endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), pharmacokinetics and safety. Results: From Jun-2021 to Jan-2024, 40 patients with advanced HCC were enrolled. The median age was 54 (36-71) years. As of 31-Jan-2024, of the 40 pts, 4 pts (10.0%) showed PR and 15 (37.5%) had SD. ORR was 21.1% and DCR was 47.5%. The median PFS was 3.55 (95% CI 2.89-8.31) months and median OS was 13.4 (95% CI 11.0-NA) months. Any-grade TRAEs occurred in 75% pts (30/40), with 22.5% Grade 3 (9/40). The most common TRAEs were Aspartate aminotransferase increased (22.5%), total bilirubin increased (20%), albuminuria (20%), Hypoalbuminemia (15%) and gamma-glutamyl transferase increased (15%). Four patients (10%) discontinued DX1002 due to TRAEs. No death-related cases occurred. Conclusions: Initial data shows DX1002 demonstrated manageable safety profile and promising anti-tumor potential in pre-treated advanced hepatocellular carcinoma. Further exploration of DX1002 in HCC is warranted. Clinical trial information: ChiCTR2400080296.