624PD - A phase III trial of muparfostat (PI-88) as adjuvant therapy in patients with hepatitis virus related hepatocellular carcinoma (HV-HCC) after resection

Abstract

Background: Muparfostat is an investigational new drug which deters tumor growth by blocking tumor angiogenesis and prevents tumor cells from spreading via heparanase inhibition. Previous phase II trial of muparfostat demonstrated good tolerability and favorable clinical response. Methods: This international multicenter clinical trial was conducted in Asia-Pacific region (Taiwan, Korea, China, and Hong-Kong) from 2011. A total of 520 HV-HCC patients after surgical resection were randomized (1:1) to receive injection of either muparfostat (160 mg/day, 4-days-on/3-days-off, 3-weeks-on/1-week-off) or placebo for 52 weeks and followed up for 96 weeks. The primary endpoint was centrally assessed disease-free survival (DFS). Secondary endpoints included overall survival (OS), time to recurrence, and safety. Results: Baseline patient demographics and characteristics were balanced between the treatment and placebo arms. All subjects completed the 52-week treatment. After interim analysis in 2014, the trial was concluded in 2015. The final intention-to-treat analysis (N = 519) yielded a non-significant result (p > 0.05) on DFS, not reaching the primary end point. Nevertheless, per-protocol analysis (N = 423) revealed a possible positive protective effect in subgroup patients with microvascular invasion. Muparfostat showed a significant prolongation in the disease-free time after completion of the 1-year treatment (hazard ratio: 0.13, 95% CI: 0.017 - 0.991, p = 0.049). Muparfostat had a good safety profile. There were five clinically suspected cases of heparin-induced thrombocytopenia but only one was confirmed. Conclusions: Despite the DFS was not improved in the overall treatment group, muparfostat could significantly prolong the DFS in the microvascular-invasion subgroup, comprising 40% of the trial population. The finding potentiated muparfostat as single therapy or in combination with other anti-cancer agents for future HCC adjuvant therapy trials. Clinical trial identification: PATRON/NCT01402908 Legal entity responsible for the study: Medigen Biotechnology Corporation Funding: Medigen Biotechnology Corporation Disclosure: P-J. Chen: Honorarium from Medigen Biotechnology Corporation. K-L. Lai: Employee of Medigen Biotechnology Corporation. All other authors have declared no conflicts of interest.