Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: A randomized phase II trial for safety and optimal dosage

Backgrond/Aims: Hepatocellular carcinoma recurrence after curative treatment adversely influences clinical outcome. It is important to explore adjuvant therapies. This phase II/stage 1 multi-center, randomized trial investigated the safety, optimal dosage and preliminary efficacy of PI-88, a novel heparanase inhibitor, in the setting of post-operative recurrence of HCC according to a Simon's 2-stage design. Methods: Three groups were included: one untreated arm (Group A) and two PI-88 arms (Group B: 160 mg/day; Group C: 250 mg/day). Treatment groups received PI-88 over nine 4-week treatment cycles, followed by a 12-week treatment-free period. Safety and optimal dosage were assessed. Results: Overall, 172 patients were randomized and 168 were included in the intention-to-treat (ITT) population. Treatment-related adverse effects included cytopenia, injection site hemorrhage, PT prolongation, etc. Four serious adverse events were possibly related to PI-88 treatment. One (1.8%) group B patients and six (10.5%) group C had hepatotoxicity-related withdrawals. Among the ITT population, 29 patients (50%) in Group A, 35 (63%) in Group B, and 22 (41%) in Group C remained recurrence-free at completion. Calculated T-1 value suggested 160 mg/day treatment satisfied the criteria for the next stage of the trial. Conclusions: PI-88 at 160 mg/day is optimal and safe, and shows preliminary efficacy as an adjunct therapy for postoperative HCC. (c) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights.