title: Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage.
abstract: OBJECTIVE
  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 post-operative HCC.
authors.affiliation: Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, 1 Chang-Te Street, Taipei 10002, Taiwan.
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Liu
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
authors.forename: Deng-Yn
authors.initials: DY
authors.lastname: Lin
authors.forename: Cheng-Chung
authors.initials: CC
authors.lastname: Wu
authors.forename: Long-Bin
authors.initials: LB
authors.lastname: Jeng
authors.forename: Pin-Wen
authors.initials: PW
authors.lastname: Lin
authors.forename: King-Tong
authors.initials: KT
authors.lastname: Mok
authors.forename: Wei-Chen
authors.initials: WC
authors.lastname: Lee
authors.forename: Hong-Zen
authors.initials: HZ
authors.lastname: Yeh
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Ho
authors.forename: Sheng-Shun
authors.initials: SS
authors.lastname: Yang
authors.forename: Ching-Chih
authors.initials: CC
authors.lastname: Lee
authors.forename: Ming-Chin
authors.initials: MC
authors.lastname: Yu
authors.forename: Rey-Heng
authors.initials: RH
authors.lastname: Hu
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Peng
authors.forename: Kuan-Lang
authors.initials: KL
authors.lastname: Lai
authors.forename: Stanley Shi-Chung
authors.initials: SS
authors.lastname: Chang
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000601:surgery*; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D009844:Oligosaccharides / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D000099175:Heparanase
chemical_list: D004791:Enzyme Inhibitors; D005966:Glucuronidase; D009844:Oligosaccharides; D000099175:Heparanase; C120158:phosphomannopentaose sulfate