Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase II trial for safety and optimal dosage.
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.
Liu
Chun-Jen
CJ
Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, 1 Chang-Te Street, Taipei 10002, Taiwan.
Lee
Po-Huang
PH
Lin
Deng-Yn
DY
Wu
Cheng-Chung
CC
Jeng
Long-Bin
LB
Lin
Pin-Wen
PW
Mok
King-Tong
KT
Lee
Wei-Chen
WC
Yeh
Hong-Zen
HZ
Ho
Ming-Chih
MC
Yang
Sheng-Shun
SS
Lee
Ching-Chih
CC
Yu
Ming-Chin
MC
Hu
Rey-Heng
RH
Peng
Cheng-Yuan
CY
Lai
Kuan-Lang
KL
Chang
Stanley Shi-Chung
SS
Chen
Pei-Jer
PJ
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
D004791:Enzyme Inhibitors; D005966:Glucuronidase; D009844:Oligosaccharides; D000099175:Heparanase; C120158:phosphomannopentaose sulfate