title: Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma.
abstract: OBJECTIVE
  To evaluate the safety, pharmacokinetics and antitumor activity of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma (HCC).
  
  
  METHODS
  HCC patients of Child-Pugh A or B who progressed on, or were intolerant to, sorafenib were eligible for this phase 1 trial. We used a standard 3 + 3 dose-escalation design with a 28-day cycle at dose levels of 50, 100, 200 and 400 mg/day. Tumor responses were assessed using the modified Response Evaluation Criteria in Solid Tumors.
  
  
  RESULTS
  Twenty-four patients were enrolled, of whom 23 received OPB-31121 (20 males; median age, 65 years). The most common adverse drug reactions were nausea (87.0%), vomiting (82.6%), diarrhea (69.6%), fatigue/malaise (52.2%), anorexia (47.8%) and peripheral sensory neuropathy (26.1%). The recommended dose for OPB-31121 was determined to be 200 mg. Six patients had stable disease for 8 weeks or more, resulting in disease control rates of 25.0-42.9%. In the 200-mg dose cohort, three of seven patients had stable disease and a median time to progression of 61.0 days. The maximum concentration and area under the plasma concentration-time curve of OPB-31121 were dose proportional.
  
  
  CONCLUSIONS
  OPB-31121 demonstrated insufficient antitumor activity for HCC. Furthermore, peripheral nervous system-related toxicities may negatively affect long-term administration of OPB-31121. Therefore, it was deemed difficult to continue the clinical development of OPB-31121 for treating advanced HCC and further investigation is expected in the agent with favorable profile in this category.
authors: National Cancer Center Hospital.
authors: Takuji
authors: T
authors: Okusaka
authors: National Cancer Center Hospital.
authors: Hideki
authors: H
authors: Ueno
authors: National Cancer Center Hospital East, Kashiwa.
authors: Masafumi
authors: M
authors: Ikeda
authors: National Cancer Center Hospital East, Kashiwa.
authors: Shuichi
authors: S
authors: Mitsunaga
authors: Japanese Foundation for Cancer Research.
authors: Masato
authors: M
authors: Ozaka
authors: Japanese Foundation for Cancer Research.
authors: Hiroshi
authors: H
authors: Ishii
authors: Otsuka Pharmaceutical, Tokyo.
authors: Osamu
authors: O
authors: Yokosuka
authors: Otsuka Pharmaceutical, Tokyo.
authors: Yoshihiko
authors: Y
authors: Ooka
authors: Chiba University Hospital, Chiba.
authors: Ryo
authors: R
authors: Yoshimoto
authors: Fujii Memorial Research Institute, Otsuka Pharmaceutical, Otsu.
authors: Yasuo
authors: Y
authors: Yanagihara
authors: Shunan Memorial Hospital, Yamaguchi, Japan.
authors: Kiwamu
authors: K
authors: Okita
keywords: OPB-31121; advanced hepatocellular carcinoma; dose escalation; phase 1 trial; recommended dose; signal transducer and activator of transcription-3 inhibitor