Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma

Aim 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. Conclusion 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.