Lessons learned: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models.In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed.Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B-cell lymphoma.
Background: OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models.
Methods: Open-label, phase I trial of OPB-111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB-111077 daily in 28-day cycles until loss of clinical benefit.
Results: Eighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose-limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment-emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB-111077 reached micromolar drug concentrations, had an elimination half-life of approximately 1 day, and reached steady-state by day 8. A durable partial response was observed in one subject with diffuse large B-cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days).
Conclusion: OPB-111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B-cell lymphoma. Overall, modest efficacy was observed against unselected tumors.
经验总结
OPB‐111077是STAT3和线粒体氧化磷酸化的新型抑制剂, 在临床前模型中显示出有极具前景的抗癌活性。
在针对非选择性晚期癌症患者进行的这一首项OPB‐111077人体I期研究中, 治疗期出现的不良事件（最常见的是恶心、疲劳和呕吐）的强度通常为轻度至中度, 并且可以进行医学管理。
总体而言, 进行OPB‐111077单药治疗后仅观察到中度临床活性。在弥漫性大B细胞淋巴瘤受试者中观察到明显的抗肿瘤活性。
摘要
背景.OPB‐111077是STAT3和线粒体氧化磷酸化的新型抑制剂, 在临床前模型中显示出有极具前景的抗癌活性。
方法. 本项是OPB‐111077治疗无可用的获益记载疗法的晚期癌症的开放标签I期试验。在非选择性受试者中经过初始剂量递增研究后, 进行剂量扩展研究。患者每日接受OPB‐111077口服给药, 以28天为一周期, 直至丧失临床获益。
结果.18例受试者进入剂量递增研究, 127例受试者进行剂量扩展研究。在300 mg和400 mg QD剂量下观察到剂量限制性毒性；最大耐受性剂量定义为250 mg QD。经常报告的治疗期出现的不良事件（TEAE）包括恶心、疲劳和呕吐。TEAE通常为轻度至中度, 并且可以进行医学管理。OPB‐111077达到微摩尔药物浓度, 消除半衰期约为1天, 至第8天达到稳态。在一例弥漫性大B细胞淋巴瘤受试者中观察到部分缓解持续时间较长。7例肿瘤类型不同的受试者病情稳定或出现轻微缓解达至少8个治疗周期（224天）。
结论.OPB‐111077通常具有良好的耐受性, 其药代动力学特征足以支持进一步的临床开发。在一例弥漫性大B细胞淋巴瘤受试者中观察到明显的临床活性。总体而言, 观察到对非选择性肿瘤有中度疗效。
Trial registration: ClinicalTrials.gov NCT01711034.
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