التفاصيل البيبلوغرافية
| العنوان: |
A First‐in‐Human Phase I Study of OPB‐111077, a Small‐Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers. |
| المؤلفون: |
Tolcher, Anthony, Flaherty, Keith, Shapiro, Geoffrey I., Berlin, Jordan, Witzig, Thomas, Habermann, Thomas, Bullock, Andrea, Rock, Edwin, Elekes, Agnes, Lin, Chester, Kostic, Dusan, Ohi, Naoto, Rasco, Drew, Papadopoulos, Kyriakos P., Patnaik, Amita, Smith, Lon, Cote, Gregory M. |
| المصدر: |
Oncologist; Jun2018, Vol. 23 Issue 6, p658-e72, 10p, 7 Charts, 3 Graphs |
| مصطلحات موضوعية: |
ANTINEOPLASTIC agents, B cell lymphoma, CLINICAL trials, CLINICAL drug trials, FATIGUE (Physiology), TRANSCRIPTION factors, TUMORS, TREATMENT effectiveness, SEVERITY of illness index |
| الملخص (بالإنجليزية): |
Abstract: 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. [ABSTRACT FROM AUTHOR] |
| Abstract (Chinese): |
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。 [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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