دورية أكاديمية
Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies.
| العنوان: | Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies. |
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| المؤلفون: | Wong AL; Department of Haematology-Oncology, National University Health System; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System; Cancer Science Institute., Soo RA; Department of Haematology-Oncology, National University Health System; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System; Cancer Science Institute., Tan DS; Department of Medical Oncology, National Cancer Centre., Lee SC; Department of Haematology-Oncology, National University Health System; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System; Cancer Science Institute., Lim JS; Department of Haematology-Oncology, National University Health System; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System., Marban PC; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System., Kong LR; Cancer Science Institute., Lee YJ; Cancer Science Institute., Wang LZ; Cancer Science Institute; Departments of Pharmacology., Thuya WL; Cancer Science Institute., Soong R; Cancer Science Institute., Yee MQ; Cancer Science Institute., Chin TM; Department of Haematology-Oncology, National University Health System; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System; Cancer Science Institute., Cordero MT; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System., Asuncion BR; Cancer Science Institute., Pang B; Cancer Science Institute., Pervaiz S; Physiology, Yong Loo Lin School of Medicine., Hirpara JL; Cancer Science Institute., Sinha A; Department of Diagnostic Imaging, National University Health System, Singapore., Xu WW; Otsuka Beijing Research Institute, Beijing, China., Yuasa M; Otsuka Pharmaceutical Co., Ltd, Chiyoda-ku., Tsunoda T; Otsuka Pharmaceutical Co., Ltd, Chiyoda-ku., Motoyama M; Otsuka Pharmaceutical Co., Ltd, Chiyoda-ku., Yamauchi T; Fuji Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd, Chiyoda-ku, Japan., Goh BC; Department of Haematology-Oncology, National University Health System; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System; Cancer Science Institute; Departments of Pharmacology. Electronic address: phcgbc@nus.edu.sg. |
| المصدر: | Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2015 May; Vol. 26 (5), pp. 998-1005. Date of Electronic Publication: 2015 Jan 21. |
| نوع المنشور: | Clinical Trial, Phase I; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: England NLM ID: 9007735 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1569-8041 (Electronic) Linking ISSN: 09237534 NLM ISO Abbreviation: Ann Oncol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2020- : London : Elsevier Original Publication: Dordrecht ; Boston : Kluwer Academic Publishers, c1990- |
| مواضيع طبية MeSH: | Antineoplastic Agents/*pharmacokinetics , Biomarkers, Tumor/*antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/*drug therapy , Lung Neoplasms/*drug therapy , STAT3 Transcription Factor/*antagonists & inhibitors, Administration, Oral ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/blood ; Asia ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Biotransformation ; Carcinoma, Non-Small-Cell Lung/blood ; Carcinoma, Non-Small-Cell Lung/diagnosis ; Carcinoma, Non-Small-Cell Lung/genetics ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; ErbB Receptors/genetics ; Female ; Half-Life ; Humans ; Lung Neoplasms/blood ; Lung Neoplasms/diagnosis ; Lung Neoplasms/genetics ; Male ; Maximum Tolerated Dose ; Metabolic Clearance Rate ; Middle Aged ; Molecular Targeted Therapy ; Mutation ; Phosphorylation ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Treatment Outcome |
| مستخلص: | Background: The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors. Patients and Methods: Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1-14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing. Results: Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr(705)) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor exposure. Conclusion: OPB-51602 demonstrates promising antitumor activity, particularly in NSCLC. Its long half-life and poorer tolerability of continuous dosing, compared with intermittent dosing, suggest that less frequent dosing should be explored. Clinicaltrialsgov Identifier: NCT01184807. (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.) |
| فهرسة مساهمة: | Keywords: STAT3 inhibitor; biomarker; phase I; refractory solid malignancies |
| سلسلة جزيئية: | ClinicalTrials.gov NCT01184807 |
| المشرفين على المادة: | 0 (Antineoplastic Agents) 0 (Biomarkers, Tumor) 0 (STAT3 Transcription Factor) 0 (STAT3 protein, human) EC 2.7.10.1 (EGFR protein, human) EC 2.7.10.1 (ErbB Receptors) |
| تواريخ الأحداث: | Date Created: 20150123 Date Completed: 20160519 Latest Revision: 20220416 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1093/annonc/mdv026 |
| PMID: | 25609248 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1569-8041 |
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| DOI: | 10.1093/annonc/mdv026 |