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
dc.contributor.author | Wong, A. | |
dc.contributor.author | Soo, R. | |
dc.contributor.author | Tan, D. | |
dc.contributor.author | Lee, S. | |
dc.contributor.author | Lim, J. | |
dc.contributor.author | Marban, P. | |
dc.contributor.author | Kong, L. | |
dc.contributor.author | Lee, Y. | |
dc.contributor.author | Wang, L. | |
dc.contributor.author | Thuya, W. | |
dc.contributor.author | Soong, R. | |
dc.contributor.author | Yee, M. | |
dc.contributor.author | Chin, T. | |
dc.contributor.author | Cordero, M. | |
dc.contributor.author | Asuncion, B. | |
dc.contributor.author | Pang, B. | |
dc.contributor.author | Pervaiz, Shazib | |
dc.contributor.author | Hirpara, J. | |
dc.contributor.author | Sinha, A. | |
dc.contributor.author | Xu, W. | |
dc.contributor.author | Yuasa, M. | |
dc.contributor.author | Tsunoda, T. | |
dc.contributor.author | Motoyama, M. | |
dc.contributor.author | Yamauchi, T. | |
dc.contributor.author | Goh, B. | |
dc.date.accessioned | 2017-03-17T08:29:10Z | |
dc.date.available | 2017-03-17T08:29:10Z | |
dc.date.created | 2017-02-19T19:31:45Z | |
dc.date.issued | 2015 | |
dc.identifier.citation | Wong, A. and Soo, R. and Tan, D. and Lee, S. and Lim, J. and Marban, P. and Kong, L. et al. 2015. 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. Annals of Oncology. 26 (5): pp. 998-1005. | |
dc.identifier.uri | http://hdl.handle.net/20.500.11937/50956 | |
dc.identifier.doi | 10.1093/annonc/mdv026 | |
dc.description.abstract |
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.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<sup>705</sup>) 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. | |
dc.publisher | Oxford University Press | |
dc.title | 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 | |
dc.type | Journal Article | |
dcterms.source.volume | 26 | |
dcterms.source.number | 5 | |
dcterms.source.startPage | 998 | |
dcterms.source.endPage | 1005 | |
dcterms.source.issn | 0923-7534 | |
dcterms.source.title | Annals of Oncology | |
curtin.department | School of Biomedical Sciences | |
curtin.accessStatus | Open access via publisher |
Files in this item
Files | Size | Format | View |
---|---|---|---|
There are no files associated with this item. |