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dc.contributor.authorWong, A.
dc.contributor.authorSoo, R.
dc.contributor.authorTan, D.
dc.contributor.authorLee, S.
dc.contributor.authorLim, J.
dc.contributor.authorMarban, P.
dc.contributor.authorKong, L.
dc.contributor.authorLee, Y.
dc.contributor.authorWang, L.
dc.contributor.authorThuya, W.
dc.contributor.authorSoong, R.
dc.contributor.authorYee, M.
dc.contributor.authorChin, T.
dc.contributor.authorCordero, M.
dc.contributor.authorAsuncion, B.
dc.contributor.authorPang, B.
dc.contributor.authorPervaiz, Shazib
dc.contributor.authorHirpara, J.
dc.contributor.authorSinha, A.
dc.contributor.authorXu, W.
dc.contributor.authorYuasa, M.
dc.contributor.authorTsunoda, T.
dc.contributor.authorMotoyama, M.
dc.contributor.authorYamauchi, T.
dc.contributor.authorGoh, B.
dc.identifier.citationWong, 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.

© 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.publisherOxford University Press
dc.titlePhase 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.typeJournal Article
dcterms.source.titleAnnals of Oncology
curtin.departmentSchool of Biomedical Sciences
curtin.accessStatusOpen access via publisher

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