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    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

    Access Status
    Open access via publisher
    Authors
    Wong, A.
    Soo, R.
    Tan, D.
    Lee, S.
    Lim, J.
    Marban, P.
    Kong, L.
    Lee, Y.
    Wang, L.
    Thuya, W.
    Soong, R.
    Yee, M.
    Chin, T.
    Cordero, M.
    Asuncion, B.
    Pang, B.
    Pervaiz, Shazib
    Hirpara, J.
    Sinha, A.
    Xu, W.
    Yuasa, M.
    Tsunoda, T.
    Motoyama, M.
    Yamauchi, T.
    Goh, B.
    Date
    2015
    Type
    Journal Article
    
    Metadata
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    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.
    Source Title
    Annals of Oncology
    DOI
    10.1093/annonc/mdv026
    ISSN
    0923-7534
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/50956
    Collection
    • Curtin Research Publications
    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.

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