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
MetadataShow full item record
© 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.
Showing items related by title, author, creator and subject.
Phase I trial of the oral PARP inhibitor olaparib in combination with paclitaxel for first- or second-line treatment of patients with metastatic triple-negative breast cancerDent, R.; Lindeman, G.; Clemons, M.; Wildiers, H.; Chan, Arlene; McCarthy, N.; Singer, C.; Lowe, E.; Watkins, C.; Carmichael, J. (2013)Introduction: This Phase I study evaluated the safety, tolerability and efficacy of olaparib, a potent oral poly(ADP-ribose) polymerase (PARP) inhibitor, in combination with paclitaxel in patients with metastatic ...
In Patients with Established RA, Positive Effects of a Randomised Three Month WBV Therapy Intervention on Functional Ability, Bone Mineral Density and Fatigue Are Sustained for up to Six MonthsPrioreschi, A.; Makda, M.; Tikly, M.; McVeigh, Joanne (2016)Functional ability is often impaired for people with rheumatoid arthritis (RA), rendering these patients highly sedentary. Additionally, patients with RA often take medication known to negatively affect bone mass. Thus ...
The role of functional, radiological and self-reported measures in predicting clinical outcome in spondylotic cervical radiculopathyAgarwal, Shabnam (2011)BackgroundCervical radiculopathy (CR) results in significant disability and pain and is commonly treated conservatively with satisfactory clinical outcomes. However, a considerable number of patients require surgery to ...