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.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  NCT01184807.
authors.affiliation: 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.
authors.forename: A L
authors.initials: AL
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: R A
authors.initials: RA
authors.lastname: Soo
authors.affiliation: Department of Medical Oncology, National Cancer Centre.
authors.forename: D S
authors.initials: DS
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: S C
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Department of Haematology-Oncology, National University Health System; Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System.
authors.forename: J S
authors.initials: JS
authors.lastname: Lim
authors.affiliation: Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System.
authors.forename: P C
authors.initials: PC
authors.lastname: Marban
authors.affiliation: Cancer Science Institute.
authors.forename: L R
authors.initials: LR
authors.lastname: Kong
authors.affiliation: Cancer Science Institute.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Cancer Science Institute; Departments of Pharmacology.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Cancer Science Institute.
authors.forename: W L
authors.initials: WL
authors.lastname: Thuya
authors.affiliation: Cancer Science Institute.
authors.forename: R
authors.initials: R
authors.lastname: Soong
authors.affiliation: Cancer Science Institute.
authors.forename: M Q
authors.initials: MQ
authors.lastname: Yee
authors.affiliation: 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.
authors.forename: T M
authors.initials: TM
authors.lastname: Chin
authors.affiliation: Haematology Oncology Research Group, National University Cancer Institute of Singapore, National University Health System.
authors.forename: M T
authors.initials: MT
authors.lastname: Cordero
authors.affiliation: Cancer Science Institute.
authors.forename: B R
authors.initials: BR
authors.lastname: Asuncion
authors.affiliation: Cancer Science Institute.
authors.forename: B
authors.initials: B
authors.lastname: Pang
authors.affiliation: Physiology, Yong Loo Lin School of Medicine.
authors.forename: S
authors.initials: S
authors.lastname: Pervaiz
authors.affiliation: Cancer Science Institute.
authors.forename: J L
authors.initials: JL
authors.lastname: Hirpara
authors.affiliation: Department of Diagnostic Imaging, National University Health System, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Otsuka Beijing Research Institute, Beijing, China.
authors.forename: W W
authors.initials: WW
authors.lastname: Xu
authors.affiliation: Otsuka Pharmaceutical Co., Ltd, Chiyoda-ku.
authors.forename: M
authors.initials: M
authors.lastname: Yuasa
authors.affiliation: Otsuka Pharmaceutical Co., Ltd, Chiyoda-ku.
authors.forename: T
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Otsuka Pharmaceutical Co., Ltd, Chiyoda-ku.
authors.forename: M
authors.initials: M
authors.lastname: Motoyama
authors.affiliation: Fuji Memorial Research Institute, Otsuka Pharmaceutical Co. Ltd, Chiyoda-ku, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.affiliation: 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.
authors.forename: B C
authors.initials: BC
authors.lastname: Goh
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001208:Asia; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: STAT3 inhibitor; biomarker; phase I; refractory solid malignancies