title: Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD) and biologic activity of OPB-31121, an oral inhibitor of STAT3, administered twice daily (BID) to subjects with advanced solid tumors.
  
  
  METHODS
  Subjects received escalating doses of OPB-31121 BID for the first 21 days of each 28-day cycle in a standard 3 + 3 design. Dose-limiting toxicities (DLTs), safety, pharmacokinetics, and antitumor activity were assessed.
  
  
  RESULTS
  Thirty subjects were treated twice daily with OPB-31121 at 6 dose levels: 50 mg (n = 4); 70 mg (n = 3); 140 mg (n = 3); 200 mg (n = 4); 300 mg (n = 9); 350 mg (n = 7). There were no DLTs observed until 300 mg BID (Grade 3 lactic acidosis). At the next dose level (350 mg BID), two subjects had DLTs (Grade 3 vomiting and Grade 3 diarrhea). Thus, 300 mg BID was declared the MTD. OPB-31121-related adverse events included nausea (80 %), vomiting (73 %), diarrhea (63 %), and fatigue (33 %), all of which were primarily grade 1/2. Pharmacokinetics demonstrated high inter-subject variability with exposures 146- to 4,788-fold lower than target concentrations from tumor-bearing mouse models. No objective responses were observed, and all subjects who completed two cycles of treatment had disease progression at their first assessment.
  
  
  CONCLUSIONS
  Twice-daily administration of OPB-31121 was feasible up to doses of 300 mg. The pharmacokinetic profile was unfavorable, and no objective responses were observed.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA, jbendell@tnonc.com.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.forename: Patricia
authors.initials: P
authors.lastname: Bricmont
authors.forename: Agnes
authors.initials: A
authors.lastname: Elekes
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Rock
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000140:Acidosis, Lactic / Q000139:chemically induced / Q000503:physiopathology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced / Q000503:physiopathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015507:Drugs, Investigational / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005240:Feasibility Studies; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000503:physiopathology; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D012720:Severity of Illness Index
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D050796:STAT3 Transcription Factor