Cancer Chemotherapy and Pharmacology

, Volume 74, Issue 1, pp 125–130

Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors

  • Johanna C. Bendell
  • David S. Hong
  • Howard A. BurrisIII
  • Aung Naing
  • Suzanne F. Jones
  • Gerald Falchook
  • Patricia Bricmont
  • Agnes Elekes
  • Edwin P. Rock
  • Razelle Kurzrock
Original Article

Abstract

Purpose

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.

Keywords

STAT3 OPB-31121 Dose escalation Solid tumors 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Johanna C. Bendell
    • 1
  • David S. Hong
    • 2
  • Howard A. BurrisIII
    • 1
  • Aung Naing
    • 2
  • Suzanne F. Jones
    • 1
  • Gerald Falchook
    • 2
  • Patricia Bricmont
    • 3
  • Agnes Elekes
    • 3
  • Edwin P. Rock
    • 3
  • Razelle Kurzrock
    • 2
    • 4
  1. 1.Sarah Cannon Research Institute/Tennessee OncologyPLLCNashvilleUSA
  2. 2.MD Anderson Cancer CenterHoustonUSA
  3. 3.Otsuka Pharmaceutical Development and Commercialization, IncPrincetonUSA
  4. 4.Center for Personalized Cancer TherapyUC San Diego Moores Cancer CenterSan DiegoUSA

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