Faculty Collaboration Database

Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors. Cancer Chemother Pharmacol 2014 Jul;74(1):125-30

Date

05/14/2014

Pubmed ID

24819685

DOI

10.1007/s00280-014-2480-2

Scopus ID

2-s2.0-84903816370 (requires institutional sign-in at Scopus site)   90 Citations

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.

Author List

Bendell JC, Hong DS, Burris HA 3rd, Naing A, Jones SF, Falchook G, Bricmont P, Elekes A, Rock EP, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acidosis, Lactic
Antineoplastic Agents
Biological Availability
Cohort Studies
Colorectal Neoplasms
Diarrhea
Disease Progression
Dose-Response Relationship, Drug
Drug Administration Schedule
Drugs, Investigational
Feasibility Studies
Female
Half-Life
Humans
Male
Middle Aged
Nausea
Neoplasms
STAT3 Transcription Factor
Severity of Illness Index