Cancer Res Treat.  2015 Oct;47(4):607-615. 10.4143/crt.2014.249.

Phase I Study of OPB-31121, an Oral STAT3 Inhibitor, in Patients with Advanced Solid Tumors

• Oh DY
• Lee SH
• Han SW
• Kim MJ
• Kim TM
• Kim TY
• Heo DS
• Yuasa M
• Yanagihara Y
• Bang YJ

• KMID: 2403378
• DOI: http://doi.org/10.4143/crt.2014.249

Abstract

PURPOSE
OPB-31121 is an oral STAT3 inhibitor with a good preclinical antitumor activity. This phase I dose-escalation study of OPB-31121 was conducted to determine maximum-tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor efficacy in patients with advanced solid tumors.
MATERIALS AND METHODS
Patients received OPB-31121 once daily for 28 days of each cycle followed by 2 weeks rest. A standard 3+3 design was used for dose-escalation. Safety and response were evaluated by the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) ver. 3.0 and Response Evaluation Criteria in Solid Tumor (RECIST) ver. 1.0, respectively.
RESULTS
Twenty-five patients were treated with OPB-31121 at five dose levels: 100 mg (n=4), 200 mg (n=3), 400 mg (n=3), 600 mg (n=7), and 800 mg (n=8). Seven patients discontinued treatment during cycle 1 for various reasons other than study drug-related adverse events. Among 18 patients who were evaluable for dose-limiting toxicity (DLT), three DLTs were observed: one DLT (grade 3 vomiting) at 600 mg and two DLTs (grade 3 vomiting, grade 3 diarrhea) at 800 mg. The MTD was determined as 800 mg/day. Common adverse events were gastrointestinal adverse event including nausea (84%), vomiting (80%), and diarrhea (72%). Pharmacokinetics did not demonstrate dose-proportionality of OPB-31121. Eight patients had stable disease and 10 patients had disease progression. Two patients (1 colon cancer, 1 rectal cancer) showed tumor shrinkage. One gastric cancer patient continued treatment up to cycle 13 before disease progression.
CONCLUSION
This study demonstrates feasibility of STAT3 inhibition in patients with advanced solid tumor. OPB-31121, at the MTD of 800 mg/day, was safe and relatively well tolerated, and has a preliminary antitumor activity.

Keyword

OPB-31121; STAT3; STAT3 inhibitor; Solid tumor; Phase I

MeSH Terms

Colonic Neoplasms
Diarrhea
Disease Progression
Humans
Nausea
Pharmacokinetics
Stomach Neoplasms
Vomiting

Figure

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  Fig. 1. Plasma concentration versus time profiles of OPB-31121 following oral administration of OPB-31121 on day 1 (A) and on day 28 (B).

Reference

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