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Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with
Johanna C Bendell1, David S Hong, Howard A Burris
1Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3322 West End Avenue, Suite 900, Nashville, TN, 37203, USA, jbendell@tnonc.com.
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.
Insights
The maximum tolerated dose of OPB-31121, a STAT3 inhibitor, was 300 mg twice daily. However, the drug showed poor pharmacokinetics and no antitumor activity in advanced solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- STAT3 signaling is implicated in various cancers.
- Targeting STAT3 is a strategy for cancer therapy.
- OPB-31121 is an oral inhibitor of STAT3.
Purpose of the Study:
- Determine the maximum tolerated dose (MTD) of OPB-31121.
- Assess the biologic activity of OPB-31121.
- Evaluate safety and pharmacokinetics of OPB-31121 in advanced solid tumors.
Main Methods:
- Phase I clinical trial using a 3 + 3 dose escalation design.
- OPB-31121 administered orally twice daily (BID).
- Dose-limiting toxicities (DLTs), safety, pharmacokinetics, and antitumor activity were assessed.
Main Results:
- The MTD was determined to be 300 mg BID.
- Common adverse events included nausea, vomiting, diarrhea, and fatigue.
- Pharmacokinetics showed high inter-subject variability, with exposures lower than predicted.
- No objective responses were observed; all patients experienced disease progression.
Conclusions:
- Twice-daily OPB-31121 is feasible up to 300 mg.
- The drug's pharmacokinetic profile is unfavorable.
- OPB-31121 did not demonstrate antitumor activity in this study.
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