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A First-in-Human Phase I Study of OPB-111077, a Small-Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in
Anthony Tolcher1, Keith Flaherty2, Geoffrey I Shapiro3
1South Texas Accelerated Research Therapeutics, San Antonio, Texas, USA.
Lessons Learned:
OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation that exhibited promising anticancer activity in preclinical models.In this first-in-human phase I study of OPB-111077 in unselected advanced cancers, treatment-emergent adverse events, most frequently nausea, fatigue, and vomiting, were generally mild to moderate in intensity and could be medically managed.Overall, only modest clinical activity was observed after OPB-111077 given as monotherapy. Notable antitumor activity was seen in a subject with diffuse large B-cell lymphoma.
Background:
OPB-111077 is a novel inhibitor of STAT3 and mitochondrial oxidative phosphorylation with promising anticancer activity in preclinical models.
Methods:
Open-label, phase I trial of OPB-111077 in advanced cancers with no available therapy of documented benefit. Initial dose escalation in unselected subjects was followed by dose expansion. Patients received oral OPB-111077 daily in 28-day cycles until loss of clinical benefit.
Results:
Eighteen subjects enrolled in dose escalation, and 127 in dose expansion. Dose-limiting toxicities were observed at 300 mg and 400 mg QD; maximum tolerated dose was defined as 250 mg QD. Frequently reported treatment-emergent adverse events (TEAEs) included nausea, fatigue, and vomiting. TEAEs were generally mild to moderate and could be medically managed. OPB-111077 reached micromolar drug concentrations, had an elimination half-life of approximately 1 day, and reached steady-state by day 8. A durable partial response was observed in one subject with diffuse large B-cell lymphoma. Seven subjects with diverse tumor types had stable disease or minor responses for at least eight treatment cycles (224 days).
Conclusion:
OPB-111077 is generally well tolerated, and its pharmacokinetic profile is sufficient for further clinical development. Notable clinical activity was observed in a subject with diffuse large B-cell lymphoma. Overall, modest efficacy was observed against unselected tumors.
Insights
This phase I trial investigated OPB-111077, a novel STAT3 and mitochondrial inhibitor, in advanced cancers. While generally well-tolerated, it showed modest overall efficacy, with a notable response in diffuse large B-cell lymphoma.
Area of Science:
- Oncology
- Pharmacology
Background:
- OPB-111077 is a novel STAT3 and mitochondrial oxidative phosphorylation inhibitor.
- Preclinical studies showed promising anticancer activity.
Purpose of the Study:
- Evaluate the safety and tolerability of OPB-111077 in a first-in-human phase I study.
- Determine the maximum tolerated dose (MTD) and pharmacokinetic profile.
- Assess preliminary clinical activity in patients with advanced cancers.
Main Methods:
- Open-label, phase I trial with dose escalation and expansion.
- Patients received oral OPB-111077 daily in 28-day cycles.
- Unselected patients with advanced cancers and no documented benefit from prior therapy were enrolled.
Main Results:
- 145 subjects enrolled (18 in dose escalation, 127 in dose expansion).
- Maximum tolerated dose (MTD) established at 250 mg QD; dose-limiting toxicities at 300-400 mg QD.
- Common adverse events: nausea, fatigue, vomiting; generally mild to moderate.
- Pharmacokinetics: ~1-day half-life, steady-state by day 8.
- One durable partial response in diffuse large B-cell lymphoma; stable disease or minor responses in 7 subjects.
Conclusions:
- OPB-111077 is generally well-tolerated with adequate pharmacokinetics for further development.
- Modest overall clinical activity observed in unselected advanced cancers.
- Significant antitumor activity noted in one patient with diffuse large B-cell lymphoma.
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