A First-in-Human Phase I Study of OPB-111077, a Small-Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers.

Abstract

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.

• Authors: Anthony Tolcher, Keith Flaherty, Geoffrey I Shapiro, Jordan Berlin, Thomas Witzig, Thomas Habermann, Andrea Bullock, Edwin Rock, Agnes Elekes, Chester Lin, Dusan Kostic, Naoto Ohi, Drew Rasco, Kyriakos P Papadopoulos, Amita Patnaik, Lon Smith, Gregory M Cote
• Journal: The oncologist (Oncologist) Vol. 23 Issue 6 Pg. 658-e72 (06 2018) ISSN: 1549-490X [Electronic] England
• PMID: 29511132 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©AlphaMed Press; the data published online to support this summary is the property of the authors.

Chemical References

• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, pathology)
• STAT3 Transcription Factor (pharmacology, therapeutic use)