TY - JOUR
T1 - A First-in-Human Phase I Study of OPB-111077, a Small-Molecule STAT3 and Oxidative Phosphorylation Inhibitor, in Patients with Advanced Cancers
AU - Tolcher, Anthony
AU - Flaherty, Keith
AU - Shapiro, Geoffrey I.
AU - Berlin, Jordan
AU - Witzig, Thomas
AU - Habermann, Thomas
AU - Bullock, Andrea
AU - Rock, Edwin
AU - Elekes, Agnes
AU - Lin, Chester
AU - Kostic, Dusan
AU - Ohi, Naoto
AU - Rasco, Drew
AU - Papadopoulos, Kyriakos P.
AU - Patnaik, Amita
AU - Smith, Lon
AU - Cote, Gregory M.
N1 - Publisher Copyright:
©AlphaMed Press; the data published online to support this summary is the property of the authors
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
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U2 - 10.1634/theoncologist.2017-0325
DO - 10.1634/theoncologist.2017-0325
M3 - Article
C2 - 29511132
AN - SCOPUS:85048851637
SN - 1083-7159
VL - 23
SP - 658-e72
JO - Oncologist
JF - Oncologist
IS - 6
ER -