A first-in-human phase I study of OPB-111077, a small-molecule STAT3 and oxidative phosphorylation inhibitor, in patients with advanced cancers
Open accessAbstract
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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OPB-111077 demonstrated only modest responses against unselected tumors with objective responses in only two patients with diffuse large B-cell lymphoma.
“OPB-OPB‐111077 demonstrated only modest responses against unselected tumors with objective responses observed in only two patients with diffuse large B‐cell lymphoma.”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Tolcher et al., 2018
The Discussion says OPB-111077 had minimal clinical activity against unselected tumors overall, supporting the claim of modest responses. But it reports a partial response in one subject with diffuse large B-cell lymphoma, not objective responses in two. (LLM, conf=0.90)
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Cites
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“Drugrelated AEs were reported as mild and manageable and included nausea, fatigue, and vomiting (Tolcher et al., 2018).”
Background
- Authors
- Tolcher, A., Flaherty, K., Shapiro, G. I., Berlin, J., Witzig, T., Habermann, T., Bullock, A., Rock, E., Elekes, A., Lin, C., Kostic, D., Ohi, N., Rasco, D., Papadopoulos, K. P., Patnaik, A., Smith, L., & Cote, G. M.
- Affiliations
- South Texas Accelerated Research Therapeutics (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Vanderbilt University (US)
- Mayo Clinic (US)
- Beth Israel Deaconess Medical Center (US)
- Otsuka (United States) (US)
- Otsuka Pharmaceutical Development and Commercialization, Princeton, New Jersey, USA
- Otsuka (Japan) (JP)
- Corresponding author
- Rock, Edwin
- ORCID
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03-06
- Volume
- 23
- Issue
- 6
- Pages
- 658-e72
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC6067949
- OpenAlex
- W2793160291
- Cited by
- 57
- References
- 2
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 7 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 15 · 2019: 8 · 2018: 2
- FWCI
- 3.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Otsuka Pharmaceutical
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK058404)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- STAT3 inhibitor, advanced cancer, diffuse large B-cell lymphoma, maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, anticancer activity, treatment-emergent adverse events, small molecule anticancer agents
- MeSH terms
- Female, Humans, Male, Middle Aged, Neoplasms, STAT3 Transcription Factor
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