Biomarker­driven phase Ib clinical trial of OPB­111077 in acute myeloid leukemia.

OPB-111077 is a novel, highly specific oral signal transducer and activator of transcription 3 inhibitor that has exhibited good efficacy against solid and blood cancers, including acute myeloid leukemia (AML), in preclinical models. In the present study, a phase 1b, two-stage, 3+3 dose-escalation clinical trial [dose level (DL)1 of 200 mg/day and DL2 of 250 mg/day on a once daily dose schedule in 28-day cycles] was conducted to assess the maximum tolerated dose (MTD), safety profile and the preliminary antitumor activity of OPB-111077 in patients with high-risk AML. A preliminary preclinical analysis evaluated the anti-proliferative activity of OPB-111077 in 19 patients with AML with a Vivia Biotech ex vivo PharmaFlow precision medicine test. A total of 12 patients were ultimately enrolled in the trial: 5 patients (42%) were treated with DL1, and 7 (58%) were escalated to DL2 of OPB-111077. Dose-limiting toxicities were not observed and the MTD was not reached. In addition, the most frequently reported treatment-emergent adverse events were nausea, vomiting and fatigue. Finally, clinical activity (overall response) was observed in 3 patients (25%). On the whole, the present study demonstrates that OPB-111077 exhibits a good safety and tolerability profile and an acceptable clinical response in patients with high-risk AML. A biomarker-driven design is useful for selecting the study population upfront.

Mitochondrial Plasticity Promotes Resistance to Sorafenib and Vulnerability to STAT3 Inhibition in Human Hepatocellular Carcinoma.

The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profound reprogramming of mitochondria function and marked activation of genes required for mitochondrial protein translation and biogenesis. Mitochondrial ribosomal proteins and components of translation and import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patients show similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated (pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionable target to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727, reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. These results sustain the importance of mitochondria plasticity in response to sorafenib and identify a clinically actionable strategy for improving the treatment efficacy in HCC patients.

Phase I Dose-Finding Study of OPB-111077, a Novel STAT3 Inhibitor, in Patients with Advanced Hepatocellular Carcinoma.

PURPOSE: The signal transducer and activator of transcription 3 (STAT3) signaling pathway might be a promising therapeutic target for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was a multicenter, open-label, non-comparative, dose escalating phase I study of OPB-111077, an oral STAT3 inhibitor, in patients with advanced HCC who failed on sorafenib. Continuous dosing (daily administration, 50 to 400 mg) and intermittent dosing (4-days on/3-days off administration: 300 to 900 mg) regimens were evaluated and the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended dose (RD) were the primary endpoints. RESULTS: A total of 33 patients (19 for continuous dosing and 14 for intermittent dosing) were enrolled. One patient experienced a DLT with grade 3 dizziness, but the MTD was identified in neither the continuous nor the intermittent dosing cohorts. The RDs were determined to be 250 mg for the continuous dosing regimen and 600 mg for the intermittent dosing regimen. There was no treatment-related death; five patients (15.2%) had grade 3-4 toxicities including thrombocytopenia (6%), fatigue (3%), and dizziness (3%). No patients achieved complete or partial responses and the median progression-free survival was 1.4 months (95% confidence interval, 0.8 to 2.8). CONCLUSION: OPB-111077 was well tolerated in patients with advanced HCC after sorafenib failure, but only showed limited preliminary efficacy outcomes. Further investigation of the role of the STAT3 signaling pathway in HCC and the development of biomarkers for STAT3 inhibitors are warranted.

AACR-NCI-EORTC - 27th International Symposium - Molecular Targets and Cancer Therapeutics (November 5-9, 2015 - Boston, Massachusetts, USA).

The 27th joint meeting of the European Organization for Research and Treatment of Cancer, National Cancer Institute and the American Association of Cancer Research (EORTC-NCI-AACR) International Conference on Molecular Targets and Cancer Therapeutics was held this year in Boston. Approximately 3,000 international academics, scientists and pharmaceutical industry representatives discussed new discoveries in the field of molecular biology of cancer and presented the latest information on drug discovery, preclinical research, clinical research and target selection in oncology. This report summarizes data on advances in cancer drug discovery.

Phase I Dose-Finding Study of OPB-111077, a Novel STAT3 Inhibitor, in Patients with Advanced Hepatocellular Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The signal transducer and activator of transcription 3 (STAT3) signaling pathway might be a promising therapeutic target for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This study was a multicenter, open-label, non-comparative, dose escalating phase I study of OPB-111077, an oral STAT3 inhibitor, in patients with advanced HCC who failed on sorafenib. Continuous dosing (daily administration, 50 to 400 mg) and intermittent dosing (4-days on/3-days off administration: 300 to 900 mg) regimens were evaluated and the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended dose (RD) were the primary endpoints. RESULTS: A total of 33 patients (19 for continuous dosing and 14 for intermittent dosing) were enrolled. One patient experienced a DLT with grade 3 dizziness, but the MTD was identified in neither the continuous nor the intermittent dosing cohorts. The RDs were determined to be 250 mg for the continuous dosing regimen and 600 mg for the intermittent dosing regimen. There was no treatment-related death; five patients (15.2%) had grade 3-4 toxicities including thrombocytopenia (6%), fatigue (3%), and dizziness (3%). No patients achieved complete or partial responses and the median progression-free survival was 1.4 months (95% confidence interval, 0.8 to 2.8). CONCLUSION: OPB-111077 was well tolerated in patients with advanced HCC after sorafenib failure, but only showed limited preliminary efficacy outcomes. Further investigation of the role of the STAT3 signaling pathway in HCC and the development of biomarkers for STAT3 inhibitors are warranted.