Cancer Res Treat.  2019 Apr;51(2):510-518. 10.4143/crt.2018.226.

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

• Yoo C
• Kang J
• Lim HY
• Kim JH
• Lee MA
• Lee KH
• Kim TY
• Ryoo BY

• KMID: 2464398
• DOI: http://doi.org/10.4143/crt.2018.226

Abstract

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.

Keyword

Dose limiting toxicity; Hepatocellular carcinoma; OPB-111077; Phase 1; STAT3 transcription factor

MeSH Terms

Biomarkers
Carcinoma, Hepatocellular*
Cohort Studies
Disease-Free Survival
Dizziness
Fatigue
Humans
Maximum Tolerated Dose
STAT3 Transcription Factor
Thrombocytopenia
Biomarkers
STAT3 Transcription Factor

Figure

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  Fig. 1. Study design. Dose escalation in the continuous dosage schedule with once daily administration (A) and the intermittent dosage schedule with 4-days on/3-days off administration (B).

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  Fig. 2. Waterfall plot of the changes in the target lesion. 4d on/3d off, 4-days on/3-days off administration.

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  Fig. 3. Kaplan-Meier estimates of progress-free survival in overall patients. The median value was 1.4 months (95% confidence interval 0.8 to 2.8).

Reference

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