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

Affiliations
  • 1Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. ryooby@amc.seoul.kr
  • 2Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
  • 3Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
  • 4Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
  • 5Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

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

  • 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).

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

  • 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

References

1. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011; 365:1118–27.
Article
2. Jung KW, Won YJ, Oh CM, Kong HJ, Lee DH, Lee KH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2014. Cancer Res Treat. 2017; 49:292–305.
Article
3. Bruix J, Sherman M; American Association for the Study of Liver D. Management of hepatocellular carcinoma: an update. Hepatology. 2011; 53:1020–2.
Article
4. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359:378–90.
Article
5. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009; 10:25–34.
Article
6. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389:56–66.
Article
7. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017; 389:2492–502.
Article
8. Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008; 18:254–67.
Article
9. Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010; 140:197–208.
Article
10. Toffanin S, Friedman SL, Llovet JM. Obesity, inflammatory signaling, and hepatocellular carcinoma-an enlarging link. Cancer Cell. 2010; 17:115–7.
Article
11. Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, et al. An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell. 2011; 147:1233–47.
12. Zhou M, Yang H, Learned RM, Tian H, Ling L. Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis. Nat Commun. 2017; 8:15433.
Article
13. Yan Q, Jiang L, Liu M, Yu D, Zhang Y, Li Y, et al. ANGPTL1 interacts with integrin alpha1beta1 to suppress HCC angiogenesis and metastasis by inhibiting JAK2/STAT3 signaling. Cancer Res. 2017; 77:5831–45.
14. Lin L, Amin R, Gallicano GI, Glasgow E, Jogunoori W, Jessup JM, et al. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-beta signaling. Oncogene. 2009; 28:961–72.
15. Llovet JM, Villanueva A, Lachenmayer A, Finn RS. Advances in targeted therapies for hepatocellular carcinoma in the genomic era. Nat Rev Clin Oncol. 2015; 12:408–24.
Article
16. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014; 14:736–46.
Article
17. Wong AL, Soo RA, Tan DS, Lee SC, Lim JS, Marban PC, et al. Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies. Ann Oncol. 2015; 26:998–1005.
Article
18. Oh DY, Lee SH, Han SW, Kim MJ, Kim TM, Kim TY, et al. Phase I study of OPB-31121, an oral STAT3 inhibitor, in patients with advanced solid tumors. Cancer Res Treat. 2015; 47:607–15.
Article
19. Okusaka T, Ueno H, Ikeda M, Mitsunaga S, Ozaka M, Ishii H, et al. Phase 1 and pharmacological trial of OPB-31121, a signal transducer and activator of transcription-3 inhibitor, in patients with advanced hepatocellular carcinoma. Hepatol Res. 2015; 45:1283–91.
Article
20. Tolcher A, Flaherty K, Shapiro GI, Berlin J, Witzig T, Habermann T, et al. A first-in-human phase I study of OPB-111077, a small-molecule STAT3 and oxidative phosphorylation inhibitor, in patients with advanced cancers. Oncologist. 2018; 23:658–e72.
Article
21. Zhu AX, Park JO, Ryoo BY, Yen CJ, Poon R, Pastorelli D, et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015; 16:859–70.
Article
22. Zhu AX, Kudo M, Assenat E, Cattan S, Kang YK, Lim HY, et al. Effect of everolimus on survival in advanced hepatocellular carcinoma after failure of sorafenib: the EVOLVE-1 randomized clinical trial. JAMA. 2014; 312:57–67.
23. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: results from the randomized phase III BRISKPS study. J Clin Oncol. 2013; 31:3509–16.
Article
24. Li WC, Ye SL, Sun RX, Liu YK, Tang ZY, Kim Y, et al. Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clin Cancer Res. 2006; 12:7140–8.
Article
25. Deisseroth A, Kaminskas E, Grillo J, Chen W, Saber H, Lu HL, et al. U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis. Clin Cancer Res. 2012; 18:3212–7.
Article
26. Zhang M, Liu Q, Mi S, Liang X, Zhang Z, Su X, et al. Both miR-17-5p and miR-20a alleviate suppressive potential of myeloidderived suppressor cells by modulating STAT3 expression. J Immunol. 2011; 186:4716–24.
Article
Full Text Links
  • CRT
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr