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Efficacy and Safety of Bavituximab in Combination with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Arm, Open-Label, Phase II Clinical Trial

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Abstract

Background

Bavituximab, an immunomodulator, targets phosphatidylserine (PS), a membrane lipid externalized on tumor and endothelial cells in response to sorafenib.

Objective

The objective of this phase II study was to assess the efficacy of combination bavituximab and sorafenib in advanced hepatocellular carcinoma (HCC).

Methods

In this single-arm phase II study, patients with HCC determined to be unresectable with Eastern Cooperative Oncology Group (ECOG) score ≤ 2, Child–Pugh score A/B7 received intravenous bavituximab 3 mg/kg weekly and oral sorafenib 400 mg twice daily until disease progression or intolerable toxicity. We investigated time to progression (TTP) for patients receiving combination bavituximab and sorafenib compared with that for sorafenib-only historical controls.

Results

In total, 38 patients were accrued. The median follow-up was 6.1 months. Patient characteristics were as follows: median age 61 years; male 82%; hepatitis C virus 79%; Black 39%, Hispanic 26%, White 29%; previous treatment 39%; macrovascular invasion 84%; and extrahepatic metastases 24%. The median TTP was 6.7 months (95% confidence interval [CI] 4–17). The median overall survival was 6.1 months (95% CI 5–8), and the median disease-specific survival was 8.6 months (95% CI 6–14). Two patients experienced partial responses; none had a complete response. The disease control rate was 58%. Treatment-related adverse events were observed in 63% of patients, with the most commonly reported therapy-related symptoms being diarrhea (32%), fatigue (26%), and anorexia (24%).

Conclusions

The efficacy of adding bavituximab to sorafenib for the treatment of advanced HCC was inconclusive; however, the combination regimen did not exacerbate toxicities associated with single-agent sorafenib.

ClinicalTrials.gov identifier

NCT01264705.

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References

  1. Global Burden of Disease Cancer Collaboration, Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3:524–48.

    PubMed Central  Google Scholar 

  2. European Association for the Study of the Liver, European Organisation for Research and Treatment of Cancer. EASL–EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2012;56:908–43.

    Google Scholar 

  3. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–109.

    CAS  PubMed  Google Scholar 

  4. Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2007;59:561–74.

    CAS  PubMed  Google Scholar 

  5. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–90.

    CAS  PubMed  Google Scholar 

  6. Cheng A-L, Kang Y-K, Chen Z, Tsao C-J, 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.

    CAS  PubMed  Google Scholar 

  7. Mokdad AA, Singal AG, Yopp AC. Advances in local and systemic therapies for hepatocellular cancer. Curr Oncol Rep. 2016;18:9.

    PubMed  Google Scholar 

  8. Ran S, Downes A, Thorpe PE. Increased exposure of anionic phospholipids on the surface of tumor blood vessels. Cancer Res. 2002;62:6132–40.

    CAS  PubMed  Google Scholar 

  9. Daleke DL. Regulation of transbilayer plasma membrane phospholipid asymmetry. J Lipid Res. 2003;44:233–42.

    CAS  PubMed  Google Scholar 

  10. Jennewein M, Lewis MA, Zhao D, Tsyganov E, Slavine N, He J, et al. Vascular imaging of solid tumors in rats with a radioactive arsenic-labeled antibody that binds exposed phosphatidylserine. Clin Cancer Res. 2008;14:1377–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Huang X, Bennett M, Thorpe PE. A monoclonal antibody that binds anionic phospholipids on tumor blood vessels enhances the antitumor effect of docetaxel on human breast tumors in mice. Cancer Res. 2005;65:4408–16.

    CAS  PubMed  Google Scholar 

  12. Riedl S, Rinner B, Asslaber M, Schaider H, Walzer S, Novak A, et al. In search of a novel target—Phosphatidylserine exposed by non-apoptotic tumor cells and metastases of malignancies with poor treatment efficacy. Biochim Biophys Acta BBA Biomembr. 2011;1808:2638–45.

    CAS  Google Scholar 

  13. Beck AW, Luster TA, Miller AF, Holloway SE, Conner CR, Barnett CC, et al. Combination of a monoclonal anti-phosphatidylserine antibody with gemcitabine strongly inhibits the growth and metastasis of orthotopic pancreatic tumors in mice. Int J Cancer. 2006;118:2639–43.

    CAS  PubMed  Google Scholar 

  14. He J, Luster TA, Thorpe PE. Radiation-enhanced vascular targeting of human lung cancers in mice with a monoclonal antibody that binds anionic phospholipids. Clin Cancer Res. 2007;13:5211–8.

    CAS  PubMed  Google Scholar 

  15. He J, Yin Y, Luster TA, Watkins L, Thorpe PE. Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin Cancer Res Off J Am Assoc Cancer Res. 2009;15:6871–80.

    CAS  Google Scholar 

  16. Cheng X, Li L, Thorpe PE, Yopp AC, Brekken RA, Huang X. Antibody-mediated blockade of phosphatidylserine enhances the antitumor effect of sorafenib in hepatocellular carcinomas xenografts. Ann Surg Oncol. 2016;23:583–91.

    PubMed  Google Scholar 

  17. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature. 1997;390:350–1.

    CAS  PubMed  Google Scholar 

  18. Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest. 1998;101:890–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gaipl US, Beyer TD, Baumann I, Voll RE, Stach CM, Heyder P, et al. Exposure of anionic phospholipids serves as anti-inflammatory and immunosuppressive signal–implications for antiphospholipid syndrome and systemic lupus erythematosus. Immunobiology. 2003;207:73–81.

    CAS  PubMed  Google Scholar 

  20. Chen X, Doffek K, Sugg SL, Shilyansky J. Phosphatidylserine regulates the maturation of human dendritic cells. J Immunol Baltim Md. 1950;2004(173):2985–94.

    Google Scholar 

  21. Luster TA, He J, Huang X, Maiti SN, Schroit AJ, de Groot PG, et al. Plasma protein β-2-glycoprotein 1 mediates interaction between the anti-tumor monoclonal antibody 3g4 and anionic phospholipids on endothelial cells. J Biol Chem. 2006;281:29863–71.

    CAS  PubMed  Google Scholar 

  22. Ran S, He J, Huang X, Soares M, Scothorn D, Thorpe PE. Antitumor effects of a monoclonal antibody that binds anionic phospholipids on the surface of tumor blood vessels in mice. Clin Cancer Res. 2005;11:1551–62.

    CAS  PubMed  Google Scholar 

  23. Belzile O, Huang X, Gong J, Carlson J, Schroit AJ, Brekken RA, et al. Antibody targeting of phosphatidylserine for the detection and immunotherapy of cancer. ImmunoTargets Ther. 2018;7:1–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Yopp AC, Mansour JC, Beg MS, Arenas J, Trimmer C, Reddick M, et al. Establishment of a multidisciplinary hepatocellular carcinoma clinic is associated with improved clinical outcome. Ann Surg Oncol. 2014;21:1287–95.

    PubMed  Google Scholar 

  25. R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2015. https://www.R-project.org/.

  26. Plummer M, Best N, Cowles K, Vines K. CODA: convergence diagnosis and output analysis for MCMC. R News. 2006;6:7–11.

    Google Scholar 

  27. Lunn D, Spiegelhalter D, Thomas A, Best N. The BUGS project: evolution, critique and future directions. Stat Med. 2009;28:3049–67.

    PubMed  Google Scholar 

  28. Cheng A-L, Kang Y-K, Lin D-Y, Park J-W, Kudo M, Qin S, et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol. 2013;31:4067–75.

    CAS  PubMed  Google Scholar 

  29. Cainap C, Qin S, Huang W-T, Chung IJ, Pan H, Cheng Y, et al. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial. J Clin Oncol. 2015;33:172–9.

    CAS  PubMed  Google Scholar 

  30. Johnson PJ, Qin S, Park J-W, Poon RTP, Raoul J-L, Philip PA, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study. J Clin Oncol. 2013;31:3517–24.

    CAS  PubMed  Google Scholar 

  31. Gu L, Liu H, Fan L, Lv Y, Cui Z, Luo Y, et al. Treatment outcomes of transcatheter arterial chemoembolization combined with local ablative therapy versus monotherapy in hepatocellular carcinoma: a meta-analysis. J Cancer Res Clin Oncol. 2014;140:199–210.

    CAS  PubMed  Google Scholar 

  32. Bruix J, Raoul J-L, Sherman M, Mazzaferro V, Bolondi L, Craxi A, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol. 2012;57:821–9.

    CAS  PubMed  Google Scholar 

  33. Abdel-Rahman O. Impact of baseline characteristics on outcomes of advanced HCC patients treated with sorafenib: a secondary analysis of a phase III study. J Cancer Res Clin Oncol. 2018;144:901–8.

    CAS  PubMed  Google Scholar 

  34. Bruix J, Cheng A-L, Meinhardt G, Nakajima K, De Sanctis Y, Llovet J. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies. J Hepatol. 2017;67:999–1008.

    CAS  PubMed  Google Scholar 

  35. Faivre S, Raymond E, Boucher E, Douillard J, Lim HY, Kim JS, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol. 2009;10:794–800.

    CAS  PubMed  Google Scholar 

  36. Kudo M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia F, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet Lond Engl. 2018;391:1163–73.

    CAS  Google Scholar 

  37. Azad NS, Aragon-Ching JB, Dahut WL, Gutierrez M, Figg WD, Jain L, et al. Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy. Clin Cancer Res. 2009;15:1411–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol. 2010;66:357–71.

    CAS  PubMed  Google Scholar 

  39. Fukudo M, Ito T, Mizuno T, Shinsako K, Hatano E, Uemoto S, et al. Exposure-toxicity relationship of sorafenib in Japanese patients with renal cell carcinoma and hepatocellular carcinoma. Clin Pharmacokinet. 2014;53:185–96.

    CAS  PubMed  Google Scholar 

  40. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046–54.

    CAS  PubMed  Google Scholar 

  41. Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhu AX, Park JO, Ryoo B-Y, Yen C-J, 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.

    CAS  PubMed  Google Scholar 

  44. Lee S, Kim BK, Kim SU, Park JY, Kim DY, Ahn SH, et al. Early α-fetoprotein response predicts survival in patients with advanced hepatocellular carcinoma treated with sorafenib. J Hepatocell Carcinoma. 2015;2:39–47.

    PubMed  PubMed Central  Google Scholar 

  45. Nakazawa T, Hidaka H, Takada J, Okuwaki Y, Tanaka Y, Watanabe M, et al. Early increase in α-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol. 2013;25:683–9.

    CAS  PubMed  Google Scholar 

  46. Yau T, Yao TJ, Chan P, Wong H, Pang R, Fan ST, et al. The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. Oncologist. 2011;16:1270–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 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 Lond Engl. 2017;389:2492.

    CAS  Google Scholar 

  48. Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology. 2017;93(Suppl 1):147–59.

    PubMed  Google Scholar 

  49. Kelley RK, Abou-Alfa GK, Bendell JC, Kim T-Y, Borad MJ, Yong W-P, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J Clin Oncol. 2017;35:4073.

    Google Scholar 

  50. Gray MJ, Gong J, Hatch MMS, Nguyen V, Hughes CCW, Hutchins JT, et al. Phosphatidylserine-targeting antibodies augment the anti-tumorigenic activity of anti-PD-1 therapy by enhancing immune activation and downregulating pro-oncogenic factors induced by T-cell checkpoint inhibition in murine triple-negative breast cancers. Breast Cancer Res BCR. 2016;18:50.

    PubMed  Google Scholar 

  51. Freimark BD, Gong J, Ye D, Gray MJ, Nguyen V, Yin S, et al. Antibody-mediated phosphatidylserine blockade enhances the antitumor responses to CTLA-4 and PD-1 antibodies in melanoma. Cancer Immunol Res. 2016;4:531–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Monzon JG, Hay AE, McDonald GT, Pater JL, Meyer RM, Chen E, et al. Correlation of single arm versus randomised phase 2 oncology trial characteristics with phase 3 outcome. Eur J Cancer Oxf Engl. 1990;2015(51):2501–7.

    Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA

    Ali A. Mokdad & Adam C. Yopp

  2. Department of Medicine, Division of Medical Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA

    Hao Zhu, Muhammad S. Beg, Yull Arriaga & Jonathan E. Dowell

  3. Department of Medicine, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA

    Amit G. Singal

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  1. Ali A. Mokdad
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Corresponding author

Correspondence to Adam C. Yopp.

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Funding

This work was supported by Peregrine Pharmaceuticals, Inc.

Conflict of interest

AAM, HZ, YA, JD, and ACY have no conflicts of interest that might be relevant to the contents of this manuscript. MSB has served in a consulting/advisory role for Cegene, Ipsen, Genentech/Roche, Guardant Health, and Boston Biomedical; on a speaker’s bureau for Ipsen, Genentech/Roche, and Bristol-Myers Squibb; and has received research funding from Gelgene, Bristol-Myers Squibb, AstraZeneca/MedImmune, Merk Serono, Agios, Five Prime Therapeutics, MedImuune, Tolero Pharmaceuticals, ArQule, Genetech, Sillajen, and CASI Pharmaceuticals. AGS has served in a consultant/advisory role for Eisai, Exelixis, Bayer, and BMS and on a speaker’s bureau for Bayer and BMS.

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Mokdad, A.A., Zhu, H., Beg, M.S. et al. Efficacy and Safety of Bavituximab in Combination with Sorafenib in Advanced Hepatocellular Carcinoma: A Single-Arm, Open-Label, Phase II Clinical Trial. Targ Oncol 14, 541–550 (2019). https://doi.org/10.1007/s11523-019-00663-3

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  • DOI: https://doi.org/10.1007/s11523-019-00663-3

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