Targeted Oncology

, Volume 14, Issue 5, pp 541–550 | Cite as

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

  • Ali A. Mokdad
  • Hao Zhu
  • Muhammad S. Beg
  • Yull Arriaga
  • Jonathan E. Dowell
  • Amit G. Singal
  • Adam C. YoppEmail author
Original Research Article



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


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


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.


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%).


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. identifier



Compliance with Ethical Standards


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.

Supplementary material

11523_2019_663_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 kb)


  1. 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.PubMedCentralGoogle Scholar
  2. 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. 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.PubMedGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedGoogle Scholar
  7. 7.
    Mokdad AA, Singal AG, Yopp AC. Advances in local and systemic therapies for hepatocellular cancer. Curr Oncol Rep. 2016;18:9.PubMedGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. 9.
    Daleke DL. Regulation of transbilayer plasma membrane phospholipid asymmetry. J Lipid Res. 2003;44:233–42.PubMedGoogle Scholar
  10. 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.PubMedPubMedCentralGoogle Scholar
  11. 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.PubMedGoogle Scholar
  12. 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.Google Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.Google Scholar
  16. 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.PubMedGoogle Scholar
  17. 17.
    Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. Immunosuppressive effects of apoptotic cells. Nature. 1997;390:350–1.PubMedGoogle Scholar
  18. 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.PubMedPubMedCentralGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 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. 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.PubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 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.PubMedPubMedCentralGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. 25.
    R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2015.
  26. 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. 27.
    Lunn D, Spiegelhalter D, Thomas A, Best N. The BUGS project: evolution, critique and future directions. Stat Med. 2009;28:3049–67.PubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.Google Scholar
  37. 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.PubMedPubMedCentralGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. 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.PubMedPubMedCentralGoogle Scholar
  42. 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.PubMedPubMedCentralGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.PubMedPubMedCentralGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. 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.PubMedPubMedCentralGoogle Scholar
  47. 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.Google Scholar
  48. 48.
    Kudo M. Immuno-oncology in hepatocellular carcinoma: 2017 update. Oncology. 2017;93(Suppl 1):147–59.PubMedGoogle Scholar
  49. 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. 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.PubMedGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ali A. Mokdad
    • 1
  • Hao Zhu
    • 2
  • Muhammad S. Beg
    • 2
  • Yull Arriaga
    • 2
  • Jonathan E. Dowell
    • 2
  • Amit G. Singal
    • 3
  • Adam C. Yopp
    • 1
    Email author
  1. 1.Department of Surgery, Division of Surgical OncologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of Medicine, Division of Medical OncologyUniversity of Texas Southwestern Medical CenterDallasUSA
  3. 3.Department of Medicine, Division of Digestive and Liver DiseasesUniversity of Texas Southwestern Medical CenterDallasUSA

Personalised recommendations