Digestive Diseases and Sciences

, Volume 64, Issue 4, pp 1050–1057 | Cite as

Design and Endpoints of Clinical Trials, Current and Future

  • Morris ShermanEmail author


With the advent of several new systemic agents for the treatment of hepatocellular carcinoma and the prospect of more to come it is expected that many more clinical trials will be undertaken to establish the best treatment paradigm(s). In order to help develop the most efficient and most relevant clinical trials this review concentrates on endpoints that have been used in the past. Survival is the gold standard. None of the surrogate endpoints correspond completely with survival. In addition, alternative clinical trial designs are presented that may be more efficient than the usual phase I, II, and III clinical trial strategy that has been used in the past.


Hepatocellular carcinoma Clinical trial design Clinical trial endpoints 


Compliance with ethical standards

Conflict of interest

The author declare that they have no conflict of interest.


  1. 1.
    Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.CrossRefGoogle Scholar
  2. 2.
    Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;J389:56–66.CrossRefGoogle Scholar
  3. 3.
    Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163–1173.CrossRefGoogle Scholar
  4. 4.
    Zhu, AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM. REACH-2: a randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. J Clin Oncol. 2018;36:4003.Google Scholar
  5. 5.
    Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry A, Rimassa L, Ryoo BY. Cabozantinib versus placebo in patients) with advanced hepatocellular carcinoma who have received prior sorafenib: results from the randomized phase 3 CELESTIAL trial. J Clin Oncol. 2018;36:4019.Google Scholar
  6. 6.
    Llovet JM, Decaens T, Raoul JL, 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 BRISK-PS study. J Clin Oncol. 2013;31:3509–3516.CrossRefGoogle Scholar
  7. 7.
    Zhu AX, Rosmorduc O, Evans TR, et al. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2015;33:559–566.CrossRefGoogle Scholar
  8. 8.
    Rimassa L, Assenat E, Peck-Radosavljevic M, et al. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study. Lancet Oncol. 2018;19:682–693.CrossRefGoogle Scholar
  9. 9.
    Forner A, Ayuso C, Varela M, et al. Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable? Cancer. 2009;115:616–623.CrossRefGoogle Scholar
  10. 10.
    Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30:52–60.CrossRefGoogle Scholar
  11. 11.
    Weng Z, Ertle J, Zheng S, et al. Choi criteria are superior in evaluating tumor response in patients treated with transarterial radioembolization for hepatocellular carcinoma. Oncol Lett. 2013;6:1707–1712.CrossRefGoogle Scholar
  12. 12.
    Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421–430.CrossRefGoogle Scholar
  13. 13.
    Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis. 2010;30:61–74.CrossRefGoogle Scholar
  14. 14.
    Reig M, Rimola J, Torres F, et al. Postprogression survival of patients with advanced hepatocellular carcinoma: rationale for second-line trial design. Hepatology. 2013;58:2023–2031.CrossRefGoogle Scholar
  15. 15.
    Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.CrossRefGoogle Scholar
  16. 16.
    Khalaf N, Ying J, Mittal S, et al. Natural history of untreated hepatocellular carcinoma in a US cohort and the role of cancer surveillance. Clin Gastroenterol Hepatol. 2017;15:273–281.CrossRefGoogle Scholar
  17. 17.
    Toyoda H, Lai PB, O’Beirne J, et al. Long-term impact of liver function on curative therapy for hepatocellular carcinoma: application of the ALBI grade. Br J Cancer. 2016;114:744–750.CrossRefGoogle Scholar
  18. 18.
    Lurie JD, Morgan TS. Pros and cons of pragmatic clinical trials. J Comp Eff Res. 2013;2:53–58.CrossRefGoogle Scholar
  19. 19.
    Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130:417–422.Google Scholar
  20. 20.
    Redman MW, Allegra CJ. The master protocol concept. Semin Oncol. 2015;42:724.CrossRefGoogle Scholar
  21. 21.
    Mandrekar SJ, Dahlberg SE, Simon R. Improving clinical trial efficiency: thinking outside the box. Am Soc Clin Oncol Educ Book. 2015.
  22. 22.
    Lopez-Chavez A, Thomas A, Rajan A, et al. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol. 2015;33:1000–10077.CrossRefGoogle Scholar
  23. 23.
    Bretz F, Koenig F, Brannath W, Glimm E, Posch M. Tutorial in biostatistics: adaptive designs for confirmatory clinical trials. Stat Med. 2009;28:1181–1217.CrossRefGoogle Scholar
  24. 24.
    Menis J, Hasan B, Besse B. New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response. Eur Respir Rev. 2014;23:367–378.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Toronto Center for Liver Diseases, Toronto General Hospital EN 9-227University Health NetworkTorontoCanada

Personalised recommendations