The Many Different Designs of Phase II Trials in Oncology

  • Rachel P. Riechelmann
  • Raphael L. C. Araújo
  • Axel Hinke
Chapter

Abstract

Phase II trials are an important component of drug development in oncology. Their objective is to screen for preliminary signals of efficacy of new anticancer agents and to provide further information on drug toxicity. Many different phase II trial designs have been envisioned and utilized according to cancer behavior, type of drug effects on tumors, study endpoints, and treatment settings. The trials are generally classified as either single- or multiple-arm non-randomized trials or randomized phase II trials. Within each group, there are numerous different designs, with the most common ones being single-arm phase II trials, biomarker-driven trials, randomized “pick the winner” trials, randomized controlled phase II studies, randomized discontinuation trials, and crossover studies. The aim of this chapter is to provide an overview of the different designs of phase II cancer trials and to discuss the advantages and disadvantages of each design.

Keywords

Phase II clinical trials Randomized clinical trials Oncology Cancer 

References

  1. 1.
    Riechelmann RP, Dounaevskaia V, Krzyzanowska MK. Quality of reporting primary outcomes in phase II cancer trials. J Clin Oncol. 2008;26(33):5486–8.CrossRefGoogle Scholar
  2. 2.
    Saad ED, Sasse EC, Borghesi G, et al. Formal statistical testing and inference in randomized phase II trials in medical oncology. Am J Clin Oncol. 2013;36(2):143–5.CrossRefGoogle Scholar
  3. 3.
    Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2017;45(2):228–47.CrossRefGoogle Scholar
  4. 4.
    Schilsky RL. End points in cancer clinical trials and the drug approval process. Clin Cancer Res. 2002;8(4):935–8.PubMedGoogle Scholar
  5. 5.
    Cassileth BR. Clinical trials: time for action. J Clin Oncol. 2003;21(5):765–6.CrossRefGoogle Scholar
  6. 6.
    Adjei AA, Christian M, Ivy P. Novel designs and end points for phase II clinical trials. Clin Cancer Res. 2009;15(6):1866–72.CrossRefGoogle Scholar
  7. 7.
    Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623–32.CrossRefGoogle Scholar
  8. 8.
    Pietrantonio F, Petrelli F, Coinu A, et al. Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis. Eur J Cancer. 2017;51(5):587–94.CrossRefGoogle Scholar
  9. 9.
    Mariani L, Marubini E. Content and quality of currently published phase II cancer trials. J Clin Oncol. 2000;18(2):429.CrossRefGoogle Scholar
  10. 10.
    Gehan EA. The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. J Chronic Dis. 1961;13:346–53.CrossRefGoogle Scholar
  11. 11.
    Fleming TR. One-sample multiple testing procedure for phase II clinical trials. Biometrics. 1982;38(1):143–51.CrossRefGoogle Scholar
  12. 12.
    Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989;10(1):1–10.CrossRefGoogle Scholar
  13. 13.
    Simon R, Wittes RE, Ellenberg SS. Randomized phase II clinical trials. Cancer Treat Rep. 1985;69(12):1375–81.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1(1):44–53.CrossRefGoogle Scholar
  15. 15.
    Renfro LA, An M-W, Mandrekar SJ. Precision oncology: a new era of cancer clinical trials. Cancer Lett. 2017;387:121–6.CrossRefGoogle Scholar
  16. 16.
    Rubinstein LV, Korn EL, Freidlin B, et al. Design issues of randomized phase II trials and a proposal for phase II screening trials. J Clin Oncol. 2005;23(28):7199–206.CrossRefGoogle Scholar
  17. 17.
    da Rocha Lino A, Abrahão CM, Brandão RM, Gomes JR, Ferrian AM, Machado MC, Buzaid AC, Maluf FC, Peixoto RD. Role of gemcitabine as second-line therapy after progression on FOLFIRINOX in advanced pancreatic cancer: a retrospective analysis. J Gastrointest Oncol. 2015;6(5):511–5.  https://doi.org/10.3978/j.issn.2078-6891.2015.041. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Amery W, Dony J. A clinical trial design avoiding undue placebo treatment. J Clin Pharmacol. 1975;15:674–9.CrossRefGoogle Scholar
  19. 19.
    Stadler WM, Rosner G, Small E, et al. Successful implementation of the randomized discontinuation trial design: an application to the study of the putative antiangiogenic agent carboxyaminoimidazole in renal cell carcinoma—CALGB 69901. J Clin Oncol. 2005;23(16):3726–32.CrossRefGoogle Scholar
  20. 20.
    Ratain MJ, Eisen T, Stadler WM, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24(16):2505–12.CrossRefGoogle Scholar
  21. 21.
    Freidlin B, Simon R. Evaluation of randomized discontinuation design. J Clin Oncol. 2005;23(22):5094–8.CrossRefGoogle Scholar
  22. 22.
    Schaid DJ, Wieand SAM, Therneau TM. Optimal two-stage screening designs for survival comparisons. Biometrika. 1990;77(3):507–13.CrossRefGoogle Scholar
  23. 23.
    Korn EL. Design issues in randomized phase II/III trials. J Clin Oncol. 2012;30:667–71.CrossRefGoogle Scholar
  24. 24.
    Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273–81.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Rachel P. Riechelmann
    • 1
  • Raphael L. C. Araújo
    • 2
  • Axel Hinke
    • 3
  1. 1.Department of Clinical OncologyAC Camargo Cancer CenterSão PauloBrazil
  2. 2.Department of Upper Gastrointestinal and Hepato-Pancreato-Biliary SurgeryBarretos Cancer HospitalBarretosBrazil
  3. 3.CCRCDüsseldorfGermany

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