The Annals of Applied Statistics

Bayesian phase I/II adaptively randomized oncology trials with combined drugs

Ying Yuan and Guosheng Yin

Full-text: Open access

Abstract

We propose a new integrated phase I/II trial design to identify the most efficacious dose combination that also satisfies certain safety requirements for drug-combination trials. We first take a Bayesian copula-type model for dose finding in phase I. After identifying a set of admissible doses, we immediately move the entire set forward to phase II. We propose a novel adaptive randomization scheme to favor assigning patients to more efficacious dose-combination arms. Our adaptive randomization scheme takes into account both the point estimate and variability of efficacy. By using a moving reference to compare the relative efficacy among treatment arms, our method achieves a high resolution to distinguish different arms. We also consider groupwise adaptive randomization when efficacy is late-onset. We conduct extensive simulation studies to examine the operating characteristics of the proposed design, and illustrate our method using a phase I/II melanoma clinical trial.

Article information

Source
Ann. Appl. Stat., Volume 5, Number 2A (2011), 924-942.

Dates
First available in Project Euclid: 13 July 2011

Permanent link to this document
https://projecteuclid.org/euclid.aoas/1310562211

Digital Object Identifier
doi:10.1214/10-AOAS433

Mathematical Reviews number (MathSciNet)
MR2840181

Zentralblatt MATH identifier
1232.62155

Keywords
Adaptive randomization dose finding drug combination

Citation

Yuan, Ying; Yin, Guosheng. Bayesian phase I/II adaptively randomized oncology trials with combined drugs. Ann. Appl. Stat. 5 (2011), no. 2A, 924--942. doi:10.1214/10-AOAS433. https://projecteuclid.org/euclid.aoas/1310562211


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References

  • Clayton, D. G. (1978). A model for association in bivariate life tables and its application in epidemiological studies of familial tendency in chronic disease incidence. Biometrika 65 141–152.
  • Conaway, M. R., Dunbar, S. and Peddada, S. D. (2004). Designs for single- or multiple-agent phase I trials. Biometrics 60 661–669.
  • Genest, C. and Rivest, L.-P. (1993). Statistical inference procedures for bivariate Archimedean copula. J. Amer. Statist. Assoc. 88 1034–1043.
  • Gilks, W. R., Best, N. G. and Tan, K. K. C. (1995). Adaptive rejection Metropolis sampling. Appl. Statist. 44 455–472.
  • Gooley, T. A., Martin, P. J., Fisher, L. D. and Pettinger, M. (1994). Simulation as a design tool for phase I/II clinical trial: An example from bone marrow transplantation. Controlled Clinical Trial 15 450–462.
  • Hougaard, P. (1986). A class of multivariate failure time distribution. Biometrika 73 671–678.
  • Huang, X., Biswas, S., Oki, Y., Issa, J.-P. and Berry, D. A. (2007). A parallel phase I/II clinical trial design for combination therapies. Biometrics 63 429–436.
  • Jennison, C. and Turnbull, B. (2000). Group Sequential Methods With Applications to Clinical Trials. Chapman and Hall/CRC, London.
  • Karrison, T., Huo, D. and Chappell, R. (2003). Group sequential, response-adaptive designs for randomized clinical trials. Controlled Clinical Trials 24 506–522.
  • Kramar, A., Lebecq, A. and Candalh, E. (1999). Continual reassessment methods in phase I trials of the combination of two drugs in oncology. Stat. Med. 18 1849–1864.
  • Korn, E. L. and Simon, R. (1993). Using the tolerable-dose diagram in the design of phase I combination chemotherapy trials. Journal of Clinical Oncology 11 794–801.
  • Nelson, R. B. (2006). An Introduction to Copulas, 2nd ed. Springer, New York.
  • O’Quigley, J., Hughes, M. D. and Fenton, T. (2001). Dose-finding designs for HIV studies. Biometrics 57 1018–1029.
  • O’Quigley, J., Pepe, M. and Fisher, L. (1990). Continual reassessment method: A practical design for phase 1 clinical trials in cancer. Biometrics 46 33–48.
  • Rosenberger, W. F. and Lachin, J. M. (2002). Randomization in Clinical Trials: Theory and Practice. Wiley, New York.
  • Simon, R. and Korn, E. L. (1990). Selecting drug combination based on total equivalence dose (dose intensity). Journal of the National Cancer Institute 82 1469–1476.
  • Storer, B. E. (1989). Design and analysis of phase I clinical trials. Biometrics 45 925–937.
  • Thall, P. F. and Cook, J. (2004). Dose-finding based on toxicity-efficacy trade-offs. Biometrics 60 684–693.
  • Thall, P. F., Millikan, R. E., Müller, P. and Lee, S.-J. (2003). Dose-finding with two agents in phase I oncology trials. Biometrics 59 487–496.
  • Thall, P. F. and Russell, K. E. (1998). A strategy for dose-finding and safety monitoring based on efficacy and adverse outcomes in phase I/II clinical trials. Biometrics 54 251–264.
  • Wang, K. and Ivanova, A. (2005). Two-dimensional dose finding in discrete dose space. Biometrics 61 217–222.
  • Yin, G., Li, Y. and Ji, Y. (2006). Bayesian dose-finding in phase I/II trials using toxicity and efficacy odds ratio. Biometrics 62 777–784.
  • Yin, G. and Yuan, Y. (2009). Bayesian dose finding in oncology for drug combinations by copula regression. Appl. Statist. 58 211–224.
  • Yin, G. and Yuan, Y. (2010). Rejoinder to the discussion of “Bayesian dose finding in oncology for drug combinations by copula regression.” Appl. Statist. 59 544–546.
  • Yuan, Z., Chappell, R. and Bailey, H. (2007). The continual reassessment method for multiple toxicity grades: A Bayesian quasi-likelihood approach. Biometrics 63 173–179.
  • Yuan, Y. and Yin, G. (2009). Bayesian dose-finding by jointly modeling toxicity and efficacy as time-to-event outcomes. Appl. Statist. 58 719–736.