Statistical Science

Dose Finding with Escalation with Overdose Control (EWOC) in Cancer Clinical Trials

Mourad Tighiouart and André Rogatko

Full-text: Open access

Abstract

Traditionally, the major objective in phase I trials is to identify a working-dose for subsequent studies, whereas the major endpoint in phase II and III trials is treatment efficacy. The dose sought is typically referred to as the maximum tolerated dose (MTD). Several statistical methodologies have been proposed to select the MTD in cancer phase I trials. In this manuscript, we focus on a Bayesian adaptive design, known as escalation with overdose control (EWOC). Several aspects of this design are discussed, including large sample properties of the sequence of doses selected in the trial, choice of prior distributions, and use of covariates. The methodology is exemplified with real-life examples of cancer phase I trials. In particular, we show in the recently completed ABR-217620 (naptumomab estafenatox) trial that omitting an important predictor of toxicity when dose assignments to cancer patients are determined results in a high percent of patients experiencing severe side effects and a significant proportion treated at sub-optimal doses.

Article information

Source
Statist. Sci., Volume 25, Number 2 (2010), 217-226.

Dates
First available in Project Euclid: 19 November 2010

Permanent link to this document
https://projecteuclid.org/euclid.ss/1290175843

Digital Object Identifier
doi:10.1214/10-STS333

Mathematical Reviews number (MathSciNet)
MR2789991

Zentralblatt MATH identifier
1328.62598

Keywords
Cancer phase I trials dose-limiting toxicity escalation with overdose control tolerated dose optimal Bayesian feasible

Citation

Tighiouart, Mourad; Rogatko, André. Dose Finding with Escalation with Overdose Control (EWOC) in Cancer Clinical Trials. Statist. Sci. 25 (2010), no. 2, 217--226. doi:10.1214/10-STS333. https://projecteuclid.org/euclid.ss/1290175843


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References

  • Adcock, C. J. (1997). Sample size determination: A review. The Statistician 46 261–283.
  • Babb, J. and Rogatko, A. (2004). Contemporary Biostatistical Methods in Clinical Trial. Bayesian Methods for Cancer Phase I Clinical Trials 1–39. Dekker, New York.
  • Babb, J., Rogatko, A. and Zacks, S. (1998). Cancer Phase I clinical trials: Efficient dose escalation with overdose control. Stat. Med. 17 1103–1120.
  • Babb, J. S. and Rogatko, A. (2001). Patient specific dosing in a cancer phase I clinical trial. Statist. Med. 20 2079–2090.
  • Braun, T. M., Levine, J. E. and Ferrara, J. L. M. (2003). Determining a maximum tolerated cumulative dose: Dose reassignment within the TITE-CRM. Controlled Clinical Trials 24 669–681.
  • Cheng, J. D., Babb, J. S., Langer, C., Aamdal, S., Robert, F., Engelhardt, L. R., Fernberg, O., Schiller, J., Forsberg, G., Alpaugh, R. K., Weiner, L. M. and Rogatko, A. (2004). Individualized patient dosing in phase I clinical trials: The role of EWOC in PNU-214936. J. Clin. Oncol. 22 602–609.
  • Cheung, Y. K. (2005). Coherence principles in dose-finding studies. Biometrika 92 863–873.
  • Cheung, Y. K. and Chappell, R. (2000). Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics 56 1177–1182.
  • Chu, P. L., Lin, Y. and Shih, W. J. (2009). Unifying CRM and EWOC designs for phase I cancer clinical trials. J. Statist. Plann. Inference 139 1146–1163.
  • Cox, D. R. (1972). Regression models and life-tables. J. R. Stat. Soc. Ser. B Stat. Methodol. 34 187–220.
  • Dillman, R. O. and Koziol, J. A. (1992). Phase I cancer trials: Limitations and implications. Molecular Biotherapy 4 117–121.
  • Faries, D. (1994). Practical modifications of the continual reassessment method for phase I cancer clinical trials. J. Biopharm. Statist. 4 147–164.
  • Garrett-Mayer, E. (2006). The continual reassessment method for dose-finding studies: A tutorial. Clinical Trials 3 57–71.
  • Gatsonis, C. and Greenhouse, J. B. (1992). Bayesian methods for phase I clinical trials. Stat. Med. 11 1377–1389.
  • Goodman, S. N., Zahurak, M. L. and Piantadosi, S. (1995). Some practical improvements in the continual reassessment method for phase I studies. Stat. Med. 14 1149–1161.
  • Ivanova, A. (2006). Escalation, group and A + B designs for dose-finding trials. Stat. Med. 25 3668–3678.
  • Lin, Y. and Shih, W. J. (2001). Statistical properties of the traditional algorithm-based designs for phase I cancer clinical trials. Biostatistics 2 203–215.
  • Lunn, D. J., Thomas, A., Best, N. and Spiegelhalter, D. (2000). WinBUGS—a Bayesian modelling framework: Concepts, structure, and extensibility. Statist. Comput. 10 325–337.
  • Moller, S. (1995). An extension of the continual reassessment methods using a preliminary up-and-down design in a dose finding study in cancer patients, in order to investigate a greater range of doses. Stat. Med. 14 911–922.
  • NCI (2003). Common toxicity criteria for adverse events v3.0 (CTCAE).
  • 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.
  • O’Quigley, J., Shen, L. Z. and Gamst, A. (1999). Two-sample continual reassessment method. J. Biopharm. Statist. 9 17–44.
  • Piantadosi, S., Fisher, J. D. and Grossman, S. (1998). Practical implementation of a modified continual reassessment method for dose-finding trials. Cancer Chemother. Pharmacol. 41 429–436.
  • Roberts, T. G. J., Goulart, B., Squitieri, L., Stallings, S. C., Halpern, E. F., Chabner, B. A., Gazelle, G. S., Finkelstein, S. N. and Clark, J. W. (2004). Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. J. Amer. Med. Assoc. 292 2130–2140.
  • Rogatko, A., Ghosh, P., Vidakovic, B. and Tighiouart, M. (2008). Patient-specific dose adjustment in the cancer clinical trial setting. Pharm. Med. 22 345–350.
  • Rogatko, A., Tighiouart, M. and Xu, Z. (2005). EWOC 2.1 application software. Available at http://sisyphus.emory.edu/software.php.
  • Rosenberger, W. F. and Haines, L. M. (2002). Competing designs for phase I clinical trials: A review. Stat. Med. 21 2757–2770.
  • Storer, B. E. (2001). An evaluation of phase I clinical trial designs in the continuous dose-response setting. Stat. Med. 20 2399–2408.
  • Tighiouart, M. and Rogatko, A. (2006). Dose Finding in Drug Development. Dose Finding in Oncology–Parametric Methods 59–72. Springer, New York.
  • Tighiouart, M. and Rogatko, A. (2006). Statistical Methods for Dose-Finding Experiments. Dose Escalation with Overdose Control 173–188. Wiley, New York.
  • Tighiouart, M., Rogatko, A. and Babb, J. S. (2005). Flexible Bayesian methods for cancer phase I clinical trials. Dose escalation with overdose control. Stat. Med. 24 2183–2196.
  • Tighiouart, M., Rogatko, A. and Xu, Z. (2007). Incorporating patient’s characteristics in cancer phase I clinical trials using escalation with overdose control. In Joint Statistical Meetings. Salt Lake City.
  • Ting, N. (2006). Dose Finding in Drug Development. Springer, New York.
  • Whitehead, J. (1997). Bayesian decision procedures with application to dose-finding studies. Int. J. Pharm. Med. 11 201–208.
  • Xu, Z., Tighiouart, M. and Rogatko, A. (2007). EWOC 2.1: Interactive software for dose escalation in cancer phase I clinical trials. Drug Inform. J. 41 221–228.
  • Zacks, S., Rogatko, A. and Babb, J. (1998). Optimal Bayesian-feasibile dose escalation for cancer phase I trials. Statist. Probab. Lett. 38 215–220.
  • Zohar, S. and Chevret, S. (2001). The continual reassessment method: Comparison of Bayesian stopping rules for dose-ranging studies. Stat. Med. 20 2827–2843.
  • Zohar, S., Latouche, A., Taconner, M. and Chevret, S. (2003). Software to compute and conduct sequential Bayesian phase I or II dose-ranging clinical trials with stopping rules. Comput. Methods Programs Biomed. 72 117–125.