Abstract
In the last 20 years, breakthroughs in the understanding of cancer cell biology resulted in the development of MTAs that are targeted to the unique genetics of each tumor and each patient. MTAs modulate specific aberrant pathways in cancer cells while sparing normal tissues, so that some MTAs do not necessarily need to be administered at their MTD to have maximal efficacy. Therefore, dose-finding methods that take into account the bivariate-correlating outcomes of both efficacy and toxicity are required for the clinical development of MTAs. In addition, the dose–efficacy model for MTAs is necessary to capture the specific relation between efficacy and the dose level. The efficacy may increase initially with the dose level but then reaches a plateau; however, this situation may not always be the case. Several powerful methods taking into account such a dose–efficacy relationship inherent in MTAs were devised recently. In this chapter, we overview the existing dose-finding methods intended to determine the optimal dose in singe-agent trials of MTAs.
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References
Cai, C., Yuan, Y., Ji, Y.: A Bayesian dose finding design for oncology clinical trials of combinational biological agents. Appl. Stat. 63, 159–173 (2014)
Cheung, Y.K., Chappell, R.: Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics 56, 1177–1182 (2000)
Cheung, Y.K., Thall, P.F.: Monitoring the rates of composite events with censored data in phase II clinical trials. Biometrics 58, 89–97 (2002)
Fox, E., Curt, G., Balis, F.: Clinical trial design for target-based therapy. Oncologist 7, 401–409 (2002)
Hirakawa, A.: An adaptive dose-finding approach for correlated bivariate binary and continuous outcomes in phase I oncology trials. Stat. Med. 31, 516–532 (2012)
Hoering, A., Mitchell, A., LeBlanc, M., Crowley, J.: Early phase trial design for assessing several dose levels for toxicity and efficacy for targeted agents. Clin. Trials 10, 422–429 (2013)
Hunsberger, S., Rubinstein, L.V., Dancey, J., Korn, E.L.: Dose escalation trial designs based on a molecularly targeted endpoint. Stat. Med. 24, 2171–2181 (2005)
Islam, M.A., Chowdhury, R.I., Briollais, L.: A bivariate binary model for testing dependence in outcomes. Bull. Malays. Math. Sci. Soc. 35, 845–858 (2012)
Le Tourneau, C., Dieras, V., Tresca, P., Cacheux, W., Paoletti, X.: Current challenges for the early clinical development of anticancer drugs in the era of molecularly targeted agents. Target Oncol. 5, 65–72 (2015)
Riviere, M.K., Yuan, Y., Dubois, F., Zohar, S.: A Bayesian dose finding design for clinical trials combining a cytotoxic agent with a molecularly targeted agent. Appl. Stat. 64, 215–229 (2015)
Riviere, M.K., Yuan, Y., Jourdan, J.H., Dubois, F., Zohar, S.: Phase I/II dose-finding design for molecularly targeted agent: plateau determination using adaptive randomization. Stat. Methods Med. Res. (2016). https://doi.org/10.1177/0962280216631763
Rukhin, A.L.: Asymptotic behavior of estimators of the change-point in a binomial probability. J. Appl. Stat. Sci. 1, 1–12 (1995)
Sato, H., Hirakawa, A., Hamada, C.: An adaptive dose-finding method using a change-point model for molecularly targeted agents in phase I trials. Stat. Med. 35, 4093–4109 (2016)
Thall, P.F., Cook, J.D.: Dose-finding based on efficacy-toxicity trade-offs. Biometrics 60, 684–693 (2004)
Wages, N.A., Tait, C.: Seamless phase I/II adaptive design for oncology trials of molecularly targeted agents. J. Biopharm. Stat. 25, 903–920 (2015)
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Hirakawa, A., Sato, H., Daimon, T., Matsui, S. (2018). Dose Finding for Molecularly Targeted Agents (MTAs). In: Modern Dose-Finding Designs for Cancer Phase I Trials: Drug Combinations and Molecularly Targeted Agents. SpringerBriefs in Statistics(). Springer, Tokyo. https://doi.org/10.1007/978-4-431-55573-5_4
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DOI: https://doi.org/10.1007/978-4-431-55573-5_4
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