Abstract
Phase I studies with anticancer drugs are used to evaluate safety and tolerability and to choose a recommended phase II dose (RP2D). Traditionally, phase I trial designs are rule-based, but for several years there is a trend towards model-based designs. Simulations have shown that model-based designs perform better, faster and are safer to establish the RP2D than rule-based designs. However, the superiority of model-based designs has never been confirmed based on true trial performance in practice. To aid evidence-based decisions for designing phase I trials, we compared publications of model-based and rule-based phase I trials in oncology. We reviewed 172 trials that have been published in the last 2 years and assessed the following operating characteristics: efficiency (trial duration, population size, dose-levels), patient safety (dose-limiting toxicities (DLTs)) and treatment optimality (percentage of patients treated below and at or above the recommended phase 2 dose). Our results showed a non-significant but clinically relevant difference in trial duration. Model-based trials needed 10 months less than rule-based trials (26 versus 36 months; p = 0.25). Additionally, fewer patients were treated at dose-levels below the RP2D (31 % versus 40 %; p = 0.73) while safety was preserved (13 % DLTs versus 14 % DLTs). In this review, we provide evidence to encourage the use of model-based designs for future phase I studies, based on a median of 10 months of time gain, acceptable toxicity rates and minimization of suboptimal treatment.
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References
Le Tourneau C, Lee JJ, Siu LL (2009) Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst 101(10):708–720
Jaki T, Clive S, Weir CJ (2013) Principles of dose finding studies in cancer: a comparison of trial designs. Cancer Chemother Pharmacol 71(5):1107–1114
A Iasonos, J O’Quigley (2014) Adaptive dose-finding studies: a review of model-guided phase I clinical trials. J Clin Oncol 32(23):2505–2511
Le Tourneau C, Gan HK, Razak ARA, Paoletti X (2012) Efficiency of new dose escalation designs in dose-finding phase I trials of molecularly targeted agents. PLoS ONE 7(12):e51039
Harrington JA, Wheeler GM, Sweeting MJ, Mander AP, Jodrell DI (2013) Adaptive designs for dual-agent phase I dose-escalation studies. Nat Rev Clin Oncol 10(5):277–288
Mandrekar SJ (2014) Dose-finding trial designs for combination therapies in oncology. J Clin Oncol 32(2):65–67
European Medicines Agency Committe for Medicinal Products for Human Use, “Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design,” 2007. [Online]. Available: http://www.ema.europa.eu/docs/
U.S. Food and Drug Administration (2010) Guidance for industry: adaptive design clinical trials for drugs and biologics 2010. [Online]. Available: http://www.fda.gov/downloads/Drugs/Guidances/ucm201790.pdf
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A (2007) Translation of innovative designs into phase I trials. J Clin Oncol 25(31):4982–4986
Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS (2000) Phase I clinical trial design in cancer drug development. J Clin Oncol 18(3):684–692
Zhou Y (2004) Choice of designs and doses for early phase trials. Fundam Clin Pharmacol 18(3):373–378
O’Quigley J, Pepe M, Fisher L (1990) Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 46(1):33–48
R Core Team (2014) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria., 2014. [Online]. Available: http://www.r-project.org/
Sessa C, Shapiro GI, Bhalla KN, Britten C, Jacks KS, Mita M, Papadimitrakopoulou V, Pluard T, Samuel TA, Akimov M, Quadt C, Fernandez-Ibarra C, Lu H, Bailey S, Chica S, Banerji U (2013) First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res 19(13):3671–3680
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van Brummelen, E.M.J., Huitema, A.D.R., van Werkhoven, E. et al. The performance of model-based versus rule-based phase I clinical trials in oncology. J Pharmacokinet Pharmacodyn 43, 235–242 (2016). https://doi.org/10.1007/s10928-016-9466-0
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DOI: https://doi.org/10.1007/s10928-016-9466-0