Moreno Ursino (1), Emmanuelle Comets (2,3), Frederike Lentz (4), Corinne Alberti (5), Tim Friede (6), Nigel Stallard (7) and Sarah Zohar (1)
(1) INSERM, UMRS 1138, team 22, CRC, University Paris 5, University Paris 6, Paris, France, (2) INSERM, CIC 1414, University Rennes-1, Rennes, France, (3) INSERM, IAME, UMR 1137, University Paris Diderot, Paris, France, (4) Federal Institute for Drugs and Medical Devices, Bonn, Germany, (5) INSERM, UMR 1123, Hôpital Robert-Debré, APHP, University Paris 7, Paris, France, (6) Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany, (7) Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, The University of Warwick, UK
Objectives: To review and extend existing methods which take into account PK measurements in sequential adaptive designs for early dose-finding studies in small populations, and to evaluate the impact of PK measurements on the selection of the maximum tolerated dose (MTD).
Methods: This work is set in the context of phase I dose-finding studies in oncology, where the objective is to determine the MTD while limiting the number of patients exposed to high toxicity. We assume toxicity to be related to a PK measure of exposure, and consider 6 possible dose levels. Three Bayesian phase I methods from the literature were modified and compared to the standard continual reassessment method (CRM) through simulations. In these methods PK measurement, more precisely the AUC, is present as covariate for a link function of probability of toxicity [1,3] and/or as dependent variable in linear regression versus dose [2,3].
We simulated trials based on a model for the TGF-β inhibitor LY2157299 in patients with glioma [4]. The PK model was reduced to a one-compartment model with first-order absorption as in [5], in order to achieve a closed solution for the probability of toxicity. Toxicity was assumed to occur when the value of a function of AUC was above a given threshold, either in the presence or absence of inter-individual variability (IIV). For each scenario, we simulated 1000 trials with 30, 36 and 42 patients.
Results: Methods which incorporate PK measurements had good performance when informative prior knowledge was available in term of Bayesian prior distribution on parameters. On the other hand, keeping fixed the priors information, methods that included PK values as covariate were less exible and led to trials with more toxicities than the same trials with CRM.
Conclusions: Incorporating PK values as covariate did not alter the efficiency of estimation of MTD when the prior was well specified. The next step will be to assess the impact on the estimation of the dose-concentration-toxicity curve for the different approaches and to explore the introduction of fully model-based PK/PD in dose allocation rules.
References:
[1] Piantadosi, S. and Liu, G. (1996). Improved designs for dose escalation studies using pharmacokinetic measurements. Statistics in Medicine, 15(15): 1605 – 1618.
[2] Patterson, S., Francis, S., Ireson, M., Webber, D., and Whitehead, J. (1999). A novel Bayesian decision procedure for early-phase dose-finding studies. Journal of biopharmaceutical statistics, 9(4): 583 – 597.
[3] Whitehead, J., Zhou, Y., Hampson, L., Ledent, E., and Pereira, A. (2007). A Bayesian approach for dose-escalation in a phase I clinical trial incorporating pharmacodynamic endpoints. Journal of Biopharmaceutical Statistics, 17(6), 1117 – 1129.
[4] Gueorguieva, I., Cleverly, A. L., Stauber, A., Pillay, N. S., Rodon, J. A., Miles, C. P., Yingling, J. M. and Lahn, M. M. (2014). Defining a therapeutic window for the novel TGF-β inhibitor LY2157299 monohydrate based on a pharmacokinetic/pharmacodynamic model. British Journal of Clinical Pharmacology, 77: 796 – 807.
[5] Lestini G., Dumont C., Mentr F. (2014). Two-stage adaptive designs in nonlinear mixed-effects models: an evaluation by simulation for a pharmacokinetic (PK) and pharmacodynamic (PD) model in oncology. PAGE 23, Abstr 3168
Acknowledgments: This research has received funding from the European Union’s Framework Programme for research, technological development and demonstration under grant agreement no 602144. This work was part of the InSPiRe project but does not necessarily represent the view of all InSPiRe partners.
Reference: PAGE 24 () Abstr 3366 [www.page-meeting.org/?abstract=3366]
Poster: Methodology - Other topics