Performance of phase-I dose finding designs with and without a run-in intra-patient dose escalation stage.
dose escalation
dose-finding
intra-patient
maximum tolerated dose
phase-I
Journal
Pharmaceutical statistics
ISSN: 1539-1612
Titre abrégé: Pharm Stat
Pays: England
ID NLM: 101201192
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
revised:
05
08
2022
received:
21
03
2022
accepted:
03
10
2022
pubmed:
27
10
2022
medline:
15
3
2023
entrez:
26
10
2022
Statut:
ppublish
Résumé
Dose-finding designs for phase-I trials aim to determine the recommended phase-II dose (RP2D) for further phase-II drug development. If the trial includes patients for whom several lines of standard therapy failed or if the toxicity of the investigated agent does not necessarily increase with dose, optimal dose-finding designs should limit the frequency of treatment with suboptimal doses. We propose a two-stage design strategy with a run-in intra-patient dose escalation part followed by a more traditional dose-finding design. We conduct simulation studies to compare the 3 + 3 design, the Bayesian Optimal Interval Design (BOIN) and the Continual Reassessment Method (CRM) with and without intra-patient dose escalation. The endpoints are accuracy, sample size, safety, and therapeutic efficiency. For scenarios where the correct RP2D is the highest dose, inclusion of an intra-patient dose escalation stage generally increases accuracy and therapeutic efficiency. However, for scenarios where the correct RP2D is below the highest dose, intra-patient dose escalation designs lead to increased risk of overdosing and an overestimation of RP2D. The magnitude of the change in operating characteristics after including an intra-patient stage is largest for the 3 + 3 design, decreases for the BOIN and is smallest for the CRM.
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
236-247Informations de copyright
© 2022 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.
Références
Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical trials. JNCI: J Nat Cancer Inst. 2009;101:708-720.
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. Translation of innovative designs into phase I trials. J Clin Oncol. 2007;25:4982-4986.
van Brummelen EM, Huitema AD, van Werkhoven E, et al. The performance of model-based versus rule-based phase I clinical trials in oncology. J Pharmacokinet Pharmacodyn. 2016;43:235-242.
O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics. 1990;46:33-48.
Paoletti X, Ezzalfani M, Le Tourneau C. Statistical controversies in clinical research: requiem for the 3+ 3 design for phase I trials. Ann Oncol. 2015;26:1808-1812.
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a comparison of trial designs. Cancer Chemother Pharmacol. 2013;71:1107-1114.
Braun TM. The current design of oncology phase I clinical trials: progressing from algorithms to statistical models. Chin Clin Oncol. 2014;3:2.
Liu S, Yuan Y. Bayesian optimal interval designs for phase I clinical trials. J R Stat Soc Ser C Appl Stat. 2015;64:507-523.
Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-finding trials. Clin Trials. 2010;7:653-663.
Yan F, Mandrekar SJ, Yuan Y. Keyboard: a novel Bayesian toxicity probability interval design for phase I clinical trials. Clin Cancer Res. 2017;23:3994-4003.
Simon R, Rubinstein L, Arbuck SG, Christian MC, Freidlin B, Collins J. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997;89:1138-1147.
Heitmann JS, Walz JS, Pflügler M, et al. Protocol of a prospective, multicentre phase I study to evaluate the safety, tolerability and preliminary efficacy of the bispecific PSMAxCD3 antibody CC-1 in patients with castration-resistant prostate carcinoma. BMJ Open. 2020;10:e039639.
Newman MJ, Benani DJ. A review of blinatumomab, a novel immunotherapy. J Oncol Pharm Pract. 2016;22:639-645.
Wheeler GM, Mander AP, Bedding A, et al. How to design a dose-finding study using the continual reassessment method. BMC Med Res Methodol. 2019;19:1-15.
Paoletti X, Kramar A. A comparison of model choices for the continual reassessment method in phase I cancer trials. Stat Med. 2009;28:3012-3028.
Sweeting M, Mander A, Sabin T. Bcrm: Bayesian continual reassessment method designs for phase I dose-finding trials. J Stat Software. 2013;54:1-26.
Yan F, Zhang L, Zhou Y, Pan H, Liu S, Yuan Y. BOIN: an R package for designing single-agent and drug-combination dose-finding trials using Bayesian optimal interval designs. J Stat Software. 2020;94:1-32.
Iasonos A, Wilton AS, Riedel ER, Seshan VE, Spriggs DR. A comprehensive comparison of the continual reassessment method to the standard 3 + 3 dose escalation scheme in phase I dose-finding studies. Clin Trials. 2008;5:465-477.
Zhu Y, Hwang W-T, Li Y. Evaluating the effects of design parameters on the performances of phase I trial designs. Contemp Clin Trials Commun. 2019;15:100379.