title: A product of independent beta probabilities dose escalation design for dual-agent phase I trials.
abstract: Dual-agent trials are now increasingly common in oncology research, and many proposed dose-escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single-agent phase I trials, where a 3 + 3 rule-based design is often still used. To expedite this process, new dose-escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve-free (nonparametric) design for a dual-agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose-escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R, Stata and Excel are available for implementation.
authors: MRC Biostatistics Unit Hub for Trials Methodology Research, Institute of Public Health, University Forvie Site, Cambridge, CB2 0SR, U.K.
authors: Adrian P
authors: AP
authors: Mander
authors: Michael J
authors: MJ
authors: Sweeting
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods* / Q000592:standards / Q000706:statistics & numerical data; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016015:Logistic Models; D020714:Maximum Tolerated Dose; D012107:Research Design; D018709:Statistics, Nonparametric
keywords: adaptive design; dose escalation; dual-agent trial; nonparametric; phase I clinical trial
references: Pharm Stat. 2012 May-Jun;11(3):258-66
references: 22411472
references: Biometrics. 2003 Jun;59(2):430-40
references: 12926728
references: Biometrics. 2005 Jun;61(2):343-54
references: 16011680
references: Stat Med. 2006 Jun 30;25(12):2018-26
references: 16220476
references: Biometrics. 2005 Mar;61(1):217-22
references: 15737096
references: Biometrics. 2000 Jun;56(2):609-15
references: 10877324
references: Stat Med. 2010 Jul 30;29(17):1808-24
references: 20658549
references: Biometrics. 2010 Sep;66(3):805-12
references: 19995354
references: Biometrics. 2011 Dec;67(4):1555-63
references: 21361888
references: Stat Med. 2008 Jun 15;27(13):2420-39
references: 18344187
references: Nat Rev Clin Oncol. 2013 May;10(5):277-88
references: 23507740
references: Contemp Clin Trials. 2010 Jan;31(1):105-7
references: 19879974
references: Clin Trials. 2010 Dec;7(6):653-63
references: 20935021
references: Biometrics. 2002 Mar;58(1):237-40
references: 11890321
references: Biometrics. 2009 Sep;65(3):866-75
references: 18759848
references: Clin Trials. 2007;4(3):235-44
references: 17715248
references: J Stat Plan Inference. 2011 Aug 1;141(8):2633-2644
references: 21643478
references: Stat Biopharm Res. 2013 Jan 1;5(2):105-115
references: 24436776
references: Biometrics. 2003 Sep;59(3):487-96
references: 14601749