title: Continual reassessment method for dose escalation clinical trials in oncology: a comparison of prior skeleton approaches using AZD3514 data.
abstract: The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship ("prior skeleton") and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses.
  
  
  
  Post-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches.
  
  
  
  All methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches.
  
  
  
  Prior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important.
  
  
  
  NCT01162395 , Trial date of first registration: July 13, 2010.
authors: PHASTAR, Unit 2, 2a Bollo Lane, London, W4 5LE, UK.|AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.
authors: Gareth D
authors: GD
authors: James
authors: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.|Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital, Edinburgh, EH4 2XR, UK.
authors: Stefan N
authors: SN
authors: Symeonides
authors: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.
authors: Jayne
authors: J
authors: Marshall
authors: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK.
authors: Julia
authors: J
authors: Young
authors: AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK. glen.clack@astrazeneca.com.
authors: Glen
authors: G
authors: Clack
mesh_terms: D000465:Algorithms; D000726:Androgen Antagonists / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001499:Bayes Theorem; D017321:Clinical Trials, Phase I as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008962:Models, Theoretical; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy; D011724:Pyridazines / Q000008:administration & dosage
chemical_list: C583656:AZD3514; D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D011724:Pyridazines
keywords: Bayesian; Clinical trial; Continual reassessment method; Oncology; Phase 1; Skeleton