title: Early phase trial design for assessing several dose levels for toxicity and efficacy for targeted agents.
abstract: BACKGROUND
  Traditional phase I trials are designed to be conservative. Many times a traditional phase I trial design stops at a dose level below the maximal tolerated dose (MTD), thus potentially treating patients at a suboptimal level in all subsequent trials. This has been confirmed by our recent simulation studies.
  
  
  OBJECTIVE
  We propose a phase I/II trial design to determine the most promising dose level in terms of toxicity and efficacy for cytostatic or targeted agents. This design evaluates three dose levels for efficacy and toxicity using a modified phase II selection design. The dose levels include the phase I recommended dose (RD) in addition to the dose levels immediately below and above that level.
  
  
  METHODS
  This phase I/II trial design uses a two-step approach. In the first step, a traditional phase I trial design is used to get close to a good dose level. The second step consists of a modified selection design, randomizing patients to three dose levels: the phase I RD level and the dose levels immediately below and above the phase I RD level. Both efficacy and toxicity are used to determine a good or best dose level. Appropriate toxicity stopping rules in the phase II portion of the trial are implemented as part of such a trial. We perform simulation studies for a variety of toxicity and efficacy scenarios to determine the operating characteristics of this design and compare those to our originally proposed trial where we only explore dose levels at and below the phase I RD in the second phase of the trial, as well as to the traditional setting where a phase I trial is followed by a single-arm phase II trial at the phase I RD.
  
  
  RESULTS
  The 3-arm modified selection design exploring the dose levels immediately above and below as well as the RD performs as well or better than the 2-arm modified selection design or the single-arm design for almost all toxicity and efficacy scenario combinations tested.
  
  
  CONCLUSIONS
  We demonstrate that this design has a higher success rate at identifying a good or best dose level when exploring dose levels immediately above and below the RD in the early phase II setting, in most cases without needing larger sample sizes.
authors.affiliation: Cancer Research and Biostatistics, 1730 Minor Avenue, Seattle, WA 98101, USA. antje@crab.org
authors.forename: Antje
authors.initials: A
authors.lastname: Hoering
authors.forename: Alan
authors.initials: A
authors.lastname: Mitchell
authors.forename: Michael
authors.initials: M
authors.lastname: LeBlanc
authors.forename: John
authors.initials: J
authors.lastname: Crowley
mesh_terms: D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D003198:Computer Simulation; D054697:Cytostatic Agents / Q000008:administration & dosage* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016015:Logistic Models; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy; D016032:Randomized Controlled Trials as Topic; D012107:Research Design
chemical_list: D054697:Cytostatic Agents