title: Phase I trial design for solid tumor studies of targeted, non-cytotoxic agents: theory and practice.
abstract: BACKGROUND
  New targeted, non-cytotoxic anticancer agents, such as small-molecule kinase inhibitors, pose challenges to the current phase I paradigm of dose selection based on toxicity. Moreover, increasing the drug dose to toxicity may be unnecessary for drug effect, making the use of maximum tolerated dose as a surrogate of effective dose inappropriate in the phase I setting. Because little is known about the optimal methods of recommended phase II dose selection of targeted, non-cytotoxic therapies, we reviewed the strategies that were used in completed phase I studies of these drugs.
  
  
  METHODS
  We retrieved 60 publications of phase I studies involving 31 single agents representative of the most common targets of interest in the oncology literature. For each publication, we abstracted data regarding patient population, starting dose, methods of dose escalation and determination of recommended phase II dose, and inclusion of correlative studies in study conduct.
  
  
  RESULTS
  Of the 60 completed phase I studies, 36 used toxicity and eight used pharmacokinetic data as endpoints for selection of the recommended phase II dose. Nontraditional endpoints, such as measures of molecular drug effects in tumor or surrogate tissue or functional imaging studies, were not routinely incorporated into the study design and rarely formed the primary basis for dose selection.
  
  
  CONCLUSIONS
  To date, phase I studies of targeted anticancer agents have generally used traditional endpoints for selection of the recommended phase II dose. More research is needed to define suitable molecular measures of drug effect and the means to incorporate them in the early drug development process.
authors.affiliation: National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada. wparulekar@ctg.queensu.ca
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Parulekar
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eisenhauer
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D017322:Clinical Trials, Phase II as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents