title: Risks and benefits associated with novel phase 1 oncology trial designs.
abstract: BACKGROUND
  Although aggressive dose escalation strategies were designed to improve the risk-benefit profile of phase 1 oncology trials, they have not been adequately studied. The prevalence of several novel trial designs and their association with a variety of clinical endpoints was evaluated.
  
  
  METHODS
  A review of the literature was performed to identify phase 1 oncology studies of cytotoxic agents published from 2002 through 2004.
  
  
  RESULTS
  Of 955 phase 1 oncology articles initially identified, 149 studies, comprising 4532 patients, were analyzed. Only 34% of studies utilized aggressive dose escalation schemes, 22% permitted intrapatient dose escalation, and only 28% enrolled fewer than 3 patients to any dose level. Studies that allowed intrapatient dose escalation or used fewer than 3 patients per dose were not associated with different rates of response or toxicity, nor did they increase the number of patients who received the recommended phase 2 dose. However, aggressive dose escalations were associated with increased rates of both hematologic (17% vs 10%) and nonhematologic (17% vs 13%) toxicity with similar response rates. Only studies that used conservative dose escalation designs and those that studied U.S. Food and Drug Administration (FDA)-approved agents required fewer patients to complete a trial. Trials of FDA-approved agents were also associated with higher response rates than trials of non-FDA-approved agents (10% vs 2%), without an increased risk of toxicity.
  
  
  CONCLUSIONS
  Several novel aggressive design strategies intended to improve the risk-benefit profile of phase 1 oncology trials are not associated with improved clinical outcome, and may be harmful in certain instances.
authors.affiliation: Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Shlomo A
authors.initials: SA
authors.lastname: Koyfman
authors.forename: Manish
authors.initials: M
authors.lastname: Agrawal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Garrett-Mayer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krohmal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wolf
authors.forename: Ezekiel J
authors.initials: EJ
authors.lastname: Emanuel
authors.forename: Cary P
authors.initials: CP
authors.lastname: Gross
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents