title: Meta-analysis of the relationship between dose and benefit in phase I targeted agent trials.
abstract: BACKGROUND
  To date, the primary objective of phase I trials has been to safely select the maximum tolerated dose (MTD) of a drug or drug combination for utilization in subsequent trials. Although conventional cytotoxic chemotherapy is generally more effective at the MTD than molecularly targeted agents (MTAs), recent single-institution data suggest that molecularly targeted agent may not require an MTD for efficacy. We analyzed patient outcome results in MTA phase I trials at multiple institutions throughout North America sponsored by the National Cancer Institute's Cancer Therapy Evaluation Program.
  
  
  METHODS
  We retrospectively collected and analyzed data on patients treated on monotherapy phase I trials investigating novel MTAs with a defined MTD from 2000 to 2009. Logistic regression analysis was used to test whether there was an increase in the probability of a response as dose increased. A Cox proportional hazards model was used to determine if overall survival increased with increasing dose. All statistical tests were two-sided.
  
  
  RESULTS
  We analyzed 1908 patients treated on 55 eligible clinical trials. The probability of both overall response (complete response plus partial response) and overall survival increased with increasing dose (odds ratio for increased response = 1.56, P = .10; hazard ratio for death = 0.37, P = .008) when controlling for study as a covariate.
  
  
  CONCLUSIONS
  Patients treated in the context of phase I trials with MTAs continue to derive reasonable clinical benefit. Contrary to other single institution data, our data suggest clinical benefit in terms of increasing response and overall survival with increasing dose.
authors.affiliation: Karmanos Cancer Institute, Department of Oncology, Detroit, MI, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Gupta
authors.forename: Sally
authors.initials: S
authors.lastname: Hunsberger
authors.forename: Scott A
authors.initials: SA
authors.lastname: Boerner
authors.forename: Larry
authors.initials: L
authors.lastname: Rubinstein
authors.forename: Robert
authors.initials: R
authors.lastname: Royds
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017321:Clinical Trials, Phase I as Topic; D015986:Confounding Factors, Epidemiologic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019337:Hematologic Neoplasms / Q000188:drug therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D020714:Maximum Tolerated Dose; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D016017:Odds Ratio; D018579:Patient Selection; D016016:Proportional Hazards Models; D012074:Remission Induction; D012107:Research Design; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents