title: A review of dose-limiting events in phase I trials: antimetabolites show unpredictable relationships between dose and toxicity.
abstract: BACKGROUND
  In a sample of NCIC CTG phase I trials we noted that studies of antimetabolites were frequently confounded by the occurrence of dose-limiting toxicities (DLT) at doses well below those ultimately recommended (recommended dose, RD) for further study, necessitating frequent expansion of dose levels and usually a change to more conservative dose escalation. This slowed development, exposed patients to ineffective doses of drugs, and raises concerns about the safety of current trial designs which include a single patient per dose level. Conversely, some patients treated at the RD may be receiving inadequate doses of anticancer drugs. To determine if this was a general phenomenon, we undertook a review of the results of a large group of phase I trials of cytotoxic agents.
  
  
  METHODS
  Starting dose (SD), number of dose levels, dose at first DLT (D-DLT), maximum tolerated doses (MTD, dose at which DLT is seen in two or more patients) and RD were extracted from the NCI-Canada phase I trial database, and from a literature survey of phase I studies published between 1985 and 1999. Combination phase I and phase Ib studies were excluded.
  
  
  RESULTS
  The review included 33 trials with antimetabolites and 60 with other cytotoxic agents. The median ratio D-DLT/MTD was 0.33 for antimetabolites and 0.75 for other cytotoxic agents (P < 0.01). Similarly, the median ratio D-DLT/RD was 0.43 for antimetabolites and 1 for other cytotoxic agents (P < 0.01). The median number of dose levels tested was nine for antimetabolites and six for other cytotoxic agents.
  
  
  CONCLUSIONS
  Statistically significant differences in the ratios D-DLT/MTD and D-DLT/RD between antimetabolites and other cytotoxic compounds were noted, confirming our initial observations that unpredictable DLT occurs earlier and at lower dose levels in phase I clinical trials of antimetabolites than would be expected as compared to other classes ofcytotoxic agents. Toxicity thus appears to be incompletely predicted by dose alone for antimetabolites. DLT may occur in certain patients at doses well below the RD. Current phase I design may not be ideal for development of these compounds, and should focus on pharmacodynamic endpoints in addition to traditional pharmacokinetic and clinical endpoints.
authors.affiliation: Investigational New Drug Program, National Cancer Institute of Canada Clinical Trial Group, Queens University, Kingston, Ontario. lseymour@ctg.queensu.ca
authors.forename: L
authors.initials: L
authors.lastname: Seymour
authors.forename: E
authors.initials: E
authors.lastname: Eisenhauer
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D017321:Clinical Trials, Phase I as Topic; D012189:Retrospective Studies
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents