Risks and benefits associated with novel phase 1 oncology trial designs

Cancer. 2007 Sep 1;110(5):1115-24. doi: 10.1002/cncr.22878.


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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Clinical Trials, Phase I as Topic*
  • Dose-Response Relationship, Drug
  • Humans
  • Neoplasms / drug therapy*
  • Risk Assessment
  • Treatment Outcome


  • Antineoplastic Agents