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Related Experiment Videos

Phase I trial design: are new methodologies being put into practice?

S F Dent1, E A Eisenhauer

  • 1NCIC Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|August 1, 1996
PubMed
Summary

Most phase I cancer trials rarely use new dose escalation methods. Standardizing the definition of dose-limiting toxicity (DLT) is crucial for selecting the best phase II dose.

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Area of Science:

  • Oncology
  • Clinical Pharmacology
  • Drug Development

Background:

  • Phase I studies aim to determine optimal drug doses for further clinical trials.
  • Traditional phase I designs face challenges regarding ethics, starting dose selection, and dose escalation speed.
  • New methodologies have been proposed to improve phase I trial efficiency and safety.

Purpose of the Study:

  • To evaluate the adoption rate of novel phase I trial designs in recent clinical studies.
  • To assess the impact of these new approaches on trial outcomes.
  • To identify areas for standardization in phase I trial conduct.

Main Methods:

  • A systematic review of phase I trials for single-agent cytotoxic drugs published between 1993 and 1995 was conducted.
  • Data abstracted included starting dose rationale, toxicology, dose escalation methods, definition of dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase II dose.

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  • Trials were categorized into initial studies of new agents (group A) and repeat studies of existing agents (group B).

    • Main Results:

    • 46 phase I trials were analyzed, with 27 being first-in-human studies of new agents.
    • Modified Fibonacci dose escalation was common in initial studies, while fixed increments were used in repeat studies.
    • Significant variability existed in the definition of DLT, and the MTD and recommended phase II dose were often conflated.

    Conclusions:

    • Novel phase I trial methodologies, particularly for dose escalation, are underutilized in practice.
    • Prospective evaluation of new methodologies is needed to optimize safety and efficacy in early-phase trials.
    • Lack of standardized DLT definitions hinders consistent phase II dose selection, necessitating industry-wide agreement.