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[Dose finding methods for targeted agents: new perspectives]

X Paoletti1, S Postel-Vinay, V Servois

  • 1Service de biostatistique, Inserm U900, Institut Curie, 26, rue d'Ulm, Paris, France. xavier.paoletti@curie.net

Bulletin Du Cancer
|January 12, 2011
PubMed
Abstract

Insights

Determining the optimal dose for molecularly targeted therapies requires moving beyond the Maximum Tolerated Dose (MTD). New methods incorporating sensitive endpoints are crucial for effective phase II trial dose selection.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trial Design

Background:

  • Traditional cytotoxic drug dosing relies on Maximum Tolerated Dose (MTD) determined by severe toxicity.
  • Molecularly Targeted Therapies (MTA) may have different dose-activity-toxicity relationships.
  • Relevance of MTD in MTA era requires re-evaluation.

Purpose of the Study:

  • To review potential outcomes for optimal dose definition in MTA.
  • To present innovative statistical dose-finding methodologies.
  • To assess the suitability of MTD for MTA dose selection.

Main Methods:

  • Review of relevant endpoints for dose determination.
  • Exploration of advanced statistical dose-finding methods.
  • Consideration of longitudinal data (tumor growth, toxicity) and continuous outcomes.

Main Results:

  • MTD identification remains important for Phase I trials.
  • MTD alone is insufficient for recommending Phase II trial doses.
  • Novel, sensitive, and discriminatory endpoints are needed for dose ranking.

Conclusions:

  • Phase I dose-finding for MTA should identify MTD but incorporate other endpoints for Phase II recommendations.
  • Endpoints need to be sensitive and discriminatory for ranking doses, not necessarily surrogates of clinical benefit.
  • Lessons from other medical specialties' dose-ranging trials could inform MTA strategies.

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