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Maximum tolerated dose: clinical endpoint for a bygone era?

Chris H Takimoto1

  • 1Translational Medicine, Ortho Biotech Oncology R&D, Radnor, PA 19087, USA. ctakimot@its.jnj.com

Targeted Oncology
|April 21, 2009
PubMed

Insights

The maximum tolerated dose (MTD) is no longer the sole basis for selecting phase II doses in cancer drug development. Optimal dosing for targeted therapies requires a comprehensive evaluation beyond toxicity.

Area of Science:

  • Oncology
  • Clinical Pharmacology
  • Drug Development

Background:

  • The maximum tolerated dose (MTD) has historically guided phase II dose selection for cytotoxic chemotherapy.
  • Molecular targeted therapies possess specific mechanisms of action, challenging the MTD paradigm.

Purpose of the Study:

  • To re-evaluate the role of the MTD in phase I oncology trials for targeted therapies.
  • To emphasize the need for optimal dose selection strategies for novel anticancer agents.

Main Methods:

  • Review of current practices in phase I oncology trial dose determination.
  • Analysis of the impact of targeted therapies on dose selection strategies.

Main Results:

  • Target inhibition by molecular therapies can occur at doses below MTD.
  • MTD determination in phase I trials remains valuable but should not be blindly applied for phase II recommendations.

Conclusions:

  • Optimal dose selection for targeted cancer agents requires comprehensive data evaluation, potentially deferring final decisions until randomized phase II trials.
  • Future oncology clinical trial designs must adapt to this paradigm shift in dose selection.

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