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Maximum tolerated dose: clinical endpoint for a bygone era?
1Translational Medicine, Ortho Biotech Oncology R&D, Radnor, PA 19087, USA. ctakimot@its.jnj.com
Targeted Oncology
|April 21, 2009
Summary
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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