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Estimating the dose-toxicity curve in completed phase I studies
Alexia Iasonos1, Irina Ostrovnaya
1Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. iasonosa@mskcc.org
Statistics in Medicine
|February 23, 2011
Summary
This study introduces a new method for analyzing phase I clinical trial data to find a more accurate maximum tolerated dose (MTD). The constrained maximum likelihood estimation (CMLE) method is shown to be superior to the standard
Area of Science:
- Clinical Trials Methodology
- Biostatistics
- Pharmacometrics
Background:
- Limited methodology exists for analyzing prospective phase I trial data.
- The standard '3+3' method may select a suboptimal maximum tolerated dose (MTD).
- Deviations from trial design complicate MTD determination with standard methods.
Purpose of the Study:
- To propose and evaluate a retrospective analysis method for phase I trials.
- To determine if a more accurate MTD can be identified compared to the standard method.
- To confirm or amend the recommended phase II dose using retrospective data.
Main Methods:
- Constrained maximum likelihood estimation (CMLE) for retrospective analysis.
- Comparison with weighted Continual Reassessment Method (CRM-w) and isotonic regression.
- Simulation of phase I trials following the standard '3+3' design.
Main Results:
- CMLE more accurately selects the true MTD compared to the standard '3+3' method.
- CMLE performance is comparable or superior to isotonic regression and CRM-w.
- Confidence intervals for toxicity probabilities are estimated using cumulative toxicity data.
Conclusions:
- CMLE offers a more accurate approach to MTD determination in phase I trials.
- Retrospective analysis with CMLE can refine dose selection for phase II trials.
- The proposed method provides a valuable tool for analyzing completed phase I trials.
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