A nonparametric Bayesian method for dose finding in drug combinations cancer trials.
Zahra S Razaee1, Galen Cook-Wiens1, Mourad Tighiouart1
1Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Statistics in Medicine
|January 25, 2022
Summary
This study introduces an adaptive design for early-phase cancer trials to find the maximum tolerated dose (MTD) of drug combinations. The novel nonparametric Bayesian approach effectively estimates toxicity and guides dose selection for improved cancer drug development.
Area of Science:
- Clinical Trial Design
- Biostatistics
- Oncology
Background:
- Early-phase cancer trials require robust designs to identify safe and effective drug combinations.
- Estimating the maximum tolerated dose (MTD) is crucial for guiding subsequent clinical development.
- Existing methods may not fully capture the complexities of dose-limiting toxicities in combination therapies.
Purpose of the Study:
- To propose an adaptive trial design for estimating the MTD in early-phase drug-combination cancer studies.
- To develop a nonparametric Bayesian model for characterizing dose-limiting toxicity (DLT) probabilities.
- To implement a modified continual reassessment method for dose allocation.
Main Methods:
- Utilized a nonparametric Bayesian model with beta priors for dose-limiting toxicity (DLT) probability.
- Employed a modified continual reassessment scheme for adaptive dose allocation across patient cohorts.
- Calculated updated DLT probabilities using a Gibbs sampler with a data-prior weighting mechanism.
Main Results:
- The proposed algorithm successfully recommends one or more dose combinations as the MTD.
- Application to a Phase I trial of CB-839 and Gemcitabine demonstrated the method's feasibility.
- Operating characteristics show the new design is comparable to existing methodologies.
Conclusions:
- The adaptive nonparametric Bayesian design offers a viable approach for early-phase combination cancer trials.
- This method provides a structured framework for estimating MTD while managing toxicity.
- The design shows promise for optimizing dose selection in the development of novel cancer therapeutics.
Keywords:
Phase I clinical trialsdrug combinationsmaximum tolerated dosenonparametric adaptive designpartial orderingMore Related Videos
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