Dose Finding in Oncology Trials Guided by Ordinal Toxicity Grades Using Continuous Dose Levels
Abstract
:1. Introduction
2. Materials and Methods
2.1. Model
2.2. Likelihood and Model Reparameterization
2.3. Prior Specification
2.4. Trial Design
3. Design Properties
- (i)
- Overdose Control: Each time patients are ready to be enrolled to the trial, we seek a dose to allocate to these patients while controlling the posterior probability of exposing them to toxic dose levels.
- (ii)
- Toxicity-Dependent Dose Escalation: If the maximum grade of toxicity experienced by patient k is grade 2, then the dose allocated to patient is lower than the dose that would have been given to patient had the maximum grade of toxicity experienced by patient k been grade 0 or 1.
- (iii)
- Coherence: If patient k treated at dose level experiences DLT, then the dose allocated to patient satisfies . Similarly, if patient k does not experience DLT and has no grade 2 toxicity, then the dose allocated to patient satisfies .
4. Application to Real-Life Example
4.1. DZ-002 Phase 1 Trial
4.2. Design Operating Characteristics
4.3. Comparing Ordinal Toxicity to Binary Toxicity
5. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Conflicts of Interest
Appendix A. Model Robustness
Scenarios | Safety | Efficiency | ||||
---|---|---|---|---|---|---|
Model | True MTD (mg/kg) | Ave DLT Rate | % Trials with DLT Rate > | Estimated MTD | Average Bias | Percent Selection |
7.76 | 0.33 | 5% | 7.94 | 0.98 | 64% | |
7.76 | 0.33 | 2.0% | 7.79 | 0.82 | 61% | |
7.76 | 0.32 | 3.3% | 8.19 | 1.23 | 67% |
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Scenarios | Safety | Efficiency | ||||
---|---|---|---|---|---|---|
True MTD (mg/kg) | Ave DLT Rate | % Trials with DLT Rate > | Estimated MTD | Average Bias | Percent Selection | |
1: (0.12, 0.50, 0.95) | 4.53 | 0.38 | 22% | 5.04 | 1.30 | 65% |
2: (0.03, 0.50, 0.90) | 7.76 | 0.33 | 5% | 7.94 | 0.98 | 64% |
3: (0.01, 0.50, 0.40) | 14.02 | 0.22 | 0.0% | 13.6 | −0.36 | 78% |
4: (0.12, 0.80, 0.95) | 4.53 | 0.38 | 23% | 5.09 | 1.35 | 65% |
5: (0.03, 0.80, 0.90) | 7.76 | 0.34 | 5% | 7.96 | 0.99 | 63% |
6: (0.01, 0.80, 0.40) | 14.02 | 0.23 | 0% | 13.72 | −0.33 | 80% |
7: (0.20, 0.30, 0.70) | 5.21 | 0.35 | 12% | 6.56 | 1.98 | 74% |
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Tighiouart, M.; Rogatko, A. Dose Finding in Oncology Trials Guided by Ordinal Toxicity Grades Using Continuous Dose Levels. Entropy 2024, 26, 687. https://doi.org/10.3390/e26080687
Tighiouart M, Rogatko A. Dose Finding in Oncology Trials Guided by Ordinal Toxicity Grades Using Continuous Dose Levels. Entropy. 2024; 26(8):687. https://doi.org/10.3390/e26080687
Chicago/Turabian StyleTighiouart, Mourad, and André Rogatko. 2024. "Dose Finding in Oncology Trials Guided by Ordinal Toxicity Grades Using Continuous Dose Levels" Entropy 26, no. 8: 687. https://doi.org/10.3390/e26080687