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A Clinical Trial Assessing the Safety, Efficacy, and Delivery of Olive-Oil-Based Three-Chamber Bags for Parenteral Nutrition
Published on: September 20, 2019
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Sequential or combined designs for Phase I/II clinical trials? A simulation study.
Caroline Rossoni1,2, Aurélie Bardet1,2, Birgit Geoerger3
1Biostatistics and Epidemiology Department, Gustave Roussy, Villejuif, France.
Clinical Trials (London, England)
|September 21, 2019
Summary
For pediatric Phase I/II trials, combining dose-escalation with expansion cohorts is recommended for identifying safe and active cancer drugs. Reassessing the maximum tolerated dose during expansion improves decision accuracy, especially with narrow therapeutic indexes common in oncology.
Area of Science:
- Clinical trial design
- Pharmacology
- Oncology
Background:
- Phase I and Phase II clinical trials are increasingly combined to identify safe and active drug doses.
- Two primary designs for combined Phase I/II trials are debated: dose-escalation followed by expansion, or joint efficacy-toxicity modeling.
- This study evaluates these designs within a pediatric Phase I/II platform trial context.
Purpose of the Study:
- To compare the operating characteristics of different Phase I/II clinical trial designs.
- To determine the most effective design for identifying active and tolerable agents in pediatric oncology.
- To assess the impact of therapeutic index width on design performance.
Main Methods:
- Simulations were used to assess operating characteristics of dose-escalation followed by expansion cohort (DE-EC) designs, with and without reassessment (DE-ECext), and efficacy-toxicity (EffTox) designs.
- The probability of correctly identifying an active and tolerable agent was evaluated across various dose-toxicity-activity scenarios.
- The study focused on a pediatric Phase I/II platform trial setting.
Main Results:
- For agents with a large therapeutic index, the efficacy-toxicity design achieved a higher correct decision rate (96.0%) compared to DE-EC (76.1%) and DE-ECext (79.6%).
- When no doses were active, DE-ECext showed the highest correct decision rate (69.2%), followed by DE-EC (55.9%) and efficacy-toxicity (47%).
- In narrow therapeutic index scenarios, common in oncology, DE-ECext (67.2%) and DE-EC (64.3%) outperformed the efficacy-toxicity design (48.0%).
Conclusions:
- The sequential dose-escalation followed by an expansion cohort design is recommended for pediatric oncology trials, particularly those with narrow therapeutic indexes.
- Re-estimating the maximum tolerated dose during the expansion cohort is crucial for improving trial outcomes.
- Challenges remain in Phase I/II designs due to population variations and evaluation lag times for toxicity and activity.
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