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Reducing sample sizes in two-stage phase II cancer trials by using continuous tumour shrinkage end-points
James M S Wason1, Adrian P Mander, Tim G Eisen
1MRC Biostatistics Unit, Hub for Trials Methodology Research, Cambridge, United Kingdom. james.wason@mrc-bsu.cam.ac.uk
Abstract:
Reducing the number of patients required for a clinical trial is important for shortening development time. Phase II cancer trials assess the tumour-shrinking effect of a novel compound through a binary end-point formed from the percentage change in total lesion diameter. We compare single-arm two-stage designs which use the binary end-point to those which directly use the continuous end-point. Using the continuous end-point results in lower expected and maximum sample sizes. For larger trials the reduction is around 37%. This assumes that the dichotomisation point of the continuous end-point is chosen to give the best sample size, with the trial design using the binary end-point performing even worse otherwise. We consider a previous trial designed using a Simon two-stage design and show that if the continuous end-point had been used, the expected and maximum sample sizes of the trial would be reduced by around 50%. Using the continuous end-point in a two-stage cancer trial results in large sample size reductions. The methods discussed in this paper work best when the number of complete responses is low, as is true in several types of cancer. We discuss what could be done if this is not the case.
Insights
Using continuous end-points in two-stage cancer trials significantly reduces patient numbers. This method lowers expected and maximum sample sizes, accelerating drug development timelines.
Area of Science:
- Clinical Trials
- Oncology Research
- Biostatistics
Background:
- Clinical trial efficiency is crucial for timely drug development.
- Phase II cancer trials often use binary endpoints based on tumor shrinkage.
- Optimizing sample size reduces trial costs and duration.
Purpose of the Study:
- To compare the efficiency of single-arm two-stage clinical trial designs using binary versus continuous endpoints.
- To quantify the sample size reductions achievable by employing continuous endpoints in cancer trials.
Main Methods:
- Comparison of two-stage trial designs utilizing binary endpoints (percentage change in total lesion diameter) versus continuous endpoints.
- Analysis of expected and maximum sample sizes for both design types.
- Evaluation of a previously designed Simon two-stage trial using the continuous endpoint approach.
Main Results:
- Continuous endpoints result in significantly lower expected and maximum sample sizes compared to binary endpoints.
- Sample size reductions can reach approximately 37% for larger trials and up to 50% when applied to existing trial designs.
- The benefits are most pronounced when the number of complete responses is low, common in certain cancers.
Conclusions:
- Employing continuous endpoints in two-stage cancer trials offers substantial sample size reductions.
- This approach can accelerate the development of novel cancer compounds by improving trial efficiency.
- Further considerations are discussed for scenarios with a high number of complete responses.
