Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Sep;77(3):1075-1088.
doi: 10.1111/biom.13358. Epub 2020 Sep 10.

A batch-effect adjusted Simon's two-stage design for cancer vaccine clinical studies

Chenguang Wang  1 , Zhixin Wang  2 , Gary L Rosner  1 , Warner K Huh  2 , Richard B S Roden  1 , Sejong Bae  2
Affiliations

A batch-effect adjusted Simon's two-stage design for cancer vaccine clinical studies

Chenguang Wang et al. Biometrics. 2021 Sep.

Abstract

In the development of cancer treatment vaccines, phase II clinical studies are conducted to examine the efficacy of a vaccine in order to screen out vaccines with minimal activity. Immune responses are commonly used as the primary endpoint for assessing vaccine efficacy. With respect to study design, Simon's two-stage design is a popular format for phase II cancer clinical studies because of its simplicity and ethical considerations. Nonetheless, it is not straightforward to apply Simon's two-stage design to cancer vaccine studies when performing immune assays in batches, as outcomes from multiple patients may be correlated with each other in the presence of batch effects. This violates the independence assumption of Simon's two-stage design. In this paper, we numerically explore the impact of batch effects on Simon's two-stage design, propose a batch-effect adjusted Simon's two-stage design, demonstrate the proposed design by both a simulation study and a therapeutic human papillomavirus vaccine trial, and briefly introduce a software that implements the proposed design.

Keywords: Simon's two-stage design; batch effect; cancer vaccine; clinical trial design; phase II study.

PubMed Disclaimer

Figures

FIGURE 1
FIGURE 1
Differences between mass function Pr(X1 = x|s(1), p) and Binomial(n1, p) for n1 = 30 and batch sizes 3, 6, 15, and 30.
FIGURE 2
FIGURE 2
Data generation scenarios. Left: Densities of the multiplicative batch effect γ, additive batch effect η, and random error ϵ. Middle: Densities of the pre-vaccination number of T cells (Y0) and post-vaccination number of T cells (Y1 ). Right: Densities of the proliferation index (Y1/Y0) with the dashed lines corresponding to the 10th, 50th, and 90th percentiles.
FIGURE 3
FIGURE 3
Type I error probabilities and power based on the Simon’s optimal two-stage design for different methods. The results are based on 5000 replications.
See this image and copyright information in PMC

References

    1. Alter O, Brown PO and Botstein D (2000) Singular value decomposition for genome-wide expression data processing and modeling. Proceedings of the National Academy of Sciences, 97, 10101–10106. - PMC - PubMed
    1. Altman JD, Moss PA, Goulder PJ, Barouch DH, McHeyzer-Williams MG, Bell JI, et al., (1996) Phenotypic analysis of antigen-specific t lymphocytes. Science, 274, 94–96. - PubMed
    1. Andtbacka R, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al., (2015) Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. Journal of Clinical Oncology, 33, 2780–2788. - PubMed
    1. Benito M, Parker J, Du Q, Wu J, Xiang D, Perou CM, et al., (2004) Adjustment of systematic microarray data biases. Bioinformatics, 20, 105–114. - PubMed
    1. BIPM, IEC, IFCC, ILAC, ISO, IUPAC, IUPAP and OIML. (2012) The international vocabulary of metrology–basic and general concepts and associated terms (vim), 3rd edition. jcgm 200: 2012. JCGM (Joint Committee for Guides in Metrology).

Publication types

Substances