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
. 2018;113(523):1016-1027.
doi: 10.1080/01621459.2017.1383260. Epub 2018 Jun 28.

A Bayesian Phase I/II Trial Design for Immunotherapy

Suyu Liu  1 , Beibei Guo  2 , Ying Yuan  3
Affiliations

A Bayesian Phase I/II Trial Design for Immunotherapy

Suyu Liu et al. J Am Stat Assoc. 2018.

Abstract

Immunotherapy is an innovative treatment approach that stimulates a patient's immune system to fight cancer. It demonstrates characteristics distinct from conventional chemotherapy and stands to revolutionize cancer treatment. We propose a Bayesian phase I/II dosefinding design that incorporates the unique features of immunotherapy by simultaneously considering three outcomes: immune response, toxicity and efficacy. The objective is to identify the biologically optimal dose, defined as the dose with the highest desirability in the risk-benefit tradeoff. An Emax model is utilized to describe the marginal distribution of the immune response. Conditional on the immune response, we jointly model toxicity and efficacy using a latent variable approach. Using the accumulating data, we adaptively randomize patients to experimental doses based on the continuously updated model estimates. A simulation study shows that our proposed design has good operating characteristics in terms of selecting the target dose and allocating patients to the target dose.

Keywords: Bayesian adaptive design; Immunotherapy; dose finding; immune response; phase I/II trial; risk-benefit tradeoff.

PubMed Disclaimer

Figures

Figure 1:
Figure 1:. Dose-response curves for the 8 scenarios in the simulation study.
The dotted, dashed, and solid lines are the toxicity (πt), efficacy (πE), and immune response (E(YI)) curves, respectively. Toxicity and efficacy are plotted against the left y-axis, and the immune response is plotted against the right y-axis. Target doses are indicated by circles.
Figure 2:
Figure 2:. Sensitivity analysis with three different prior estimates of α′s in scenarios 1–4.
In each plot, at each dose level, the three bars from left to right correspond to the results with prior estimates (α^0,α^1,α^2,α^3) = ( 1, 5, 0.5, 2), (2, 4, 0.4, 3), and (1.5, 6, 0.6, 2.5), respectively.
Figure 3:
Figure 3:. Sensitivity analysis with two different prior distributions of model parameters under scenarios 1–4.
In each plot, at each dose level, the two bars represent the results under two different prior distributions.
See this image and copyright information in PMC

References

    1. Bachmayr-Heyda A, Aust S, Heinze G, Polterauer S, Grimm C, Braicu EI, Sehouli J, Lambrechts S, Vergote I, Mahner S, et al. (2013) Prognostic impact of tumor infiltrating CD8+ T cells in association with cell proliferation in ovarian cancer patients-a study of the OV- CAD consortium. BMC Cancer 13:422, doi: 10.1186/1471-2407-13-422. - DOI - PMC - PubMed
    1. Braun TM. The bivariate continual reassessment method: extending the CRM to phase I trials of two competing outcomes. Controlled clinical trials 2002; 23: 240–256. - PubMed
    1. Brody J, Kohrt H, Marabelle A and Levy R (2011), Active and passive immunotherapy for lymphoma: proving principles and improving results. Journal of Clinical Oncology, 29, 1864–1875 - PubMed
    1. Cha E and Fong L (2011), Immunotherapy for prostate cancer: biology and therapeutic approaches Journal of Clinical Oncology, 27, 3677–3686. - PMC - PubMed
    1. Cox DR (1972) Regression models and life-tables (with discussion). Journal of the Royal Statistical Society, Series Bb 34: 187–220.

LinkOut - more resources