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Review
. 2024 Jun;21(3):298-307.
doi: 10.1177/17407745231220661. Epub 2024 Jan 11.

Adaptive phase I-II clinical trial designs identifying optimal biological doses for targeted agents and immunotherapies

Yong Zang  1   2 , Beibei Guo  3 , Yingjie Qiu  1 , Hao Liu  4 , Mateusz Opyrchal  5 , Xiongbin Lu  6
Affiliations
Review

Adaptive phase I-II clinical trial designs identifying optimal biological doses for targeted agents and immunotherapies

Yong Zang et al. Clin Trials. 2024 Jun.

Abstract

Targeted agents and immunotherapies have revolutionized cancer treatment, offering promising options for various cancer types. Unlike traditional therapies the principle of "more is better" is not always applicable to these new therapies due to their unique biomedical mechanisms. As a result, various phase I-II clinical trial designs have been proposed to identify the optimal biological dose that maximizes the therapeutic effect of targeted therapies and immunotherapies by jointly monitoring both efficacy and toxicity outcomes. This review article examines several innovative phase I-II clinical trial designs that utilize accumulated efficacy and toxicity outcomes to adaptively determine doses for subsequent patients and identify the optimal biological dose, maximizing the overall therapeutic effect. Specifically, we highlight three categories of phase I-II designs: efficacy-driven, utility-based, and designs incorporating multiple efficacy endpoints. For each design, we review the dose-outcome model, the definition of the optimal biological dose, the dose-finding algorithm, and the software for trial implementation. To illustrate the concepts, we also present two real phase I-II trial examples utilizing the EffTox and ISO designs. Finally, we provide a classification tree to summarize the designs discussed in this article.

Keywords: Bayesian adaptive design; Immunotherapy; dose optimization; phase I–II trial; targeted agent.

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Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
An illustrative example for maximum tolerated dose (MTD) and optimal biological dose (OBD).
Figure 2.
Figure 2.
Diagram of the phase I-II design
Figure 3.
Figure 3.
The schematic for the Gen I-II design. Blue color indicates the doses under evaluation. Red color indicates doses that are overly toxic or less efficacious. Golden color indicates the selected optimal dose.
Figure 4.
Figure 4.
The dose-finding procedures for the hydroxychloroquine trial example.
Figure 5.
Figure 5.
Classification tree for all the discussed phase I-II designs.
See this image and copyright information in PMC

References

    1. Sledge GW. What is target therapy. Journal of Clinical Oncology 2005; 23: 1614–1615. - PubMed
    1. Wu HC, Chang DK and Huang CT. Targeted therapy for cancer. Journal of Cancer Molecules 2006; 2: 57–66.
    1. Topalian SL, Weiner GJ and Pardol DMl. Cancer immunotherapy comes of age. Journal of Clinical Oncology 2011; 23: 4828–4836. - PMC - PubMed
    1. Couzin-Frankel J Cancer immunotherapy. Science 2013; 324: 1432–1433. - PubMed
    1. Makkouk A and Weiner GJ. Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Research 2015; 75: 5–10. - PMC - PubMed

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