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Adaptive designs for dual-agent phase I dose-escalation studies

Nature Reviews Clinical Oncology volume 10, pages 277–288 (2013)Cite this article

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Abstract

Anticancer agents used in combination are fundamental to successful cancer treatment, particularly in a curative setting. For dual-agent phase I trials, the goal is to identify drug doses and schedules for further clinical testing. However, current methods for establishing the recommended phase II dose for agents in combination can fail to fully explore drug interactions. With increasing numbers of anticancer drugs requiring testing, new adaptive model-based trial designs that improve on current practice have been proposed, although uptake has been minimal. We describe the methods available and discuss some of the opportunities and challenges faced in dual-agent phase I trials, as well as giving examples of trials in which adaptive designs have been implemented successfully. Improving the design and execution of phase I trials of drug combinations critically relies on collaboration between the statistical and clinical communities to facilitate the implementation of adaptive, model-based designs.

Key Points

  • Combination therapy is the mainstay of life-prolonging cancer treatments and increasingly uses both traditional cytotoxic and targeted agents

  • Standard rule-based methods for dual-agent clinical trial design have considerable limitations, including slow dose-escalation and that they only consider the outcome of the last cohort to guide escalation

  • Adaptive model-based clinical trial designs can be more accurate in recommending combinations to take forward into phase II trials and provide greater flexibility for investigators

  • Additional features of model-based designs can be extended to include measurements of chronic toxicity, efficacy, pharmacokinetics and pharmacodynamics, which can be particularly attractive in trials of targeted agents

  • Successful examples of model-based designs in practice exist and their further use is strongly encouraged

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Figure 1: Example of a 2D dose surface formed by drug A and drug B.
Figure 2: Mean dose–toxicity relationship for an example trial using the continual reassessment method before the trial begins (blue line), after five patients (orange line) and after 25 patients at the end of the trial (purple line).
Figure 3: Examples of dose-escalation studies using a | standard method of dose escalation, with drug A fixed at its RP2D when administered alone (RP2DA), and b | exploration of full dose surface to find possible RP2D combinations.
Figure 4: Example of a 3 + 3 + 3 escalation study.
Figure 5: Selection of three RP2D combinations based on an example trial using a known model.31
Figure 6: Illustration of a simple dose combination grid, showing all possible simple orders that satisfy the known partial ordering of dose combinations with respect to toxicity.
Figure 7: Dose grid and zones.71

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Acknowledgements

The authors would like to thank the referees for their helpful comments and contribution to the manuscript. J. A. Harrington and G. M. Wheeler are both PhD students whose research is funded by Cancer Research UK and the Medical Research Council UK, respectively. G. M. Wheeler, A. P. Mander and M. J. Sweeting are supported by the Medical Research Council (Grant number G0800860).

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Authors and Affiliations

  1. Department of Oncology, University of Cambridge, Box 279, S4 Block, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, UK

    Jennifer A. Harrington & Duncan I. Jodrell

  2. Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK

    Jennifer A. Harrington & Duncan I. Jodrell

  3. MRC Biostatistics Unit Hub for Trials Methodology Research, Institute of Public Health, Robinson Way, Cambridge, CB2 0SR, UK

    Graham M. Wheeler, Michael J. Sweeting & Adrian P. Mander

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J. A. Harrington and G. M. Wheeler contributed equally to the research of the data for the article, discussion of the article content, writing of the manuscript and review of the manuscript before submission. The remaining authors contributed to the discussion of the article content and edited the manuscript before submission.

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Harrington, J., Wheeler, G., Sweeting, M. et al. Adaptive designs for dual-agent phase I dose-escalation studies. Nat Rev Clin Oncol 10, 277–288 (2013). https://doi.org/10.1038/nrclinonc.2013.35

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