American Association for Cancer Research
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Supplementary Figure S1: DTP-Heatmap of risk of lowest dose being too toxic from Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making

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posted on 2023-03-31, 19:20 authored by Christina Yap, Lucinda J. Billingham, Ying Kuen Cheung, Charlie Craddock, John O'Quigley

DTP-Heatmap of risk of lowest dose being too toxic. This figure presents a heatmap to highlight any case where there is a high chance that the lowest dose is too toxic (greater than 0.3 DLT rate) based on the accumulated data in each pathway for the first three complete cohorts, C1-C3. This is computed for pathways where the current recommended dose is the lowest dose (Light Yellow, Yellow, Orange, Red represent increasing risks that the lowest dose is too toxic

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Cancer Research UK

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ARTICLE ABSTRACT

The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440–7. ©2017 AACR.

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