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Abstract:
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In phase 1 dose escalation studies, dose limiting toxicities are defined as adverse events of concern occurring during a predefined time window after first dosing of patients. Standard dose escalation designs, such as the continual reassessment method, only utilize this binary DLT information. Thus, late DLTs are usually not accounted for when guiding the dose escalation and finally defining the maximum tolerated dose of the drug, which brings safety concerns for patients. Previously, several extensions of the CRM, such as the TITE-CRM (Cheung et al, 2000) and the DA-CRM (Liu et al, 2013), have been proposed to handle this issue without needing to extend the time window and hence prolonging trial duration. However, none of them have controlled the risk of overdosing explicitly as in the EWOC design (Babb et al, 1998). Here we propose a rolling dose escalation with overdose control using a two-parameter logistic regression model. A simulation study has been conducted to show the favorable performance of the design. Several practical operation restrictions to further protect the patients have been explored. An application will illustrate the practical benefits of the proposed design.
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