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Pharmacometrics-Enabled DOse OPtimization (PEDOOP) for Seamless Phase I-II Trials in Oncology (2309.17259v2)

Published 29 Sep 2023 in stat.AP

Abstract: We consider a dose-optimization design for first-in-human oncology trial that aims to identify a suitable dose for late-phase drug development. The proposed approach, called the Pharmacometrics-Enabled DOse OPtimization (PEDOOP) design, incorporates observed patient-level pharmacokinetics (PK) measurements and latent pharmacodynamics (PD) information for trial decision making and dose optimization. PEDOOP consists of two seamless phases. In phase I, patient-level time-course drug concentrations, derived PD effects, and the toxicity outcomes from patients are integrated into a statistical model to estimate the dose-toxicity response. A simple dose-finding design guides dose escalation in phase I. At the end of the phase I dose finding, a graduation rule is used to assess the safety and efficacy of all the doses and select those with promising efficacy and acceptable safety for a randomized comparison against a control arm in phase II. In phase II, patients are randomized to the selected doses based on a fixed or adaptive randomization ratio. At the end of phase II, an optimal biological dose (OBD) is selected for late-phase development. We conduct simulation studies to assess the PEDOOP design in comparison to an existing seamless design that also combines phases I and II in a single trial.

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Authors (4)
  1. Shijie Yuan (12 papers)
  2. Zhanbo Huang (4 papers)
  3. Jiaxin Liu (31 papers)
  4. Yuan Ji (50 papers)
Citations (1)

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