Pharmacometrics-Enabled DOse OPtimization (PEDOOP) for Seamless Phase I-II Trials in Oncology
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arXiv
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| Auteurs principaux: | , , , |
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| Format: | Preprint |
| Publié: |
2023
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| _version_ | 1866916292380852224 |
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| author | Yuan, Shijie Huang, Zhanbo Liu, Jiaxin Ji, Yuan |
| author_facet | Yuan, Shijie Huang, Zhanbo Liu, Jiaxin Ji, Yuan |
| contents | 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. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2309_17259 |
| institution | arXiv |
| publishDate | 2023 |
| record_format | arxiv |
| spellingShingle | Pharmacometrics-Enabled DOse OPtimization (PEDOOP) for Seamless Phase I-II Trials in Oncology Yuan, Shijie Huang, Zhanbo Liu, Jiaxin Ji, Yuan Applications 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. |
| title | Pharmacometrics-Enabled DOse OPtimization (PEDOOP) for Seamless Phase I-II Trials in Oncology |
| topic | Applications |
| url | https://arxiv.org/abs/2309.17259 |