Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial
Background: Escalation With Overdose Control (EWOC) designs are increasingly used to ensure dose-toxicity curve of investigational oncology drugs is efficiently characterized during dose escalation steps. We propose a novel EWOC-based method that integrates the longitudinal pharmacokinetic (PK) data...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-04-01
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| Series: | Contemporary Clinical Trials Communications |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2451865422000187 |
| _version_ | 1818143386193887232 |
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| author | Sandrine Micallef Alexandre Sostelly Jiawen Zhu Paul G. Baverel Francois Mercier |
| author_facet | Sandrine Micallef Alexandre Sostelly Jiawen Zhu Paul G. Baverel Francois Mercier |
| author_sort | Sandrine Micallef |
| collection | DOAJ |
| description | Background: Escalation With Overdose Control (EWOC) designs are increasingly used to ensure dose-toxicity curve of investigational oncology drugs is efficiently characterized during dose escalation steps. We propose a novel EWOC-based method that integrates the longitudinal pharmacokinetic (PK) data of individual patients in a Bayesian forecasting exposure-safety framework. Methods: The method, called exposure-driven EWOC (ED-EWOC), relies on a population PK model coupled with a Bayesian logistic regression model to make dose recommendation for the next cohort of patients. Results: We applied ED-EWOC to a real oncology clinical trial in parallel to a traditional EWOC approach. We found that for comparable priors, ED-EWOC dose recommendations were equivalent to the one suggested by EWOC when PK is dose proportional with low inter-individual variability. Conclusion: This case example demonstrates that ED-EWOC is logistically feasible during a trial conduct when PK bioanalysis can be expedited in the dose escalation phase. Overall, we anticipate that exposure-guided Bayesian designs could benefit patients and drug developers to identify the optimal dose steps of novel compounds entering the clinic with suspected liability in PK or that exhibit large inter-individual variability. |
| first_indexed | 2024-12-11T11:30:50Z |
| format | Article |
| id | doaj.art-a52fc09ad4fd4cc3980f2b87feecd43c |
| institution | Directory Open Access Journal |
| issn | 2451-8654 |
| language | English |
| last_indexed | 2024-12-11T11:30:50Z |
| publishDate | 2022-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Contemporary Clinical Trials Communications |
| spelling | doaj.art-a52fc09ad4fd4cc3980f2b87feecd43c2022-12-22T01:08:53ZengElsevierContemporary Clinical Trials Communications2451-86542022-04-0126100901Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trialSandrine Micallef0Alexandre Sostelly1Jiawen Zhu2Paul G. Baverel3Francois Mercier4Clinical Pharmacology, F. Hoffmann-La Roche AG, Basel, SwitzerlandClinical Pharmacology, F. Hoffmann-La Roche AG, Basel, SwitzerlandBiostatistics, Genentech, Inc., San Francisco, USAClinical Pharmacology, F. Hoffmann-La Roche AG, Basel, SwitzerlandBiostatistics, F. Hoffmann-La Roche AG, Basel, Switzerland; Corresponding author.Background: Escalation With Overdose Control (EWOC) designs are increasingly used to ensure dose-toxicity curve of investigational oncology drugs is efficiently characterized during dose escalation steps. We propose a novel EWOC-based method that integrates the longitudinal pharmacokinetic (PK) data of individual patients in a Bayesian forecasting exposure-safety framework. Methods: The method, called exposure-driven EWOC (ED-EWOC), relies on a population PK model coupled with a Bayesian logistic regression model to make dose recommendation for the next cohort of patients. Results: We applied ED-EWOC to a real oncology clinical trial in parallel to a traditional EWOC approach. We found that for comparable priors, ED-EWOC dose recommendations were equivalent to the one suggested by EWOC when PK is dose proportional with low inter-individual variability. Conclusion: This case example demonstrates that ED-EWOC is logistically feasible during a trial conduct when PK bioanalysis can be expedited in the dose escalation phase. Overall, we anticipate that exposure-guided Bayesian designs could benefit patients and drug developers to identify the optimal dose steps of novel compounds entering the clinic with suspected liability in PK or that exhibit large inter-individual variability.http://www.sciencedirect.com/science/article/pii/S2451865422000187Adaptive designsEscalation with overdose control (EWOC)Bayesian inferencesPopulation pharmacokinetic modelingExposure |
| spellingShingle | Sandrine Micallef Alexandre Sostelly Jiawen Zhu Paul G. Baverel Francois Mercier Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial Contemporary Clinical Trials Communications Adaptive designs Escalation with overdose control (EWOC) Bayesian inferences Population pharmacokinetic modeling Exposure |
| title | Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial |
| title_full | Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial |
| title_fullStr | Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial |
| title_full_unstemmed | Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial |
| title_short | Exposure driven dose escalation design with overdose control: Concept and first real life experience in an oncology phase I trial |
| title_sort | exposure driven dose escalation design with overdose control concept and first real life experience in an oncology phase i trial |
| topic | Adaptive designs Escalation with overdose control (EWOC) Bayesian inferences Population pharmacokinetic modeling Exposure |
| url | http://www.sciencedirect.com/science/article/pii/S2451865422000187 |
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