Meta-analyses of phase I dose-finding studies: Application for the development of protein kinase inhibitors in oncology.

Autor: Caquelin L; Univ Rennes, CHU Rennes, Inserm, Centre d'investigation clinique de Rennes (CIC1414), Service de Pharmacologie Clinique, Institut de Recherche en Santé, Environnement et Travail (Irset), UMR S 1085, EHESP, Rennes, France., Badra P; Univ Rennes, CHU Rennes, Inserm, Centre d'investigation clinique de Rennes (CIC1414), Service de Pharmacologie Clinique, Institut de Recherche en Santé, Environnement et Travail (Irset), UMR S 1085, EHESP, Rennes, France.; ReCAP/F-CRIN, INSERM, Paris, France., Poulain L; Univ Rennes, CHU Rennes, Inserm, Centre d'investigation clinique de Rennes (CIC1414), Service de Pharmacologie Clinique, Institut de Recherche en Santé, Environnement et Travail (Irset), UMR S 1085, EHESP, Rennes, France., Laviolle B; Univ Rennes, CHU Rennes, Inserm, Centre d'investigation clinique de Rennes (CIC1414), Service de Pharmacologie Clinique, Institut de Recherche en Santé, Environnement et Travail (Irset), UMR S 1085, EHESP, Rennes, France., Ursino M; ReCAP/F-CRIN, INSERM, Paris, France.; Unit of Clinical Epidemiology, Assistance Publique-Hôpitaux de Paris, CHU Robert Debré, Inserm CIC-EC 1426, Paris, France.; Inserm, Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, Paris, France.; Inria Paris, Paris, France., Locher C; Univ Rennes, CHU Rennes, Inserm, Centre d'investigation clinique de Rennes (CIC1414), Service de Pharmacologie Clinique, Institut de Recherche en Santé, Environnement et Travail (Irset), UMR S 1085, EHESP, Rennes, France.; ReCAP/F-CRIN, INSERM, Paris, France.
Jazyk: angličtina
Zdroj: Research synthesis methods [Res Synth Methods] 2024 Nov; Vol. 15 (6), pp. 964-977. Date of Electronic Publication: 2024 Aug 05.
DOI: 10.1002/jrsm.1747
Abstrakt: This study aimed to assess the feasibility of applying two recent phase I meta-analyses methods to protein kinase inhibitors (PKIs) developed in oncology and to identify situations where these methods could be both feasible and useful. This ancillary study used data from a systematic review conducted to identify dose-finding studies for PKIs. PKIs selected for meta-analyses were required to have at least five completed dose-finding studies involving cancer patients, with available results, and dose escalation guided by toxicity assessment. To account for heterogeneity caused by various administration schedules, some studies were divided into study parts, considered as separate entities in the meta-analyses. For each PKI, two Bayesian random-effects meta-analysis methods were applied to model the toxicity probability distribution of the recommended dose and to estimate the maximum tolerated dose (MTD). Meta-analyses were performed for 20 PKIs including 96 studies corresponding to 115 study parts. The median posterior probability of toxicity probability was below the toxicity thresholds of 0.20 for 70% of the PKIs, even if the resulting credible intervals were very wide. All approved doses were below the MTD estimated for the minimum toxicity threshold, except for one, for which the approved dose was above the MTD estimated for the maximal threshold. The application of phase I meta-analysis methods has been feasible for the majority of PKI; nevertheless, their implementation requires multiple conditions. However, meta-analyses resulted in estimates with large uncertainty, probably due to limited patient numbers and/or between-study variability. This calls into question the reliability of the recommended doses.
(© 2024 The Author(s). Research Synthesis Methods published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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