Meta-analyses of phase I dose-finding studies: Application for the development of protein kinase inhibitors in oncology.
meta‐analysis
phase I clinical trials
protein kinase inhibitors
random‐effects
recommended dose
Journal
Research synthesis methods
ISSN: 1759-2887
Titre abrégé: Res Synth Methods
Pays: England
ID NLM: 101543738
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
revised:
02
07
2024
received:
13
09
2023
accepted:
13
07
2024
medline:
6
8
2024
pubmed:
6
8
2024
entrez:
5
8
2024
Statut:
aheadofprint
Résumé
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.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Author(s). Research Synthesis Methods published by John Wiley & Sons Ltd.
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