Pre-clinical animal models are poor predictors of human toxicities in phase 1 oncology clinical trials
Menée à partir de l'analyse de brochures d'investigation et des données d'essais cliniques de phase I portant sur 108 anticancéreux, cette étude met en évidence une faible corrélation entre les résultats de toxicité de ces essais cliniques et les résultats de toxicité des études précliniques réalisées sur des modèles animaux
Background : Our objective was to determine the correlation between preclinical toxicity found in animal models (mouse, rat, dog and monkey) and clinical toxicity reported in patients participating in Phase 1 oncology clinical trials.
Methods : We obtained from two major early-Phase clinical trial centres, preclinical toxicities from investigational brochures and clinical toxicities from published Phase 1 trials for 108 drugs, including small molecules, biologics and conjugates. Toxicities were categorised according to Common Terminology Criteria for Adverse Events version 4.0. Human toxicities were also categorised based on their reported clinical grade (severity). Positive predictive values (PPV) and negative predictive values (NPV) were calculated to determine the probability that clinical studies would/would not show a particular toxicity category given that it was seen in preclinical toxicology analysis. Statistical analyses also included kappa statistics, and Matthews (MCC) and Spearman correlation coefficients.
Results : Overall, animal toxicity did not show strong correlation with human toxicity, with a median PPV of 0.65 and NPV of 0.50. Similar results were obtained based on kappa statistics and MCC.
Conclusions : There is an urgent need to assess more novel approaches to the type and conduct of preclinical toxicity studies in an effort to provide better predictive value for human investigation.
British Journal of Cancer , résumé, 2020