Abstract
AbstractThe rarity of childhood cancer, and high cure rates, mean only a limited number of novel therapies can be tested in patients with relapsed or refractory disease. Despite this, most novel therapeutic strategies fail in early phase trials. Of those that successfully pass through the different stages of clinical development, there is little evidence to identify the factors that influenced success. To better improve clinical success rates, we examined the impact of 23 preclinical and trial design variables for their influence on the success of 135 Phase 2 paediatric oncology clinical trials. Trial success was determined by an objective assessment of patient response, with data analysed using Fisher’s Exact or Pearson’s Chi-Square tests, and multivariate analysis using logistic regression models. For 61% of trials (83/135), no relevant preclinical experiments were performed. For those trials where preclinical studies were carried out (52/135 [39%]), there was no evidence the conduct of any preclinical experiments made the trial more likely to succeed. The only factors that positively influenced success related to trial design. Trials that evaluated patients with a single histological cancer type were significantly more likely to succeed than those that assessed multiple cancer types (67% versus 47%, 27%, and 17% for 1, 2–3, 4–7 and 8+; P<0·005). Liquid or solid tumour trials were more successful than central nervous system trials, or combined trials (67%, 61%, 37%, and 23%; P=0·005). Trials of combination therapies were more successful than single agents (70% versus 28%; P<0·005). Trials initiated based on adult studies were less likely to be successful, whereas trials initiated based on prior paediatric studies were more successful. Overall, the results of this study have the potential to change the way not only preclinical research is conducted and assessed prior to trial initiation but how clinical research is designed and performed moving forward.
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