A comparative analysis of paediatric dose-finding trials of molecularly targeted agent with adults' trials

Abstract

Background: Dose-finding phase I trials in children are usually carried out once clinical data have already been accumulated in the adult population. The objectives, place and role of paediatric dose-finding trials are investigated in the era of molecularly targeted agents (MTAs).

Methods: Phase I paediatric oncology trials of MTAs approved in adults before June 15th, 2012 were reviewed. The recommended phase II dose (RPIID) was compared to the body surface area (BSA)-adjusted approved dose in adults. Toxicity profile was compared to the findings from the corresponding adult phase I trials.

Results: Fifteen MTAs out of a total of 25 MTAs approved in the adult population have been evaluated in 19 single-agent phase I paediatric trials. Trials included a median of 30 children with a median of four dose levels. The paediatric RPIID ranged between 90% and 130% of the BSA-adjusted approved dose in adults for 70% of the trials (75% of compounds). Overall, 63% of children did not receive an optimal dose. The most marked discrepancy involved sunitinib. Safety profiles described in phase I paediatric trials were usually similar to those reported in the adult population.

Conclusions: These data suggest that dose-finding studies might not be necessary for all the MTAs in children. Except in the case of a narrow therapeutic index, early-phase trials validating pharmacokinetics, pharmacodynamic markers and efficacy findings from adults while controlling for toxicity appear to be a possible alternative to accelerate drug development in paediatric oncology.