CONDUCT OF PHASE-I TRIALS IN CHILDREN WITH CANCER

Purpose and Methods: Future progress in the care of children with canc er requires appropriate evaluations of promising new agents for pediat ric indications, beginning with well-conducted phase I trials. This re port summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European inve stigators. The primary objective of pediatric phase I trials is to def ine safe and appropriate doses and schedules of new agents that can su bsequently be used in phase II trials to test for activity against spe cific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are ev aluated in adult patients than can be systematically evaluated in chil dren. Considerations used in prioritizing agents include activity in x enograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. Results a nd Conclusion: Distinctive characteristics of pediatric phase I trials , in comparison to adult phase I trials, include the necessity for mul tiinstitutional participation and their higher starting dose (typicall y 80% of the adult maximum-tolerated dose [MTD]), both of which reflec t the relative unavailability of appropriate patients. the application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I tri als are safely conducted and reliably identify appropriate doses and s chedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.