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Conduct of phase I trials in children with cancer
M Smith1, M Bernstein, W A Bleyer
1Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD 20892, USA. smithm@ctep.nci.nih.gov
Insights
Pediatric phase I trials are crucial for evaluating new cancer drugs in children, defining safe doses and schedules for further study. These trials differ from adult studies, often requiring multi-institutional collaboration and higher starting doses.
Area of Science:
- Pediatric oncology
- Clinical pharmacology
- Drug development
Background:
- Advancing pediatric cancer care necessitates rigorous evaluation of novel therapeutic agents.
- Phase I trials are the foundational step for assessing new drugs in children.
- Prioritizing investigational agents for pediatric evaluation is critical due to limited resources.
Purpose of the Study:
- To establish guidelines for conducting pediatric phase I trials.
- To define safe and effective doses and schedules for new anti-cancer agents in children.
- To ensure new agents are suitable for subsequent phase II trials against childhood malignancies.
Main Methods:
- Consensus guidelines developed by American and European investigators.
- Focus on defining maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT).
- Emphasis on uniform eligibility criteria and standard definitions.
Main Results:
- Pediatric phase I trials necessitate multi-institutional participation.
- Starting doses are typically higher (80% of adult MTD) due to patient availability.
- Standardized criteria ensure safe conduct and reliable identification of appropriate doses.
Conclusions:
- Pediatric phase I trials are essential for advancing pediatric cancer treatment.
- Uniform criteria and definitions ensure reliable and safe drug evaluation.
- Pharmacokinetic profiling is incorporated where feasible to understand drug behavior in children.
Purpose And Methods:
Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent.
Results And Conclusion:
Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect 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 trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.