© 2004 by Oxford University Press
© 2004 Oxford University Press
ARTICLE |
Phase I Trial Design for Solid Tumor Studies of Targeted, Non-Cytotoxic Agents: Theory and Practice
Affiliation of authors: National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston, Ontario, Canada.
Correspondence to: Wendy Parulekar, MD, FRCPC, National Cancer Institute of Canada Clinical Trials Group, 10 Stuart St., Queen’s University, Kingston, ON, Canada K7L 3N6 (e-mail: wparulekar{at}ctg.queensu.ca)
Background: New targeted, non-cytotoxic anticancer agents, such as small-molecule kinase inhibitors, pose challenges to the current phase I paradigm of dose selection based on toxicity. Moreover, increasing the drug dose to toxicity may be unnecessary for drug effect, making the use of maximum tolerated dose as a surrogate of effective dose inappropriate in the phase I setting. Because little is known about the optimal methods of recommended phase II dose selection of targeted, non-cytotoxic therapies, we reviewed the strategies that were used in completed phase I studies of these drugs. Methods: We retrieved 60 publications of phase I studies involving 31 single agents representative of the most common targets of interest in the oncology literature. For each publication, we abstracted data regarding patient population, starting dose, methods of dose escalation and determination of recommended phase II dose, and inclusion of correlative studies in study conduct. Results: Of the 60 completed phase I studies, 36 used toxicity and eight used pharmacokinetic data as endpoints for selection of the recommended phase II dose. Nontraditional endpoints, such as measures of molecular drug effects in tumor or surrogate tissue or functional imaging studies, were not routinely incorporated into the study design and rarely formed the primary basis for dose selection. Conclusions: To date, phase I studies of targeted anticancer agents have generally used traditional endpoints for selection of the recommended phase II dose. More research is needed to define suitable molecular measures of drug effect and the means to incorporate them in the early drug development process.
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Editorial about this Article
- Nontoxicity Endpoints in Phase I Trial Designs for Targeted, Non-Cytotoxic Agents
- Edward L. Korn
J Natl Cancer Inst 2004 96: 977-978.[Extract] [Full Text] [PDF]
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