Journal of Clinical Oncology, Vol 18, Issue 3
(February), 2000: 684
© 2000 American Society for Clinical Oncology
Phase I Clinical Trial Design in Cancer Drug Development
By E. A. Eisenhauer,
P. J. O’Dwyer,
M. Christian,
J. S. Humphrey
From the National Cancer Institute of Canada Clinical Trials Group, Queen’s University, Kingston, Canada; Department of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT.
Address reprint requests to Elizabeth Eisenhauer, MD, NCIC Clinical Trials Group, 82-84 Barrie St, Queen’s University, Kingston, Ontario, Canada K7L 3N6; email eeisenhauer{at}ctg.queensu.ca
ABSTRACT: The past decade has seen the publication of a number of new proposals for the design of phase I trials of anticancer agents. The purpose of these proposals has been to address ethical concerns about treating excessive numbers of patients at subtherapeutic doses of a new agent and to increase the overall efficiency of the process while enhancing the precision of the recommended phase II dose. In early 1998, a workshop of phase I investigators was held under the sponsorship of Bristol-Myers Squibb Pharmaceutical Research Institute (Wallingford, CT) to review the experience to date with novel phase I methodologies, with a particular focus on their efficiency and safety. This report summarizes the material presented. It was concluded that for phase I trials of antineoplastics (cytotoxics), which begin at 0.1 mouse-equivalent LD10 doses, evidence to date suggests that the historic approach of using a modified Fibonacci escalation and three patients per dose level is not necessary and is seldom used. One patient per dose level and more rapid escalation schemes, both empirically based and statistically based, are commonly used with apparent safety. There remain questions, however: Which of the dose escalation schemes is optimal? Are there alternatives to toxicity as a phase I end point, and will these end points be reliable in defining active doses? Answering these questions in a reasonable time frame will be important if new anticancer agents are not to suffer undue delays in phase I evaluation.
Report of a workshop on phase I trials design chaired by E.A.E. and P.J.O. and organized by Bristol-Myers Squibb, including summaries of presentations by E.A.E., J. Verweij, J. Collins, A. Rogatko, E. Rowinsky, M. Christian, P. Lorusso, H. Calvert, and M. Ratain, and as well the conclusions and final comments of the participants and coauthors.
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