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Journal of the National Cancer Institute Advance Access originally published online on May 12, 2009
JNCI Journal of the National Cancer Institute 2009 101(10):708-720; doi:10.1093/jnci/djp079
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© 2009 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

REVIEW

Dose Escalation Methods in Phase I Cancer Clinical Trials

Christophe Le Tourneau, J. Jack Lee, Lillian L. Siu

Affiliations of authors: Division of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, ON, Canada (CLT, LLS); Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX (JJL)

Correspondence to: Lillian L. Siu, MD, FRCPC, Division of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, University of Toronto, 610 University Ave, Ste 5-718, Toronto, ON, Canada M5G 2M9 (e-mail: lillian.siu{at}uhn.on.ca)

Phase I clinical trials are an essential step in the development of anticancer drugs. The main goal of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual. Here we review dose escalation methods for phase I trials, including the rule-based and model-based dose escalation methods that have been developed to evaluate new anticancer agents. Toxicity has traditionally been the primary endpoint for phase I trials involving cytotoxic agents. However, with the emergence of molecularly targeted anticancer agents, potential alternative endpoints to delineate optimal biological activity, such as plasma drug concentration and target inhibition in tumor or surrogate tissues, have been proposed along with new trial designs. We also describe specific methods for drug combinations as well as methods that use a time-to-event endpoint or both toxicity and efficacy as endpoints. Finally, we present the advantages and drawbacks of the various dose escalation methods and discuss specific applications of the methods in developmental oncotherapeutics.

Manuscript received October 27, 2008; revised February 17, 2009; accepted March 4, 2009.


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J Natl Cancer Inst 2009 101: 695. [Extract] [Full Text] [PDF]



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S. Zohar and J. O'Quigley
Re: Dose Escalation Methods in Phase I Cancer Clinical Trials
J Natl Cancer Inst, November 5, 2009; (2009) djp400v1.
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 JNCI J Natl Cancer InstHome page
C. Le Tourneau, J. J. Lee, and L. L. Siu
Response
J Natl Cancer Inst, November 5, 2009; (2009) djp401v1.
[Full Text] [PDF]


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