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Review
. 2009 May 20;101(10):708-20.
doi: 10.1093/jnci/djp079. Epub 2009 May 12.

Dose escalation methods in phase I cancer clinical trials

Christophe Le Tourneau  1 , J Jack Lee, Lillian L Siu
Affiliations
Review

Dose escalation methods in phase I cancer clinical trials

Christophe Le Tourneau et al. J Natl Cancer Inst. .

Abstract

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.

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Figures

Figure 1
Figure 1
Typical dose–toxicity and dose–efficacy curves for cytotoxic agents. This example illustrates that at dose x, the probability of efficacy is 30% and the probability of toxicity is 10%; hence, the therapeutic index of the drug at dose x is 10% divided by 30% = 1/3.
Figure 2
Figure 2
Graphical depiction of dose escalation methods for phase I cancer clinical trials. Each box represents a cohort comprising the indicated number of patients treated at a given dose level. A) Simple up-and-down design. B) Traditional 3+3 design. C) Accelerated titration design. Dashed arrows represent intrapatient dose escalation. D) Pharmacologically guided dose escalation. E) Modified continual reassessment method. F) Escalation with overdose control. “Overdosing or excessive overdosing” refers to doses that exceed the MTD. DLT = dose-limiting toxicity; SD = starting dose; RD = recommended dose; DL = dose level; AUC = area under the curve for drug concentration as a function of time; p(DLT at next DL) = probability of dose-limiting toxicity at the next dose level.
Figure 3
Figure 3
Strategies for dose escalation in phase I trials testing combinations of two drugs. White bars represent drug 1, gray bars represent drug 2. A) Alternate dose escalation. B) Simultaneous dose escalation. C) Single-agent dose escalation. D) Compromised dose escalation with only one of the two agents achieving full dose escalation. DL = dose level.
Figure 4
Figure 4
Dose escalations methods used in phase I cancer clinical trials published between January 1, 2007, and December 1, 2008. Asterisk indicates that model fitting was not performed in any of the seven ATD trials to establish the recommended dose for phase II trials. ATD = accelerated titration design; mCRM = modified continual reassessment method; TITE-CRM = time-to-event continual reassessment method.
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