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. 2011 Feb 15;17(4):640-6.
doi: 10.1158/1078-0432.CCR-10-1262. Epub 2010 Dec 6.

Seamless phase I-II trial design for assessing toxicity and efficacy for targeted agents

Antje Hoering  1 , Mike LeBlanc, John Crowley
Affiliations

Seamless phase I-II trial design for assessing toxicity and efficacy for targeted agents

Antje Hoering et al. Clin Cancer Res. .

Abstract

Purpose: The premise for phase I trials for cytostatic agents is different from that of cytotoxic agents. For cytostatic agents, toxicity and efficacy do not necessarily increase monotonically with increasing dose levels, but likely plateau after they reach maximal toxicity or efficacy. Here, we propose a phase I-II trial design to assess both toxicity and efficacy to find the best dose as well as a good dose.

Experimental design: We propose a 2-step dose-finding trial for assessing both toxicity and efficacy for a targeted agent. The 1st step uses a traditional phase I trial design. This step only assesses toxicity and finds the maximal tolerated dose (MTD). For the 2nd step, we propose a modified phase II selection design for 2 or 3 dose levels at and below the MTD to determine efficacy and evaluate each dose level by both efficacy and toxicity.

Results and conclusion: Simulation studies are done on several combinations of toxicity and efficacy scenarios to assess the operating statistics of our proposed trial design. We then compare our results with a traditional phase I trial followed by a single-arm phase II trial using the same total sample size. The proposed design does better in most cases than a traditional design using the same overall sample size. This design allows assessing a few dose levels more closely for both efficacy and toxicity and provides greater certainty of having correctly determined the best dose level before launching into a large efficacy trial.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1
Figure 1
Possible response scenarios as a function of dose level. The marginal probabilities as a function of dose level are plotted.
Figure 2
Figure 2
Possible toxicity scenarios as a function of dose level. The marginal probabilities as a function of dose level are plotted.
Figure 3
Figure 3
Possible ways to select a good dose or the best dose level using our proposed design for response scenarios R1 and R2. Good dose levels as defined by toxicity and efficacy are in red. The best dose levels are circled in blue.
See this image and copyright information in PMC

References

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