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Abstract:
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Drug combination therapy has become the mainstream approach to cancer treatment. One fundamental feature that makes combination trials different from single-agent trials is the existence of the maximum tolerated dose (MTD) contour, i.e, multiple MTDs. Thus, unlike single agent phase I trials targeting to find single MTD, it is challenging to find the MTD contour for combination trials. We propose a new design, called waterfall design, to find the MTD contour for drug combination trials. The most prominent advantage of our design is its simplicity to implement in practice. Taking the divide-and-conquer strategy, the waterfall design divides the task of finding the MTD contour into a sequence of one-dimensional dose finding subtasks. Dose escalation/de-escalation rule is prespecified in a fashion similar to the 3+3 design. In addition, we extend our approach to a phase I/II design with the goal of finding the MTD with the highest efficacy. Simulation studies show that our design substantially outperforms some existing designs. The proposed design is safer and has higher probabilities to identify the true MTD contour.
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