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Mol Cancer Ther. 2007 Apr;6(4):1180-5.

The randomized discontinuation trial: a phase II design to assess growth-inhibitory agents.

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Section of Hematology/Oncology, University of Chicago, 5841 South Maryland, MC2115, Chicago, IL 60637, USA.


An increasing number of putative anticancer targets and drugs have been identified with many of these expected to be growth inhibitory. Clinical development of these agents in the phase II setting is challenging because tumor shrinkages, or at least tumor shrinkages that meet the standard definitions of objective response, are not expected. Time to progression end points are however problematic because expected times in the absence of therapy (the null hypothesis) cannot be predicted accurately, thus requiring trials to enroll a concurrent control group. Another problem is that the patient population that will benefit from a new drug remains poorly defined in early-phase development. The randomized discontinuation trial design addresses both of these issues. All patients are initially treated with the drug; patients with an objective response continue therapy; patients who do not progress or experience excess toxicity within a prespecified "run-in" period are then randomized to continuing or discontinuing therapy in a double-blind, placebo controlled manner. Despite certain limitations that need to be recognized, the ability of this design to "select" a cohort most likely to benefit and to rigorously evaluate the disease-stabilizing activity of an investigational agent provides multiple advantages.

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