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Design Issues of Randomized Phase II Trials and a Proposal for Phase II Screening Trials

From the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD

Address reprint requests to Lawrence V. Rubinstein, PhD, Room 8130, 6130 Executive Plaza, Rockville, MD 20852; e-mail: rubinsteinl{at}ctep.nci.nih.gov

Future progress in improving cancer therapy can be expedited by better prioritization of new treatments for phase III evaluation. Historically, phase II trials have been key components in the prioritization process. There has been a long-standing interest in using phase II trials with randomization against a standard-treatment control arm or an additional experimental arm to provide greater assurance than afforded by comparison to historic controls that the new agent or regimen is promising and warrants further evaluation. Relevant trial designs that have been developed and utilized include phase II selection designs, randomized phase II designs that include a reference standard-treatment control arm, and phase II/III designs. We present our own explorations into the possibilities of developing "phase II screening trials," in which preliminary and nondefinitive randomized comparisons of experimental regimens to standard treatments are made (preferably using an intermediate end point) by carefully adjusting the false-positive error rates ( or type I error) and false-negative error rates (ß or type II error), so that the targeted treatment benefit may be appropriate while the sample size remains restricted. If the ability to conduct a definitive phase III trial can be protected, and if investigators feel that by judicious choice of false-positive probability and false-negative probability and magnitude of targeted treatment effect they can appropriately balance the conflicting demands of screening out useless regimens versus reliably detecting useful ones, the phase II screening trial design may be appropriate to apply.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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