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

TLDR

Phase II trials, especially randomized designs with a standard‑treatment control arm, have long been central to prioritizing new cancer therapies for phase III evaluation, and various designs such as selection, randomized, and phase II/III have been developed to improve this process. The authors propose phase II screening trials that use randomized comparisons to standard treatments with intermediate endpoints, adjusting type I and II error rates to balance detecting useful regimens while keeping sample sizes small. The design involves randomized comparisons to standard treatment using intermediate endpoints, with error rates tuned to balance screening efficacy and sample size constraints. When error rates and targeted effects are judiciously chosen, phase II screening trials can protect the feasibility of definitive phase III studies while effectively distinguishing useful from ineffective regimens.

Abstract

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 (α or type I error) and false-negative error rates (β 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.