More Randomization in Phase II Trials: Necessary but not Sufficient

Historically, phase II trials in oncology were generally single armed, constructed to distinguish between a tumor response rate felt to indicate a lack of promise (often 5%) and a rate that would indicate potential benefit (often 20%), with a one-sided type I error rate of 5%–10% and a type II error rate of 10%–20% (1). The dominant use of this design was based on the premise that an agent that could not produce a tumor response rate of 20% was not likely to produce a clinically meaningful overall survival (OS) or progression- free survival (PFS) benefit in subsequent phase III testing. Recent trends in oncology drug development have challenged this paradigm. Many phase II trials are now designed to assess the promise of a molecularly targeted agent, given either alone or in combination with another regimen. In many cases, these agents are not anticipated to produce or improve tumor response rates; rather, the desired outcome from their use is improved PFS or OS through means other than direct cell killing as evidenced by tumor shrinkage (2). In general, PFS is the preferred endpoint for such phase II trials. PFS is statistically more efficient than OS because the time to achieve the endpoint of PFS is substantially shorter, and the treatment effect is not diluted by salvage treatment. However, in a situation with no effective salvage therapy and/or a disease with concerns regarding the timing of progression assessment, OS could be chosen as the endpoint. Such trials can be single-arm studies, compared with historical controls, or can be randomized.The review by Sharma et al (3) in this issue of the Journal is a welcome addition to the growing chorus in favor of increased randomization in phase II trials for agents with little likelihood for single-agent tumor regression and for which endpoints such as PFS are used. This promotion of randomization is already having dramatic effect. Current records of the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) reveal that only 1.5% (68/4437) of the completed NCI-sponsored phase II studies were randomized. In contrast, 28% (69/243) of the currently active phase II studies are randomized, and of the trials activated after December 31, 2009, 37% are randomized. A primary reason for this increase is the appreciation, in the trial design and review process, that even a modest upward drift in the PFS of the study population compared with historical controls, which is indepen-dent of the effect of the new agent being tested, can inflate the type I error rate approximately threefold (4). For example, a drift from 50% to 55% in the control 4-month PFS rate, when not accounted for, will increase the type I error of a single-arm Simon optimal trial (5) targeting a 70% 4-month PFS from 0.10 to 0.26. Coupled with this is the realization that such an upward drift over time is relatively likely for PFS as the standard of care improves (6).It is widely accepted that a substantial portion of phase II trials will still be appropriately single arm (1,6–8). This includes trials of agents for which tumor regression is anticipated based on mechanism of action, as well as early phase II monotherapy trials to establish a tumor response signal of biological efficacy. Additionally, monotherapy and combination trials with PFS endpoints in diseases with no effective standard therapy and established stable historical controls (eg, recurrent glioblastoma) can be justified. For OS, an historical database for melanoma has proven useful for designing single-arm studies (9). In some situations, adjustment for observed differences in the distribution of known prognostic factors between the historical database and the observed single arm study can