Estimation of Progression-Free Survival for All Treated Patients in the Randomized Discontinuation Trial Design

Abstract

The randomized discontinuation trial (RDT) design is an enrichment-type design that has been used in a variety of diseases to evaluate the efficacy of new treatments. The RDT design seeks to select a more homogeneous group of patients, consisting of those who are more likely to show a treatment benefit if one exists. In oncology, the RDT design has been applied to evaluate the effects of cytostatic agents, that is, drugs that act primarily by slowing tumor growth rather than shrinking tumors. In the RDT design, all patients receive treatment during an initial, open-label run-in period of duration T. Patients with objective response (substantial tumor shrinkage) remain on therapy while those with early progressive disease are removed from the trial. Patients with stable disease (SD) are then randomized to either continue active treatment or switched to placebo. The main analysis compares outcomes, for example, progression-free survival (PFS), between the two randomized arms. As a secondary objective, investigators may seek to estimate PFS for all treated patients, measured from the time of entry into the study, by combining information from the run-in and post run-in periods. For t ≤ T, PFS is estimated by the observed proportion of patients who are progression-free among all patients enrolled. For t > T, the estimate can be expressed as Ŝ(t) = p̂_OR × Ŝ_OR(t - T) + p̂_SD × Ŝ_SD(t - T), where p̂_OR is the estimated probability of response during the run-in period, p̂_SD is the estimated probability of SD, and Ŝ_OR(t - T) and Ŝ_SD(t - T) are the Kaplan-Meier estimates of subsequent PFS in the responders and patients with SD randomized to continue treatment, respectively. In this article, we derive the variance of Ŝ(t), enabling the construction of confidence intervals for both S(t) and the median survival time. Simulation results indicate that the method provides accurate coverage rates. An interesting aspect of the design is that outcomes during the run-in phase have a negative multinomial distribution, something not frequently encountered in practice.

Keywords: Confidence limits; Enrichment design; Negative multinomial distribution; Phase II clinical trials.

Figure 1

Randomized discontinuation trial design. The online version of this figure is in color.

Figure 2

Estimated progression-free survival (solid line) and pointwise 95% confidence intervals (dotted lines) following treatment with sorafenib, measured from start of treatment. Confidence intervals are based on the log transformation. The online version of this figure is in color.

Figure 3

Estimated progression-free survival (solid line) and OR and SD components (dashed lines). For T > 84 days, the solid line is the weighted average of the dashed lines (weights = 0.549 and 0.451, respectively).