Selecting promising treatments in randomized Phase II cancer trials with an active control

Abstract

The primary objective of Phase II cancer trials is to evaluate the potential efficacy of a new regimen in terms of its antitumor activity in a given type of cancer. Due to advances in oncology therapeutics and heterogeneity in the patient population, such evaluation can be interpreted objectively only in the presence of a prospective control group of an active standard treatment. This paper deals with the design problem of Phase II selection trials in which several experimental regimens are compared to an active control, with an objective to identify an experimental arm that is more effective than the control or to declare futility if no such treatment exists. Conducting a multi-arm randomized selection trial is a useful strategy to prioritize experimental treatments for further testing when many candidates are available, but the sample size required in such a trial with an active control could raise feasibility concerns. In this study, we extend the sequential probability ratio test for normal observations to the multi-arm selection setting. The proposed methods, allowing frequent interim monitoring, offer high likelihood of early trial termination, and as such enhance enrollment feasibility. The termination and selection criteria have closed form solutions and are easy to compute with respect to any given set of error constraints. The proposed methods are applied to design a selection trial in which combinations of sorafenib and erlotinib are compared to a control group in patients with non-small-cell lung cancer using a continuous endpoint of change in tumor size. The operating characteristics of the proposed methods are compared to that of a single-stage design via simulations: The sample size requirement is reduced substantially and is feasible at an early stage of drug development.

Figure 1

Effects of cohort size on the operating characteristics of the sequential designs when σ = 0.346. The designs are specified with ${\mathit{\text{a}}}_0^{\ast }=0.120$ and d* = 12σ². Th top panel shows the PCS of SPRT (dashed line) and ELIM₀ (solid line) with a fixed N_max = 138 (indicated by “F”) and with sample size re-estimation (indicated by “R”). The bottom panel shows the sample size distribution of ELIM₀ with sample size re-estimation. Each box spans the interquartile range, the darker line inside is the mean, and the lighter median; the dashed line in each figure indicate the median sample size of the single-stage design.

Figure 2

Effects of cohort size on the operating characteristics of the sequential designs when σ = 0.415. The designs are specified with ${\mathit{\text{a}}}_0^{\ast }=0.120$ and d* = 12σ². Th top panel shows the PCS of SPRT (dashed line) and ELIM₀ (solid line) with a fixed N_max = 138 (indicated by “F”) and with sample size re-estimation (indicated by “R”). The bottom panel shows the sample size distribution of ELIM₀ with sample size re-estimation. Each box spans the interquartile range, the darker line inside is the mean, and the lighter median; the dashed line in each figure indicate the median sample size of the single-stage design.