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.

Key Words:

• Noninferiority test
• Probability of correct selection
• Sample size re-estimation
• Sequential elimination
• Sequential probability ratio test
• Symmetric boundaries
• Type I error

ACKNOWLEDGMENT

This work was supported by NIH Grant R01 NS055809-01.

Notes

†Under the null, μ₀ = μ₁ = μ₂ = −0.05.

‡Under the alternative, μ₀ = μ₁ = −0.05 and μ₂ = 0.13.

Note: The designs are calibrated with respect to δ = 0.18 and σ₀ = 0.346 for a selection trial with K = 2, α = 0.1, and β = 0.2. For SPRT and ELIM₀, , and N _max = 138.