Abstract

Simon’s two-stage design and the admissible two-stage design have been commonly used in practice for single-arm phase II clinical trials when the primary endpoint is binary. The ethical benefit of the two-stage design over the single-stage design is attained by the early termination of the trial when the treatment seems to be inactive. While Simon’s optimal design is the two-stage design that minimizes the expected number of subjects under the null hypothesis, the probability of falsely declaring futility after the first stage frequently seems undesirably high. In Simon’s minimax design, however, it is often the case that a high proportion of the total planned subjects are evaluated in the first stage, and thus the ethical benefit may not be achieved. In this paper, we propose modified minimax and optimal two-stage designs which guarantee not only type I and II error rates but also reasonable sample size proportions in the first stage, while maintaining the probability of falsely declaring futility under a pre-selected level. The characteristics of the modified two-stage design will be compared with those of Simon’s and the admissible two-stage design. The modified minimax design yields a design that requires modest increase in 29% of cases, while the modified optimal design saves 1 to 13 subjects in 81% of cases for β = 0.2. The modified design approach provides investigators with an alternative when the sample sizes of Simon’s designs are severely unbalanced or the Type II error is unacceptably high after the first stage.

Highlights

  • The primary objective of phase II cancer clinical trials is to seek an early indication of anti-tumor activity of a novel treatment and to make a “go/no-go” decision for a larger and more definitive phase III trial

  • The ethical benefit of the two-stage design over the single-stage design is attained by the early termination of the trial when the treatment seems to be inactive

  • The modified design approach provides investigators with an alternative when the sample sizes of Simon’s designs are severely unbalanced or the Type II error is unacceptably high after the first stage

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Summary

Introduction

The primary objective of phase II cancer clinical trials is to seek an early indication of anti-tumor activity of a novel treatment and to make a “go/no-go” decision for a larger and more definitive phase III trial. The two-stage design for a single-arm phase II clinical trial with binary endpoint has a history dating back to Gehan [2]. The ethical benefit of the two-stage design over the single-stage design is attained by the early termination of the trial when the treatment seems to be inactive. Simon’s two-stage design [3] has been commonly used in practice for single-arm phase II cancer clinical trials when the primary endpoint is binary. Within the framework of two-stage design, the trial will be early terminated if n1 subjects are evaluated in the first stage and the number of responders is less than or equal to r1. If the trial proceeds to the second stage, a total of n subjects will be evaluated and the null hypothesis fails to be rejected if r or fewer responders are observed

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