START: single‐to‐double arm transition design for phase II clinical trials

Abstract

Phase II clinical trials designed for evaluating a drug's treatment effect can be either single‐arm or double‐arm. A single‐arm design tests the null hypothesis that the response rate of a new drug is lower than a fixed threshold, whereas a double‐arm scheme takes a more objective comparison of the response rate between the new treatment and the standard of care through randomization. Although the randomized design is the gold standard for efficacy assessment, various situations may arise where a single‐arm pilot study prior to a randomized trial is necessary. To combine the single‐ and double‐arm phases and pool the information together for better decision making, we propose a Single‐To‐double ARm Transition design (START) with switching hypotheses tests, where the first stage compares the new drug's response rate with a minimum required level and imposes a continuation criterion, and the second stage utilizes randomization to determine the treatment's superiority. We develop a software package in R to calibrate the frequentist error rates and perform simulation studies to assess the trial characteristics. Finally, a metastatic pancreatic cancer trial is used for illustrating the decision rules under the proposed START design.