Designing Clinical Trials That Accept New Arms: An Example in Metastatic Breast Cancer

J Clin Oncol. 2017 Sep 20;35(27):3160-3168. doi: 10.1200/JCO.2016.70.1169. Epub 2017 May 22.

Abstract

Purpose The majority of randomized oncology trials are two-arm studies that test the efficacy of new therapies against a standard of care, thereby assigning a large proportion of patients to nonexperimental therapies. In contrast, multiarm studies efficiently share a common control arm while evaluating multiple experimental therapies. A major bottleneck for traditional multiarm trials is the requirement that all therapies-often drugs from different companies-have to be available at the same time when the trial starts. We evaluate the potential gains of a platform design-the rolling-arms design-that adds and removes arms on a rolling basis. Methods We define the rolling-arms design with the goal of minimizing the complexity of random assignment and data analyses of a platform trial. We then evaluate its potential advantages in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Multiple pharmaceutical companies currently test CDK4/6 inhibitors in combination with letrozole in independent two-arm trials. We conducted a simulation study to quantify the reduction in sample size, number of patients treated with the standard of care, and the average time to treatment discovery if these therapies had been tested in a rolling-arms trial. Results A rolling-arms platform design with two to five experimental treatments can reduce the overall sample size requirement by up to 30% compared with standard two-arm studies. It assigns up to 60% fewer patients to the control arm compared with five independent trials that test distinct treatments. Moreover, under realistic scenarios, effective experimental treatments are discovered up to 15 months earlier compared with separate two-arm trials. Conclusion The rolling-arms platform design is applicable to a broad variety of diseases, and under realistic scenarios, it is substantially more efficient than standard two-arm randomized trials.

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Female
  • Humans
  • Randomized Controlled Trials as Topic*
  • Research Design*
  • Sample Size

Substances

  • Antineoplastic Agents