• Issues in applying multi-arm multi-stage methodology to a clinical trial in prostate cancer: the MRC STAMPEDE trial.

      Sydes, Matthew R; Parmar, Mahesh K B; James, Nicholas D; Clarke, Noel W; Dearnaley, David P; Mason, Malcolm D; Morgan, Rachel C; Sanders, Karen; Royston, Patrick; MRC Clinical Trials Unit, London, UK. matthew.sydes@ctu.mrc.ac.uk (2009)
      BACKGROUND: The multi-arm multi-stage (MAMS) trial is a new paradigm for conducting randomised controlled trials that allows the simultaneous assessment of a number of research treatments against a single control arm. MAMS trials provide earlier answers and are potentially more cost-effective than a series of traditionally designed trials. Prostate cancer is the most common tumour in men and there is a need to improve outcomes for men with hormone-sensitive, advanced disease as quickly as possible. The MAMS design will potentially facilitate evaluation and testing of new therapies in this and other diseases. METHODS: STAMPEDE is an open-label, 5-stage, 6-arm randomised controlled trial using MAMS methodology for men with prostate cancer. It is the first trial of this design to use multiple arms and stages synchronously. RESULTS: The practical and statistical issues faced by STAMPEDE in implementing MAMS methodology are discussed and contrasted with those for traditional trials. These issues include the choice of intermediate and final outcome measures, sample size calculations and the impact of varying the assumptions, the process for moving between trial stages, stopping accrual to each trial arm and overall, and issues around perceived trial complexity. CONCLUSION: It is possible to use the MAMS design to initiate and undertake large scale cancer trials. The results from STAMPEDE will not be known for some years but the lessons learned from running a MAMS trial are shared in the hope that other researchers will use this exciting and efficient method to perform further randomised controlled trials. TRIAL REGISTRATION: ISRCTN78818544, NCT00268476.
    • STAMPEDE: Systemic Therapy for Advancing or Metastatic Prostate Cancer--a multi-arm multi-stage randomised controlled trial.

      James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Anderson, John; Popert, Richard J; Sanders, Karen; Morgan, Rachel C; Stansfeld, J; et al. (2008-10)
    • Systemic therapy for advancing or metastatic prostate cancer (STAMPEDE): a multi-arm, multistage randomized controlled trial.

      James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Anderson, John; Popert, Richard J; Sanders, Karen; Morgan, Rachel C; Stansfeld, J; et al. (2009-02)
      There is a need to improve the outcomes for men with high-risk localised, nodal or metastatic prostate cancer, or with aggressively relapsing disease after initial therapy for local disease. This group of men is currently managed with long-term hormone therapy. Thus we aim to evaluate the toxicity and efficacy of three different systemic therapies (docetaxel, zoledronic acid and celecoxib) used alone or combined at the initiation of hormone manipulation for high-risk prostate cancer. A novel statistical design (multi-arm, multistage method) simultaneously tests multiple distinct strategies in parallel against a single control arm. The trial has several 'stages', from initial confirmation of safety to a phase III assessment of survival, with a series of intervening activity stages. This method provides a means of assessing several agents more quickly and efficiently, and allows inactive treatments to be dropped from further study at an early stage. STAMPEDE has been designed to address in parallel the activity and efficacy of these agents for this patient group. It is a flagship randomized clinical trial for academic research into prostate cancer in the UK. More than 500 patients have been recruited on schedule, confirming the acceptability of this complex trial design to patients and clinicians. The trial targets a population of approximately 3000 patients. STAMPEDE is a major new trial with a novel design applicable to the synchronous testing of several agents. It is hoped that the results will improve outcomes for patients with high-risk prostate cancer. The design could be applicable to the study of new therapies in other cancer types. Continued efforts are required by the urological cancer community to maintain the excellent recruitment shown to date.