title: Analysis of phase II methodologies for single-arm clinical trials with multiple endpoints in rare cancers: An example in Ewing's sarcoma.
abstract: Trials run in either rare diseases, such as rare cancers, or rare sub-populations of common diseases are challenging in terms of identifying, recruiting and treating sufficient patients in a sensible period. Treatments for rare diseases are often designed for other disease areas and then later proposed as possible treatments for the rare disease after initial phase I testing is complete. To ensure the trial is in the best interests of the patient participants, frequent interim analyses are needed to force the trial to stop promptly if the treatment is futile or toxic. These non-definitive phase II trials should also be stopped for efficacy to accelerate research progress if the treatment proves to be particularly promising. In this paper, we review frequentist and Bayesian methods that have been adapted to incorporate two binary endpoints and frequent interim analyses. The Eurosarc Trial of Linsitinib in advanced Ewing Sarcoma (LINES) is used as a motivating example and provides a suitable platform to compare these approaches. The Bayesian approach provides greater design flexibility, but does not provide additional value over the frequentist approaches in a single trial setting when the prior is non-informative. However, Bayesian designs are able to borrow from any previous experience, using prior information to improve efficiency.
authors: 1 Centre for Statistics in Medicine (CSM), University of Oxford, Botnar Research Centre, Oxford, UK.|2 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Nuffield Orthopaedic Centre, Oxford, UK.
authors: P
authors: P
authors: Dutton
authors: 1 Centre for Statistics in Medicine (CSM), University of Oxford, Botnar Research Centre, Oxford, UK.|2 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Nuffield Orthopaedic Centre, Oxford, UK.
authors: S B
authors: SB
authors: Love
authors: 3 Cancer Research Clinical Trials Unit (Cancer Sciences), School of Cancer Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors: L
authors: L
authors: Billingham
authors: 2 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), University of Oxford, Nuffield Orthopaedic Centre, Oxford, UK.|4 Oxford Molecular Pathology Institute, Sir William Dunn School (OMPI, SWDS), University of Oxford, Oxford, UK.
authors: A B
authors: AB
authors: Hassan
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001499:Bayes Theorem; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D015233:Models, Statistical; D018579:Patient Selection; D011336:Probability; D011719:Pyrazines / Q000627:therapeutic use*; D035583:Rare Diseases / Q000628:therapy*; D018401:Sample Size; D012512:Sarcoma, Ewing / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D000970:Antineoplastic Agents; D007093:Imidazoles; D011719:Pyrazines
keywords: Bayesian clinical trial; early stopping; multiple endpoints; phase II; multi-stage design