@article{bd3ddb0b1d144e80b8a7e310a7713daa,
title = "Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma",
abstract = "Background Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials. Methods A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative. Results Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care. Conclusion The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.",
keywords = "clinical trials, glioblastoma, phase II, phase III",
author = "Mandel, {Jacob J.} and Shlomit Yust-Katz and Patel, {Akash J.} and David Cachia and DIane Liu and Minjeong Park and Ying Yuan and Kent, {Thomas A.} and {De Groot}, {John F.}",
note = "Funding Information: Our study also showed the evolution of imaging criteria as a surrogate endpoint, with various phase II studies using different criteria. Notably, the criteria for response in imaging data are changing yet again with the use of immunotherapy, spurring the creation of new, specialized imaging response criteria for brain tumors.50The impact of the new imaging criteria remains speculative, as one theory for why such a large proportion of phase III solid tumor trials in cancer fail is that imaging endpoints/criteria are an inadequate surrogate for overall survival. It has been shown that a greater magnitude of response is associated with a better prognosis, but current trial endpoints do not measure quantitative improvements in response magnitude.51Therefore, the Biomarkers Consortium of the Foundation for the National Institutes of Health created the Volumetric CT for Precision Analysis of Clinical Trial Results project to collect imaging data from large phase III trials in non–small cell lung, renal cell, and colorectal carcinomas to develop and assess whatever quantitative imaging metrics most reliably predict trial results. Volumetric imaging might improve the reliability of using imaging data as an endpoint for response to therapy in glioblastoma trials, although a recent study found that in the BELOB trial, volumetric methods were not superior to 2-dimensional Response Assessment in Neuro-Oncology criteria for response evaluation. Alternatively, it has been proposed that examining the growth rate of a tumor after treatment may be the optimal way to evaluate the treatment{\textquoteright}s value.52 Publisher Copyright: {\textcopyright} The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.",
year = "2018",
month = jan,
day = "1",
doi = "10.1093/neuonc/nox144",
language = "English (US)",
volume = "20",
pages = "113--122",
journal = "Neuro-oncology",
issn = "1522-8517",
publisher = "Oxford University Press",
number = "1",
}