Clinical Trial Endpoints

To summarize the discussion sessions from the first Brain Tumor Clinical Trials Endpoints Workshop on imaging-related endpoints held on January 30, 2014 in Bethesda, MD. The workshop was sponsored by the Jumpstarting Brain Tumor Drug Development Coalition with participation by the U.S. Food and Drug Administration (FDA).

The Jumpstarting Brain Tumor Drug Development Coalition (which includes the National Brain Tumor Society, Accelerate Brain Cancer Cure, Musella Foundation for Brain Tumor Research and Information, and the Society for Neuro-Oncology) is sponsoring workshops to evaluate and improve the use of a variety of endpoints in brain tumor clinical trials, with a goal of advancing the development of treatments for glioblastoma multiforme (GBM). These workshops bring together key stakeholders (clinicians, researchers, industry, patient advocates, the National Cancer Institute, and the FDA) to discuss issues related to the development and use of endpoints, and to develop action plans that will ultimately lead to greater clarity and interest in the pursuit of clinical trials that can achieve FDA approval of new brain tumor therapies. The discussions and action items that come of out these workshops are meant to inform and guide the neuro-oncology and clinical trial sponsor community.

The first of these workshops was held in Bethesda, Maryland, on January 30, 2014. This workshop’s discussion was focused on the capability of neuro-imaging to accurately assess GBM response to therapies, and the use of current and emerging imaging-based endpoints in clinical trials. Specifically, stakeholders discussed how to overcome the variables in medical imaging, such as image acquisition parameters, which have hindered the ability to accurately assess brain tumor response to therapies, and how to best incorporate endpoints that rely on imaging into clinical trials.

The workshop began with three formal preliminary presentations to establish context for the day’s discussions: “Efficacy Endpoints in Glioblastoma Multiforme Clinical Trials – A Regulatory Perspective,” “Avastin & the Basis of Approval for GBM in 2009,” and “Current Brain Tumor Imaging Protocols in Multicenter Trials.” After the preliminary presentations, the workshop continued with four panel-led discussions. The panels consisted of experts in neuro-oncology and neuro-radiology including FDA officials, industry representatives, and medical/academic researchers. After a short overview presentation by each panel, a two-part discussion period followed: (1) response by panelists to central questions posed by the moderator, and (2) facilitated audience question and answer.

The workshop produced a number of suggested action items intended to represent a starting point for future work in the area of imaging brain tumor response to treatment in clinical trials. The Jumpstarting Brain Tumor Drug Development Coalition will continue to work with our advisors and the FDA to identify outstanding issues needed to move the community closer to more, and better, treatments. There was consensus that the RANO criteria should continue to serve as the standard response criteria in brain tumor clinical trials. However, the imaging elements of RANO would benefit from additional clarification, including a clearer definition of response tailored to the type of therapy under investigation. It was suggested that further research be conducted to understand the RANO criteria’s evaluation of imaging based response rate, and the Coalition will aid this effort. Additionally, the Coalition will lead in the formation of a working group that will address and develop guidance materials for the standardization of image acquisition and analysis within brain tumor clinical trials. The goal is for this guidance to be adopted by all sponsors of brain tumor clinical trials, as well as to demonstrate that the brain tumor research and clinical trial environment is innovative, adaptive, and ready for further investment by academia, pharmaceutical companies, and the government.

Specifically, stakeholders: 1) identified multiple concepts of interest addressing both how a patient feels and how the patient functions, and began determining which sign(s), symptom(s), and function(s) are of priority to patients, and which can be measured in a clinical trial setting; 2) examined COAs that are available for use now in brain tumor clinical trials, and determined the priorities for refinement of the existing measures and necessary elements needed for development of novel COAs for future use in trials; and 3) defined how the COA will be used to determine clinical benefit and recommended clinical trial designs for COA validation and use in patients with a brain tumor.

To summarize the discussion sessions in the Brain Tumor Clinical Trial Endpoints Workshop on Clinical Outcome Assessments (COAs) held on October 15, 2014 in Bethesda, MD.

The second Brain Tumor Clinical Trial Endpoints Workshop was designed to afford the brain tumor community a better understanding of what it will take to improve measurement of COA endpoints and optimize these measures to advance their inclusion into adult primary brain tumor clinical trials evaluating therapeutic agents. The discussions also sought to identify specific, practical action plans to develop new measures, as well as increase the use of existing COA endpoints in future brain tumor clinical trials.

Specifically, stakeholders: 1) identified multiple concepts of interest addressing both how a patient feels and how the patient functions, and began determining which sign(s), symptom(s), and function(s) are of priority to patients, and which can be measured in a clinical trial setting; 2) examined COAs that are available for use now in brain tumor clinical trials, and determined the priorities for refinement of the existing measures and necessary elements needed for development of novel COAs for future use in trials; and 3) defined how the COA will be used to determine clinical benefit and recommended clinical trial designs for COA validation and use in brain tumor patients.

The workshop produced a number of suggested action items intended to represent a starting point for future work in the area of COA use in brain tumor clinical trials. The Jumpstarting Brain Tumor Drug Development Coalition is committed to forming a planning group to discuss the consensus points and create a strategy to advance this initiative, in coordination with the outcomes of the first endpoints workshop on imaging.

Although malignant glioma patients are stricken with a number of symptoms, it was agreed upon that identification of a modest list of disease-related symptoms are needed. In order to reach this goal, a working group needs to be formed in which consensus can be made on the priority symptoms, as well as the tool(s) for measuring these symptoms. Ideally, this group will utilize existing clinical trial data and existing (MDASI) and emerging (NFBrSI-24) tools and work towards the development of a symptom PRO measure in which the items correspond to the other concepts of interest being measured in the trial.