High-grade glioma therapy: adding flexibility in trial design to improve patient outcomes

ABSTRACT

Introduction

Outcomes for patients with high grade gliomas have changed little over the past thirty years. This realization prompted renewed efforts to increase flexibility in the design and conduct of clinical brain tumor trials.

Areas covered

This manuscript reviews the development of clinical trial methods, challenges and considerations of flexible clinical trial designs, approaches to improve identification and testing of active agents for high grade gliomas, and evaluation of their delivery to the central nervous system.

Expert opinion

Flexibility can be introduced in clinical trials in several ways. Flexible designs tout smaller sample sizes, adaptive modifications, fewer control arms, and inclusion of multiple arms in one study. Unfortunately, modifications in study designs cannot address two challenges that are largely responsible for the lack of progress in treating high grade gliomas: 1) the identification of active pharmaceutical agents and 2) the delivery of these agents to brain tumor tissue in therapeutic concentrations. To improve the outcomes of patients with high grade gliomas efforts must be focused on the pre-clinical screening of drugs for activity, the ability of these agents to achieve therapeutic concentrations in non-enhancing tumors, and a willingness to introduce novel compounds in minimally pre-treated patient populations.

KEYWORDS:

• Blood–brain barrier
• clinical trial design
• endpoints
• glioblastoma
• flexibility
• high grade glioma
• neoadjuvant
• next generation sequencing

Article highlights

•Major factors limiting progress in the treatment of high grade gliomas include: 1) the paucity of active agents in this disease, 2) the ability of the blood–brain barrier to limit drug entry especially in non-enhancing regions of the tumor and 3) the heterogenous nature of this cancer.

•Although flexible clinical trial designs offer promise in many diseases and settings, these trial designs will not address the unique challenges presented in HGG that are listed above.

•Future clinical trials should focus on testing novel agents in minimally pre-treated patients, delivery to the brain tumor in effective concentrations, and combinations of rationally-targeted therapies.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Conflict of interest

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by National Cancer Institute P30CA006973 funding the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.