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Perioperative clinical trials for glioma: Raising the bar
Angela Mweempwa1, Mark A Rosenthal1, James Dimou2
1Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
Abstract:
Gliomas are a heterogeneous group of primary brain cancers with poor survival despite multimodality therapy that includes surgery, radiation and chemotherapy. Numerous clinical trials have investigated systemic therapies in glioma, but have largely been negative. Multiple factors have contributed to the lack of progress including tumour heterogeneity, the tumour micro-environment and presence of the blood-brain barrier, as well as extrinsic factors relating to trial design, such as the lack of a contemporaneous biopsy at the time of treatment. A number of strategies have been proposed to progress new agents into the clinic. Here, we review the progress of perioperative, including phase 0 and 'window of opportunity', studies and provide recommendations for trial design in the development of new agents for glioma. The incorporation of pre- and post-treatment biopsies in glioma early phase trials will provide valuable pharmacokinetic and pharmacodynamic data and also determine the target or biomarker effect, which will guide further development of new agents. Perioperative 'window of opportunity' studies must use drugs with a recommended-phase-2-dose, known safety profile and adequate blood-brain barrier penetration. Drugs shown to have on-target effects in perioperative trials can then be evaluated further in a larger cohort of patients in an adaptive trial to increase the efficiency of drug development.
Insights
Developing new glioma treatments requires improved clinical trial designs. Perioperative studies with biopsies are crucial for evaluating drug efficacy and guiding future development of novel agents for brain cancer.
Area of Science:
- Neuro-oncology
- Clinical trial design
- Pharmacology
Background:
- Gliomas are aggressive primary brain tumors with poor prognoses despite standard treatments.
- Systemic therapy trials for gliomas have yielded limited success due to tumor complexity and the blood-brain barrier.
- Current trial designs often lack critical data on drug activity within the tumor.
Purpose of the Study:
- To review the progress of perioperative studies (Phase 0, window of opportunity) in glioma drug development.
- To provide recommendations for optimizing early-phase clinical trial designs for novel glioma agents.
- To emphasize the importance of incorporating biopsies for assessing drug effects.
Main Methods:
- Review of existing literature on perioperative and window of opportunity studies in glioma.
- Analysis of factors contributing to trial failures and proposed solutions.
- Formulation of recommendations for future trial designs, including biopsy integration.
Main Results:
- Perioperative studies, particularly those with pre- and post-treatment biopsies, offer valuable pharmacokinetic and pharmacodynamic data.
- Biopsies help determine target engagement and biomarker effects, crucial for guiding drug development.
- Window of opportunity studies require drugs with established safety and blood-brain barrier penetration.
Conclusions:
- Integrating pre- and post-treatment biopsies in early-phase glioma trials is essential for efficient drug development.
- Perioperative studies can identify promising agents with on-target effects for further evaluation.
- Adaptive trial designs can enhance the efficiency of developing new glioma therapies.
