Meningioma is the most common central nervous system (CNS) tumor and accounts for approximately 30% of all CNS tumors. For meningioma recurring after surgery and radiation therapy, there is no effective medical therapy. Repeat surgery or radiation therapy may be possible, but they are temporizing measures with limited durable relief. PD-L1 expression in meningioma is increased for recurrent tumors or prior radiation therapy, and a recent case study reported significant reduction of an intracranial meningioma after 6 months of PD-L1 blockade. Radiation has been shown to augment immune response when combined with PD-L1 blockade. Proton radiation therapy has higher relative biological effectiveness (RBE) and may further amplify the above immunological signals. Combination of proton radiation therapy administered concurrently with PD-L1 inhibitor may maximize immune response for recurrent meningioma. However, confirmation of the increased immunogenicity or increased tumor infiltrating lymphocytes using the combination of radiation therapy and PD-L1 blockade have not been confirmed in patients. The proposed study will be a single institution, single-arm, open-label, phase Ib study to combine neoadjuvant avelumab (a PD-L1 inhibitor) with hypofractionated proton therapy of 20 CGE (cobalt gray equivalent) over 5 fractions followed by planned surgery for recurrent radiation-refractory meningioma. This study is designed to provide proof of concept to demonstrate on-target effect of the combination to increase immunogenicity by directly examining the resected tumor for immune response and to evaluate preliminary clinical efficacy
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
9
-10mg/kg IV
-Proton therapy will start concurrently with the first dose of avelumab (up to 3 days before or after is permissible) and will be administered once daily during weekdays (Monday through Friday).
-Standard of care
Washington University School of Medicine
St Louis, Missouri, United States
Immunogenicity as measured by changes of CD8+/CD4+ tumor infiltrating lymphocytes (TILs) in recurrent radiation-refractory meningioma
-The change of CD8+/CD4+ TILs in the tumor specimens over time will be compared using paired t-test or Wilcoxon rank-sum test as appropriate and plotted using the box plot. The association between TILs increase and clinical response will also be explored by comparing the differences in theses biomarkers between responders versus non-responders using t-test or Mann-Whitney rank-sum test as appropriate.
Time frame: Through time of progression (up to 6 months after completion of treatment - estimated to be 12 months)
Safety of proton therapy and avelumab in combination as measured by The number and percentage of subjects experiencing each type of adverse event will be tabulated by severity, and relationship to treatment.
If appropriate, confidence intervals will be used to characterize the precision of the estimate.
Time frame: 6 months after completion of treatment (estimated to be 12 months)
Radiological response
* 95% confidence intervals will be calculated * Response and progression will be evaluated in this study using the modified updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline
Time frame: 3 months of immunotherapy
Pathologic response
-Will be evaluated by board-certified neuropathologist on formalin-fixed paraffin-embedded tumor specimens stained with hematoxylin and eosin, where responders are defined as ≥30% necrosis/reactive changes and ≤50% viable tumor.
Time frame: 3 months of immunotherapy
Progression-free survival (PFS)
* PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. * Median PFS and their 95% confidence intervals will be assessed using Kaplan-Meier product limit methods.
Time frame: Through 2 years after completion of treatment (estimated to be 2.5 years)
Overall survival (OS)
-Median OS and their 95% confidence intervals will be assessed using Kaplan-Meier product limit methods.
Time frame: Through 2 years after completion of treatment (estimated to be 2.5 years)
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