A Phase Ib Study of Neoadjuvant Avelumab and Hypofractionated Proton Radiation Therapy Followed by Surgery for Recurrent Radiation-refractory Meningioma
Overview
- Phase
- Phase 1
- Intervention
- Avelumab
- Conditions
- Meningioma
- Sponsor
- Washington University School of Medicine
- Enrollment
- 9
- Locations
- 1
- Primary Endpoint
- Immunogenicity as measured by changes of CD8+/CD4+ tumor infiltrating lymphocytes (TILs) in recurrent radiation-refractory meningioma
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
Brief Summary
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
Investigators
Eligibility Criteria
Inclusion Criteria
- •Diagnosis of recurrent or progressive histologically confirmed WHO grade I-III meningioma which has failed maximal safe resection and radiation therapy.
- •At least one prior surgery with available archival formalin-fixed paraffin-embedded (FFPE) tumor blocks. In the case that tumor block is unavailable, unstained tissue sections may be used in its place.
- •Prior treatment must include external beam radiation, radiosurgery, or combination of both.
- •Deemed eligible for additional partial resection by treating physician and determined to be safe to receive 3 months of neoadjuvant therapy before planned surgery.
- •Age ≥ 18 years old.
- •Karnofsky performance status (KPS) ≥
- •Adequate organ and bone marrow function (as defined by the following laboratory values):
- •Absolute neutrophil count ≥ 1.5 × 10⁹ cells per L
- •Platelet count ≥ 100 × 10⁹ platelets per L
- •Hemoglobin ≥ 9 g/dL but transfusion allowed
Exclusion Criteria
- •Previous treatment with PD-1 or PD-L1 directed therapy.
- •Active infection requiring systemic therapy.
- •Uncontrolled intercurrent illness including, but not limited to, clinically significant (i.e. active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), congestive heart failure (≥ NYHA class II), unstable angina pectoris, or serious cardiac arrhythmia requiring medication.
- •Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
- •Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
- •Currently receiving any other investigational agents.
- •Current use of immunosuppressive medication, EXCEPT for the following:
- •Intranasal, inhaled, topical steroids, or local steroid injection (e.g. intra-articular injection)
- •Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent
- •Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
Arms & Interventions
Avelumab + Proton Therapy
* Avelumab will be started concurrently with proton therapy (up to 3 days before or after is permissible) and administered every 2 weeks for 3 months * Proton therapy 20 CGE (cobalt gray equivalent) will be given over 5 daily fractions of 4 CGE per day during weekdays * After 3 months of avelumab, patient will have a brain MRI evaluation, and radiological response will be assigned based on the iRANO criteria. Surgery will be performed as per routine clinical care * If the brain MRI after 3 months of avelumab shows complete response with no signs of residual tumor, no surgery will be indicated, and the patient may continue to take adjuvant avelumab for an additional 3 months. * After the patient has recovered from the surgery and if deemed medically eligible by the treating physician to receive additional immunotherapy, avelumab will be restarted and administered every 2 weeks for an additional 3 months
Intervention: Avelumab
Avelumab + Proton Therapy
* Avelumab will be started concurrently with proton therapy (up to 3 days before or after is permissible) and administered every 2 weeks for 3 months * Proton therapy 20 CGE (cobalt gray equivalent) will be given over 5 daily fractions of 4 CGE per day during weekdays * After 3 months of avelumab, patient will have a brain MRI evaluation, and radiological response will be assigned based on the iRANO criteria. Surgery will be performed as per routine clinical care * If the brain MRI after 3 months of avelumab shows complete response with no signs of residual tumor, no surgery will be indicated, and the patient may continue to take adjuvant avelumab for an additional 3 months. * After the patient has recovered from the surgery and if deemed medically eligible by the treating physician to receive additional immunotherapy, avelumab will be restarted and administered every 2 weeks for an additional 3 months
Intervention: Proton Therapy
Avelumab + Proton Therapy
* Avelumab will be started concurrently with proton therapy (up to 3 days before or after is permissible) and administered every 2 weeks for 3 months * Proton therapy 20 CGE (cobalt gray equivalent) will be given over 5 daily fractions of 4 CGE per day during weekdays * After 3 months of avelumab, patient will have a brain MRI evaluation, and radiological response will be assigned based on the iRANO criteria. Surgery will be performed as per routine clinical care * If the brain MRI after 3 months of avelumab shows complete response with no signs of residual tumor, no surgery will be indicated, and the patient may continue to take adjuvant avelumab for an additional 3 months. * After the patient has recovered from the surgery and if deemed medically eligible by the treating physician to receive additional immunotherapy, avelumab will be restarted and administered every 2 weeks for an additional 3 months
Intervention: Surgery
Outcomes
Primary Outcomes
Immunogenicity as measured by changes of CD8+/CD4+ tumor infiltrating lymphocytes (TILs) in recurrent radiation-refractory meningioma
Time Frame: Through time of progression (up to 6 months after completion of treatment - estimated to be 12 months)
-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.
Secondary Outcomes
- 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.(6 months after completion of treatment (estimated to be 12 months))
- Radiological response(3 months of immunotherapy)
- Pathologic response(3 months of immunotherapy)
- Progression-free survival (PFS)(Through 2 years after completion of treatment (estimated to be 2.5 years))
- Overall survival (OS)(Through 2 years after completion of treatment (estimated to be 2.5 years))