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Neoadjuvant Avelumab and Hypofractionated Proton Radiation Therapy Followed by Surgery for Recurrent Radiation-refractory Meningioma

This study is not yet open for participant recruitment.
Verified September 2017 by Washington University School of Medicine
Sponsor:
ClinicalTrials.gov Identifier:
NCT03267836
First Posted: August 30, 2017
Last Update Posted: September 11, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Pfizer
Information provided by (Responsible Party):
Washington University School of Medicine
  Purpose
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

Condition Intervention Phase
Meningioma Meningioma, Adult Drug: Avelumab Radiation: Proton Therapy Procedure: Surgery Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Study of Neoadjuvant Avelumab and Hypofractionated Proton Radiation Therapy Followed by Surgery for Recurrent Radiation-refractory Meningioma

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • 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 2 years after start of treatment) ]
    -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 Outcome Measures:
  • 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. [ Time Frame: 30 days after completion of treatment (estimated to be 7 months) ]
    If appropriate, confidence intervals will be used to characterize the precision of the estimate.

  • Radiological response [ Time Frame: 3 months of immunotherapy ]
    • 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

  • Pathologic response [ Time Frame: 3 months of immunotherapy ]
    -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.

  • Progression-free survival (PFS) [ Time Frame: Through 2 years after completion of treatment ]
    • 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.

  • Overall survival (OS) [ Time Frame: Through 2 years after completion of treatment ]
    -Median OS and their 95% confidence intervals will be assessed using Kaplan-Meier product limit methods.


Estimated Enrollment: 12
Anticipated Study Start Date: December 2017
Estimated Study Completion Date: June 30, 2020
Estimated Primary Completion Date: June 30, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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
  • 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
Drug: Avelumab
-10mg/kg IV
Other Name: Bavencio
Radiation: Proton Therapy
-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).
Procedure: Surgery
-Standard of care

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • 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. 6. Karnofsky performance status (KPS) ≥ 60.
  • 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
    • Total bilirubin concentration of ≤ 1.5 × the upper limit of normal [ULN] range
    • Aspartate aminotransferase and alanine aminotransferase concentrations of ≤ 2.5 × ULN)
    • Estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula.
  • Dexamethasone dose ≤ 4mg daily.
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in the study, she must inform her treating physician immediately.
  • Able to understand and willing to sign an IRB approved written informed consent document.

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)
  • Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
  • Prior organ transplantation including allogeneic stem cell transplantation.
  • Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
  • Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines.
  • History of allergic reactions or hypersensitivity attributed to compounds of similar chemical or biologic composition to avelumab or other agents used in the study (or monoclonal antibodies).
  • Persisting toxicity related to prior therapy (CTCAE > grade 1); however, alopecia, sensory neuropathy ≤ grade 2, or other ≤ grade 2 not constituting a safety risk based on the investigator's judgment are acceptable.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03267836


Contacts
Contact: Jiayi Huang, M.D. 314-362-8567 jiayi.huang@wustl.edu

Locations
United States, Missouri
Washington University School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: Jiayi Huang, M.D.    314-362-8567    jiayi.huang@wustl.edu   
Principal Investigator: Jiayi Huang, M.D.         
Sub-Investigator: Jian Campian, M.D., Ph.D.         
Sub-Investigator: Michael Chicoine, M.D.         
Sub-Investigator: Gavin Dunn, M.D., Ph.D.         
Sub-Investigator: Albert Kim, M.D., Ph.D.         
Sub-Investigator: Clifford Robinson, M.D.         
Sub-Investigator: Xiaowei Wang, Ph.D.         
Sub-Investigator: George Ansstas, M.D.         
Sub-Investigator: Milan Chheda, M.D., Ph.D.         
Sponsors and Collaborators
Washington University School of Medicine
Pfizer
Investigators
Principal Investigator: Jiayi Huang, M.D. Washington University School of Medicine
  More Information

Additional Information:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT03267836     History of Changes
Other Study ID Numbers: 17-x261
First Submitted: August 29, 2017
First Posted: August 30, 2017
Last Update Posted: September 11, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Meningioma
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Vascular Tissue
Meningeal Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Nervous System Diseases
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs