Anaplastic Meningioma, Atypical Meningioma, Hemangiopericytoma
Conditions
Brief summary
A Phase II, Open-label, Single Arm Trial of Pembrolizumab for Refractory Atypical and Anaplastic Meningioma
Detailed description
This is a multicenter, prospective, single arm, open label, interventional study. The goal of this study, is to evaluate feasibility and efficacy of pembrolizumab for the treatment of recurrent or progressive meningioma (WHO grades II-III) or hemangiopericytoma (HPC). All patients will receive IV pembrolizumab, at a dose of 200mg, every 3 weeks. Patients will be treated until disease progression or intolerable toxicity. Treatment can be stopped after one year of treatment in case of stable disease or completer response, with re-initiation of treatment upon progression. Expression of PD1 and PD-L1 will be tested, on tumor cells, using IHC staining on biopsy material obtained from previous surgeries. All patients will have a baseline neurologic and clinical exam, MRI scan, a brain dedicated CT-PET scan, a baseline cognitive exam and QOL assessment with a dedicated questionnaire. Patients will have a clinical and neurological exam every treatment cycle. MRI scan will be repeated after 2 months from the beginning of the trial drug administration and then every 2-3 months. There are no designated and specific criteria for response assessment in the treatment of meningioma. Therefore, response evaluation will be made using the RECIST 1.1 criteria, as used for solid tumors. The trial will allow the continuation of pembrolizumab in case of stable or improved clinical response, when pseudo-progression is suspected in the MRI. In addition, response assessment will also be made according to the RANO criteria, as used for high grade glioma. This will be compared to the RECIST evaluation, but will not be used for treatment decision making.
Interventions
DRUGPembrolizumab
anti PD-L1
Sponsors
Rabin Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Be willing and able to provide written informed consent/assent for the trial. 2. Be 18 years of age on day of signing informed consent. 3. Have measurable disease based on RECIST 1.1. 4. Histologically, previously proven, grade II or III meningioma, HPC or classic radiographic features of a recurrent surgically inaccessible atypical or anaplastic meningioma. 5. All patients would have to have recurrence despite radiotherapy, unless radiotherapy is contraindicated. 6. No limit on the number of prior surgeries, radiation or radiosurgery treatments. 7. No limit on prior systemic therapies - chemotherapy or biological agents. 8. Patients who received stereotactic radiosurgery (SRS) are eligible without histologic documentation of recurrence if at least 6 months have passed from previous SRS treatment, and preferably, but not necessarily a 2-fluoro-2-deoxy-D-glucose PET imaging demonstrated hypermetabolism. 9. KPS≥50% 10. At least 4 weeks since any prior therapy. 11. Life expectancy of at least 4 months. 12. Dexamethasone use will be allowed up to a dose of 2mg per day. Steroids dose should be reduced or stopped 7 days prior to treatment with study drug. 13. Demonstrate adequate organ function as defined in Table 1, all screening labs should be performed within 10 days of treatment initiation. Table 1 Adequate Organ Function Laboratory Values Hematological Absolute neutrophil count (ANC)≥1,500 /mcL Platelets≥100,000 / mcL Hemoglobin≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) Renal Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl)≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases Albumin >2.5 mg/dL Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT)≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants a Creatinine clearance should be calculated per institutional standard. 14. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 15. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 16. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
Exclusion criteria
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 2. Has a diagnosis of immunodeficiency or is receiving other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 3. Patients who are steroid dependent and cannot reduce the dexamethasone dose to a maximal dose of 2mg per day. 4. Has a known history of active TB (Bacillus Tuberculosis) 5. Hypersensitivity to pembrolizumab or any of its excipients. 6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. 7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. * Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. 8. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 9. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 11. Has known history of, or any evidence of active, non-infectious pneumonitis. 12. Has an active infection requiring systemic therapy. 13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). 19. Has received a live vaccine within 30 days of planned start of study therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | 6 months after starting treatment | 6 months PFS refers to the percentage of patients in a study who remain alive and whose disease has not worsened 6 months after starting treatment. To determine the 6 months PFS rate for patients with recurrent or progressive meningioma on pembrolizumab therapy we used the RANO meningioma criteria. The Response Assessment in Neuro-Oncology meningioma criteria are guidelines used to evaluate treatment response in meningioma patients, incorporating both radiological and clinical factors. Tumor response is classified into categories such as: complete response (CR), where the tumor disappears. Partial response (PR) with a 50% or more reduction in tumor size. Minor response (MR) between 25% to 50% reduction in tumor size. Stable disease (SD) indicating minimal change, and progressive disease (PD) defined by at least a 25% increase in tumor size, new lesions, or worsening clinical symptoms. these criteria emphasize the use of consistent imaging techniques such as MRI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | from date of diagnosis until date of death from any cause | Overall survival (OS) is a term used in reference to treatments for cancer. It refers to the time which begins at diagnosis and up to the time of death. |
| Overall Progression Free Survival (PFS) | From the initiation of treatment to the occurrence of disease progression or death. | To determine the overall progression free survival (PFS) rate for patients with recurrent or progressive meningioma on pembrolizumab therapy we used the RANO meningioma criteria. The Response Assessment in Neuro-Oncology meningioma criteria are guidelines used to evaluate treatment response in meningioma patients, incorporating both radiological and clinical factors. Tumor response is classified into categories such as: complete response (CR), where the tumor disappears. Partial response (PR) with a 50% or more reduction in tumor size. Minor response (MR) between 25% to 50% reduction in tumor size. Stable disease (SD) indicating minimal change, and progressive disease (PD) defined by at least a 25% increase in tumor size, new lesions, or worsening clinical symptoms. these criteria emphasize the use of consistent imaging techniques such as MRI. |
Countries
Israel
Participant flow
Recruitment details
18 adult patients with histologically or radiologically proven recurrent or progressive meningioma (grade I to III) or anaplastic SFT who were treated in a single institution from 2018 to 2022 (15 patients with recurrent meningioma and 3 with anaplastic SFT). Patients were recruited at least 6 months after treatment with stereotactic radiosurgery.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 IV Pembrolizumab 200mg, given every 3 weeks until disease progression, intolerable toxicity or up to 2 years of treatment.
Pembrolizumab: anti PD-L1 18 patients received treatment | 18 |
| Total | 18 |
Baseline characteristics
| Characteristic | Arm 1 |
|---|---|
| Age, Customized | 64.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| KPS at baseline | 60 units on a scale |
| Multifocal disease | 14 Participants |
| Number of previous radiation therapy courses | 2 radiation therapy courses |
| Number of previous surgeries | 3 surgeries |
| Number of previous systemic therapies | 0 systemic therapies |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 9 Participants |
| Tumor type Anaplastic meningioma | 1 Participants |
| Tumor type Anaplastic solitary fibrous tumor | 3 Participants |
| Tumor type Atypical meningioma | 11 Participants |
| Tumor type Recurrent grade I meningioma | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 4 / 18 |
| other Total, other adverse events | 3 / 18 |
| serious Total, serious adverse events | 0 / 18 |
Outcome results
Primary
Progression Free Survival (PFS)
6 months PFS refers to the percentage of patients in a study who remain alive and whose disease has not worsened 6 months after starting treatment. To determine the 6 months PFS rate for patients with recurrent or progressive meningioma on pembrolizumab therapy we used the RANO meningioma criteria. The Response Assessment in Neuro-Oncology meningioma criteria are guidelines used to evaluate treatment response in meningioma patients, incorporating both radiological and clinical factors. Tumor response is classified into categories such as: complete response (CR), where the tumor disappears. Partial response (PR) with a 50% or more reduction in tumor size. Minor response (MR) between 25% to 50% reduction in tumor size. Stable disease (SD) indicating minimal change, and progressive disease (PD) defined by at least a 25% increase in tumor size, new lesions, or worsening clinical symptoms. these criteria emphasize the use of consistent imaging techniques such as MRI.
Time frame: 6 months after starting treatment
Population: all participants who were assigned to the group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 | Progression Free Survival (PFS) | 2 Participants |
Primary
Progression Free Survival (PFS)
12 months PFS refers to the percentage of patients in a study who remain alive and whose disease has not worsened 12 months after starting treatment. To determine the 12 months PFS rate for patients with recurrent or progressive meningioma on pembrolizumab therapy we used the RANO meningioma criteria. The Response Assessment in Neuro-Oncology meningioma criteria are guidelines used to evaluate treatment response in meningioma patients, incorporating both radiological and clinical factors. Tumor response is classified into categories such as: complete response (CR), where the tumor disappears. Partial response (PR) with a 50% or more reduction in tumor size. Minor response (MR) between 25% to 50% reduction in tumor size. Stable disease (SD) indicating minimal change, and progressive disease (PD) defined by at least a 25% increase in tumor size, new lesions, or worsening clinical symptoms. these criteria emphasize the use of consistent imaging techniques such as MRI.
Time frame: 12 months after starting treatment
Population: all participants who were assigned to the group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 | Progression Free Survival (PFS) | 2 Participants |
Secondary
Overall Progression Free Survival (PFS)
To determine the overall progression free survival (PFS) rate for patients with recurrent or progressive meningioma on pembrolizumab therapy we used the RANO meningioma criteria. The Response Assessment in Neuro-Oncology meningioma criteria are guidelines used to evaluate treatment response in meningioma patients, incorporating both radiological and clinical factors. Tumor response is classified into categories such as: complete response (CR), where the tumor disappears. Partial response (PR) with a 50% or more reduction in tumor size. Minor response (MR) between 25% to 50% reduction in tumor size. Stable disease (SD) indicating minimal change, and progressive disease (PD) defined by at least a 25% increase in tumor size, new lesions, or worsening clinical symptoms. these criteria emphasize the use of consistent imaging techniques such as MRI.
Time frame: From the initiation of treatment to the occurrence of disease progression or death.
Population: all participants who were assigned to the group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Overall Progression Free Survival (PFS) | 2.2 month |
Secondary
Overall Survival (OS)
Overall survival (OS) is a term used in reference to treatments for cancer. It refers to the time which begins at diagnosis and up to the time of death.
Time frame: from date of diagnosis until date of death from any cause
Population: all participants who were assigned to the group
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 | Overall Survival (OS) | 40 month |