Phase II Trial of Pembrolizumab in Recurrent or Residual High Grade Meningioma

Study Overview
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Brief Summary
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This research study is studying a drug as a possible treatment for High Grade Meningioma. The drug involved in this study is an immunotherapy drug called pembrolizumab

Detailed Description
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This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. Investigational means that the drug is being studied. The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this specific disease but it has been approved for other uses. In this research study, the investigators are studying pembrolizumab in participants with meningioma. Research studies have shown that meningioma tumor cells express a gene called PD-L1. The investigators will be looking to determine whether the study drug may may stop meningioma tumors from growing.

Official Title
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Phase II Trial of Pembrolizumab in Recurrent or Residual High Grade Meningioma

Conditions
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High Grade Meningioma

Intervention / Treatment
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* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Documentation Of Disease --Histologic Documentation: Histologically proven recurrent or residual intracranial or metastatic meningioma or meningioma with extracranial spread Progressive OR residual disease, as defined by the following: Progressive disease, as defined as an increase in size of the measurable primary lesion on imaging by 25% or more (bidirectional area). The change must occur between scans separated by no more than 24 months. Residual measurable disease: For Grade II or III meningioma, residual measurable disease immediately after surgery without requirement for progression. Residual measurable disease will be defined by bidimensionally measurable lesions with clearly defined margins by MRI scans, with a minimum diameter of 10mm in both dimensions. Post radiation patients: Patients with measurable and progressive meningioma who have received radiation are potentially eligible, but need to show evidence of progressive disease in the radiated field after completion of radiation. At least 24 weeks must have elapsed from completion of radiation to registration. Patients that have progressive disease outside of the radiation field do not need to wait 24 weeks from completion of radiation. Measurable Disease: Measurable disease is defined by a bidimensionally measurable main lesion on MRI or CT images (MRI preferred) with clearly defined margins and ≥ 10 mm. Multifocal disease is allowed as long as one lesion meets criteria for measurable disease and progressive disease. Prior Treatment Prior medical therapy is allowed but not required. Meningioma that have resulted from prior radiation therapy are allowed. No limit on number of prior therapies. No chemotherapy, other investigational agents within 14 days of study treatment. No other concurrent investigational agents or other meningioma-directed therapy (chemotherapy, radiation) while on study. For patients treated with external beam radiation, interstitial brachytherapy or radiosurgery, an interval > 24 weeks must have elapsed from completion of XRT to registration. Stable dose of dexamethasone 2mg or less for 7 days prior to initiation of treatment Recovered to CTCAE grade 1 or less toxicity from other agents with exception of alopecia and fatigue. No craniotomy within 28 days of registration. Not pregnant and not nursing: A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). 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. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Age ≥ 18 years ECOG Performance Status < 2 Patient history: Patients with history of NF may have other stable CNS tumors (schwannoma, acoustic neuroma or ependymoma) if lesions have been stable for 6 months. Metastatic meningiomas (as defined by extracranial meningiomas) and meningioma with extra-cranial spread are allowed. Required Initial Laboratory Values Participants must have normal organ and marrow function as defined in Table 1, all screening labs should be performed within 14 days of treatment initiation. Required Initial Laboratory Values System Laboratory Value 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 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 Creatinine clearance should be calculated per institutional standard. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Ability to understand and the willingness to sign a written informed consent document. Stable dose of dexamethasone 2mg or less for 7 days prior to initiation of treatment Exclusion Criteria: Participants who have had chemotherapy, targeted small molecule therapy or study therapy within 14 days of protocol treatment, or those who have not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 2 weeks earlier. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Participants with brainstem lesions Participants who are receiving any other investigational agents. Participants who have a diagnosis of an immunodeficiency. Requires treatment with high dose systemic corticosteroids defined as dexamethasone >2mg/day or bioequivalent within 7 days of initiating therapy. Has received systemic immunosuppressive treatments, aside from systemic corticosteroids as described in Section 5.7, within three months of start of study drug Hypersensitivity to pembrolizumab or any of its excipients Has a known history of active TB (Bacillus Tuberculosis) Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 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. 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 or stable NF-related neoplasms (Section 3.1.7). 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. Has known history of, or any evidence of active, non-infectious pneumonitis. Has an active infection requiring systemic therapy. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). HIV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pembrolizumab. In addition, these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. Unable to undergo brain MRI.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pembrolizumab<br>Pembrolizumab will be administered every 3 weeks Pembrolizumab will be administered through IV infusion | Drug: Pembrolizumab<br>* pembrolizumab binds to PD-1, an inhibitory signaling receptor expressed on the surface of activated T cells, and blocks the binding to and activation of PD-1 by its ligands, which results in the activation of T-cell-mediated immune responses against tumor cells<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival at 6 Months (PFS6) | Progression-free survival at 6 months is defined as not having disease progression per RANO (response assessment in neuro-oncology) criteria or death from any cause within six months of the first day of treatment with pembrolizumab. Contrast-enhanced cranial magnetic resonance imaging (MRI) was performed every 6 weeks to assess patient response to treatment. Progressive disease is defined per RANO criteria as the appearance of a new lesion, an increase in the size of a patient's existing lesions, or clear clinical worsening (seizures, medication side effects, complications of therapy, cerebrovascular events, infection, etc.) | up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is defined as the time from protocol registration until death due to any cause. The follow-up of patients who were alive at the time of analysis was censored at the date of last assessment of vital status. 90% confidence intervals for median OS were estimated using log(-log(survival)) methodology. | Up to 35 months | 
| Overall Survival (OS) at 3 Months | OS benchmarked at 3 months measures the percentage of participants who are still alive at 3 months, after study registration and receiving study therapy. | 3 months | 
| Overall Survival (OS) at 6 Months | OS benchmarked at 6 months measures the percentage of participants who are still alive at 6 months, after study registration and receiving study therapy. | 6 months | 
| Percentage of Participants With Treatment-related Adverse Events | All adverse events (AEs) recorded during the trial were summarized for all patients who received one or more doses of pembrolizumab. This outcome measure includes adverse events assessed as at least possibly related to study therapy and grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) version 4. | Up to 26 months | 
| Number of Participants With Intracranial Response | Intracranial response is defined as complete response (CR), partial response (PR), or stable disease (SD) by RANO (response assessment for neuro-oncology) criteria. Intracranial response was assessed by contrast-enhanced cranial magnetic resonance imaging (MRI) every 6 weeks. CR: complete disappearance of all enhancing measurable and non-measurable disease sustained for 4+ weeks, no new lesions, stable/decreasing corticosteroids, and patient is stable and improved clinically. Participants with non-measurable disease cannot have a CR; the best possible response is SD. PR: greater than or equal to 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for 4+ weeks, no progression of non-measurable disease, no new lesions, stable/decreasing corticosteroids, and patient is stable or improved clinically. SD: does not qualify for CR, PR, or disease progression and patient is stable clinically. | Up to 25 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Meningioma