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

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.

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.