Phase II Trial of Pembrolizumab in Recurrent or Residual High Grade Meningioma
Phase: PHASE2
Conditions: High Grade Meningioma
Sponsor: Massachusetts General Hospital

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DF/HCC Protocol #:  17-296
TITLE: Phase II Trial of Pembrolizumab in Recurrent or Residual High Grade  
Meningioma
Coordinating Center:
Massachusetts General Hospital
*Principal Investigators (PI):
Priscilla Brastianos, MD
Massachusetts General Hospital
55 Fruit Street, Yawkey 9E
Boston, MA
PBRASTIANOS@mgh.harvard.edu
Sandro Santagata, MD, PhD
Brigham and Women’s Hospital
Dana Farber Cancer Institute
77 Avenue Louis Pasteur
Boston, MA
ssantagata@partners.org
Other Investigators:
Dan Cahill, MD PhD
Massachusetts General Hospital
Boston, MA
William Curry, MD
Massachusetts General Hospital
Boston, MA
Frederick Barker, MD
Massachusetts General Hospital
Boston, MA
Ian F. Dunn, MD
Dana-Farber Cancer Institute
Boston, MA
Kevin Oh, MD
Massachusetts General Hospital
Boston, MA
Elizabeth Gerstner, MD
Massachusetts General Hospital
Boston, MA
NCT number: NCT03279692

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Statistician:
Study Coordinator: 
Anita Giobbie-Hurder
Edwin Nunez
Department of Biostatistics
Massachusetts General Hospital
& Computational Biology
Yawkey 9E, 55 Fruit Street
Dana-Farber Cancer Institute
Telephone: 617-643-4395
Fax: 617-726-4319
enunez2@mgh.harvard.edu
Agent(s):  Pembrolizumab
IND #:  133213 
IND Sponsor: Priscilla K. Brastianos, MD 
Protocol Type / Version # / Version Date:
Revised / Version 6 / Jan, 20, 2023

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SCHEMA
• Measurable disease
• Biopsy-proven
meningioma
• Progressive or residual
disease
Pembrolizumab q3 weeks
• Baseline brain MRI
• Brain MRI every 2 cycles
• Blood test every 2 cycles
Progression
or Toxicity

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TABLE OF CONTENTS
SCHEMA.........................................................................................................................................3
1.1
Study Design...............................................................................................................5
1.2
Primary Objective.......................................................................................................5
1.3
Secondary Objectives..................................................................................................5
1.4
Exploratory Objectives ...............................................................................................5
2.
BACKGROUND ......................................................................................................................5
2.1
Meningioma................................................................................................................5
2.2
Pembrolizumab (MK-3475)........................................................................................6
2.3
Rationale .....................................................................................................................8
2.4
Correlative Studies Background .................................................................................9
3.0
PARTICIPANT SELECTION................................................................................................9
3.3
Inclusion of Women and Minorities .........................................................................13
4. REGISTRATION PROCEDURES ...........................................................................................13
4.1 General Guidelines for DF/HCC Institutions ..............................................................13
4.2 Registration Process for DF/HCC Institutions.............................................................13
5. TREATMENT PLAN................................................................................................................13
5.1 Treatment Regimen......................................................................................................13
5.2 Pre-Treatment Criteria .................................................................................................14
5.3 Agent Administration...................................................................................................14
5.4 General Concomitant Medication and Supportive Care Guidelines............................15
5.5 Supportive Care Guidelines for Events of Clinical Interest and Immune 
Related Adverse Events (irAEs)............................................................................17
5.6 Acceptable Concomitant Medications.........................................................................20
5.7 Prohibited Concomitant Medication............................................................................21
5.8 Diet...............................................................................................................................22
5.9 Contraception...............................................................................................................22
5.10 Use in Pregnancy .......................................................................................................22
5.11 Use in Nursing Women..............................................................................................23
5.12 Criteria for Taking a Participant Off Protocol Therapy.............................................23
5.13 Duration of Follow Up...............................................................................................24
5.14 Criteria for Taking a Participant Off Study ...............................................................24
6. DOSING DELAYS/DOSE MODIFICATIONS .......................................................................24
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ....................................26
7.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Overall PI and to Merck.........................................................................................26
7.2 Reporting of Pregnancy and Lactation to the Overall PI and to Merck.......................27
7.3 Immediate Reporting of Adverse Events to the Overall PI and to Merck...................27

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7.4 Events of Clinical Interest............................................................................................28
7.5 Criteria for Taking a Participant Off Study .................................................................29
7.6 Overall PI Responsibility for Reporting Adverse Events............................................31
7.7 Adverse Event Characteristics.....................................................................................31
7.8 Expedited Adverse Event Reporting............................................................................32
8. PHARMACEUTICAL INFORMATION..................................................................................33
8.1 Pembrolizumab ............................................................................................................33
8.2 Description...................................................................................................................33
8.3 Form.............................................................................................................................34
8.4 Packaging and Labeling Information...........................................................................34
8.5 Clinical Supplies Disclosure........................................................................................34
8.6 Storage, Handling and Preparation Requirements.......................................................34
8.7 Administration .............................................................................................................35
8.8 Ordering.......................................................................................................................36
8.9 Accountability..............................................................................................................36
8.10 Destruction and Return ..............................................................................................36
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ................................................37
9.1 Exploratory Laboratory Correlative Studies................................................................37
9.2 Background..................................................................................................................37
9.3 Methodology................................................................................................................37
9.3.1 RNAscope assay and evaluation...............................................................................37
9.3.2 Immunohistochemistry and evaluation.....................................................................37
9.3.3 RNA-sequencing.......................................................................................................38
9.3.4 Whole exome sequencing .........................................................................................38
9.3.5 Imaging Correlative Studies .....................................................................................39
9.4 Collection and Shipping of Tissue Specimen(s)..........................................................41
10. STUDY CALENDAR .............................................................................................................41
11. MEASUREMENT OF EFFECT .............................................................................................44
12
End of Treatment/Intervention...............................................................................................55
12.1 Duration of Treatment................................................................................................55
12.1.1 CR, PR, or SD.........................................................................................................55
12.1.2 Disease Progression ................................................................................................55
12.2 Definitions and Follow-up Requirements..................................................................55
12.3 Extraordinary Medical Circumstances.......................................................................56
13.0
Statistical Considerations....................................................................................................56
14
PUBLICATION PLAN .........................................................................................................58
REFERENCES ..............................................................................................................................59
APPENDIX A
PERFORMANCE STATUS CRITERIA...........................................................62

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OBJECTIVES
1.1
Study Design
This is a Phase 2 study of pembrolizumab in patients with recurrent or progressive high-grade 
meningioma. 
1.2
Primary Objective
To estimate the progression-free survival at 6 months of pembrolizumab in recurrent 
high-grade meningioma (WHO grade II atypical meningioma and WHO grade III 
anaplastic meningioma) 
1.3
Secondary Objectives
1. To determine the toxicity of pembrolizumab in patients with recurrent high-grade 
meningioma (WHO grade II atypical meningioma and WHO grade III anaplastic 
meningioma) 
2. To estimate the overall survival of patients with recurrent high-grade meningioma 
receiving pembrolizumab
3. To estimate the response rate of patients with recurrent high grade meningioma receiving 
pembrolizumab
1.4
Exploratory Objectives
1. To determine molecular biomarkers of response using RNAscope in situ hybridization 
methodologies for immune checkpoint markers, immunohistochemistry to characterize 
the immune infiltrate and next generation DNA and RNA sequencing.
2. To determine if changes in brain MRI parameters correlate with tumor response.
2. BACKGROUND
2.1
Meningioma
Meningiomas are the most common primary brain tumor, with a prevalence of 170,000 cases in 
the US and an annual incidence of 18,000 new cases. Most meningiomas are of the typical 
variety – World Health Organization (WHO) grade I. However, depending on their location 
within the nervous system, grade I meningiomas can cause significant morbidity or mortality. 
Even after surgical resection, recurrence rates can be as high as 20%1-3, and patients with grade I 
tumors have reduced long-term survival. 
Approximately 20% of meningiomas are atypical (WHO grade II) and anaplastic (WHO grade 
III), defined by increased mitoses, necrosis, higher nuclear to cytoplasmic ratios, or histologic 
appearance resembling carcinoma, sarcoma, or melanoma4. Recurrence rates for WHO grade II 
and III meningiomas are 40% and 80%, respectively3. The prognosis of atypical and anaplastic 
meningiomas is poor, with 5-year overall survival rates between 47-65%5,6. 
Treatment options, particularly for the atypical or anaplastic meningiomas, are limited5. 
Radiation is frequently used as an adjunct to surgery; however, there are no effective 
chemotherapeutic options when surgery and radiation fail to offer durable long-term disease 

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control7. Traditional cytotoxic agents have minimal activity in this setting8,9, and targeted agents 
in unselected patients10 have demonstrated modest benefit at best. Response rate has been 0% in 
nearly all studies of systemic therapy in recurrent tumors of all grades9,11-13. A poor 
understanding of what drives meningioma development has hampered the development of 
therapeutic agents to supplement surgery and radiation. Therefore these patients have limited 
therapeutic options and effective treatments are greatly needed.  While genomic studies have 
revealed mutations in oncogenes such as SMO and AKT in a small subset of meningioma14,15, 
most tumors do not have mutations that can be targeted.  Studies of high grade tumors have 
failed to reveal obvious drivers of malignant progression, rendering these tumors exceedingly 
challenging to treat.
2.2
Pembrolizumab (MK-3475)
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been 
resolved.  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade.  
The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from 
that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  PD-1 was 
shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, 
B-cells, T regs and Natural Killer cells.  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be 
induced in a variety of cell types, including non-hematopoietic tissues as well as in various 
tumors.  Both ligands are type I transmembrane receptors containing both IgV- and IgC-like 
domains in the extracellular region and contain short cytoplasmic regions with no known 
signaling motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered 
through the T-cell receptor.  

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PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 
has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  200mg IV Q3W will be the dose and 
schedule utilized in this protocol to test for initial tumor activity.  Recent data from other clinical 
studies within the MK-3475 program has shown that a lower dose of MK-3475 and a less 
frequent schedule may be sufficient for target engagement and clinical activity.
Analysis of pharmacokinetic data for MK-3475 administered Q2W and Q3W showed slow 
systemic clearance, limited volume of distribution, and a long half-life.  Pharmacodynamic data 
(IL-2 release assay) suggested that peripheral target engagement is durable (>21 days).  This PK 
and pharmacodynamic data provides scientific rationale for using a Q3W dosing schedule.  
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 patients. Within the resulting population PK model, clearance and volume parameters 
of MK-3475 were found to be dependent on body weight. The relationship between clearance 
and body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all 
body weights.  MK-3475 has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 
2 mg/kg Q3W body weight based regimen are anticipated to remain well within the established 
exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins 
are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population 
PK evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there 
are no anticipated changes in exposure between different indication settings.

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The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.
2.3
Rationale
Recently, great strides in immunotherapies have been made in the management of a number of 
malignancies namely the development of the immune checkpoint inhibitors targeting cytotoxic 
T-lymphocyte antigen 4 (CTLA4) and the programmed cell death (PD1) receptor-ligand (PDL1, 
PDL1). However, the role of these inhibitors in meningioma has not been explored. Preclinical 
data demonstrates an increase in PD-L1 expression as meningioma tumor grade increases and a 
decrease in the number of T-cells in higher grade meningioma 16. Because there are no effective 
medical treatments for recurrent WHO grade II atypical and WHO grade III anaplastic 
meningioma17 we characterized the immune infiltrate of meningioma and investigated the 
expression of molecules that might render these tumors susceptible to checkpoint blockade16. We 
characterized the immune infiltrate of 291 meningiomas including WHO grade I-III 
meningiomas using immunohistochemistry and we examined the expression of PD-L1 mRNA by 
RNAscope in situ hybridization and PD-L1 protein by immunohistochemistry and flow 
cytometry. In meningioma, the tumor infiltrating lymphocytes are predominantly T cells. In 
atypical and anaplastic meningioma, there is a sharp decrease in the number of T cells, including 
the numbers of CD4+ and CD8+ T cells and there is also an increase in the number of FOXP3 
expressing immunoregulatory (Treg) cells. PD-L1 mRNA and protein expression is increased in 
atypical and anaplastic meningioma. Using patient derived meningioma cells, we confirmed that 
PD-L1 is expressed in meningioma cells themselves, and not solely in infiltrating immune cells. 
This work indicates that high-grade meningioma harbor an immunosuppressive tumor 
microenviroment and that increased Treg cells and elevated PD-L1 may contribute to the 
aggressive phenotype of these tumors.
We now hypothesize that patients with meningioma expressing PD-L1 will respond to 

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checkpoint blockade with pembrolizumab. We are thus proposing a prospective Phase 2 study of 
the PD-1 inhibitor pembrolizumab in patients with recurrent high grade (WHO grade II and III) 
using a dose schedule that has demonstrated efficacy in systemic tumors18. We propose to 
investigate the activity of pembrolizumab in a single cohort. We propose to incorporate 
monitoring with MR imaging, and pathology correlates from tissue resections (IHC markers for 
characterizing the immune infiltrate including PD-1 expressing cells and PD-L1 expression of 
the tumors via IHC and mRNA in situ hybridization/quantitative RNAscope), and next 
generation DNA sequencing and RNA-sequencing to identify genetic and imaging predictors of 
response.
2.4
Correlative Studies Background
2.4.1
Molecular Correlatives
Our objectives are to use next generation sequencing technologies to identify genetic predictors 
of response to immune checkpoint inhibitor blockade using clinical samples collected as part of 
clinical care. Our group has extensive experience in genomic characterization of a number of 
brain tumors including craniopharyngioma, brain metastases and their matched peripheral 
primaries and meningioma 14,19,20.  We will use whole exome or targeted exome sequencing 
panels that cover genes implicated in meningioma development and progression to identify 
markers of response.  We will characterize mutations, gene rearrangements and copy number 
alterations from this data.  RNA-sequencing will also be used to identify signatures of response. 
We will also characterize and quantify the levels of PD-1 and PD-L1 mRNA expression in the 
tumor samples using an in situ hybridization technology (RNAscope) as well as to characterize 
the immune infiltrate using immunohistochemistry markers and image quantification.  Our goal 
is to use these techniques to identify genetic, mRNA and proteomic  predictors of response to 
checkpoint inhibitors. 
2.4.2
Imaging Correlatives
MRI is a very useful tool to non-invasively probe tumor response to treatment and is already part 
of the routine management of patients with meningioma.  Imaging correlatives will be performed 
as outlined in Section 9.3.5.
3.0
PARTICIPANT SELECTION 
3.1
Eligibility Criteria
3.1.1
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 a measurable 
meningioma lesion on imaging by greater than 25% (bidirectional area). 
The change must occur between scans separated by no more than 24 
months. 

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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 measurable 
lesions with clearly defined margins by MRI scans, with a minimum 
diameter of 10mm in one dimension. 
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. ≥ 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.
3.1.2
Measurable Disease: Measurable disease is defined by a main lesion measurable on 
MRI or CT images (MRI preferred) with clearly defined margins and ≥ 10 mm in one 
dimension. Multifocal disease is allowed as long as one lesion meets criteria for 
measurable disease and progressive disease. For measurable disease, refer to Section 
11.0
3.1.3
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 at least 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 21 days of registration. 

Grade I meningiomas will be allowed as long as they meet criteria for progression as 
defined by 3.1.1.
3.1.4
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 

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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.  
3.1.5
Age ≥ 18 years
3.1.6
ECOG Performance Status ≤ 2
3.1.7
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.
3.1.8
Metastatic meningiomas (as defined by extracranial meningiomas) and meningioma 
with extra-cranial spread are allowed.
3.1.9
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.
Table 1: 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 
calculateda 
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 g/dL
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time 
≤1.5 X ULN unless subject is receiving 
anticoagulant 
therapy

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(PT)
Activated 
Partial 
Thromboplastin Time (aPTT)
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
aCreatinine clearance should be calculated per institutional standard.
3.1.10
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.
3.1.11
Ability to understand and the willingness to sign a written informed consent 
document.
3.2 Exclusion Criteria
3.2.1
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.  
3.2.2
Participants with brainstem lesions
3.2.3
Participants who are receiving any other investigational agents.
3.2.4
Participants who have a diagnosis of an immunodeficiency.
3.2.5
Requires treatment with high dose systemic corticosteroids defined as dexamethasone 
>2mg/day or bioequivalent within at least 7 days of initiating therapy.
3.2.6
Has received systemic immunosuppressive treatments, aside from systemic 
corticosteroids as described in Section 5.7, within three months of start of study drug
3.2.7
Has a known hypersensitivity to pembrolizumab or any of its excipients
3.2.8
Has a known history of active TB  (Bacillus Tuberculosis)
3.2.9
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.
3.2.10
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
3.2.11
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.
3.2.12
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).
3.2.13
Has active autoimmune disease that has required systemic treatment in the past 2 

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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. 
3.2.14
Has known history of, or any evidence of active, non-infectious pneumonitis.
3.2.15
Has a known active infection requiring systemic therapy.
3.2.16
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
3.2.17
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.
3.2.18
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
3.2.19
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.
3.2.20
Unable to undergo brain MRI.
3.3
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.
4. REGISTRATION PROCEDURES
4.1 General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist.
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
4.2 Registration Process for DF/HCC Institutions
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.  

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16
5. TREATMENT PLAN
5.1 Treatment Regimen
Pembrolizumab will be administered every 3 weeks, with 21 consecutive days defined as a 
treatment cycle. Treatment will be administered on an outpatient basis.  Reported adverse events 
and potential risks are described in Section 7.  Appropriate dose modifications are described in 
Section 6.  No investigational or commercial agents or therapies other than those described 
below may be administered with the intent to treat the participant's malignancy.
The treatment to be used in this trial is outlined below in the table below.
Table 2: Dose of Pembrolizumab
Drug
Dose/Potency
Dose 
Frequency
Route 
of 
Administration
Regimen/Treatment 
Period
Cycle Length
Pembrolizumab
200 mg 
Q3W
IV infusion
Day 1 of each 3 week 
cycle
3 weeks
5.2 Pre-Treatment Criteria
Informed consent will be obtained after the study has been fully explained to the subject and 
before the conduct of any screening procedures or assessments. If screening assessments occur 
within 7 days before start of study treatment, then they may serve as the baseline Cycle 1 Day 1 
study tests and do not need to be repeated.
Pretreatment criteria will be assessed within 14 days of the first dose of study treatment to 
establish eligibility and baseline values. This will be considered the baseline clinical evaluation. 
Subsequent changes from screening physical exam (PE) findings that meet the definition of an 
AE will be recorded on the AE page of the eCRFs.
Demographic information and baseline characteristics will be collected at the Screening Visit. 
Standard demographic parameters include age, sex, and race/ethnicity (recorded in accordance 
with prevailing regulations). Baseline characteristics will include ECOG PS (Appendix A), 
disease status, medical histories, prior and concomitant medications, and PE findings. 
5.3 Agent Administration
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed in the Study Calendar (Section 10).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons.
All trial treatments will be administered on an outpatient basis.
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 

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should make every effort to target infusion timing to be as close to 30 minutes as possible. 
 
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution.
5.4 General Concomitant Medication and Supportive Care Guidelines
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Merck Clinical team.  The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician. 

Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of prophylactic 
antiemetic therapy according to standard institutional practice. Subjects should be 
strongly encouraged to maintain liberal oral fluid intake. 

Anti-infectives: Subjects with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 

Immune-related adverse events: See Section 6.0 and Events of Clinical Interest Guidance 
Document for supportive care guidelines, including use of corticosteroids, regarding 
diagnosis and management of adverse experiences of a potential immunologic etiology. 
Management of Infusion Reactions: Signs and symptoms usually develop during or 

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shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
Table 3 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475).
Table 3 Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication 
at 
subsequent dosing
Grade 1
Mild 
reaction; 
infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator.
None
Grade 2
Requires 
infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic 
medications 
indicated for < =24 hrs
Stop 
Infusion 
and 
monitor 
symptoms.
Additional 
appropriate 
medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator.
If symptoms resolve within one 
hour of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g., from 
100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 
toxicity 
despite 
adequate 
premedication 
should 
be 
permanently discontinued from 
further 
trial 
treatment 
administration.
Subject 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK-
3475) with:
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication 
and/or 
brief 
interruption of infusion); 
recurrence 
of 
symptoms 
Stop Infusion.
Additional 
appropriate 
medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDS
No subsequent dosing

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NCI CTCAE Grade
Treatment
Premedication 
at 
subsequent dosing
following 
initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal 
impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory 
support 
indicated
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject 
is deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
Subject 
is 
permanently 
discontinued from further trial 
treatment administration.
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration.
5.5 Supportive Care Guidelines for Immune Related Adverse Events (irAEs)
Adverse events (both non-serious and serious) associated with pembrolizumab exposure 
may represent an immunologic etiology.  These adverse events may occur shortly after 
the first dose or several months after the last dose of treatment. Pembrolizumab must be 
withheld for drug-related toxicities and severe or life-threatening AEs as per the Table 
below. See Section 6.0 for supportive care guidelines, including use of corticosteroids. 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents 
if symptoms do not improve with administration of corticosteroids.   Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid 
dose is decreased.
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin or other etiologic causes prior to labeling an adverse event as an irAE. 
Subjects who develop a Grade 2 or higher irAE should be discussed immediately with the 
overall Principal Investigator or designee. The treatment guidelines are intended to be 
applied when the investigator determines the events to be related to pembrolizumab.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. Suggested conditional procedures, 
as appropriate, can be found in the ECI guidance document.

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Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 6.0 
for dose modification. 

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed.
o
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

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
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 

Cerebral Edema
Due to the immunologic nature of pembrolizumab administration, cerebral edema could 
theoretically result as a consequence of pembrolizumab administration due to immune 
infiltration of the brain. Symptoms related to cerebral edema may include headache or 
neurologic deficit that is either new or worsened. Patients with any signs or symptoms of 
cerebral edema should be treated as clinically appropriate including initiation or 
increased systemic corticosteroid dosing, treatment with an osmotic diuretic or surgical 
decompression. Subsequent pembrolizumab dosing should be immediately interrupted if 
significant clinical symptoms attributable to cerebral edema develop. Treatment with 
additional pembrolizumab doses may only be re-initiated if clinically significant 
symptoms attributable to cerebral edema have resolved to grade ≤ 1 or pre-treatment 
baseline. Patients who develop CTCAE 4.0 grade-4 cerebral edema attributable to 
pembrolizumab administration should not receive further pembrolizumab doses and 
should discontinue study therapy.
Recommendations to manage irAEs not detailed elsewhere in the protocol are detailed in 
Table 4. 
Table 4 Dose Modification and Toxicity Management Guidelines for Immune-related AEs 
Associated with Pembrolizumab

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General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at 
least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been 
reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity 
grade or 
conditions 
(CTCAEv
4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or 
other therapies 
Monitor and follow-up 
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 
4, or 
recurrent 
Grade 2
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper

Monitor participants for signs 
and symptoms of pneumonitis

Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment

Add prophylactic antibiotics 
for opportunistic infections
Grade 2 or 
3
Withhold
Diarrhea / 
Colitis 
Grade 4
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper

Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with 
or without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus).

Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis. 

Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion.
Grade 2
Withhold

Administer 
corticosteroids (initial 
dose of 0.5- 1 mg/kg 
prednisone or 
equivalent) followed by 
taper
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 3 or 
4 
Permanently 
discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 

Monitor with liver function 
tests (consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable

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equivalent) followed by 
taper
Type 1 
diabetes 
mellitus 
(T1DM) or 
Hyperglyce
mia
Newly 
onset 
T1DM or 
Grade 3 or 
4 
hyperglyce
mia 
associated 
with 
evidence of 
-cell 
failure
Withhold

Initiate insulin 
replacement therapy for 
participants with T1DM 

Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 

Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes.
Grade 2
Withhold
Hypophysiti
s
Grade 3 or 
4 
Withhold or 
permanently 
discontinue1 

Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.  

Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency) 
Grade 2
Continue 
Hyperthyroi
dism 
Grade 3 or 
4 
Withhold or 
permanently 
discontinue1

Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as 
appropriate 

Monitor for signs and 
symptoms of thyroid 
disorders. 
Hypothyroid
ism
Grade 2-4
Continue 

Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) per 
standard of care

Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis 
and Renal 
dysfunction
Grade 3 or 
4 
Permanently 
discontinue

Administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper.

Monitor changes of renal 
function
Grade 1 or 
2
Withhold
Myocarditis
Grade 3 or 
4
Permanently 
discontinue

Based on severity of 
AE administer 
corticosteroids

Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes
Intolerable/ 
persistent 
Grade 2
Withhold
All other 
immune-
related AEs
Grade 3
Withhold or 
discontinue 
based on the type 
of event.  Events 
that require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 

Based on type and 
severity of AE 
administer 
corticosteroids 

Ensure adequate evaluation to 
confirm etiology and/or 
exclude other causes

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Syndrome, 
encephalitis
Grade 4 or 
recurrent 
Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is 
required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal 
replacement therapy or achieved metabolic control (in case of T1DM).  
5.6 Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.4.
5.7 Prohibited Concomitant Medication
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic lesion may be allowed at the 
investigator’s discretion. If radiation is given to a solitary lesion at the 
investigator's discretion, then the patient is considered to have progressive 
disease, but may continue on treatment if patient is clinically stable.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: intranasal influenza vaccines (e.g., Flu-Mist®), measles, mumps, rubella, 
varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 

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
Systemic glucocorticoids for any purpose other than to treat edema related to the 
meningioma or supportive post-operative management or to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  Intranasal, inhaled or 
topical corticosteroids (<5% of body surface area) for the treatment of mild/moderate 
asthma, allergies or dermatitis are permitted. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Overall PI. Physiologic 
replacement of glucocorticoids as maintenance therapy for adrenal insufficiency are 
permitted. Standard doses of hydrocortisone for maintenance therapy are 10–20 
mg/m2/day divided 2–4 times per day. For a subject with a body surface area (BSA) of 
1.73 m2, this translates to a total dose of 34.6 mg of hydrocortisone per day. The 
equivalent dose of dexamethasone is 1.2 mg per day. Some subjects may additionally 
receive mineralocorticoid- replacement maintenance therapy with fludrocortisone. The 
maintenance dose of fludrocortisone for this indication is 0.05–0.1 mg/day. 
Antihistamines and other non- steroidal anti-allergy medications are also permitted. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive 
other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
5.8 Diet
Subjects should maintain a normal diet unless modifications are required to manage an adverse 
event such as diarrhea, nausea or vomiting.
5.9 Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).

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Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period defined in section 7.2-Reporting of Pregnancy and 
Lactation to the Overall PI and to Merck.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study.
5.10 Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Overall PI and to Merck without delay and 
within 24 hours to the Overall PI and within 2 working days to Merck if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).  
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Overall PI.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Overall PI and to Merck and followed as described above and in 
Section 7.2.
5.11 Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment.
5.12 Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies:

Confirmed radiographic disease progression
Note: For unconfirmed radiographic disease progression, please see Section 11.3.3
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved.

Intercurrent illness that prevents further administration of treatment

Unacceptable adverse event(s)

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
Participant demonstrates an inability or unwillingness to comply with trial regimen 
and/or documentation requirements

Participant decides to withdraw from the protocol therapy

General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator

The subject has a confirmed positive serum pregnancy test

Subject is lost to follow-up

Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
An ODQ Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol 
therapy. 
This 
form 
can 
be 
found 
on 
the 
DF/HCC 
website 
at 
http://www.dfhcc.harvard.edu/research/clinical-research-support/document-library-forms-sops-
etc/.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Priscilla Brastianos at 617-724-6881. 
5.13 Duration of Follow Up
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events will be collected for 90 days after the end of treatment as 
described in Section 7.3).  Subjects who discontinue for reasons other than progressive disease 
will have post-treatment follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented 
disease progression each subject will be followed by telephone for overall survival until death, or 
withdrawal of consent, whichever occurs first.
5.14 Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Lost to follow-up

Withdrawal of consent for data submission

Death

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The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore. 
6. DOSING DELAYS/DOSE MODIFICATIONS
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for dose delays and dose 
modifications. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website.
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non- 
hematological toxicity ≥ Grade 3 including laboratory abnormalities despite appropriate 
replacement therapies when appropriate, and severe or life-threatening AEs as per Table 5.
Table 5 Dose modification guidelines for drug-related adverse events
Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting Treatment
Treatment Discontinuation
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks
Diarrhea/Colitis
4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose
AST, 
ALT, 
or 
Increased Bilirubin
3-4
Permanently discontinue
(see exception below)a
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) 
or 
Hyperglycemia
T1DM or 
3-4
Hold pembrolizumab for new onset Type 
1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure
Resume pembrolizumab when patients are clinically and 
metabolically stable
Hypophysitis
2-4
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks
Hyperthyroidism 
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with pembrolizumab can be 
continued 
while 
thyroid 
replacement 
therapy is instituted
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted
2b
Toxicity resolves to Grade 0-1 
Permanently discontinue if toxicity develops despite adequate 
premedication 
Infusion Reaction
3-4
Permanently discontinue
Permanently discontinue
Pneumonitis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks

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Toxicity
Hold 
Treatment 
For Grade
Timing for Restarting Treatment
Treatment Discontinuation
3-4
Permanently discontinue
Permanently discontinue
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks
Renal Failure or 
Nephritis
3-4
Permanently discontinue
Permanently discontinue
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks
All Other Drug-
Related Toxicityc
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event.
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued.
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated  for the next scheduled dose; Refer to 
Table  – Infusion Treatment Guidelines for further management details.
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the PI of the study. The reason for 
interruption should be documented in the patient's study record.
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. Merck product includes 
any pharmaceutical product, biological product, device, diagnostic agent or protocol-specified 
procedure, whether investigational (including placebo or active comparator medication) or 
marketed, manufactured by, licensed by, provided by or distributed by Merck for human use.
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.

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Adverse events may also occur in screened subjects during any pre-allocation baseline period as 
a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. Progression of the cancer under study is not 
considered an adverse event unless it is considered to be drug related by the investigator.
All adverse events will be recorded from the time of patient  registration through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.3.
7.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the Overall 
PI and to Merck
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. If an adverse 
event(s) is associated with (“results from”) the overdose of a Merck product, the adverse event(s) 
is reported as a serious adverse event, even if no other seriousness criteria are met. If a dose of 
Merck’s product meeting the protocol definition of overdose is taken without any associated 
clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event 
of Clinical Interest (ECI), using the terminology “accidental or intentional overdose without 
adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Overall PI and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220)
7.2 Reporting of Pregnancy and Lactation to the Overall PI and to Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Overall PI and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220)
7.3 Immediate Reporting of Adverse Events to the Overall PI and to Merck

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7.3.1 Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that:

Results in death;

Is life threatening;

Results in persistent or significant disability/incapacity;

Results in or prolongs an existing inpatient hospitalization;

Is a congenital anomaly/birth defect;

Is a new cancer (that is not a condition of the study);

Is associated with an overdose;

Is another important medical event 
Refer to Table 6 below for additional details regarding each of the above criteria.
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time of 
patient registration through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Overall PI and within 2 working days to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Overall PI and to Merck.
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA.
All subjects with serious adverse events must be followed up for outcome.
7.4 Events of Clinical Interest

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Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Overall PI and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). For the time 
period beginning when the consent form is signed until treatment allocation/randomization, 
any ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to 
the Overall PI and within 2 working days to Merck Global Safety if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at patient registration through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to Merck 
product, must be reported within 24 hours to the Overall PI and within 24 hours to Merck 
Global Safety.
Events of clinical interest for this trial include:
1. an overdose of Merck product, as defined in Section 7.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Overall PI, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. 
7.5 Criteria for Taking a Participant Off Study
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. All adverse events regardless of 
CTCAE grade must also be evaluated for seriousness.

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Table 6  Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not 
indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation or hospitalization indicated; disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred 
(Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of 
length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including 
hospitalization for an elective procedure] for a preexisting condition which has not worsened does not constitute a serious adverse 
event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse 
event. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be 
reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may 
require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Merck product to be discontinued?
Relationship 
to test drug 
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse 
event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of 
causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the 
adverse 
event 
based 
upon 
the 
available 
information. 
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely the Merck product 
caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other 
drug(s)/vaccine(s), or other host or environmental factors

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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to 
Merck 
product
(continued) 
Dechallenge
Was the Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose drug trial); or 
(4) Merck product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Merck product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) 
the trial is a single-dose drug trial); or (3) Merck product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO 
THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. 
CLINICAL MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with 
Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the 
Merck product or drug class pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to 
his/her best clinical judgment, including consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a 
Merck product relationship).
Yes, there is a reasonable possibility 
of Merck product relationship.
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to 
the administration of the Merck product is reasonable.  The AE is more likely explained by the Merck 
product than by another cause.
No, 
there 
is 
not 
a 
reasonable 
possibility Merck product relationship
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to 
administration of the Merck product is not reasonable OR there is another obvious cause of the AE.  (Also 
entered for a subject with overdose without an associated AE.)
7.6 Overall PI Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
7.7 Adverse Event Characteristics

CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

For expedited reporting purposes only:  
-
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided.
-
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-

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Specific Expedited Adverse Event Reporting Exclusions.

Attribution of the AE:
-
Definite – The AE is clearly related to the study treatment.
-
Probable – The AE is likely related to the study treatment.
-
Possible – The AE may be related to the study treatment.
-
Unlikely – The AE is doubtfully related to the study treatment.
-
Unrelated – The AE is clearly NOT related to the study treatment.
7.8 Expedited Adverse Event Reporting 
7.8.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 90 days of the last dose of 
treatment on the local institutional SAE form. 
7.8.2 DF/HCC Expedited Reporting Guidelines
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy. 
DF/HCC Reportable AEs
Attribution
Gr. 2 & 3 AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE Expected
Gr. 4 AE
Unexpected
Gr. 
5 
AE 
Expected 
or 
Unexpected
Unrelated
Unlikely
Not required
Not required
5 calendar days#
5 calendar days
24 hours*
Possible
Probable
Definite
Not required
5 calendar days
5 calendar days#
5 calendar days
24 hours*
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported.
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event.
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events. 
7.8.3 Expedited Reporting to the Food and Drug Administration (FDA)
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
7.8.4 Expedited Reporting to Hospital Risk Management

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Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy. 
7.8.5 Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
8. PHARMACEUTICAL INFORMATION
8.1 Pembrolizumab
Pembrolizumab is a potent and highly selective humanized mAb designed to block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 potently blocks binding 
to both ligands with half maximal inhibitory concentration (IC50) values below 1 nM. MK-3475 
enhances T cell responses in human donor blood cell cultures with an EC50 of ~0.1 to 0.3 nM.
Additional detailed information on pembrolizumab is available in the Investigator’s Brochure.
8.2 Description
Pembrolizumab (MK-3475) is a humanized anti-PD-1 mAb of the IgG4/kappa isotype with a 
stabilizing S228P sequence alteration in the fragment crystallizable (Fc) region. MK-3475 binds 
to human PD-1 and blocks the interaction between PD-1 and its ligands. The theoretical 
molecular weight of the polypeptide is 146,288 Da and its theoretical pI is 7.5. The parental 
murine anti-human PD-1 antibody (hPD-1.09A) was produced by immunizing mice with hPD-1 
DNA. The MK-3475 antibody was generated by humanization of the parental antibody by the 
Medical Research Council (Cambridge, UK) using complementarily-determining region (CDR) 
grafting technology (U.S. Patent No. 5,225,539). The gene segments encoding the variable heavy 
and light chains of MK-3475, as well as human IgG4, were codon-optimized, synthesized, and 
ligated into a vector.
A single expression plasmid, pAPD11V1-GA was constructed for the expression of both the 
heavy and light antibody chains of MK-3475. The nucleotide sequences encoding the heavy and 
light chains, along with their respective promoters and poly A signal sequences have been 
confirmed by DNA sequence analysis. The pAPD11V1-GA expression vector was subsequently 
used to transfect CHO-DXB-11 cells for the development of the MK-3475-producing cell line.
The theoretical molecular weight of the polypeptide is 146,288 Da and its theoretical pI is 7.5. 
Pembrolizumab exhibits linear pharmacokinetics at dose levels of clinical relevance (1-10 
mg/kg). It exhibits low clearance and limited volume of distribution that is typical for therapeutic 
antibodies. Mean estimated t1/2 values are 14.1-21.6 days.
The nomenclature of pembrolizumab is provided in the table below:

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Code Name 
MK 3475 (Anti-PD-1)
Other Code Name 
SCH 900475 (Anti-PD-1)
Chemical Name 
Humanized X PD-1_mAb (H409A11) IgG4
CAS Number
1374853-91-4
CAS Name
Anti-(human protein PDCD1 (programmed cell death 1))
immunoglobulin G4 (human-Mus musculus monoclonal heavy
chain) disulfide with human-Mus musculus monoclonal light
chain, dimer
Generic Name
Not available
Commercial Name
Pembrolizumab
8.3 Form
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations.
Pembrolizumab is supplied as a clear to opalescent solution that is essentially free of extraneous 
particles and may contain proteinaceous particulates. One dosage form of pembrolizumab will be 
provided by Merck in Type I glass vials intended for single use only as summarized in the 
following table:
Product Name & Potency
Dosage Form
Pembrolizumab 100 mg/ 4mL
Solution for Injection
Pembrolizumab solution for infusion is a sterile, non-pyrogenic, aqueous, preservative-free 
solution. Pembrolizumab solution for infusion contains an excess fill of 6.25 mg (equivalent to 
0.25 mL solution) to ensure the recovery of label claim of 100 mg pembrolizumab per vial 
(equivalent to 4.0 mL of solution).
8.4 Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
8.5 Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Overall PI and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
8.6 Storage, Handling and Preparation Requirements
As specified in the Pharmacy Manual for pembrolizumab as provided by the Merck. 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  

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Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
8.7 Administration
Pembrolizumab will be administered as a 30 minute IV infusion using an infusion pump 
(treatment cycle intervals may be increased due to toxicity as described in Section 6). Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). Attach the infusion 
line to the pump and prime the line, either with normal saline (at least 25 mL) or with infusion 
solution as per local SOP, before starting the infusion. Maximum infusion rate should not exceed 
6.7 ml/min through a peripheral or indwelling catheter. Use 30 mL normal saline to flush the 
infusion line at the end of the infusion if institutional guidelines allow. For more details, please 
see pharmacology manual.
Unused infusion solution should not be used for another infusion of the same participant or 
different participant.
DO NOT administer the product as an intravenous push or bolus.
DO NOT combine, dilute or administer it as an infusion with other medicinal products.
A central line is not required for Pembrolizumab administration, but may be used if available.
The following infusion set materials are compatible with Pembrolizumab

PVC infusion set that is plasticized using Di-2-ethylhexyl Terephthalate 
DEHP 

PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 

Polyethylene lined PVC infusion set 

Polyrethane 

Plybutadiene  A sterile, non-pyrogenic, low-protein binding 0.2 to 5 μm in-line 
filter made of polyethersulfone (PES) or polysulfone must be used during 
administration to remove any adventitious particles. If the infusion set does 
not contain a 0.2 to 5 μm in-line filter, it is recommended to use a 0.2 to 5 μm 
add-on filter which may contain an extension line (the materials of the 
extension line and filter should be as mentioned above). 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 μm in-line filter made of polyethersulfone 

DF/HCC Protocol #:  17-296
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39
(PES) or polysulfone must be used during administration to remove any adventitious particles. If 
the infusion set does not contain a 0.2 to 5 μm in-line filter, it is recommended to use a 0.2 to 5 
μm add-on filter which may contain an extension line (the materials of the extension line and 
filter should be as mentioned above).
8.8 Ordering
Participating Institutions will order their own investigational agent (Pembrolizumab) directly 
from Merck using the Drug Supply Request Form. Please allow for 3 weeks for drug to arrive 
after the order is submitted. The Participating Institution will ensure that the pharmacy will be 
able to receive and store the agent according to state and federal guidelines. The local IRB 
should be kept informed of who will supply the agent (i.e., Merck pharmaceuticals Inc.) so that 
any regulatory responsibilities can be met in a timely fashion.
8.9 Accountability
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
8.10 Destruction and Return
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept.

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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
9.1 Exploratory Laboratory Correlative Studies 
As outlined above in section 2.4, we will characterize pre-treatment samples and any post-
treatment samples that are resected and available using whole exome sequencing (WES), RNA-
sequencing, immunohistochemistry for immune cell markers and in situ hybridization for PD-1 
and PD-L1 mRNA.
9.2 Background
Comprehensive genomic characterization of samples collected as part of our proposed clinical 
trial will allow us to identify biomarkers of response and provide insight into mechanisms of 
resistance to immunotherapy. Pre-treatment formalin fixed paraffin embedded (FFPE) tissue 
samples will be collected within 30 days after enrollment and post-treatment FFPE samples will 
be collected in patients that progress on treatment if surgery is clinically warranted and if the 
sample tissue is available. Analytic tools for WES have been developed for our prior studies14,21-
23 and will be used to elucidate the genomic evolutionary profiles in matched tumor samples 20.  
As previously described in our work showing that meningioma cells express PD-L1, we will 
characterize PD-L1 expression, tumor infiltrating lymphocytes and PD-1 expressing 
lymphocytes. 
9.3 Methodology 
9.3.1 RNAscope assay and evaluation 
FFPE sections will be hybridized separately with Probe-Hs-PDL1-v2 and a PD-1 specific probe 
and then visualized. Probe-DapB and Probe-Hs-PPIB will be used as negative and positive 
controls respectively. Stained slides will be digitally scanned, then visually evaluated by two 
pathologists.  We will use an open-source CellProfiler image analysis software 
(http://www.cellprofiler.org/) to analyze the number of dots per cell using a customized analysis 
pipeline 
that 
we 
have 
developed, 
optimized 
and 
tested. 
(http://www.cellprofiler.org/published_pipelines.shtml). 
9.3.2 Immunohistochemistry and evaluation 
The following primary antibodies will be used to characterize the tissue pre and post-treatment 
FFPE tissue sections from this study: LCA (1:600 dilution, Cat# M0701; Dako, CA), CD3 
(1:250 dilution, Cat# A0452; Dako, CA), CD4 (1:80 dilution, Cat# M7310; Dako, CA), CD8 
(1:100 dilution, Cat# M7103; Dako, CA), CD20 (Ready to Use, Cat# N1502 RTU; Dako, CA), 
FOXP3 (1:50 dilution, Cat# 320102; Biolegend, CA), PD-1 (1:300 dilution, Cat# 315M-95; Cell 
Marque, CA), PD-L1 (1:36 dilution, Cat# 10084-R015; Sinobiological, China), PD-L1 (1:125 
dilution, Cat# 405.9A11; courtesy of Gordan Freeman lab DFCI).  We will use an Aperio 
scanner to acquire digital images from all stained slides. Digital images will be scored using 
Aperio ImageScope software. 

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Furthermore, PD-L1 expression will be measured from any remaining archival tissue and 
correlated with response. PD-L1 expression will be measured by the QualTek assay as well as 
with RNA-Seq as specified below in 9.3.3. 
9.3.3 RNA-sequencing 
RNA Sequencing from FFPE includes plating, poly-A selection and cDNA synthesis, library 
preparation, sequencing, sample identification QC, and data storage. RNA will be extracted from 
tissue sections and RNA libraries will be prepared for sequencing by NEBNext Ultra RNA 
Library Prep Kit for Illumina (New England BioLabs, Ipswich, MA), including the removal of 
large and small RNA, synthesis of cDNA, and construction of cDNA libraries. Libraries will be 
barcoded using NEBNext Multiplex Oligos for Illumina (NEB). Libraries will be sequenced 
using Illumina HiSeq 2500, with paired-end 100bp reads. We will follow the analytic pipelines 
as previously described24-27. Paired-end reads will be aligned to UCSC human transcriptome 19 
(hg19) using TopHat (Bowtie v2.0.9). Alignment quality and read distribute will be assessed via 
SAMtools (v0.1.19). Transcript assembly will be conducted using cufflinks (v2.2.1). Normalized 
expression data will be generated from aligned BAM files using cuffnorm and cuffdiff.  
Statistically significant genes differentially expressed between responder samples and non-
responders will be determined.  
9.3.4 Whole exome sequencing
Whole-exome sequencing will be performed on DNA isolated from unstained FFPE tissue 
sections and matched DNA from blood.  Sequencing will be performed to a mean depth of 100X, 
and analysis proceeded as previously described 14,19,20,28. Raw sequencing data will be processed 
using the Picard tools pipeline and the Genome Analysis Toolkit (GATK). Mutation analysis for 
single nucleotide variants (SNV) will be performed using MuTect v1.1.4, indel calling 
performed using the GATK SomaticIndelDetector tool; SNVs and indels annotated using 
Oncotator. To analyze somatic copy number alterations from whole exome data, we use the 
ReCapSeg algorithm, which assesses homologue-specific copy ratios (HSCRs) from segmental 
estimates of multipoint allelic copy-ratios at heterozygous loci incorporating the statistical 
phasing software (BEAGLE) and population haplotype panels (HAPMAP3).  Phlyogenetic 
analysis will be performed as previously described 20.  Targeted sequencing of panels of genes 
will be performed in a select subset of cases as previously described 29.
9.3.5 MRI Studies
All MRIs including baseline and any follow-up time points during the study duration should be 
sent to Dr. Elizabeth Gerstner. These studies can be batched but should be sent at least every 3 
months. The MRI can be sent in the mail via CD/DVD to Dr. Elizabeth Gerstner at the address 
below 
or 
electronically 
transferred 
via 
Partners 
Secure 
File 
Transfer 
at: 
https://transfer.partners.org/courier/web/1000@/wmLogin.html
 
For CD/DVD shipping, please label DVD with patient ID and time point. Send to:
Elizabeth Gerstner, MD

DF/HCC Protocol #:  17-296
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42
Yawkey 9E
55 Fruit Street
Boston, MA
02114
9.3.5.3 
Statistical Considerations
Exploratory analyses will be conducted. As data permit, analyses of the MRI 
parameters will be summarized by descriptive statistics, including mean, median 
and standard deviation. Differences in these parameters between responders and 
non-responders will be compared with parametric or nonparametric techniques as 
permitted by the data. For correlative analyses, Cox proportional hazards model 
will be used to explore the relationship between parameters measured at baseline 
and PFS and OS. Logistic regression will be used to explore the relationship 
between parameters measured at baseline and the binary outcome of alive and 
progression-free at 6 months (APF6).
Overall, the plan is to determine whether the baseline measurements are 
prognostic for the entire group. We will determine whether there is an association 
between the baseline measurements and response adjusting for the patient cohort. 
A priori we do not think that the association between the baseline measurements 
and response will depend on the type of mutation and treatment. However, if the 
association between baseline measurements and response are not found to be 
statistically significantly associated, we will do subgroup analyses to determine if 
there might be differences in the association between baseline variables and 
response among the groups. Specifically, we will do perform the analysis for each 
group separately. We will also do tests for interaction between the cohort group 
and the baseline variable, though these will likely not have sufficient power due to 
the small sample sizes.
The overall plan for determining whether a change in the parameters from 
baseline is associated with response is to first evaluate the association with the 
change between baseline and first MRI time point (6 weeks into therapy). An 
additional analysis will be done that uses all the available MRI assessment time 
points. To account for multiple MRI time points, we will treat the change in MRI 
from baseline as a time-dependent variable (which could change at each 
assessment).
9.4 Collection and Shipping of Tissue Specimen(s)

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Collection, Processing and Handling of Archived Specimens: For each resection, all H&E slides 
shall be made available.  In addition 1 FFPE block shall be forwarded to the address within 30 
days after patient enrollment. If an institution is unable to provide a tissue block, 20 unstained 
slides five-micron sections mounted on charged glass slides will be required. Slides will need to 
be cut with a new blade and using a fresh water bath to avoid contamination. Label the slides 
with patient ID number, accession number, and order of sections (include thickness of section if 
applicable). Do not bake or place covers slips on the slide.
Shipping of Tissue Specimen(s): Shipment on Monday through Thursday by overnight service to 
assure receipt is encouraged. Do not ship specimens on Fridays or Saturdays.
Nicole Morris 
Massachusetts General Hospital Cancer Center Protocol Office 
326 Cambridge Street, Floor 3
Boston, MA 02114
9.5 Collection and Shipping of Blood Specimen(s)
Shipping of Blood Specimen(s): Collect two 10 mL of venous blood at pre-
registration and then two 10 mL every 6 weeks in lavender top (EDTA anticoagulant) 
vacutainer tube(s). The tubes should be inverted approximately 8-10 times to mix the 
EDTA. Refrigerate (please do not freeze) sample until shipping. The sample should 
be placed in a biohazard bag and shipped according to IATA guidelines within 2-3 
hours of the blood being drawn on a cold pack (please do not use dry ice). For DFCI 
samples, call the MGH operator at 617-726-2000, ask to page 2-3389 and 2-1928, and 
leave a brief message indicating that the sample has been shipped. For any questions 
regarding samples, please contact Nathaniel Goss and/or Brian Shaw.
When samples are shipped and for any concerns regarding shipments, please
page Nathaniel Goss at 2-3389.
Brastianos Lab
Nathaniel Goss
Simches Research Center
185 Cambridge Street
Boston, MA 02114
10. STUDY CALENDAR
Scans and x-rays must be done <3 weeks prior to the start of therapy.  All eligibility labs are to 
be drawn within 14 days of day 1 (as stated in section 3.1.9). Assessments must be performed 
prior to administration of any study agent. Study assessments and agents should be administered 
within + 3 days of the protocol-specified date, unless otherwise noted.

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Trial Period:
Screening 
Phasea
Treatment Cycles (21 day cycles)b,c
End of 
Treatmentd
Post-Treatment
To be repeated beyond 
8 cyclesv
Treatment 
Cycle/Title:
Study 
Screening 
(Visit 1)
1
2 
3
4
5
6
7
8
Discon
Safety 
Follow-upe
Active 
Followupf
Longterm 
Followupg
Scheduling Window 
(Days):
-14 to 0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
discon
Every 6 
weeks 
Every 3 
months
Administrative Procedures
Informed Consenth
X
Inclusion/Exclusion 
Criteriai
X
Demographics and 
Medical Historyj
X
Prior and 
Concomitant 
Medication Reviewk
X
Pembrolizumab 
Administration
X
X
X
X
X
X
X
X
Post-study anticancer 
therapy statusf
X
X
X
X
Survival Statusg
X
X
Clinical Procedures/Assessments
Review Adverse 
Eventsl
X
X
X
X
X
X
X
X
X
X
X
Full Physical 
Examinationm
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and 
Weightn
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Statuso
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Pregnancy Test – 
Urine or Serum -
HCGp
X
PT/INR and aPTTq
X
X
CBC with 
Differentialr
X
X
X
X
X
X
X
X
X
X
Comprehensive 
Serum Chemistry 
Panels
X
X
X
X
X
X
X
X
X
X
TSHt
X
X
X
X
X
X
X
Efficacy Measurements
Tumor Imagingu
X
X
X
X
X
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Archival Tissuew
X

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Trial Period:
Screening 
Phasea
Treatment Cycles (21 day cycles)b,c
End of 
Treatmentd
Post-Treatment
To be repeated beyond 
8 cyclesv
Treatment 
Cycle/Title:
Study 
Screening 
(Visit 1)
1
2 
3
4
5
6
7
8
Discon
Safety 
Follow-upe
Active 
Followupf
Longterm 
Followupg
Scheduling Window 
(Days):
-14 to 0
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
discon
Every 6 
weeks 
Every 3 
months
Research Bloodx
X
X
X
X
X
X
aAll screening procedures to be performed within 14 days of start of study treatment, except scans which can be obtained within 21 days of starting 
study treatment, and informed consent may occur up to 28 days prior to start of study treatment
bC1D1 and Day 1 of subsequent cycles: For C1D1 screening assessments may serve as day 1 assessments if performed within 7 days before start of 
study treatment, except serum pregnancy (within 72 hours of drug) and except in the event that there are any indications that the participant’s 
condition is deteriorating for which laboratory evaluations should be repeated within 48 hours prior to initiation. C1D1 labs must meet eligibility 
criteria. For all subsequent cycles, required assessments should be performed within 3 days of scheduled cycle day 1.
cStudy drug therapy administration windows include + 3 days for each agent.
dEnd of Tx: End of treatment assessments to be performed within 7 days after last day drug administration or within 7 days after decision to end 
treatment. Assessments may continue for ongoing reportable adverse events.
e30-Day Post Drug: A contact/visit is to be performed at 30 days (+/-5 days) after the last study drug is given. This may be performed via 
documented phone conversation with a study nurse or clinician or a clinic visit. All participants will be followed until resolution or stabilization of 
any serious or reportable adverse events occurring during treatment or starting within 30 days of last study drug.
fActive Follow Up: In participants who discontinue study treatment without documented disease progression, every effort should be made to 
continue monitoring their disease status by radiologic imaging every 6 weeks (+/- 7 days) until (1) the start of new anti-cancer treatment, (2) 
documented disease progression, or (3) death whichever occurs first.
gLong Term Follow Up: participants will be followed every 3 months (+/- 1 month) via contact or medical record review until death for post-
treatment therapies, reason for stopping those therapies and survival.
hInformed Consent: Informed Consent may be obtained within 28 days of start of study treatment
iInclusion/Exclusion Criteria: source documentation providing investigator’s confirmation that the participant had met all eligibility criteria must be 
available prior to registration.
jDemographics and Medical History: to include review of treatment history for cancer, any ongoing medical conditions and medical history 
pertaining to eligibility on study and involvement during study.
kConcomitant medications and reason for administration should be documented in the case history from within 28 days before starting study 
treatment up to the 30-Day Post Drug Visit.
lAdverse event assessment: adverse events experienced by participants will be collected and recorded from the first dose of study treatment up to 
the 30-Day Post Drug Visit of the last dose of study medication (+/- 5 days depending on when 30-Day Post Drug visit/contact occurs) and all 
SAEs (related and unrelated to trial treatment) / ECIs up to 90 days after the last dose of trial
mFull Physical Exam (including neurologic exam): to be completed by the investigator or qualified designee at screening, C1D1 and start of all 
subsequent cycles.
nVital signs: weight, heart rate, blood pressure, respiration rate, temperature. Vital signs must be performed prior to administration of treatment on 
treatment days. Height required only at screening.
oPerformance Status: See Appendix A for ECOG scale.
pPregnancy Test: For women of child bearing potential, a urine pregnancy test should be performed within 72 hours of first dose of study treatment. 
If urine pregnancy results are positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
qCoagulation – PT/INR, PTT required at screening only.
rHematology: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils/ANC, lymphocytes, monocytes, 
eosinophils, basophils).
sSerum Chemistry: albumin, alkaline phosphatase (ALP), bicarbonate (HCO3 ), BUN, calcium, chloride, creatinine, glucose, lactate dehydrogenase 
(LDH) magnesium, phosphorous, potassium, SGOT (AST), SGPT (ALT), sodium, total protein, total bilirubin (if total bilirubin is greater than the 
upper limit of normal, direct should be performed), and uric acid.
tTSH will be performed at baseline, week 1, beginning of cycle 2 and then every 2 cycles. TSH results do not need to be back prior to dosing
uBrain MRI will be performed every 2 cycles. In the rare circumstance where patients have extracranial metastases, chest/abd/pelvis CT will also 
be obtained every 2 cycles. If pembrolizumab is held or interrupted, the scan schedule should be maintained at every 2 cycles.
vAs per section 5.12, completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication, whichever is 
later
wTissue collected as part of clinical care (e.g. from prior biopsy, craniotomy) will be collected.  Tissue needs to be submitted within 30 days after 
patient enrollment. See Section 9 for specimen collection requirements
xBlood will be collected at screening every 2 cycles (two 10 mL EDTA/lavender top tube) and at the end of treatment

DF/HCC Protocol #:  17-296
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11. MEASUREMENT OF EFFECT
11.1
Antitumor Effect – Intracranial Disease
For the purposes of this study, participants should be re-evaluated for intracranial response every 
6 weeks.  In addition to a baseline scan, confirmatory scans should also be obtained at 6 weeks 
following initial documentation of objective response. Response and progression will be 
evaluated in this study using the modified RANO Response Criteria.
11.2
Definitions
Evaluable for objective response.  Only those participants who have measurable CNS 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable non-measurable evaluable disease.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.2.1 Disease Parameters
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥10 mm with 
MRI.  All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters).
For multifocal intracranial disease, no more than 5 target measurable lesions (each 
≥10mm in diameter in both dimensions) should be selected for measurement. Target 
lesions should be selected on the basis of their size (lesions with longest diameter), be 
representative of other lesions and lend themselves to reproducible repeated 
measurements.
Non-measurable disease.  Unidimensionally measurable lesions, masses with 
margins not clearly defined, lesions with maximal diameter < 1cm.
11.2.2 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 

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possible to the beginning of treatment and never more than 3 weeks before the beginning 
of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
11.3
Response Criteria
11.3.1.1
Evaluation of Intracranial Lesions
Complete Response (CR):  Requires all of the following: 

complete disappearance of all enhancing measurable and nonmeasurable 
disease sustained for at least 4 weeks

no new lesions

stable or decreasing corticosteroids (the steroid dose at the time of the scan 
evaluation should be no greater than the dose at time of baseline scan)

stable or improved clinically
Participants with non-measurable disease cannot have a complete response. The best 
possible response is stable disease.
Partial Response (PR):  All of the following criteria must be met:

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 at least 4 weeks. In the absence of a confirming scan 4 weeks 
later, this scan will be considered only stable disease. 

no progression of non-measurable disease.

no new lesions

stable or reduced corticosteroid dose (the steroid dose at the time of the scan 
evaluation should be no greater than the dose at time of baseline scan)

stable or improved clinically
Progressive Disease (PD): At least one of the following must be true: 

>25% increase in the sum of products of all measurable lesions over smallest 
sum observed (over baseline if no decrease) using the same techniques as 
baseline 

clear worsening of any nonmeasurable disease*

appearance of any new enhancing lesion/site

clear clinical worsening (unless clearly unrelated to this cancer, e.g. seizures, 
medication side effects, complications of therapy, cerebrovascular events, 
infecion)

failure to return for evaluation due to death or deteriorating condition
* Progression of non-measurable CNS lesions is defined as follows: 

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
a lesion initially at baseline ≤ 5mm in diameter that increases to ≥ 10mm in 
diameter, or

a lesion initially at baseline 6-9 mm in diameter that increases by at least 5 
mm in diameter.

a lesion that is smaller than 10mm that is too complex or has poorly defined 
margins, that is now unequivocally progressing by more than 25% 
Stable Disease (SD):  All of the following criteria must be met:

Does not qualify for CR, PR or progression

All measurable and non-measurable sites must be assessed using the same 
techniques as baseline

Stable clinically. 
A summary of the response criteria is in the below:
 
Complete 
Response
Partial 
Response 
Stable Disease
Progressive 
Disease
T1-Gd+
None
> 
50% 
decrease
<50% 
decrease-
<25% increase
>25% 
increase*
New Lesion
None
None
None
Present*
Corticosteroids
Stable 
or 
decrease
Stable 
or 
decrease
Stable 
or 
decrease
Stable 
or 
increasing
Clinical Status
Stable 
or 
improved
Stable 
or 
improved
Stable 
or 
improved
Decrease*
Requirement for 
Response
All
All
All
Any*
NA=not applicable
#: Progression occurs when any of the criteria with * is present
Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioriation
11.3.1.2
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. If a response recorded at one scheduled MRI does not persist at 
the next regular scheduled MRI, the response will still be recorded based on the prior 
scan, but will be designated as a non-sustained response. If the response is sustained, 
i.e. still present on the subsequent MRI at least four weeks later, it will be recorded as 
a sustained response, lasting until the time of tumor progression. Participants without 

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measurable disease may only achieve SD or PD as their best “response.”
11.3.2 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
11.3.3 Study Continuation Beyond Initial Progressive Disease
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses which may manifest as initial 
worsening of enhancement and edema on MRI or CT scans (i.e. pseudo-progression). In 
addition, the response patterns seen with immunotherapeutics may extend beyond the 
typical time course of responses seen with cytotoxic agents, and can manifest a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions. 
For these reasons, the immune- related response criteria (irRC) have endorsed 
continuation of study therapy beyond initial radiographic evidence of progression for 
clinically stable patients undergoing immune based therapies.
Therefore, the following adaptations will be used to assess response for patients treated 
on this study:
Potential Pseudo-progression: If radiologic imaging shows initial PD, subjects who are 
not experiencing significant clinical decline, may be allowed to continue study treatment 
for up to three months. Patients who have radiographic evidence of progression after up 
to three months (as defined by progression as in 11.3.1.1), or who decline significantly at 
anytime, will be classified as progressive with the date of disease progression back-dated 
to the first date that the subject met criteria for progression and such subjects will be 
discontinued from study therapy. Three months is the most common timeframe for 
pseudo-progression observed among patients with advanced melanoma or other solid 
tumors treated with PD-1/PD-L1 immune checkpoint blockade40. 
Among patients on this study with initial radiographic PD, tumor assessment should be 

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repeated regularly in order to confirm PD with the option of continuing treatment as 
described below while awaiting radiologic confirmation of progression. If repeat imaging 
shows a stabilization or reduction in the tumor burden compared to the initial scan 
demonstrating PD, treatment may be continued / resumed. If repeat imaging after up to 
three months confirms progressive disease, then the date of disease progression will be 
the first date the subject met criteria for progression and subjects will be discontinued 
from study therapy. Subjects who have confirmed disease progression will discontinue 
study medication and enter the follow up/survival phase of the study. In determining 
whether or not the tumor burden has increased or decreased, investigators should 
consider all target lesions as well as non-target lesions.
Tumor Enhancement to Define Progression: RANO expanded the previously utilized 
Macdonald criteria41 to include the development of “significantly” increased T2 or 
FLAIR abnormality in the definition of progressive disease because such changes can be 
a major component defining radiographic progression following therapeutic use of 
VEGF/VEGFR-targeting therapeutics which are known to elicit potent anti-permeability 
changes that limit contrast uptake. However, immune based therapies are expected to be 
associated with inflammatory changes that may include edema. Therefore, our study will 
define radiographic progressive disease by assessment of enhancing tumor burden only 
and will not include assessment of T2 or FLAIR changes as outlined in RANO because:

There is no expectation that immunotherapy agents including PD-1 inhibitors will 
falsely diminish enhancing tumor burden as has been noted with anti-angiogenic 
 therapies; and 

Immune based therapies are expected to induce inflammatory responses which 
may  be associated with increased edema and T2/FLAIR changes. Such 
radiographic finding may inaccurately be interpreted to represent tumor 
progression (i.e. pseudoprogression). 
Treatment beyond evidence of radiographic PD: In subjects who have initial evidence 
of radiographic PD, it is at the discretion of the treating physician whether to continue a 
subject on study treatment for up to three months pending confirmation of PD on follow-
up imaging. This clinical judgment decision should be based on the subject’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data. 
Subjects may receive study treatment while waiting for confirmation of PD if they are not 
experiencing significant clinical decline and if:

The subject is believed to demonstrate clinical benefit from the study regimen as 
determined by the treating physician;

The subject is adequately tolerating study therapy.
When feasible, study therapy should not be discontinued until radiographic progression is 
confirmed. This allowance to continue treatment despite initial radiologic progression 
takes into account the observation that some subjects can have a transient tumor flare in 
the first few months after the start of immunotherapy, but with subsequent disease 
response42. Subjects that are exhibiting significant neurologic decline are not required to 

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have repeat imaging for confirmation of progressive disease.
Participants with progressive radiographic findings are encouraged to undergo surgical 
intervention in order to delineate pseudo-progression due to inflammation associated with 
PD-1 blockade from true tumor progression. Participants with histopathologic findings of 
significant immune infiltrate and evolving gliosis will be allowed to continue study 
therapy. In contrast, those with clear evidence of progressive tumor by histopathologic 
evaluation will be defined as progressive and discontinued from study therapy. For such 
patients, the date of tumor progression will be the first date the participant met 
radiographic criteria for PD.
11.3.4 Response Review
All brain MRI scans will be reviewed centrally by the DF/HCC Tumor Imaging Metrics 
Core (TIMC). CNS response will be assessed centrally using the criteria outlined in 
Section 11.0.
11.4
Antitumor Effect – Extracranial lesion assessments
For patients that have metastatic meningioma, participants should be re-evaluated for 
extracranial response every 6 weeks.  In addition to a baseline scan, confirmatory scans should 
also be obtained 6 weeks following initial documentation of objective response.
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria.
11.4.1 Definitions
Evaluable for Target Disease response.  Only those participants who have measurable 
disease present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for target disease response.  These 
participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 
will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at 
baseline that are evaluable but do not meet the definitions of measurable disease, have 
received at least one cycle of therapy, and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions. 
11.4.2 Disease Parameters

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Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter  to be recorded) as ≥ 20 mm by 
chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed.
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered 
non-measurable.
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow up. 

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11.4.3 Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 3 weeks before the beginning 
of the treatment.
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung; however, CT is preferable. 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT thickness is 5mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size of a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible.
11.4.4 Response Criteria
11.4.4.1
Evaluation of Target Lesions
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm.

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Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.
11.4.4.2 Evaluation of Non-Target Lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator).
11.4.4.3 Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered.

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11.4.4.4
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria.
For Participants with Measurable Disease (i.e., Target Disease)
Target 
Lesions
Non-Target 
Lesions
New 
Lesions
Overall 
Response
Best Overall Response when 
Confirmation is Required*
CR
CR
No
CR
>4 wks Confirmation**
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation**
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline**
PD
Any
Yes or No
PD
Any
PD***
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        Only for non-randomized trials with response as primary endpoint.
***      In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
For Participants with Non-Measurable Disease (i.e., Non-Target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD

‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 

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increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised
11.4.5 Duration of Response
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation.
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements. 
11.4.6 Progression-Free Survival
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive.
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation.
Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported.
11.4.7 Response Review
All non-CNS scans will be reviewed centrally by the DF/HCC Tumor Imaging Metrics 
Core (TIMC).

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12. END OF TREATMENT/INTERVENTION
12.1 Duration of Treatment
12.1.1 CR, PR, or SD
Patients who are in CR, PR or SD will continue on therapy until progression of disease, 
excessive toxicity requiring the patient to come off of treatment, or the patient withdraws from 
treatment. After treatment is discontinued, patients will be followed per the study calendar in 
section 10.0.
12.1.2 Disease Progression
Remove from protocol therapy any patient with disease progression. Document details, including 
tumor measurements, on data forms.
After disease progression, patients should be followed for survival per the study calendar 
(Section 10.0).
12.1.3 Discontinuation of study agent 
If the patient discontinues study agent, patients should be followed for disease progression and 
survival per the study calendar (Section 10.0).
12.2 Definitions and Follow-up Requirements
Definition of ineligible patients: A study participant who is registered to the trial but does not 
meet all of the eligibility criteria is deemed to be ineligible. Patients who are deemed ineligible 
may continue protocol treatment, provided the treating physician, study chair, and executive 
officer agree there are no safety concerns if the patient were to continue protocol treatment. 
Notification of the local IRB may be necessary per local IRB policies.
Definition of clinical follow-up: The follow-up period where the study participant is no longer 
receiving treatment, but is still following the study calendar for tests, exams, and correlative 
endpoints (e.g., specimen collection, quality of life, disease assessments as required by the 
study).
Definition of survival only follow-up: The follow-up period where the study participant is 
monitored for long-term endpoints, is no longer receiving study treatment, and is not required to 
follow the study calendar for tests, exams, and correlative endpoints (e.g. specimen collection, 
quality of life, disease assessments as required by the study). In this follow-up period, there is a 
schedule in which case report forms should be submitted, but the physician visits are based on 
the standard of care. 
12.2.1 Follow-up for Ineligible Patients
Study participants who are registered to the trial but deemed ineligible must complete follow-up 
requirements as specified below. 
Baseline, on-study and off-treatment notice data submission required.
12.2.2 Follow-up for Patients Never Receiving Protocol Intervention

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Study participants who are registered to the trial but who never go on to receive study 
intervention must still complete follow-up requirements as specified below. 
Baseline, on-study and off-treatment notice data submission required.
12.3 Extraordinary Medical Circumstances
If, at any time the constraints of this protocol are detrimental to the patient's health and/or the 
patient no longer wishes to continue protocol therapy, protocol therapy shall be discontinued. In 
this event:
Document the reason(s) for discontinuation of therapy on data forms.
Follow the patient for protocol endpoints as required by the Study Calendar.
13.0 STATISTICAL CONSIDERATIONS
13.1
Study Design
There will be a single phase 2 arm in this study. Patients with recurrent or residual meningioma 
will be eligible for this trial. There is no planned interim analysis. 
13.2
Endpoints
Primary Endpoints:
The primary endpoint is progression-free survival at 6 months (PFS6). PFS6 is defined as not 
having progressive disease or death within six months of the first day of treatment. Contrast-
enhanced cranial magnetic resonance imaging (MRI) will be performed every 6 weeks. Standard 
response criteria will be used (see Section 11.0).
All patients meeting the eligibility criteria that have signed the consent form and have begun 
treatment will be considered evaluable for the analysis of primary endpoint.
Secondary Endpoints:
1. 
Toxicity by CTCAE criteria (grade 3 or higher hematologic toxicity; grade 3 or higher 
neurologic toxicity) 
2. 
Overall survival 
3. 
Intracranial response as defined by RANO criteria
Exploratory Endpoints:
1. Genetic alterations
2. MRI Imaging changes
13.3 Sample Size, Accrual Rate and Study Duration
The total accrual for this phase II trial will be 26 patients in order to achieve 24 evaluable 
patients. The estimated accrual rate will be approximately 1 patients per month for this protocol. 
Twenty-six patients will be accrued within 24-28 months. Based on 6 months of follow-up, the 
total study duration will be 36 months. Both men and women of all races and ethnic groups are 
eligible for this trial. Every effort will be made to include patients from minority populations.

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13.4  Stratification Factors
NA
13.5 Interim Monitoring Plan
NA
13.6 Analysis of Primary Endpoints
The goal will be to enroll 24 patients. The primary endpoint is the rate of 6 month PFS. The trial 
will distinguish between 6 month PFS rates of 26% vs. 52%. The historical control of 6 month 
PFS is based on a recent meta-analysis showing a PFS-6 of 26% in recurrent Grade II/III 
meningiomas43 and other studies in this patient population44-46. If at least 10 patients demonstrate 
6 month PFS, among the 24 evaluable patients, the agent will be considered worthy of further 
study, yielding at least 88% power to detect a true 6 month PFS rate of at least 52%, using an 
exact binomial test with a one-sided significance level of 0.1, against the null hypothesis of 26% 
6-month PFS.
13.7 Analysis of Secondary Endpoints
Safety and Tolerability:  All adverse events recorded during the trial will be summarized for all 
patients having received one or more doses of pembrolizumab. The proportions of patients with 
grade-3 or higher hematologic toxicities or grade-3 or higher neurologic toxicities will be 
presented with 90% exact binomial confidence intervals.  The incidence of events that are new or 
worsening from the time of first dose of treatment will be summarized according to system organ 
class and/or preferred term, severity (based on CTCAE grade), type of adverse event, and 
relation to study treatment. Deaths reportable as SAEs and non-fatal serious adverse events will 
be listed by patient and tabulated by primary system organ class, and type of adverse event. 
Overall Survival: The distributions of overall survival will be summarized using the method of 
Kaplan-Meier. The follow-up of patients who are alive at the time of analysis will be censored at 
the date of last assessment of vital status.  Median OS will be presented and accompanied by 
90% confidence intervals estimated using log(-log(survival)) methodology.  Survival point 
estimates at 3 and 6 months will also be presented with confidence intervals.
Intracranial/Extracranial Response:  Contrast-enhanced cranial magnetic resonance imaging 
(MRI) will be performed every 6 weeks. The proportion of patients with intracranial response 
(CR, PR or SD by RANO) will be presented with a two-sided, 90% exact binomial confidence 
interval. 
13.8 Analysis of Exploratory Endpoints 
Biomarkers of blood and tissue:  Analyses of blood, imaging, and tissue biomarkers will be 
based on descriptive statistics, as appropriate for the biomarker.

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To examine response according to pre-treatment levels of biomarkers, the study sample will be 
divided retrospectively according to the primary endpoint of response or non-response. Pre-
treatment biomarker levels will be summarized descriptively for the two response groups and 
compared using Wilcoxon rank-sum tests for markers measured on a continuous scale, or 
Fisher’s exact tests for those measured on a categorical scale. Where appropriate, visualization of 
the relationship between baseline marker levels and the distributions of PFS or OS will employ 
Kaplan-Meier estimates stratified by biomarker levels. Medians of the time-to-event endpoints 
will be shown with two-sided 90% confidence intervals; the distributions of PFS and OS will be 
compared across biomarker strata using the log-rank test.
Changes in biomarkers between pretreatment and progression or treatment discontinuation will 
be calculated (post-pre) for each patient and summarized descriptively. In addition, the 
correlation of changes in tissue biomarkers with changes in measures of peripheral blood 
markers will be explored graphically, or by appropriate statistical methods based on data 
availability, to assess associations. 
13.9
Reporting and Exclusions
13.9.1 Evaluation of Toxicity
All participants who have received at least one dose of study medication will be 
evaluable for toxicity from the time of their first treatment.
13.9.2  Evaluation of the Primary Efficacy Endpoint
To be included in the assessment of the primary objective, patients need to receive at 
least one cycle.  If systemic progression occurs prior to the 6 week CNS response 
timepoint, patient will still be included in the analysis of primary objective.
14
PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study. 

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REFERENCES
1.
Mahmood A, Qureshi NH, Malik GM. Intracranial meningiomas: analysis of 
recurrence after surgical treatment. Acta Neurochir (Wien) 1994;126:53-8.
2.
Mathiesen T, Lindquist C, Kihlstrom L, Karlsson B. Recurrence of cranial base 
meningiomas. Neurosurgery 1996;39:2-7; discussion 8-9.
3.
Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. Meningioma grading: 
an analysis of histologic parameters. Am J Surg Pathol 1997;21:1455-65.
4.
Willis J, Smith C, Ironside JW, Erridge S, Whittle IR, Everington D. The accuracy of 
meningioma grading: a 10-year retrospective audit. Neuropathol Appl Neurobiol 2005;31:141-9.
5.
Sughrue ME, Sanai N, Shangari G, Parsa AT, Berger MS, McDermott MW. Outcome 
and survival following primary and repeat surgery for World Health Organization Grade III 
meningiomas. J Neurosurg 2010;113:202-9.
6.
Rosenberg LA, Prayson RA, Lee J, et al. Long-term experience with World Health 
Organization grade III (malignant) meningiomas at a single institution. Int J Radiat Oncol Biol 
Phys 2009;74:427-32.
7.
Wen PY, Quant E, Drappatz J, Beroukhim R, Norden AD. Medical therapies for 
meningiomas. J Neurooncol 2010;99:365-78.
8.
Chamberlain MC, Tsao-Wei DD, Groshen S. Salvage chemotherapy with CPT-11 for 
recurrent meningioma. Journal of neuro-oncology 2006;78:271-6.
9.
Chamberlain MC, Johnston SK. Hydroxyurea for recurrent surgery and radiation 
refractory meningioma: a retrospective case series. Journal of neuro-oncology 2011;104:765-71.
10.
Reardon DA, Norden AD, Desjardins A, et al. Phase II study of Gleevec(R) plus 
hydroxyurea (HU) in adults with progressive or recurrent meningioma. J Neurooncol 
2012;106:409-15.
11.
Chamberlain MC. Hydroxyurea for recurrent surgery and radiation refractory high-
grade meningioma. J Neurooncol 2012;107:315-21.
12.
Chamberlain MC, Glantz MJ. Interferon-alpha for recurrent World Health 
Organization grade 1 intracranial meningiomas. Cancer 2008;113:2146-51.
13.
Norden AD, Raizer JJ, Abrey LE, et al. Phase II trials of erlotinib or gefitinib in 
patients with recurrent meningioma. Journal of neuro-oncology 2010;96:211-7.
14.
Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing of 
meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 2013;45:285-9.
15.
Clark VE, Erson-Omay EZ, Serin A, et al. Genomic analysis of non-NF2 
meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 2013;339:1077-80.
16.
Du Z, Abedalthagafi M, Aizer AA, et al. Increased expression of the immune 
modulatory molecule PD-L1 (CD274) in anaplastic meningioma. Oncotarget 2014.
17.
Furtner J, Schopf V, Seystahl K, et al. Kinetics of tumor size and peritumoral brain 
edema before, during, and after systemic therapy in recurrent WHO grade II or III meningioma. 
Neuro-oncology 2015.
18.
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369:122-33.
19.
Brastianos PK, Taylor-Weiner A, Manley PE, et al. Exome sequencing identifies 
BRAF mutations in papillary craniopharyngiomas. Nat Genet 2014;46:161-5.
20.
Brastianos PK, Carter SL, Santagata S, et al. Genomic Characterization of Brain 

DF/HCC Protocol #:  17-296
Protocol Version Date: 01/20/2023
62
Metastases Reveals Branched Evolution and Potential Therapeutic Targets. Cancer Discov 2015.
21.
Brastianos PK, Carter SL, Santagata S, Taylor-Weiner A. Abstract: Genomic 
characterization of 101 brain metastases and paired primary tumors reveals patterns of clonal 
evolution and selection of driver mutations. AACR 2014.
22.
Brastianos PK, Taylor-Weiner A, Manley PE, et al. Exome sequencing identifies 
BRAF mutations in papillary craniopharyngiomas. Nat Genet 2014.
23.
Shankar GM, Taylor-Weiner A, Lelic N, et al. Sporadic hemangioblastomas are 
characterized by cryptic VHL inactivation. Acta neuropathologica communications 2014;2:2.
24.
Dobin A, Davis CA, Schlesinger F, et al. STAR: ultrafast universal RNA-seq aligner. 
Bioinformatics 2013;29:15-21.
25.
Li B, Dewey CN. RSEM: accurate transcript quantification from RNA-Seq data with 
or without a reference genome. BMC bioinformatics 2011;12:323.
26.
DeLuca DS, Levin JZ, Sivachenko A, et al. RNA-SeQC: RNA-seq metrics for quality 
control and process optimization. Bioinformatics 2012;28:1530-2.
27.
Brooks AN, Yang L, Duff MO, et al. Conservation of an RNA regulatory map 
between Drosophila and mammals. Genome research 2011;21:193-202.
28.
Abedalthagafi MS, Bi WL, Merrill PH, et al. ARID1A and TERT promoter mutations 
in dedifferentiated meningioma. Cancer genetics 2015;208:345-50.
29.
Abedalthagafi MS, Merrill PH, Bi WL, et al. Angiomatous meningiomas have a 
distinct genetic profile with multiple chromosomal polysomies including polysomy of 
chromosome 5. Oncotarget 2014;5:10596-606.
30.
Lamszus K LU, Schmidt NO, Stavrou D, Ergun S, Westphal M. Vascular endothelial 
growth factor, hepatocyte growth factor/scatter factor, basic fibroblast growth factor, and 
placenta growth factor in human meningiomas and their relation to angiogenesis and 
malignancy. Neurosurgery 2000;46:938-47 
31.
Zhu XP LK, Kamaly-Asl ID, et al. Quantification of endothelial permeability, 
leakage space, and blood volume in brain tumors using combined T1 and T2* contrast-enhanced 
dynamic MR imaging. J Magn Reson Imaging 2000;11:575-85.
32.
Sorensen AG BT, Zhang WT, et al. A "vascular normalization index" as potential 
mechanistic biomarker to predict survival after a single dose of cediranib in recurrent 
glioblastoma patients. Cancer Res 2009;69:5296-300.
33.
Hawighorst H ER, Knopp MV, et al. Intracranial meningeomas: time- and dose-
dependent effects of irradiation on tumor microcirculation monitored by dynamic MR imaging. 
Magn Reson Imaging 1997;15:423-32.
34.
Ludemann L GW, Wurm R, Wust P, Zimmer C. Quantitative measurement of leakage 
volume and permeability in gliomas, meningiomas and brain metastases with dynamic contrast-
enhanced MRI. Magn Reson Imaging 2005;23:833-41.
35.
Yang S LM, Zagzag D, et al. Dynamic contrast-enhanced perfusion MR imaging 
measurements of endothelial permeability: differentiation between atypical and typical 
meningiomas. AJNR Am J Neuroradiol 2003;24:1554-9.
36.
Batchelor TT SA, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine 
kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. 
Cancer Cell 2007;11:83-95.
37.
Sorensen AG EK, Polaskova P, et al. Increased survival of glioblastoma patients who 
respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 2012;72:402-7.
38.
Gerstner ER CP, Wen PY, Jain RK, Batchelor TT, Sorensen G. Infiltrative patterns of 

DF/HCC Protocol #:  17-296
Protocol Version Date: 01/20/2023
63
glioblastoma spread detected via diffusion MRI after treatment with cediranib. Neuro Oncol 
2010;12:466-72.
39.
Batchelor TT GE, Emblem KE, et al. Improved tumor oxygenation and survival in 
glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. 
Proc Natl Acad Sci U S A 2013;110:19059-64.
40.
Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody 
in patients with advanced cancer. N Engl J Med 2012;366:2455-65.
41.
Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG. Response criteria for 
phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277-80.
42.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 
2009;15:7412-20.
43.
Kaley T, Barani I, Chamberlain M, et al. Historical benchmarks for medical therapy 
trials in surgery- and radiation-refractory meningioma: a RANO review. Neuro Oncol 
2014;16:829-40.
44.
Norden AD, Ligon KL, Hammond SN, et al. Phase II study of monthly pasireotide 
LAR (SOM230C) for recurrent or progressive meningioma. Neurology 2015;84:280-6.
45.
Wen PY, Yung WK, Lamborn KR, et al. Phase II study of imatinib mesylate for 
recurrent meningiomas (North American Brain Tumor Consortium study 01-08). Neuro Oncol 
2009;11:853-60.
46.
Norden AD, Raizer JJ, Abrey LE, et al. Phase II trials of erlotinib or gefitinib in 
patients with recurrent meningioma. J Neurooncol 2010;96:211-7.

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APPENDIX A
PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no evidence 
of disease.
0
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of disease.
80
Normal activity with effort; some 
signs or symptoms of disease.
1
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work).
70
Cares for self, unable to carry on 
normal activity or to do active work.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
2
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours.
50
Requires considerable assistance and 
frequent medical care.
40
Disabled, requires special care and 
assistance.
3
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours.
30
Severely disabled, hospitalization 
indicated.  Death not imminent.
20
Very sick, hospitalization indicated. 
Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, 
fatal 
processes 
progressing rapidly.
5
Dead.
0
Dead.

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APPENDIX B
Event of clinical interest guidance document