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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 1 |
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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 2 SCHEMA  
- Brain MRI every 2 **cycles**  
  
disease Progression
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table of contents

| TABLE OF CONTENTS                                                                                                                                           |                                                                                                                           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------|
| SCHEMA                                                                                                                                                      |                                                                                                                           |
| 1.1                                                                                                                                                         | Study Design                                                                                                              |
| 1.2                                                                                                                                                         | Primary Objective                                                                                                         |
| 1.3                                                                                                                                                         | Secondary Objectives                                                                                                      |
| 1.4                                                                                                                                                         | Exploratory Objectives .                                                                                                  |
| 2.                                                                                                                                                          | BACKGROUND .                                                                                                              |
| 2.1                                                                                                                                                         | Meningioma .                                                                                                              |
| 2.2                                                                                                                                                         | Pembrolizumab (MK-3475)                                                                                                   |
| 2.3                                                                                                                                                         | RATIONALE                                                                                                                 |
| Correlative Studies Background ...............................................................................................9                             |                                                                                                                           |
| 2.4                                                                                                                                                         |                                                                                                                           |
| 3.0                                                                                                                                                         | PARTICIPANT SELECTION                                                                                                     |
| 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                                                                                                                                       |                                                                                                                           |
| 5.2 Pre-Treatment Criteria ............................................................................................................14                   |                                                                                                                           |
| 5.3 Agent Administration                                                                                                                                    |                                                                                                                           |
| 5.4 General Concomitant Medication and Supportive Care Guidelines                                                                                           |                                                                                                                           |
| 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                                                                                                                                                    |                                                                                                                           |
| 5.9 Contraception                                                                                                                                           |                                                                                                                           |
| 5.10 Use in Pregnancy                                                                                                                                       |                                                                                                                           |
| 5.11 Use in Nursing Women                                                                                                                                   |                                                                                                                           |
| 5.12 Criteria for Taking a Participant Off Protocol Therapy ....................................................23                                          |                                                                                                                           |
| 5.13 Duration of Follow Up                                                                                                                                  |                                                                                                                           |
| 5.14 Criteria for Taking a Participant Off Study .......................................................................24                                  |                                                                                                                           |
| 6. DOSING DELAYS/DOSE MODIFICATIONS                                                                                                                         |                                                                                                                           |
| 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                                                              |                                                                                                                           |
| 4                                                                                                                                                           |                                                                                                                           |  
| 7.4 Events of Clinical Interest                                                                                                                           |                            |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|
| 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                                                                                                                     |                            |
| 8. PHARMACEUTICAL INFORMATION                                                                                                                             |                            |
| 8.1 Pembrolizumab                                                                                                                                         |                            |
| 8.2 Description                                                                                                                                           |                            |
| 8.3 Form                                                                                                                                                  |                            |
| 8.4 Packaging and Labeling Information                                                                                                                    |                            |
| 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                                                                                                                                        |                            |
| 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                                                                                                                                      |                            |
| 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          |                            |
| 1. MEASUREMENT OF EFFECT ..................................................................................................................44             |                            |
| End of Treatment/Intervention                                                                                                                             |                            |
| 12                                                                                                                                                        | 12.1 Duration of Treatment |
| 12.1.1 CR, PR, or SD                                                                                                                                      |                            |
| 12.1.2 Disease Progression .                                                                                                                              |                            |
| 12.2 Definitions and Follow-up Requirements                                                                                                               |                            |
| 12.3 Extraordinary Medical Circumstances                                                                                                                  |                            |
| 13.0                                                                                                                                                      | Statistical Considerations |
| 14                                                                                                                                                        | PUBLICATION PLAN .         |
| REFERENCES .                                                                                                                                              |                            |
| PERFORMANCE STATUS CRITERIA                                                                                                                               |                            |
| APPENDIX A                                                                                                                                                |                            |  
6
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objectives 1.1 study design 2.

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
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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.  
2.1 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 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.
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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.  
8 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 Tcell 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, PDL1 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. 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.
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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 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.
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2.4 correlative studies background 2.4.1

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.
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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.
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3.0 participant selection 3.1 eligibility

Histologic Documentation: Histologically proven recurrent or residual intracranial or metastatic meningioma or meningioma with extracranial spread
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progressive or residual disease as

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. 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.
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3.1.4 not pregnant and not

A female of childbearing potential is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.
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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.
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3.1.9 required initial laboratory values

| 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  ≤1.5 X ULN unless subject is receiving  (INR) or Prothrombin Time  anticoagulant therapy13   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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.  
| (PT)                                                                                                                 | 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. Activated Partial  Thromboplastin Time (aPTT) |                                                                                                                                                                                                                                         |  
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.
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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  
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 marrowsuppressive 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.
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3.3 inclusion of women and

Both men and women of all races and ethnic groups are eligible for this trial.
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4. registration procedures 4.1 general

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.
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4.2 registration process for df/hcc

DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol Registration (SOP \#: REGIST-101) must be followed.
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5. treatment plan 5.1 treatment

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   | Route          | of     | Regimen/Treatment   | Cycle Length         |         |
|---------------------------------------------------------|----------------|--------|---------------------|----------------------|---------|
| Frequency                                               | Administration | Period |                     |                      |         |
| Pembrolizumab                                           | 200 mg         | Q3W    | IV infusion         | Day 1 of each 3 week | 3 weeks |
| cycle                                                   |                |        |                     |                      |         |
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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.
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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 16 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.
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5.4 general concomitant medication and

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.
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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 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 (MK3475) 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                                                                                                                          |             |     |         |
| 18                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                               |             |     |         |  
| 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.                                                                                                                   |                                                                     |                 |      |
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5.5 supportive care guidelines for

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. 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.
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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.
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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.
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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):
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.
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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.
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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  
| 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. Immunerelated AEs Toxicity  grade or  conditions  (CTCAEv 4.0) Action taken to  irAE management with  pembrolizumab corticosteroid and/or  other therapies  Monitor and follow-up  Pneumonitis Grade 2 Withhold   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 Diarrhea / Withhold Grade 2 or  Colitis  3  Administer  corticosteroids (initial  dose of 1-2 mg/kg  prednisone or  equivalent) followed by  taper Grade 3 or  4, or  recurrent  Grade 2 Permanently  discontinue  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  Administer  corticosteroids (initial  dose of 1-2 mg/kg  prednisone or  equivalent) followed by  taper Grade 4 Permanently  discontinue AST / ALT  elevation or  Increased  bilirubin  Monitor with liver function  tests (consider weekly or more  frequently until liver enzyme  value returned to baseline or is  stableGrade 3 or  Permanently   Administer  4  discontinue corticosteroids (initial  dose of 1-2 mg/kg  prednisone or  22   |
|---|  
| 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 antihyperglycemic in  participants with  hyperglycemia                                                                                                      |                                                                                                                                          | Monitor participants for  hyperglycemia or other signs  and symptoms of diabetes.      |                                                                                                         |                                    |                                                                              |
| Hypophysiti                                           | Grade 2                                                                                              | Withhold                                                                                                                                  |                                                                                        |                                                                                                         |                                    |                                                                              |
| s                                                     |                                                                                                     | Administer  corticosteroids and  initiate hormonal  replacements as  clinically indicated.                                                |                                                                                       | Monitor for signs and  symptoms of hypophysitis  (including hypopituitarism and  adrenal insufficiency) |                                    |                                                                              |
| Grade 3 or                                            | Withhold or                                                                                          |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| 4                                                     | permanently  discontinue1                                                                            |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| Hyperthyroi                                           | Grade 2                                                                                              | Continue                                                                                                                                  |                                                                                        |                                                                                                         |                                    |                                                                              |
| dism                                                  |                                                                                                     | Treat with non-selective  beta-blockers (eg,  propranolol) or  thionamides as  appropriate                                                |                                                                                       | Monitor for signs and  symptoms of thyroid  disorders.                                                  |                                    |                                                                              |
| Grade 3 or                                            | Withhold or                                                                                          |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| 4                                                     | permanently  discontinue1                                                                            |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| Hypothyroid                                           | Grade 2-4                                                                                            | Continue                                                                                                                                  |                                                                                       | Initiate thyroid                                                                                        |                                    |                                                                              |
| ism                                                   | replacement hormones  (eg, levothyroxine or  liothyroinine) per  standard of care                    |                                                                                                                                          | Monitor for signs and  symptoms of thyroid  disorders.                                 |                                                                                                         |                                    |                                                                              |
| Nephritis                                             | Grade 2                                                                                              | Withhold                                                                                                                                  |                                                                                        |                                                                                                         |                                    |                                                                              |
| and Renal  dysfunction                                | Grade 3 or                                                                                           | Permanently                                                                                                                               |                                                                                        |                                                                                                         |                                    |                                                                              |
| 4                                                     | discontinue                                                                                          |                                                                                                                                          | Administer  corticosteroids  (prednisone 1-2 mg/kg  or equivalent) followed  by taper. |                                                                                                        | Monitor changes of renal  function |                                                                              |
| Myocarditis                                           | Withhold                                                                                             |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| Grade 1 or  2                                         |                                                                                                     | Based on severity of  AE administer  corticosteroids                                                                                      |                                                                                       | Ensure adequate evaluation to  confirm etiology and/or  exclude other causes                            |                                    |                                                                              |
| Grade 3 or                                            | Permanently                                                                                          |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| 4                                                     | discontinue                                                                                          |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| All other                                             | Withhold                                                                                             |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| Intolerable/                                          |                                                                                                      |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |
| immunerelated AEs                                                       | persistent  Grade 2 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 |
| 23                                                    |                                                                                                      |                                                                                                                                           |                                                                                        |                                                                                                         |                                    |                                                                              |  
| 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 |
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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.
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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.  
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.
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5.8 diet

Subjects should maintain a normal diet unless modifications are required to manage an adverse event such as diarrhea, nausea or vomiting.
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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, nonbreast-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). 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.
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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 lifethreatening 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.
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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.
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5.12 criteria for taking a

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) 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-sopsetc/.  
In the event of unusual or life-threatening complications, treating investigators must immediately notify the Overall PI, Priscilla Brastianos at 617-724-6881.
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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 nonstudy 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.
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5.14 criteria for taking a

Participants will be removed from study when any of the following criteria apply:
Lost to follow-up Withdrawal of consent for data submission Death 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.
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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, nonhematological 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 Hold  Toxicity Treatment  Timing for Restarting Treatment Treatment Discontinuation For Grade 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  Diarrhea/Colitis per day within 12 weeks 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 Hold pembrolizumab for new onset Type  1 diabetes mellitus or Grade 3-4  hyperglycemia associated with evidence of  beta cell failure T1DM or  3-4 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 Toxicity does not resolve within 12 weeks of last dose or inability  3 Toxicity resolves to Grade 0-1 to reduce corticosteroid to 10 mg or less of prednisone or equivalent  per day within 12 weeks Hyperthyroidism  4 Permanently discontinue Permanently discontinue Therapy with pembrolizumab can be  Hypothyroidism continued while thyroid replacement  Therapy with pembrolizumab can be continued while thyroid  replacement therapy is instituted therapy is instituted b Toxicity resolves to Grade 0-1 Permanently discontinue if toxicity develops despite adequate  2 premedication  Infusion Reaction 3-4 Permanently discontinue Permanently discontinue Toxicity does not resolve within 12 weeks of last dose or inability  Pneumonitis 2 Toxicity resolves to Grade 0-1 to reduce corticosteroid to 10 mg or less of prednisone or equivalent  per day within 12 weeks   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Hold                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                         |                                                                                             |                                                                                                |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|---------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------|
| Toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Treatment               | Timing for Restarting Treatment                                                             | Treatment Discontinuation                                                                      |
| For Grade 3-4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Permanently discontinue | Permanently discontinue Toxicity does not resolve within 12 weeks of last dose or inability |                                                                                                |
| Renal Failure or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | 2                       | Toxicity resolves to Grade 0-1                                                              | to reduce corticosteroid to 10 mg or less of prednisone or equivalent                          |
| Nephritis                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | per day within 12 weeks |                                                                                             |                                                                                                |
| 3-4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Permanently discontinue | Permanently discontinue Toxicity does not resolve within 12 weeks of last dose or inability |                                                                                                |
| All Other DrugRelated Toxicityc                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | 3 or Severe             | Toxicity resolves to Grade 0-1                                                              | to reduce corticosteroid to 10 mg or less of prednisone or equivalent  per day within 12 weeks |
| 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 |                         |                                                                                             |                                                                                                |  
| 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.
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7. adverse events list and

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 protocolspecified procedure, whether or not considered related to the medicinal product or protocolspecified 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.  
29 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.
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7.1 definition of an overdose

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)
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7.2 reporting of pregnancy and

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)
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7.3 immediate reporting of adverse

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.
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sae reports and any other

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 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.
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events of clinical interest for

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.
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7.5 criteria for taking a

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.
table 6 evaluating adverse events
7.5 criteria for taking a

An investigator who is a qualified physician, will evaluate all adverse events as to:  
| V4.0         | CTCAE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Grade 1   | Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not   |
|--------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|--------------------------------------------------------------------------------------------------|
| Grading      | 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 | Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |           |                                                                                                  |
| to test drug | 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                                                                                                                                                                                                                                                                                |           |                                                                                                  |  
| 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  There is evidence of exposure to the Merck product. The temporal sequence of the AE onset relative to  of Merck product relationship. 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  Subject did not receive the Merck product OR temporal sequence of the AE onset relative to  possibility Merck product relationship 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.) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
table 6 evaluating adverse events
7.6 overall pi responsibility for

All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all applicable global laws and regulations.
table 6 evaluating adverse events
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.
table 6 evaluating adverse events
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 Protocol34 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.
table 6 evaluating adverse events
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.
table 6 evaluating adverse events
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 Gr. 2 & 3 AE Gr. 2 & 3 AE  Gr. 4 AE Expected                                                                                                                                                                                                                                                                      | Gr. 4 AE     | Gr.             | 5                | AE              |           |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|-----------------|------------------|-----------------|-----------|
| Expected                                                                                                                                                                                                                                                                                                                                | Unexpected   | Unexpected      | Expected         | or              |           |
| Attribution                                                                                                                                                                                                                                                                                                                             | Unexpected   |                 |                  |                 |           |
| Unrelated                                                                                                                                                                                                                                                                                                                               | Not required | Not required    | 5 calendar days# | 5 calendar days | 24 hours* |
| Unlikely Possible Probable                                                                                                                                                                                                                                                                                                              | Not required | 5 calendar days | 5 calendar days# | 5 calendar days | 24 hours* |
| Definite # 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.
table 6 evaluating adverse events
7.8.3 expedited reporting to the

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.
table 6 evaluating adverse events
7.8.4 expedited reporting to hospital

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.
table 6 evaluating adverse events
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.
table 6 evaluating adverse events
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:  
| 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                                                                                                                                                                      |
table 6 evaluating adverse events
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).
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8.4 packaging and labeling information

Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
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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.
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8.6 storage handling and preparation

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. 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.
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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 38
(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).
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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.
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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.
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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

As outlined above in section 2.4, we will characterize pre-treatment samples and any posttreatment samples that are resected and available using whole exome sequencing (WES), RNAsequencing, immunohistochemistry for immune cell markers and in situ hybridization for PD-1 and PD-L1 mRNA.
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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 studies14,2123 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.
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9.3 methodology 9.3.1 rnascope assay

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).
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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. 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.
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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 nonresponders will be determined.
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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.
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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 Yawkey 9E 55 Fruit Street Boston, MA
02114
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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).
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9.4 collection and shipping of

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