Clinical trial NCT03016091
Conditions: Atypical Meningioma Anaplastic Meningioma Hemangiopericytoma
Sponsor: Rabin Medical Center
Start date: 2018-01-01; Completion date: 2022-12-01
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase II, Open-label, Single Arm Trial of Pembrolizumab for Refractory Atypical and Anaplastic Meningioma

Detailed description:
This is a multicenter, prospective, single arm, open label, interventional study. The goal of this study, is to evaluate feasibility and efficacy of pembrolizumab for the treatment of recurrent or progressive meningioma (WHO grades II-III) or hemangiopericytoma (HPC). All patients will receive IV pembrolizumab, at a dose of 200mg, every 3 weeks. Patients will be treated until disease progression or intolerable toxicity. Treatment can be stopped after one year of treatment in case of stable disease or completer response, with re-initiation of treatment upon progression. Expression of PD1 and PD-L1 will be tested, on tumor cells, using IHC staining on biopsy material obtained from previous surgeries.

All patients will have a baseline neurologic and clinical exam, MRI scan, a brain dedicated CT-PET scan, a baseline cognitive exam and QOL assessment with a dedicated questionnaire. Patients will have a clinical and neurological exam every treatment cycle. MRI scan will be repeated after 2 months from the beginning of the trial drug administration and then every 2-3 months. There are no designated and specific criteria for response assessment in the treatment of meningioma. Therefore, response evaluation will be made using the RECIST 1.1 criteria, as used for solid tumors. The trial will allow the continuation of pembrolizumab in case of stable or improved clinical response, when pseudo-progression is suspected in the MRI. In addition, response assessment will also be made according to the RANO criteria, as used for high grade glioma. This will be compared to the RECIST evaluation, but will not be used for treatment decision making.

Arms: arm 1: IV Pembrolizumab 200mg, given every 3 weeks until disease progression or intolerable toxicity
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: anti PD-L1

Protocol documents:
Prot_SAP_000.pdf: 
 
Version 3.0 
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SPONSOR: Dr. Shlomit Yust-Katz 
 
TITLE: A Phase II, open-label, single arm trial of Pembrolizumab for Refractory 
Atypical and Anaplastic Meningioma  
 
IND NUMBER: MK-3475-415 
 
EudraCT NUMBER (Studies in Europe only – delete if N/A): 
Protocol version 3.0 - 5 APRIL  2021  


 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab 
for 
Refractory 
Atypical 
and 
Anaplastic 
Meningioma 
Trial Phase 
II 
Clinical Indication 
Atypical Meningioma, Anaplastic Meningioma, hemangiopericytoma 
Trial Type 
Interventional 
Type of control 
No control 
Route of administration 
Intra-Venous (IV) 
Trial Blinding 
Unblinded open-label 
Treatment Groups  
IV Pembrolizumab 200mg, given every 3 weeks until disease 
progression or intolerable toxicity  
Number of trial subjects 
25 
Estimated enrollment period 
2 years 
Estimated duration of trial 
4 years 
Duration of Participation 
2 years 
Estimated average length of 
treatment per patient 
6 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a multicenter, prospective, single arm, open label, interventional study. The goal of 
this study, is to evaluate feasibility and efficacy of pembrolizumab for the treatment of 
recurrent or progressive meningioma (WHO grades II–III) or hemangiopericytoma (HPC). 
All patients will receive IV pembrolizumab, at a dose of 200mg, every 3 weeks. Patients will 
be treated until disease progression or intolerable toxicity. Treatment can be stopped after 
one year of treatment in case of stable disease or completer response, with re-initiation of 
treatment upon progression. Expression of PD1 and PD-L1 will be tested, on tumor cells, 
using IHC staining on biopsy material obtained from previous surgeries.  
All patients will have a baseline neurologic and clinical exam, MRI scan,  a baseline 
cognitive exam and QOL assessment with a dedicated questionnaire. Patients will have a 
clinical and neurological exam every treatment cycle. MRI scan will be repeated after 2 
months from the beginning of the trial drug administration and then every 2-3 months. There 
are no designated and specific criteria for response assessment in the treatment of 
meningioma. Therefore, response evaluation will be made using the RECIST 1.1 criteria, as 
used for solid tumors. The trial will allow the continuation of pembrolizumab in case of 
stable or improved clinical response, when pseudo-progression is suspected in the MRI. In 
addition, response assessment will also be made according to the RANO criteria, as used for 
high grade glioma. This will be compared to the RECIST evaluation, but will not be used for 
treatment decision making.   


 
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QOL questionnaire will be repeated within 14 days of each radiographic response evaluation. 
Patients will be followed for treatment effect on QOL. Trial Diagram 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
Objective: To determine the 6 and 12 months progression free survival (PFS) rate for 
patients with recurrent or progressive meningioma on pembrolizumab therapy, using the 
RECIST 1.1 criteria. 
Hypothesis (H1):  Pembrolizumab is estimated to produce a 6 and 12 months PFS rate 
which will be at least comparable to other drugs that were tested for recurrent or progressive 
meningioma.  
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To determine OS of patients with recurrent or progressive meningioma 
treated with pembrolizumab. 
Hypothesis (H2):  Pembrolizumab is expected to have an influence on patients' OS. 
Study population:
Recurrent or 
progressive 
meningioma (WHO 
grade II-III) or 
hemangiopericytoma 
(HPC) 
Main inclusion 
criteria:
1. Histologically or 
radiologically  proven 
meningioma/ 
hemangiopericytoma
2. Documented 
progression after 
previous line of 
therapy (at least one 
RT line)
2. No limits on prior 
treatment lines
3. Age ≥18 years old
4. KPS≥50%
5. Life expectancy of 
at least 4 months
Treatment:
IV pembrolizumab 
200mg, Q3 weeks, until 
disease progression or 
drug toxicity
Primary endpoint:
6m and 12m 
progression free 
survival (PFS)
Main secondary 
endpoints:
Overall survival (OS), 
PFS, respose rate (ORR), 
toxicity, quality of life 
(QOL)


 
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(2) Objective:  To determine PFS of patients with recurrent or progressive meningioma 
treated with pembrolizumab. 
Hypothesis (H3):  Pembrolizumab is expected to have an influence on patients' PFS. 
(3) Objective:  To determine the ORR according to pembrolizumab therapy in treating 
patients with recurrent or progressive meningioma using the RECIST 1.1 criteria. 
Hypothesis (H4): Pembrolizumab effect on ORR is not entirely predictable due to 
expected immune response. This will be evaluated according to the RECIST 1.1 criteria. 
(4) Objective:  To determine pembrolizumab toxicity and safety in treating patients with 
recurrent or progressive meningioma according to the Common Terminology Criteria for 
Adverse Events (CTCAE) v4.0. 
Hypothesis (H5): Pembrolizumab is expected to have an acceptable toxicity and safety 
profile in this population of patients.  
(5) Objective:  To determine the influence of pembrolizumab on quality of life (QOL) using 
the EORTC QLQ-C30, EORTC QLQ-BN20 and EuroQoLEQ-5D. 
Hypothesis (H6): Pembrolizumab is expected to improve patients QOL. 
(6) Objective: To determine the influence of pembrolizumab on neurocognitive changes.  
Hypothesis (H7): Pembrolizumab is expected to preserve patients' neurocognitive status.  
3.3 
Exploratory Objective 
(1) 
Objective: To evaluate 6 and 12 PFS rate, OS, PFS and ORR according to PD-1 and 
PDL-1 expression status. 
(2) 
Objective: To estimate ORR to pembrolizumab therapy using MRI. 
(3) 
Objective: To estimate ORR to pembrolizumab therapy using different assessment 
methods – RECIST 1.1 criteria vs. RANO criteria.  
(4) 
Objective: To investigate the relationship between pembrolizumab treatment and 
biomarkers predicting response (e.g., PD-L1, genetic variation, serum soluble PD-L1) 
utilizing archival tumor tissue and blood sampling. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 


 
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4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [2]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [3-7]. 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) [8; 
9].  The structure of murine PD-1 has been resolved [10]. 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 [8; 11- 13]. 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 [14; 15]. 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 [16; 17]. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [18].  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 [19-21; 14].  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. PD-L1 is expressed at low levels on various 
non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. PD-L2 is thought to control immune T-cell activation in 
lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral 
tissues [14]. 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. 


 
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Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has recently been approved in the 
United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Meningioma account for 36% of all primary brain tumors and 54% of non-malignant primary 
brain tumors (22). Meningioma incidence in Israel is higher due to the wide use of head 
irradiation about 50-60 years ago for the treatment of tinea capitis (23). Atypical meningioma 
(WHO grade II) and anaplastic meningioma (WHO grade III) incidence is not well reported 
but is estimated to account for less than 10% of all meningioma cases. Yet, these tumors are 
a major therapeutic problem, with mainstay treatment that includes surgery and radiotherapy. 
For refractory or recurrent disease, after previous surgery or radiotherapy, there is no proven 
or standard management. The 6-months progression free survival (PFS) rate for these 
patients is poor. A previous study in recurrent meningioma demonstrated a PFS at 6 months 
of 0% in the atypical and anaplastic cohort (24). 
Previous trials with various systemic agents, like different chemotherapies (temozolomide, 
hydroxyurea, irinotecan, and triple therapy with cyclophosphamide + doxorubicin + 
vincristine), hormonal therapies (progesterone and estrogen modulators, somatostatin 
analogues), interferon alfa-2b, and molecularly targeted therapies, including inhibitors of 
platelet-derived growth factor receptors (PDGFRs; imatinib) and epidermal growth factor 
receptor (geﬁtinib and erlotinib), have all been disappointing (24-40). A recent study, 
examining the use of sunitinib, a multi tyrosine kinase inhibitor, showed more promising 
results than previous trials with a median PFS of 5.2 months, and a median overall survival 
(OS) of 24.6 months (41). 
As mentioned before, pembrolizumab, an anti-programmed cell death (PD) 1 antibody, acts 
to block the PD-1 inhibition on T cells producing an enhanced immune response. It was 
shown to be active in other solid tumors with a positive correlation between PD-1 expression 
and response to treatment with pembrolizumab. The PD-1 ligand (PD-L1) was found to have 
an increased expression in anaplastic meningioma (42). Giving this high expression of PD-
L1 in meningioma, and the good correlation between its presence and tumor response in 
other tumors, it stands as a reason to study the effect of pembrolizumab in refractory 
atypical/anaplastic meningiomas. 


 
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4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was 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. 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. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days). This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 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 


 
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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. 
 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
Primary: Progression free survival is an acceptable measure of clinical benefit for a non-
randomized phase II trial. As mentioned above, most meningioma patients with recurrent or 
refractory disease show tumor progression earlier than 6 months (24). Setting the endpoint 
for 6 and 12 months PFS rate ensures a disease event in many of the patients. In addition, this 
endpoint was chosen for other relevant trials, such as the sunitinib trial, making it easier for 
estimate pembrolizumab effect in comparison to other drugs. 
Secondary: Overall survival and overall PFS will be included as it is a standard assessment 
of clinical benefit in subjects with recurrent or progressive meningioma. ORR is considered 
as a marker for clinical benefit. Reporting response with immunotherapy is still controversial, 
so it will be estimated using MRI scans  
Patients Reported Outcomes: EORTC QLQ-C30, EORTC QLQ-BN20 and Euro QoLEQ-
5D questionnaire will be used for reporting QOL outcomes. Patient related outcomes 
endpoint is crucial in this population of patients with advanced, incurable disease, which 
usually already affects everyday function and QOL. 
4.2.3.2 Safety Endpoints 
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with recurrent or progressive meningioma. The primary safety 
analysis will be based on subjects who experienced toxicities as defined by CTCAE criteria. 
Safety will be assessed by quantifying the toxicities and grades experienced by subjects who 
have received pembrolizumab including serious adverse events (SAEs) and events of clinical 
interest (ECIs). Safety will be assessed by reported adverse experiences using CTCAE, 
Version 4.0. The attribution to drug, time-of-onset, duration of event, its resolution, and any 
concomitant medications administrated will be recorded. AEs will be analyzed including but 
not limited to all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific 
immune-related adverse events (irAEs) will be collected and designated as immune-related 
events of clinical interest (ECIs) as described in section 7.2.3.2. The mandatory Safety 
Follow-Up visit should be conducted approximately 30 days after the last dose of trial 


 
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treatment or before the initiation of a new anti-neoplastic treatment, whichever comes first. 
All AEs that occur prior to Safety Follow-Up Visit should be recorded. Subjects with an AE 
of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs and ECIs that occur 
within 90 days of the end of treatment or before initiation of a new anti-neoplastic treatment 
should also be followed and recorded. 
4.2.3.3 Biomarker Research 
Additional biomarker research to identify factors important for pembrolizumab therapy will 
be pursued. Tumor tissues will undergo RNA sequencing and proteomic, genomic and 
transcriptional analyses (both DNA and RNA analyses). This additional biomarker or 
genomic research maybe conducted to identify factors important for pembrolizumab therapy 
and subject response to therapy (for example, to identify risk factors for adverse events or 
who might best respond to treatment). 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Male and female subjects with recurrent or progressive meningioma or HPC of at least 18 
years of age will be enrolled in this trial. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1.   
4. Histologically, previously proven, grade II or III meningioma, HPC or classic 
radiographic features of a recurrent surgically inaccessible atypical or anaplastic 
meningioma and recurrent grade I meningioma with radiographic features of 
aggressive meningioma after failure of previous treatment with surgery and radiation 
when feasible.  
5. All patients would have to have recurrence despite radiotherapy, unless radiotherapy 
is contraindicated.  
6. No limit on the number of prior surgeries, radiation or radiosurgery treatments. 


 
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7. No limit on prior systemic therapies – chemotherapy or biological agents. 
8. Patients who received stereotactic radiosurgery (SRS) are eligible without histologic 
documentation of recurrence if at least 6 months have passed from previous SRS 
treatment.. 
9. KPS≥50%  
10. At least 4 weeks since any prior therapy. 
11. Life expectancy of at least 4 months. 
12. Dexamethasone use will be allowed up to a dose of 2mg per day. Steroids dose 
should be reduced or stopped 7 days prior to treatment with study drug. 
13. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculated creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
a Creatinine clearance should be calculated per institutional standard. 
 
14. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 


 
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urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
15. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for 
the course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
16. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.  
3. Patients who are steroid dependent and cannot reduce the dexamethasone dose to a 
maximal dose of 2mg per day. 
4. Has a known history of active TB (Bacillus Tuberculosis) 
 
5. Hypersensitivity to pembrolizumab or any of its excipients. 
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 


 
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- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   
10. Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
11. Has known history of, or any evidence of active, non-infectious pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
19. Has received a live vaccine within 30 days of planned start of study therapy. 
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. 


 
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5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg X 
mg/kg 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle 
Experimental 
 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
5.2.1.2 Dose Modification (Escalation/Titration/Other) 
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 Table 3 below. See Section 
5.6.1 for supportive care guidelines, including use of corticosteroids. 
Table 3 Dose Modification Guidelines for Drug-Related Adverse Events 
 
 
Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
Permanently discontinue 


 
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Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2a 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity b 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
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 If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose; Refer to  
Table  – Infusion Treatment Guidelines for further management details. 
b 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 Sponsor. The reason for 
interruption should be documented in the patient's study record. 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  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. 


 
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Pembrolizumab 200 mg will be administered as a 30 minutes IV infusion every 3 weeks.  
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). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Randomization or Treatment Allocation 
This is an open-label, single-arm trial; therefore, there will be no treatment allocation. All 
subjects entering this trial will receive pembrolizumab monotherapy (200 mg Q3W) 
 
5.4 
Stratification 
This is an open-label, single-arm trial; therefore, there will be no stratification between 
treatment arms. 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
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.  
5.5.1 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 7.2. 


 
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5.5.2 Prohibited Concomitant Medications 
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 solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
 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: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are 
live attenuated vaccines, and are not allowed. 
 Glucocorticoids not specified in this protocol or in doses that exceed the allowed 
specified dose. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
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. 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. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 


 
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require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
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 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 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. 
 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, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, 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. 
 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.  


 
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 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 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.  
 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 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
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 
No subsequent dosing 


 
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 5.4.2021 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
further trial treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 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.   
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 


 
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 Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
 
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 subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy. If there is any question that a subject of childbearing 


 
Version 3.0 
 5.4.2021 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
5.7.3 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 Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons. Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7.1 
 Unacceptable adverse experiences as described in Section 5.2.1.2 


 
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 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.5.5 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements). 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 7.2.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of 
the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Subjects will resume therapy at the same dose and schedule at 
the time of initial discontinuation.  Additional details are provided in Section 7.1.5.5. 
5.9 
Subject Replacement Strategy 
A subject who discontinues from the trial will not be replaced. 


 
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 5.4.2021 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 


Product:  Pembrolizumab 
 
Protocol/Amendment No.:   
 
 
 
 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
/Title: 
Pre-
screeni
ng 
(V1) 
Main 
Study 
Screen
ing 
(V2) 
1 
2  
3 
4 
To be repeated beyond 8 cycles 
Discon 
Safety 
Follo
w-up 
Follow 
Up 
Visitsb 
Survival Follow-
Up 
5 
6 
7 
8 
Days): 
 
-28 to 
-1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8 
weeks 
post 
discon 
Every 12 weeks  
dures 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
teria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
ical 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
erapy 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
ssessments 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
on 
 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
t 
x 
 
 
 
x 
 
 
 
x 
x 
 
 


Product:  Pembrolizumab 
 
Protocol/Amendment No.:   
 
 
 
 
 
 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
/Title: 
Pre-
screeni
ng 
(V1) 
Main 
Study 
Screen
ing 
(V2) 
1 
2  
3 
4 
To be repeated beyond 8 cycles 
Discon 
Safety 
Follo
w-up 
Follow 
Up 
Visitsb 
Survival Follow-
Up 
5 
6 
7 
8 
Days): 
 
-28 to 
-1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8 
weeks 
post 
discon 
Every 12 weeks  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
s/Assessments: analysis performed by LOCAL laboratory 
or 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
 
 
 
x 
x 
 
x 
 
x 
 
x 
x 
x 
 
 
 
ts 
x 
 
 
 
x 
 
 
 
x 
x 
 
 
 
 
mes 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
val 
 
 
 
 
 
 
 
 
 
 
 
 


Product:  Pembrolizumab 
 
Protocol/Amendment No.:   
 
 
 
 
 
 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
/Title: 
Pre-
screeni
ng 
(V1) 
Main 
Study 
Screen
ing 
(V2) 
1 
2  
3 
4 
To be repeated beyond 8 cycles 
Discon 
Safety 
Follo
w-up 
Follow 
Up 
Visitsb 
Survival Follow-
Up 
5 
6 
7 
8 
Days): 
 
-28 to 
-1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 
days 
post 
discon 
Every 
8 
weeks 
post 
discon 
Every 12 weeks  
ained Tissue Collection 
 
x 
 
 
 
 
 
 
 
 
od 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Product:   Pembrolizumab 
 
Protocol/Amendment No.:   
 
 
 
 
 
 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. Furthermore, additional evaluations/testing may be deemed necessary by the 
investigator and or the Sponsor for reasons related to subject safety. 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 


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Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 


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7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up.  
7.1.1.6 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to allocation. Each subject will be assigned 
only one screening number. Screening numbers must not be re-used for different subjects. 
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening visit requirements 
(screening/rescreening) are provided in Section 7.1.5.1 
7.1.1.7 Assignment of Randomization Number 
No randomization will be performed in this protocol.  
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management. Administration 
of trial medication will be witnessed by the investigator and/or trial staff. The total volume of 
pembrolizumab infused will be compared to the total volume prepared to determine 
compliance with each dose of pembrolizumab administered. The instructions for preparing 
and administering pembrolizumab are provided in the Pharmacy Manual. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is possibly an 
event of clinical interest (ECI) of a potentially immunologic etiology (termed immune-
related adverse events, or irAEs); see the separate ECI guidance document in Appendix 4 
regarding the identification, evaluation and management of potential irAEs.   


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Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   
7.1.2.4 Neurological assessment 
The investigator or qualified designee will perform a complete a full neurological assessment 
during the screening period, will be repeated after 2 months from the beginning of the trial 
drug administration and then every 2-3 months, as clinically indicated (not earlier than 2 
months and not later than 3 months) as specified in the Trial Flow Chart (Section 6.0). 
Clinically significant abnormal findings should be recorded as medical history. 
7.1.2.5 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.6 ECG 
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history. 
 
7.1.2.7  Performance Score 
The investigator or qualified designee will assess Karnofsky Performance score (see Section 
11.1) at screening, prior to the administration of each dose of trial treatment and 
discontinuation of trial treatment as specified in the Trial Flow Chart.   
7.1.2.8 Tumor Imaging and Assessment of Disease 
A baseline MRI scan will be performed. MRI scan will be repeated after 2 months from the 
beginning of the trial drug administration and then every 2-3 months, as clinically indicated 
(not earlier than 2 months and not later than 3 months) as specified in the Trial Flow Chart 


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(Section 6.0).. Imaging schedule should be maintained until exclusion from trial, including 
follow-up periods without drug administration. Response evaluation will be made with every 
scan, using the RECIST 1.1 criteria, as used for solid tumors.  
The trial will allow the continuation of pembrolizumab in case of stable or improved clinical 
response, when pseudo-progression is suspected in the MRI. Continuation of study drug 
under for suspected pseudo-progression requires consent from study PI (DL). 
7.1.2.9 Patient Reported Outcomes (PROs) 
The EuroQol EQ-5D, EORTC QLQ-C30, and EORTC QLQ-BN20 questionnaires will be 
administered by trained site personnel and completed electronically by subjects prior to all 
other study procedures in the following order: EuroQol EQ-5D first, then EORTC QLQ-C30, 
and lastly the EORTC QLQ-BN20 at the time points specified in the Trial Flow Chart. 
7.1.2.10 Tumor Tissue Collection 
All subjects will submit an archival excisional biopsy to a central lab for characterization of 
PD-L1 status. Detailed instructions for tissue collection, processing and shipment are 
provided in the Procedures Manual. 
  
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 7. 


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Table 7 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 


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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.5.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
7.1.3.2 Withdrawal from Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed. Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the subject's 
specimens will be removed from the biorepository and be destroyed. A letter will be sent 
from the Sponsor to the investigator confirming the destruction. It is the responsibility of the 
investigator to inform the subject of completion of destruction. Any analyses in progress at 
the time of request for destruction or already performed prior to the request being received by 
the Sponsor will continue to be used as part of the overall research trial data and results. No 
new analyses would be generated after the request is received. 
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens. In this situation, the request for specimen 
destruction cannot be processed. 
7.1.3.3 Calibration of Critical Equipment 
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 


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reproducible. Documentation of equipment calibration must be retained as source 
documentation at the trial site. 
Critical Equipment for this trial includes: 
 Laboratory equipment – as required for inclusion labs and trial assessments 
 Imaging equipment – as required for study objectives 
 Drug administration equipment – as required for storing, preparing, and administering 
Study treatment 
See  protocol-specified  guidance  in  the  Administrative  Binder,  Procedures  Manual  and  
Site Imaging Manual. 
7.1.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.4.1 Screening 
7.1.4.1.1 Screening Period 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following: 
 Laboratory tests and Karnofsky PS are to be performed within 10 days prior to the first 
dose of trial treatment. 
 For women of reproductive potential, a serum pregnancy test will be performed within 72 
hours prior to the first dose of trial treatment.  A urine test maybe considered if serum test 
is not appropriate. 
 Tumor sample collection is not required to be obtained within 28 days prior to the first 
dose of trial treatment. 
Subjects maybe rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. 


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7.1.4.2 Treatment Period 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures. 
7.1.4.2.1 Re-treatment criteria 
Patient who completed a treatment period of 24 months may discontinue treatment in case of 
documented complete response. These patients will be allowed to restart treatment under the 
following conditions: 
a) 
Be willing and able to provide consent for the drug re-administration. 
b) 
Show a documented disease progression on MRI, based on RECIST 1.1 criteria. 
c) 
A period of at least 2 months has passed since drug discontinuation.  
d) 
No other treatment for meningioma was given during the discontinuation time 
(i.e. surgery, radiotherapy, systemic therapy, etc.).  
e) 
KPS≥50%  
f) 
Demonstrate adequate organ function as defined in Table 1.  
g) 
Patient is not defendant on a steroids, allowing a dexamethasone dose of up to 
2mg.  
7.1.4.3 End of Post-Treatment Visits 
7.1.4.3.1 Discontinuation Visit 
The Discontinuation Visit should occur at the time study drug is discontinued for any reason. 
If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at the time 
of the mandatory Safety Follow up Visit, procedures do not need to be repeated. Procedures 
at the time of discontinuation are detailed in Section 7.1.5.3.2 Mandatory Safety Follow up 
Visit. 
7.1.4.3.2 Mandatory Safety Follow up Visit 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 


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treatment should also be followed and recorded.  Subjects who are eligible for retreatment 
with pembrolizumab (as described in Section 7.1.5.5) may have up to two safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase. 
 
7.1.4.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 8 weeks (56 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 9 weeks (± 7 days). Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, end of 
the study or if the subject begins retreatment with pembrolizumab as detailed in Section 
7.1.5.5.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart for 
Retreatment.    
7.1.4.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  
7.1.4.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
 Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 


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OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability 
AND 
 Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
 Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
 Has a KPS≥50%  
 Demonstrates adequate organ function as detailed in Section 5.1.2 
 Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
 Female subject 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 (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
 Male subject 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.   
 Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 


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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 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed, but before treatment allocation, 
must be reported by the investigator if they cause the subject to be excluded from the trial, or 
are the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded 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 
7.2.2. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.  
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 


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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 Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.1 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. All reported pregnancies 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 Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.2.1 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 another important medical event  
 Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 


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same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 8 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment allocation, 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 (reference Section 7.2.3.3 for 
additional details). that occurs to any subject must be reported within 24 hours to the Sponsor 
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 treatment allocation/randomization 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 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 (reference Section 7.2.3.3 for additional details), whether or not related to 
the Merck product, must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. 
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 following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
7.2.2.2 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 Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 


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For the time period beginning when the consent form is signed until treatment allocation any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to 
the Sponsor 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 treatment allocation/randomization 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 Sponsor and 
within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, 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.  
3. Additional adverse events: Any seizure in a patient with no history of previous seizures 
will be documented and reported. An increase in number of seizures in a patient with 
previous seizure history will have to be documented and reported, as well as a change in 
previously known pattern of seizures. 
7.2.2.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 


Product:   Pembrolizumab 
 
Protocol/Amendment No.:   
 
 
 
 
 
 
 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered 
a SAE. 
 
7.2.3 Evaluating Adverse Events 
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. 


Product:  MK-3475 
 
Protocol/Amendment No.:   
 
 
  
 
 
 
Table 8 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); 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) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. 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 to the Sponsor and to 
Merck within 2 working days. 
 
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 


Product:  MK-3475 
 
Protocol/Amendment No.:   
 
 
  
 
 
 
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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be provided by an investigator 
who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures 
that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to 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 
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 
 


Product:  MK-3475 
 
Protocol/Amendment No.:   
 
 
  
 
 
 
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 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 Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to 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) Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR 
the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 


 
 
 
 
7.2.4 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
8.1.1 Efficacy Analyses 
The intention-to-treat (ITT) population that includes all allocated subjects will serve as the 
primary population for the analyses of efficacy data in this trial. 
The primary efficacy endpoint is 6 and 12 months progression-free survival (PFS) rate (i.e., 
the proportion of subjects who did not experience progressive disease or died due to any 
cause at 6 and 12 months from randomization.) per RECIST 1.1 criteria, based on 
independent radiologists’ review. 
The secondary efficacy endpoints for this trial are overall survival (OS), progression-free 
survival (PFS) and overall response rate (ORR) per RECIST 1.1 criteria based on 
independent radiologists’ review. The analysis plan for PROs will be provided in a separate 
document before the final PFS analysis. 
8.1.2 Safety Analysis 
The All Patients as Treated (APaT) population will be used for the primary analysis of safety 
data in this study. Investigators will report adverse experiences at every visit on this study (at 
least every three weeks during treatment) using Common Terminology Criteria for Adverse 
Events, Version 4.0. The attribution to drug, time -of-onset, duration of the event, its 
resolution, and any concomitant medications administered will be reported. AEs will be 
analyzed and reported, including but not limited to Events of Clinical Interest outlined in the 
separate ECI and irAE guidance document, all AEs, SAEs, fatal AEs, and laboratory 
changes. 
8.1.3 Power and Sample Size 
With a minimum sample size of 22 patients with atypical/malignant meningioma, we will 
have 80% power to detect an improvement in the 6mPFS rate from 5% to 25% with a 
significance level of 0.05. Together with a presumed 10% drop-out of patients, the number of 
patients we want to enroll is 25. 


 
 
8.2 
Statistical Analysis Plan 
8.2.1 Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Investigator. 
8.2.2 Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 3. The study is considered to 
have met its primary objective if pembrolizumab if 6 or 12 months PFS which will be at least 
comparable to other drugs that were tested for recurrent or progressive meningioma, with a 
6mo PFS of 40% and 12mo PFS of 15%. 
8.2.3 Analysis Endpoints 
8.2.3.1 Efficacy Endpoints 
Primary  
6 and 12 months Progression-free survival rate 
6 and 12 months progression-free survival (PFS) rate is defined as the proportion of subjects 
alive at 6 and 12 months without progression or death, whichever occurs first. The first 
documented disease progression will be assessed per RECIST 1.1 criteria, based on central 
radiologists’ review. Death is considered as death due to any cause. The proportion is 
calculated from the intention-to-treat (ITT) population. 
Secondary 
Overall Survival 
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Subjects without documented death at the time of the final analysis will be censored at the 
date of the last follow-up. 
Progression-free survival 
Progression-free-survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 criteria based on central radiologists’ 
review or death due to any cause, whichever occurs first. 
Overall Response Rate (ORR) 
Overall response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based upon 
central radiologists’ review per RECIST 1.1 criteria. 


 
 
8.2.3.2 Safety Endpoints 
Safety measurements are described in Section 7. 
 
8.2.4 Analysis Population 
8.2.4.1 Efficacy Analysis Population 
The analysis of primary efficacy endpoints is based on the intention -to-treat (ITT) 
population.  
Details on the approach to handling missing data are provided in Section 8.2.5 Statistical 
Methods. 
 
8.2.4.2 Safety Analysis Populations 
The All Patients as Treated (APaT) population will be used for the analysis of safety data in 
this study. The APaT population consists of all randomized subjects who received at least 
one dose of study treatment. At least one laboratory or vital sign measurement obtained 
subsequent to at least one dose of trial treatment is required for inclusion in the analysis of 
each specific parameter. To assess change from baseline, a baseline measurement is also 
required. 
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods. 
 
8.2.5 Statistical Methods 
8.2.5.1 Statistical Methods for Efficacy Analyses 
8.2.5.1.1 6 and 12 months Progression-Free Survival (PFS) rate 
6 and 12 months progression-free survival (PFS) rate is defined as the proportion of subjects 
alive at 6 and 12 months without progression or death, whichever occurs first. The rate will 
be compared with rates described for other investigational agents using non-parametric test. 
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of the first assessment 
at which PD is objectively documented per RECIST 1.1 criteria, regardless of 
discontinuation of study drug. Death is always considered as a confirmed PD event. 
Sensitivity analyses will be performed for comparison of PFS based on investigator's 
assessment. In order to evaluate the robustness of the PFS endpoint, two sensitivity analyses 
will be performed with a different set of censoring rules. Sensitivity analysis 1 is the same as 
the primary analysis except that it censors at the last disease assessment without PD when PD 
or death is documented after more than one missed disease assessment.  Sensitivity analysis 2 
is the same as the primary analysis except that it considers discontinuation of treatment or 
initiation of new anticancer treatment, whichever occurs later, to be a PD event for subjects 
without documented PD or death. 


 
 
 
8.2.5.1.2 Progression-Free Survival (PFS)  
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve. 
Definition of PD and PFS evaluation is described in section 8.2.5.1.1. 
 
8.2.5.1.3 Overall Survival (OS) 
The Kaplan-Meier method will be used to estimate the survival curves. 
 
8.2.5.1.4 Overall Response Rate (ORR) 
Overall response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based upon 
central radiologists’ review per RECIST 1.1 criteria.  
8.2.5.1.5 Exploratory analyses 
If the number of responders permits, response duration will be summarized descriptively 
using Kaplan-Meier medians and quartiles. Only the combined subset of subjects who show a 
complete or partial response will be included in this analysis 
 
To determine whether the treatment effect is consistent across various subgroups, the primary 
and secondary endpoints will be estimated within each category of the following 
classification variables: 
 Age category (≤65, >65 years) 
 Sex (female, male) 
 Karnofsky performance status (≤80, >80) 
 PD-1 and PDL-1 expression status. 
 Biomarkers  
 
To determine whether the treatment effect is consistent across various assessment methods, 
the primary and secondary endpoints will be estimated within each category of the following 
classification variables: 
 RECIST 1.1 vs RANO criteria 
 
EORTC QLQ-C30, EORTC QLQ-BN20, EuroQoLEQ-5D, will be summarized as part of the 
exploratory analysis. Longitudinal and descriptive data analysis will be used to evaluate 
patient-reported outcomes (PRO). The detailed PRO analysis plan will be included in a 
separate document. 
 
8.2.5.2 Statistical Methods for Safety Analyses 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements. 
 


 
 
8.2.6 Extent of Exposure 
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity 
will also be summarized as appropriate. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
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. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor 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. 
9.4 
Storage and Handling Requirements 
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. 


 
 
9.5 
Returns and Reconciliation 
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.  
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. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
10.2 Compliance with Financial Disclosure Requirements 
10.3 Compliance with Law, Audit and Debarment 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
and pursue participation by calling a central contact number for further information on 
appropriate trial locations and trial site contact information.     
10.5 Quality Management System 
10.6 Data Management 
 
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12.0 APPENDICES 
12.1 Karnofsky Performance scale 
Grade 
Description 
100 
Normal; no complaints; no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self; unable to carry on normal activity or to do active 
work. 
60 
Requires occasional assistance, but is able to care for most of their 
personal needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled; requires special care and assistance. 
30 
Severely disabled; hospital admission is indicated although death not 
imminent. 
20 
Very sick; hospital admission necessary; active supportive treatment 
necessary. 
10 
Moribund; fatal processes progressing rapidly. 
0 
Dead 
* As published in Karnofsky DA Burchenal JH. (1949). "The Clinical Evaluation of Chemotherapeutic 
Agents in Cancer." In: MacLeod CM (Ed), Evaluation of Chemotherapeutic Agents. Columbia Univ 
Press. Page 196. 
 
 
12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 


 
 
12.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
12.4 Revised Assessment in Neuro-Oncology (RANO) criteria for Evaluating 
Response 
The Revised Assessment in Neuro-Oncology (RANO) criteria* was published in 2010, as an 
update to the existing MacDonald criteria as published in the Journal of Clinical Oncology: 
“Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in 
Neuro-Oncology Working Group.” Journal of Clinical Oncology. 2010 Apr 10; 28(11):1963-
72. In addition, volumetric analysis will be explored by central review for response 
assessment.