Pharmacodynamic Study of Pembrolizumab in Patients With Recurrent Glioblastoma
Phase: PHASE2
Conditions: Recurrent Glioblastoma, Recurrent Gliosarcoma
Sponsor: M.D. Anderson Cancer Center

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University of Texas MD Anderson Cancer Center 
Department of Neuro-oncology 
 
TITLE: Pharmacodynamic Study of Pembrolizumab in Patients with Recurrent 
Glioblastoma 
 
Product: Pembrolizumab  
 
Support Provided By 
Merck 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS: 
1.             TRIAL SUMMARY…………………………………………………………..……4 
                1.0   Trial summary………………………………………………………………... 
 
2.             TRIAL DESIGN……………………………………………………………………5 
                2.1   Trial design…………………………………………………………………… 
                2.2   Trial diagram…………………………………………………………………. 
                 
3.             OBJECTIVE(S) & HYPOTHESIS(ES)……………………………………………6 
3.1   Primary Objective(s) & Hypothesis (es)……………………………………… 
                3.2   Secondary Objective(s) & Hypothesis (es)…………………………………… 
               3.3   Exploratory Objectives………………………………………………………... 
 
4.           BACKGROUND & RATIONALE………………………………………………. 8 
4.1   Background…………………………………………………………………… 
                4.2   Rationale…………………………………………………………………….. 
 
5.             METHODOLOGY………………………………………………………………..14 
5.1   Entry Criteria………………………………………………………………... 
5.2   Trial treatments……………………………………………………………… 
5.3   Randomization or Treatment Allocation……………………………………. 
5.4   Stratification…………………………………………………………………. 
5.5   Concomitant Medications/Vaccinations ……………………………………. 
5.6   Rescue Medications & supportive Care……………………………………... 
5.7   Diet/ Activity/ Other considerations………………………………………… 
5.8   Subject Withdrawal/ Discontinuation Criteria………………………………. 
5.9   Subject Replacement Strategy………………………………………………. 
5.10 Clinical Criteria for Early Trial Termination………………………………... 
 
6.             TRIAL FLOW CHART…………………………………………………………...27 
                6.1   Study Flow Chart…………………………………………………………… 
 
7.             TRIAL PROCEDURES…………………………………………………………...29 
7.1   Trial procedures…………………………………………………………...… 
7.2   Assessing and Recording Adverse Events…………………………………... 
 
8.             STATISTICAL ANALYSIS PLAN………………………………………………48 
8.1   Statistical Analysis Plan Summary………………………………………….. 
 
9.             LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL    
                SUPPLIES………………………………………………………………………...50 
9.1   Investigational Product……………………………………………………… 
9.2   Packaging and labeling information………………………………………… 
9.3   Clinical Supplies Disclosure………………………………………………… 
9.4   Storage and Handling requirements…………………………………………. 

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9.5   Returns & Reconciliation……………………………………………………. 
 
10.           ADMINISTRATIVE & REGULATORY DETAILS …………………………....51 
10.1 Confidentiality…………………………………………………………….… 
10.2 Compliance with Law, Audit , and Debarment……………………………... 
10.3 Compliance with Trial Registration and Results Posting Requirements……. 
10.4 Quality Management System ……………………………………………….. 
10.5 Data Management…………………………………………………………… 
 
11.           LIST OF REFERENCES………………………………………………………....53 
 
12.           APPENDICES…………………………………………………………………….56 
12.1 Karnofsky Performance Status……………………………………………… 
                12.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE)……….. 
                12.3 Response Assessment in Neuro-oncology (RANO) Criteria ……………...... 
               12.4 MD Anderson Form for reporting SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pharmacodynamic Study of Pembrolizumab in Patients With 
Recurrent Glioblastoma 
Trial Phase 
Phase 2  
Clinical Indication 
Recurrent glioblastoma 
Trial Type 
Pharmacodynamic Study 
Type of control 
N/A 
Route of administration 
200 mg , intravenously (IV) once every 3 weeks prior to 
surgery for two doses and then restarting 200 mg Q 3wk 
following surgical resection 
Trial Blinding 
N/A 
Treatment Groups  
open label, single arm 
Number of trial subjects 
20 
Estimated duration of trial 8-9 months for trial enrollment 
Duration of Participation 
Each subject will participate in the trial from the time the 
subject signs the informed consent form through the final 
protocol specified contact. After a screening phase, eligible 
subjects will receive treatment with pembrolizumab every 3 
weeks for 2 doses prior to surgical resection. Patients will 
have a 14-21 day recovery period from surgery and then start 
again to receive treatment with pembrolizumab study 
therapy every 3 weeks and will continue until documented 
confirmed 
disease 
progression, 
unacceptable 
adverse 
event(s), 
intercurrent 
illness 
that 
prevents 
further 
administration of treatment, investigator’s decision to 
withdraw the subject, noncompliance with trial treatment or 
procedure requirements, subject receives 24 months of study 
medication, or is withdrawn for administrative reasons. 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). 
Subjects who discontinue for reasons other than disease 
progression 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. All subjects will be followed by telephone for overall 
survival until death, withdrawal of consent, or the end of the 
study. 
 
 
 
 
 
 
 
 
 

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2.0 TRIAL DESIGN 
 
2.1 
Trial Design 
This will be an open label, single arm exploratory biomarker-driven Phase 2 clinical trial in 
patients with glioblastoma at first or second recurrence. Patients must have received prior 
radiation and/or chemotherapy. Approximately 20 patients with recurrent glioblastoma who 
require reoperation for tumor progression will be treated with up to 2 doses of 
pembrolizumab prior to surgery (day -21 and day -1, prior to the surgery on day 0).  
  
During the pre-surgery phase, if, after one dose of pembrolizumab , a patient experiences 
progressive clinical symptoms, then the second dose of pembrolizumab will be deferred and 
the patient will proceed to surgery to correlate imaging changes with immunologic effects 
within the tumor. 
 
All patients enrolled on this clinical trial must have unstained slides from their original tumor 
surgery to assess PD-L1 expression. Although PD-L1 expression is not an inclusion criterion 
for enrollment, our preliminary data suggest that the majority of patients have >1% PDL-1 
tumor expression indicating that all the patients enrolled on the trial will likely have PD-L1 
expression in their archival tumor tissue specimen. In addition to the original tumor 
specimens, the recurrent surgical specimens will be sent for testing to compare the difference 
between PD-L1 expressions in recurrent and primary untreated tumor in each patient enrolled 
on the trial.  
 
Tumor tissue from the surgical resection and peripheral blood will be evaluated 
longitudinally for pharmcodynamic effects including PD-L1 expression on tumor cells, 
changes in circulating Tregs, changes in CD3+/PD-1+ T-cells, and immune modulation. In 
addition, T-cells will be isolated ex vivo from the post-treatment surgical resection specimen 
and evaluated using flow cytometry for an increase in IL-2, TNF-α, IFN-γ, perforin and 
granzyme and other pro-inflammatory cytokines indicative of a reduction in immune 
suppression. Multiple imaging biomarkers will be assessed before and after pembrolizumab 
treatment and correlated with immunological changes in the tumor. The evaluation of tissue 
PD biomarkers will be correlated with circulating biomarker effects following drug exposure 
and PFS6 to determine if treatment of recurrent glioblastoma with pembrolizumab 
monotherapy will result in an increase of the polyfunctional effector T cells:Treg ratio and 
improve the anti-tumor immune response. 
 
After recovery from surgery (approximately 2-3 weeks), patients will receive pembrolizumab 
until disease progression or the development of unacceptable toxicities. Treatment will be 
administered every 3 weeks. Cycles will be defined as every 42 days. Responses will be 
assessed by clinical examinations and MRI scans every 6 weeks. Treatment will continue 
until disease progression or completion of 24 months of treatment with pembrolizumab. The 
progression free survival at 6 months (PFS6), median duration of response, overall response 
rate (ORR), and overall survival (OS) will be determined.   
 

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2.2 
Trial Diagram 
Patients with glioblastoma at first or second recurrence who have received prior radiation 
and/or chemotherapy and require reoperation for tumor progression will be treated with up to 
2 doses of pembrolizumab prior to surgery (21 days and 1 day prior to the surgery). During 
the presurgery phase, if after one dose of pembrolizumab, a patient experiences progressive 
clinical symptoms, then the second dose of pembrolizumab will be deferred and the patient 
will proceed to surgery to correlate imaging changes with immunologic effects within the 
tumor. 
 
After recovery from surgery (approximately 2-3 weeks), patients will receive pembrolizumab 
until disease progression or the development of unacceptable toxicities. Treatment will be 
administered every 3 weeks. Cycles will be defined as every 42 days. Participants will 
remain on treatment until tumor progression, as long as there are no unacceptable toxicities 
or until completion of 24 months of treatment with pembrolizumab. Responses will be 
assessed by clinical examinations and MRI scans every 6 weeks. The MRI Brain following 
surgical resection will be considered the baseline MRI for evaluation of treatment response. 
The PFS6, median duration of response, ORR, OS will be determined.   
 
 
 
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
 
3.1 
Primary Objective(s) & Hypotheses 
Objective: The co-primary objectives of this study are to 1) evaluate immune effector 
function in resected glioblastoma tissue after treatment with intravenously administered 
pembrolizumab monotherapy in the neoadjuvant setting in patients with recurrent 
glioblastoma and 2) to correlate the progression free survival at 6 months (PFS6) with 

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objective increases in the immune effector Tcell:Treg ratio in tumor tissue as measured by ex 
vivo T-cell-specific cytokines profiling. 
 
Hypothesis: Treatment of recurrent glioblastoma with pembrolizumab monotherapy will 
result in an increase of the polyfunctional effector T cells:Treg ratio and improve the anti-
tumor immune response. Treatment with pembrolizumab monotherapy will improve the 
PFS6; Improvement in PFS6 will correlate with enhancement of the polyfunctional effector T 
cells:Treg ratio.  
 
3.2 
Secondary Objective(s) & Hypothesis 
Objective: The secondary objectives include comparison of time to progression of last prior 
therapy to time to progression on pembrolizumab, median duration of response, ORR, and 
OS, as well as and safety. 
 
Hypothesis: Treatment with pembrolizumab monotherapy will improve the OS in patients 
with recurrent glioblastoma. Improvement in OS will correlate with enhancement of the 
polyfunctional effector T cells:Treg ratio.  
 
3.3 
Exploratory Objective 
Objective: To identify imaging characteristics associated with immunological changes in 
tumor following treatment with pembrolizumab. 
 
Patients will be imaged prior to treatment and approximately 24-28 days post-first dose of 
pembrolizumab (within 24-28 hours of surgical resection) for surgical navigation purposes 
and within 24-48 hours following surgical resection to assess the extent of tumor resection.  
This imaging will incorporate the conventional MRI (T1 pre and post-contrast images, T2-
weighted images (T2WI), Fluid attenuating inversion recovery (FLAIR) images) and 
advanced MRI (MR perfusion [dynamic susceptibility contrast (DSC), dynamic contrast 
enhancement (DCE) and arterial spin labeling (ASL)], MR- diffusion, and MR 
spectroscopy), and chemical exchange saturation transfer (CEST) sequences. Imaging post-
processing will include but not be limited to modified RANO criteria, advanced quantitative 
imaging and volume tumor metrics, and voxel-by-voxel (texture, heterogeneity, energy, etc) 
imaging analysis. Both pre- and post-operative image analyses will include non-invasive 
assessments of cell death (apoptosis), active tumor proliferation, tumor invasion, tumor 
density, vascularity, vascular permeability, pH (acidity) microvascular density and metabolite 
profiles. Exploratory analyses will utilize quantitative imaging tumor metrics and texture 
maps to assess gene signatures of tumor cell apoptosis, invasion and immune cell infiltration. 
CEST imaging is non-invasive MRI technique sensitive to mobile proteins and peptides, 
respectively, and their tissue concentration. Exploratory analysis using quantitative imaging 
tumor metrics and texture maps will also be used to assess pseudoprogression, progression 
and response. These analyses will be compared to a retrospective cohort of glioblastoma 
patients that have been dichotomously analyzed for lack of inflammatory response versus 
robust intratumoral inflammatory responses to prospectively validate the sensitivity and 
specificity of this approach.  
 

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Additionally, patients will have their imaging processed prior to surgery and immediately 
post-op with treatment assessment response maps (TRAMs). TRAMs are a recently 
developed MRI-based methodology providing high resolution maps with clear differentiation 
between tumor/non-tumor tissues in brain tumor patients, unattainable by current imaging 
methods. This system is based on delayed contrast extravasation MRI where two sets of 
MRIs are acquired, 3 and 75 min on average after a conventional injection of contrast agent.  
 
In order to calculate the TRAMs, conventional MRI exams will be extended by adding the 
delayed MRI point 60-100 min post contrast injection. The MRI exams will include standard 
pre- and post-contrast T1, T2, FLAIR and perfusion-weighted MRI, as routinely performed 
in the hospital. The patient will then be let out of the MRI system and will be asked to return 
for an additional T1-weighted scan 60-100 min post contrast injection. 
 
The TRAMs will be calculated by subtracting the first T1-MRIs, acquired soon after contrast 
injection from T1-MRIs acquired at the delayed time point. These maps depict spatial 
distribution of contrast accumulation/clearance. 
 
The MRIs are then processed to provide treatment assessment response maps (TRAMs) 
clearly depicting active tumor regions in one color (blue in the maps) and non-tumor regions 
in a different color (red). Blue/tumor regions in the TRAMs represent efficient clearance of 
contrast from the tissue (the signal in the delayed MRIs < than that of the 3 min images, 
reflecting contrast clearance) while red/non-tumor regions in the TRAMs represent contrast 
accumulation (the delayed signal > than the early signal). It has been demonstrated that the 
common feature of vessels morphology in the blue regions was undamaged vessels lumens, 
while vessels in the red regions presented different stages of vessel necrosis. Therefore, one 
explanation for the difference between the two populations may be that vessels in blue/tumor 
regions provide efficient contrast clearance from the tissue, while the damaged lumens in the 
red/TEs regions are unable to clear the accumulating contrast, resulting in contrast 
accumulation.    
 
 
Baselin
e 
Pre-Op 
Post-Op 
1st assessment 
Conventional MRI 
scan 
X 
X 
X 
X 
Advance brain tumor 
imaging (ABTI) 
 
X 
X 
X 
Treatment assessment 
response maps 
(TRAMs) - delayed 
contrast (90 minute) 
scan 
 
X 
 
X 
Chemical exchange 
transfer imaging 
(CEST) 
X 
X 
X 
X 
 
 

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4.0 BACKGROUND & RATIONALE 
 
4.1 
Background 
Tumors exhibit various mechanisms of avoiding or suppressing the immune response to 
prevent their destruction and promote tumor growth. Programmed death 1(PD-1) is one such 
strategic receptor on activated T-cells that mediates immunosuppression in cancer. PD-1 
ligands PD-L1 and PD-L2, present on tumor or stromal cells, interact with the PD-1 receptor 
causing a down regulation of the T-cell response. Prior in vitro studies have shown that 
inhibition of this interaction can improve T cell responses and facilitate anti-tumor activity.  
In vitro treatment with PD-1 is also advantageous by providing preferential activation of T-
cells with specificity for the tumor avoiding immune over activation and damage to normal 
tissues. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  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) [7; 
8].  The structure of murine PD-1 has been resolved [9].  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 [7; 10; 11; 12].  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 [13; 14].  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 [15; 16]. Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [17].  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 [18; 19; 20; 13].  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 

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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 [13]. Although healthy organs express little (if any) PD-L1, a variety of 
cancers have been shown 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 [21].  This 
suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and 
should be considered as an attractive target for therapeutic intervention. 
 
Pembrolizumab (previously known as SCH 900475) 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.   
 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
 
4.2 
Rationale 
In a Phase I study of 9 patients with advanced solid tumors including non–small cell lung 
cancer, rectal cancer, melanoma, sarcoma and carcinoid treated with pembrolizumab (anti-
PD-1 monoclonal antibody), an advanced stage melanoma patient was on therapy for more 
than 6 months with a partial response, and tumor reduction was seen in 3 additional patients. 
No Grade 3 or Grade 4 drug-related adverse events were observed. 
In another recent trial consisting of patients with non-small cell lung cancer, melanoma or 
renal cell cancer treated with BMS-936559 (anti-PD-1 monoclonal antibody), 20-25% of 
patients had objective responses with durability. Furthermore, 64% of patients with response 
to this therapy were found to have responses lasting greater than one year.  This was seen in 
multiple cancer types including 47% of heavily pre-treated patients (at least three prior 
treatment regimens). Treatment was well tolerated with only 14% (41 of 296) of patients 
having Grade 3 or Grade 4 treatment-related adverse events. PD-L1 tumor expression 
appeared to play a role in response to therapy as 36% (9/25) of patients with PD-L1 positive 
tumors had objective responses whereas 0% (0/17) of patients with PD-L1 negative tumors 
responded to therapy.  
 
The anti-tumor immune reactivity within glioblastoma has been extensively studied and 
although there are quantitative anti-tumor immune effector cells present within the 
glioblastoma microenvironment, these immune cells are anergic (non-reactive) (Hussain, 
Neuro-Oncology, 2006). The purpose of the study is to provide information on whether 
Pembrolizumab can specifically restore the qualitative anti-tumor effector responses (i.e. 
TNF-α, IFN-γ, granzyme B) in the glioblastoma microenvironment.  If Pembrolizumab is not 
able to restore anti-tumor effector responses to any degree, then it is unlikely that radiation 
induced antigenic shedding would provide much additional benefit since the tumor-mediated 
immune suppression is not sufficiently reversed with this particular monotherapy.  
 
It should be noted that the preclinical published study of a clonotypic glioma treated with 
radiation in combination with checkpoint inhibition demonstrates only a very modest 

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increase in survival (Zeng, Int. J of Rad. Oncol. Biol. Phys. 2013). This particular model 
system has well documented limitations for assessing the efficacy of immunotherapy and 
recapitulating the biology of human glioblastoma. More recent published studies have 
demonstrated that monotherapy targeting the PD-1/PD-L1 axis resulted in a 200% increase in 
survival with 60% animals cured in comparison to the Zeng study in which there was only a 
8% increase in median survival. Furthermore, prior preclinical studies targeting another 
checkpoint, CTLA-4, demonstrated robust cures with >70% of mice harboring tumors 
surviving long-term (Fecci, CCR, 2007).  If the submitted clinical trial were to demonstrate 
that Pembrolizumab were to enhance the functional anti-tumor immune responses, then we 
would possibly consider an efficacy clinical trial of the combination with radiation but 
preclinical indicates that there are other superior combinatorial approaches that are more 
compelling (Wainwright, CCR, 2014).  
 
 
4.2.1 Rationale for the Trial and Selected Subject Population 
The robust clinical responses seen in a diverse group of advanced stage tumors suggests that 
PD-1 antibody therapy in other tumors may also be beneficial.  Glioblastoma is the most 
common primary brain tumor in adults and is notorious for high levels of immune 
suppressive chemokines and high numbers of infiltrating regulatory T-cells which mediate 
immune suppression. A recent study in an immune competent orthotopic mouse glioma 
model was done examining the combination of anti-PD-1 immunotherapy with radiation. 
Improved survival was seen in mice who received both radiation and anti-PD1 therapy with a 
median survival of 53 days in contrast to control mice, mice treated with anti-PD-1 antibody 
monotherapy,  or mice treated with radiation monotherapy that had a median survival of 25, 
27, and 28 days, respectively. Additionally, long term survival was also significantly 
improved in those mice that had received the combination with 20-40% alive at 6 months 
following treatment. These data suggest that PD-L1 expressing glioma tumors may benefit 
from anti-PD-1 targeted therapy.  
 
Using both immunohistochemical (IHC) staining of a glioblastoma tumor microarray and ex 
vivo flow analysis cytometry, we have found that PD-L1 is frequently expressed in most 
glioblastomas. Using IHC, PDL-1 expression ranged from 1-99% whereas ex vivo flow 
cytometry of freshly isolated glioblastoma tumors demonstrated 4-7% of glioma cells 
expressing PD-L1. 
 
Anti-PD-1 antibodies have demonstrated a significant treatment response in several advanced 
solid tumors in clinical trials as well as improved survival in mouse models of glioblastoma.  
Anti-PD-1 therapy appears to be a very promising treatment and one that deserves further 
examination in patients with glioblastoma. Specifically, the impact of immunotherapy on 
tumor biology is currently unexplored and a better understanding of the pharmacodynamics 
effect of immunotherapy on gliomas will greatly assist in the development of this therapeutic 
approach in patients with glioblastoma. 
 
The new data has been obtained lately from glioblastoma tissue microarrays using different 
antibodies to detect expression and another group has published this as an under estimate.  
Specifically, PD-L1 expression (the ligand for PD-1) was observed in 103 of 117 (88.0%) 

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newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens (Berghoff, Neuro-
Oncology, 2014).  In this latter study, the vast majority of glioma cells (>85%) were shown 
to express PD-L1. Regardless, we would like to emphasize that Pembrolizumab is not a 
direct cytotoxic molecular targeted therapeutic – the principals are different. The cut point of 
expression that is required that would induce significant tumor-induced immune suppression 
or the level of expression that correlates to a therapeutic response is unknown.  For example, 
if 1% expression is sufficient to induce profound immune suppression, then this reversal 
would afford the immunological recognition and elimination of glioblastoma cells expressing 
tumor antigens (i.e. bystander effect).  Glioblastoma are antigenically diverse and 
immunologically reactive (Doucette, CIR, 2013) commonly possessing tumor-specific 
antigens such as epidermal growth factor variant III (Heimberger, CCR, 2005) that have been 
robustly targeted for phase III registration clinical trials (Heimberger/Sampson, JCO, 2010; 
Sampson, NO, 2010).  It should be noted that these clinical trials mandated gross total 
resections to eliminate/reduce tumor mediated immune suppression. As such, if the immune 
system were not restrained by immune suppressive mechanisms such as by immune 
checkpoints, available data indicates that the tumor would be eradicated/eliminated even if 
only a minor population is mediating that effect.   
  
 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
The dose regimen of 200 mg Q3W of pembrolizumab is planned for all urothelial cancer 
trials. Available PK results in subjects with melanoma, NSCLC, and other solid tumor types 
support a lack of meaningful difference in PK exposures obtained at a given dose among 
tumor types. An open-label Phase 1 trial (PN001) in melanoma subjects is being conducted 
to evaluate the safety and clinical activity of single agent pembrolizumab.  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 pembrolizumab 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 
maximum tolerated dose (MTD) has been identified. 
 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed.  The 
clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses.  For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The overall response rate (ORR) was 
26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set 
(FAS)).  The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-
related AEs, serious drug-related AEs, death or discontinuation due to an AE was 
comparable between groups or lower in the 10 mg/kg group.   
 
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a 
given dose among tumor types.  Population PK analysis has been performed and has 

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confirmed the expectation that intrinsic factors do not affect exposure to pembrolizumab to a 
clinically meaningful extent.  Taken together, these data support the use of lower doses (with 
similar exposure to 2 mg/kg Q3W) in all solid tumor indications.  2 mg/kg Q3W is being 
evaluated in NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated 
in head and neck cancer in PN012, which are expected to provide additional data supporting 
the dose selection. 
 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on 
simulation results indicating that 200 mg will provide exposures that are reasonably 
consistent with those obtained with 2 mg/kg dose and importantly will maintain individual 
patient exposures within the exposure range established in melanoma as associated with 
maximal clinical response.  A population PK model, which characterized the influence of 
body weight and other patient covariates on exposure, has been developed using available 
data from 476 subjects from PN001.   The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with some 
tendency for individual values to range slightly higher with the 200 mg fixed dose.   The 
slight increase in PK variability predicted for the fixed dose relative to weight-based dosing 
is not expected to be clinically important given that the range of individual exposures is well 
contained within the range of exposures shown in the melanoma studies of 2 and 10 mg/kg to 
provide similar efficacy and safety.  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 tumor types and indication settings.  
 
The company (MERCK) mandated that a starting dose of 200 mg IV every 3 weeks be used 
for this trial.  This is the same dose being used in another trial in glioblastoma being started 
at Dana Farber Cancer Institute.  This decision was made by the company based on their own 
internal efficacy data.  
 
4.2.3 Rationale for Endpoints 
Pharmacodynamic (PD) effects of intravenous administered pembrolizumab monotherapy in 
resected recurrent glioblastoma tissue have yet to be explored. This study will examine if 
improved PFS6 correlates with objective reversal of immunosuppression in tumor tissue as 
measured by ex vivo T-cell-specific cytokine profiling. 
 
4.2.3.1 Efficacy Endpoints 
Tumor tissue from the surgical resection and peripheral blood will be evaluated 
longitudinally for pharmcodynamic effects including an increase of the polyfunctional 
effector T cells:Treg ratio and improvement in the anti-tumor immune response. The 
evaluation of tissue PD biomarkers will be correlated to PFS6 with objective increases in 
immune effector function (IFN-γ. IL-2, TNF-α, etc) in tumor tissue as measured by ex vivo 
T-cell-specific cytokines profiling. Improvement in PFS6 will be examined for correlation 
with enhancement of the polyfunctional effector T cells:Treg ratio. 
 
The immune system can and does cross the blood brain barrier; however anti-tumor effects 
are mitigated by tumor mediated immune suppression.  Pembrolizumab works by releasing 

2014-0820 
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the break on the immune system (immune checkpoints).  Since it is the immune system that 
mediates the direct tumor effects, the question the study is intending to address is whether the 
immune system remains activated with the glioblastoma microenvironment by using 
Pembrolizumab.  Thus, the query regarding whether the drug gets past the BBB is 
inconsequential and needs to be reframed in the context of whether the drug can induce a 
functional anti-effector response within the CNS tumor microenvironment - which is being 
directly addressed by the study.  
 
Progression-free survival, defined as the time from study enrollment until the time of first 
occurrence of disease progression, relapse, or death due to disease. Patients who are alive 
without progression or relapse will be censored at the time of last contact. The point estimate 
of 6-month progression-free survival (PFS6) will analyzed. 
 
Additionally, secondary objectives include comparison of time to progression of last prior 
therapy to time to progression on pembrolizumab, median duration of response, ORR, and 
OS will be monitored to further help evaluate efficacy of treatment of recurrent glioblastoma 
withpembrolizumab. 
 
4.2.3.2 Biomarker Research 
Multiple imaging biomarkers will be assessed before and after pembrolizumab treatment and 
correlated with pharmacodynamic changes in tumor (see section 3.3). 
Depending on funding and tissue availability, other studies to be performed will include 
mutation 
assessment, 
transcriptiome 
analysis 
(RNAseq) 
and 
copy 
number 
determination.  Protein phosphorylation analysis using RPPA will be performed if fresh 
tissue is available. 
 
5.0 METHODOLOGY 
 
5.1 
Entry Criteria 
Patients must have pathology confirmed WHO grade 4 glioblastoma, at first or second 
recurrence who require reoperation for tumor progression and have received prior radiation 
and/or chemotherapy.  
 
 
All patients enrolled on this clinical trial must have unstained slides from their original tumor 
surgery to assess PD-L1 expression.  
 
 
A baseline brain MRI will be obtained no less than 14 days prior to study enrollment, on a 
stable dose of steroids no greater than 2 mg a day of dexamethasone for at least 5 days, and is 
required prior to entrance of a patient onto the study. 
 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Recurrent glioblastoma, at first or second relapse, requiring reoperation for tumor 
progression and having already received prior radiation and/or chemotherapy.  
 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 

2014-0820 
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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 histiologically confirmed World Health Organization Grade IV malignant 
glioma (glioblastoma or gliosarcoma). Participants will be eligible if the original 
histology was low-grade glioma and a subsequent histiological diagnosis of 
glioblastoma or variants is made. 
4. Patients must be at first or second relapse and clinically require reoperation for tumor 
progression within 4 to 6 weeks.. Note: Relapse is defined as progression following 
initial therapy (i.e., radiation, chemotherapy, or radiation+ chemotherapy). If the 
participant had a surgical resection for relapsed disease and no antitumor therapy 
instituted for up to 12 weeks, this is considered one relapse. For participants who had 
prior therapy for a low grade glioma, the surgical diagnosis of a high grade glioma 
will be considered first relapse. 
5. Have measurable disease consisting of a minimal volume of 1 cm3.   
6. Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. 
7. Have a performance status of ≥ 60 on the KPS. 
8. Stable dose of steroids for 5 days, no more than 2 mg dexamethasone (or equivalent) 
total per day 
9. Demonstrate adequate organ function as defined in  
10. Table 1, all screening labs should be performed within 14 days prior to registration 
(Reference Table 1).    
 
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  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
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 
aCreatinine clearance should be calculated per institutional standard. 

2014-0820 
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11. Female subject of childbearing potential should have a negative serum pregnancy test. 
.  
12. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
13. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.  
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has been treated previously with bevacizumab  
2. Has tumor localized primarily to the brainstem or spinal cord. 
3. Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics 
delivered by local injection or convection enhanced delivery. 
4. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device 4 weeks since last dose of agent administration. 
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy > 2 mg 
of dexamethasone total per day or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of trial treatment. 
 
6. Has had a prior monoclonal antibody 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 alopecia,  ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study. 
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.   
9. Has known carcinomatous meningitis, extracranial diseaese, or multifocal disease.   
10. Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents. Subjects with 
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study. Subjects with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 
11. Has evidence of interstitial lung disease or 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 

2014-0820 
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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 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, anti-PD-L2, anti-CD137 
antibody (including ipilimumab or any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathways). 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
Testing not required. 
18. Has known history of Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected). Testing not required. 
19. Has received a live vaccine within 30 days prior to the first dose of trial treatment.  
  
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/Treat
ment Period 
Use 
Pembrolizuma
b 
200 mg 
3 weeks 
IV infusion 
24 months 
Experiment
al 
The Pembrolizumab dosing interval may be increased due to toxicity as described in 
Section 5.2.1.2. 
 
Trial treatment should begin on the day of registration or as close as possible to the date on 
which treatment is allocated/assigned. 
 
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.   
The dose amount of Pembrolizumab will be 200 mg every 3 weeks. 
 
5.2.1.2 Dose Modification  
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 3 below. 
Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
Hematological Toxicity 
1, 2 
No 
N/A 
N/A 
N/A 

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Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
 
3* 
*Excluding 
Grade 3 
neutropenia, 
anemia, and 
thrombocytopenia 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
Non-hematological toxicity 
 
Note:  Exception to be treated 
similar to grade 1 toxicity  
 Grade 2 alopecia 
 Grade 2 fatigue 
 
For 
additional 
information 
regarding 
Adverse 
Events 
with a potential Immune-
Etiology 
reference 
Section 
5.6.1.1. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks:  Same 
dose and 
schedule 
(reference 
Section 5.6.1.2 
for 
recommendations 
regarding 
pneumonitis) 
Clinical AE does 
not resolve 
within 4 weeks:  
May increase the 
dosing interval 
by  1 week for 
each occurrence 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
3, 4 
 
Yes 
 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
 
May increase the 
dosing interval 
by 1 week for 
each occurrence 
 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial 
treatment should be discontinued. At the discretion of the treating physician, subjects with a 
laboratory adverse event still at Grade 2 after 12 weeks may continue treatment in the trial 
only if asymptomatic and controlled.  For information on the management of adverse events, 
see Section 5.6.1.   
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from trial 
treatment. 
 

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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 after the scheduled Day 1 of each 
cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals 
may be increased due to toxicity as described in Section 5.2.1.2).  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). 
 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 
 
5.3 
Randomization or Treatment Allocation 
This will be an open label, single arm exploratory biomarker-driven Phase 2 clinical trial and 
thus no randomization is necessary.  
 
5.4 
Stratification 
As an open label, single arm exploratory biomarker-driven Phase 2 clinical, no stratification 
is necessary. Known prognostic factors such as age, Karnofsky performance status prior to 
treatment and extent of surgical resection may be retrospectively examined. 
 
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 final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician. However, the decision to 
continue the subject on trial therapy or vaccination schedule requires the mutual agreement 
of the Investigator and the subject.  
 
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: 
 Anti-cancer systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab  
 Radiation therapy  
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, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) 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 for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology. Patients must be on a stable dose 
of steroids no greater than 2 mg a day of dexamethasone for at least 5 days prior to 
entrance of a patient onto the study. Patients should be maintained on the lowest dose 
of steroids possible following surgery. The use of physiologic doses of corticosteroids 
may be approved after consultation with the supporting Sponsor (Merck).  
 
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 including but not limited to the items outlined below: 
 Diarrhea: 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). In 
symptomatic subjects, infectious etiologies should be ruled out, and if symptoms are 
persistent and/or severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (Grade 3), pembrolizumab will be 
permanently discontinued and treatment with systemic corticosteroids should 
be initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, corticosteroid taper should be started 
and continued over at least 1 month. 
o In subjects with moderate enterocolitis (Grade 2), pembrolizumab should be 
withheld and anti-diarrheal treatment should be started. If symptoms are 

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persistent for more than one week, systemic corticosteroids should be initiated 
(e.g., 0.5 mg/kg/day of prednisone or equivalent). When symptoms improve to 
Grade 1 or less, corticosteroid taper should be started and continued over at 
least 1 month.  Regarding guidelines for continuing treatment with 
pembrolizumab, see Section 5.2. 
o All subjects who experience diarrhea 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. 
 Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
 Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice. 
 Immune-related adverse events: Please see Section 5.6.1.1 below and the separate 
guidance document in the administrative binder regarding diagnosis and management 
of adverse experiences of a potential immunologic etiology.   
 Management of Infusion Reactions: Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness 
of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; 
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or 
exacerbation of tumor pain due to treatment); Urticaria (hives, welts, wheals); 
Vomiting. 
 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab . 
 
Table 5  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, 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
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. 
 
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 further trial treatment 
administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon. irAEs may be predicted based on the nature of the pembrolizumab 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action. Special attention should be paid to AEs that may be 
suggestive of potential irAEs. An irAE can occur shortly after the first dose or several 
months after the last dose of treatment.   

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If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of 
Clinical Interest and Immune-Related Adverse Event Guidance Document located in the 
Administrative Binder.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 6. 
Table 6  General Approach to Handling irAEs 
irAE 
Withhold/Discontinue 
pembrolizumab ? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold pembrolizumab  
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold pembrolizumab  
Discontinue 
if 
unable 
to 
reduce corticosteroid dose to < 
10 mg per day prednisone 
equivalent within 12 weeks of 
toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 
4 weeks. 
 
5.6.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab 
and have an evaluation.  The evaluation may include bronchoscopy and pulmonary function 
tests to rule out other causes such as infection.  If the subject is determined to have study 
drug associated pneumonitis, the suggested treatment plan is detailed in Table 7. 
 
Table 7  Recommended Approach to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue 
pembrolizumab ? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold pembrolizumab , 
may return to treatment if 
improves to Grade 1 or 
resolves within 12 weeks 
Systemic corticosteroids are indicated.  Taper if 
necessary. 
Grade 3 and Grade 4 
Discontinue pembrolizumab  
Systemic corticosteroids are indicated. The use of 
infliximab may be indicated as appropriate.  Refer to 
the Event of Clinical Interest and Immune-related 
Adverse Event Guidance Document for additional 
recommendations. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
 First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
 Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis  Grade 2 
 
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. 

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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.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive. Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has 
not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be 
either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
Subjects should start using birth control from study Visit 1 throughout the study period up to 
120 days after the last dose of study therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to Merck.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study. 
 
5.7.3 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 Merck without delay and 
within 24 hours 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).  If a male subject impregnates his female partner the study personnel at the site 
must be informed immediately and the pregnancy reported 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 

2014-0820 
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withdrawn by the investigator 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 
 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 treatment with pembrolizumab  
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 7.1.5.2.1. 
 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. 
 
5.9 
Subject Replacement Strategy 
Additional subjects may be enrolled to ensure that the required number of evaluable subjects 
is achieved. A subject that discontinues the trial for progressive disease or a drug related 
adverse event will not be replaced and will be counted in the evaluable population of 
subjects. 
 
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 

2014-0820 
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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. 

2014-0820 
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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screen 
Phase 
Treatment Phase 
 
End of 
Treatm
ent 
Post-Treatment 
Treatment Cycle*/Title: 
Main 
Study 
Screening  C1D1 
 
 
C2D1 
 
To be repeated beyond 4 cycles 
 
Safety 
Follow-
up 
Follow 
Up Visits 
Survival 
Follow-Up 
 
 
C1D21 surgery 
C2D21 
C3D1 
C3D21 
C4D1 
C4D21 
 
Scheduling Window* (Days): 
≤ 14 days 
prior to 
registratio
n  
-21 
-1 
0 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
30 days 
post 
discon 
Every 8 
weeks 
post 
discon 
Every 12 weeks  
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Prior therapy data obtained 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administration 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Survival Status 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
Review Adverse Events 
 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Full Physical Examination 
x 
x 
 
 
x 
 
   x 
 
x 
 
 
x 
 
 
Directed Physical Examination 
 
 
x 
 
 
x 
 
x 
 
x 
 
 
 
 
Vital Signs and Weight 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Karnofsky Performance Status 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
 
*Treatment day can have a +3 day window, excluding C1D1.  All other clinical procedures and 
assessments have a -3 day window of the scheduled infusion. 
Pregnancy Test – Serum -HCG 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Comprehensive Serum Chemistry Panel 
(see Table 9) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
 
Urinalysis 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging 
x 
 
x** 
 
x** 
 
x 
 
x 
 
 
 
x**** 
 
 
 

2014-0820 
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Trial Period: 
Screen 
Phase 
Treatment Phase 
 
End of 
Treatm
ent 
Post-Treatment 
Treatment Cycle*/Title: 
Main 
Study 
Screening  C1D1 
 
 
C2D1 
 
To be repeated beyond 4 cycles 
 
Safety 
Follow-
up 
Follow 
Up Visits 
Survival 
Follow-Up 
 
 
C1D21 surgery 
C2D21 
C3D1 
C3D21 
C4D1 
C4D21 
 
Scheduling Window* (Days): 
≤ 14 days 
prior to 
registratio
n  
-21 
-1 
0 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
30 days 
post 
discon 
Every 8 
weeks 
post 
discon 
Every 12 weeks  
Archival or Newly Obtained Tissue 
Collection 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection*** 
x 
 
 
x 
 
 
X*** 
 
 
 
 
X*** 
 
 
** C1D21 - within 72 hours prior to surgery. C2D1 - within 72 hours post surgery. 
*** Prior to cycle 1 (baseline), at the time of surgery, prior to cycle 3, 6, and 9 and at progression 
**** Subjects other than disease progression will be assessed every 8 weeks  
 
 
 

2014-0820 
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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. The treatment day can have a +3 day window, excluding C1D1.  All other clinical 
procedures and assessments have a -3 day window of the scheduled infusion. 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. 
Laboratory assessments performed as part of the screening evaluations and within 72 
hours of the first dose of study treatment, are not required to be repeated on the first 
dosing day. 
 
Furthermore, additional evaluations/testing may be deemed necessary by 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 
 
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. 
 
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. 

2014-0820 
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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. 
 
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 
7.1.1.7 Assignment of Randomization Number 
This will be an open label, single arm exploratory biomarker-driven Phase 2 clinical trial and 
thus no randomization is necessary. 

2014-0820 
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7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
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 12.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
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 (irAE). See Section 5.6.1.1 and the separate guidance document in the 
administrative binder regarding the identification, evaluation and management of AEs of a 
potential immunological etiology.   
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 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. 
7.1.2.5 Karnofsky Performance Scale (KPS) 
The investigator or qualified designee will assess KPS status (see Section 12.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial 
treatment as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
A baseline MRI brain obtained no less than 14 days prior to study enrollment, on a stable 
dose of steroids no greater than 2 mg daily for at least 5 days, is required prior to entrance of 
a patient onto the study. 
An MRI Brain will also be obtained within 72 hours prior to and within 72 hours after 
surgical resection. After recovery from surgery (approximately 2-3 weeks), patients will 
receive pembrolizumab until disease progression, the development of unacceptable toxicities 
or completion of 24 months of treatment with pembrolizumab. Treatment will be 
administered every 3 weeks. Cycles will be 42 days. Participants will remain on treatment 
until tumor progression, as long as there are no unacceptable toxicities.  
Imaging response criteria will be based on a modified version of the RANO scale (appendix 
12.3). Tumor response will be assessed with MRI scans every 6 weeks following surgery 
using modified RANO criteria (appendix 12.3) as outlined. Clinicians may repeat response 

2014-0820 
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assessment more frequently as clinically indicated. The MRI Brain following surgical 
resection will be considered the baseline MRI for evaluation of treatment response. 
Measurement of effect 
Anti-Tumor Effect Definitions 
Evaluable for objective response. Only those participants who have measurable disease 
present at baseline scan and have received at least one dose of therapy will be considered 
evaluable for response. These participants will have their response classified according to the 
definitions stated below. (Note: Participants who exhibit objective disease progression or die 
prior to the end of cycle 1 will also be considered evaluable.) 
  
Measurable disease. Bi-dimensionally, contrast-enhancing, measurable lesions with clearly 
defined margins by MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices 
which are at least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or 
surgical cavity, if necessary, requires a minimum thickness of 3 mm. If there are too many 
measurable lesions to measure at each evaluation, the investigator must choose the largest 
two to be followed before a participant is entered on study. The remaining lesions will be 
considered non-measureable for the purpose of objective response determination. Unless 
progression is observed, objective response can only be determined when all measurable and 
non-measurable lesions are assessed. 
  
Non-measurable evaluable disease. Unidimensionally measurable lesions, masses with 
margins not clearly defined, lesions with maximal diameter < 1cm. 
  
Response/Progression Categories 
 
Complete response (CR). All of the following criteria must be met: 
a) Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan 
will be considered only stable disease. 
b) No new lesions. 
c) All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
d) Participants must be on no steroids or on physiologic replacement doses only. 
e) Stable or improved non-enhancing (T2/FLAIR) lesions  
f) Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related 
  
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
 
Partial response (PR). All of the following criteria must be met: 
a) Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. In 
the absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease. 
b) No progression of non-measurable disease. 

2014-0820 
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c) No new lesions. 
d) All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
e) The steroid dose at the time of the scan evaluation should be no greater than the dose at 
time of baseline scan. 
f) Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 
g) Stable or improved, for clinical signs and symptoms present at baseline and recorded to be 
disease related clinically. 
  
Participants with non-measurable disease cannot have a partial response. The best response 
possible is stable disease. 
 
Progressive disease (PD). Any of the following criterion must be met: 
a) > 25% increase in sum of the products of perpendicular diameters of enhancing lesions 
(over best response or baseline if no decrease) on stable or increasing doses of corticosteroids 
b) Any new enhancing measurable lesion 
c) Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, infection, 
etc.). The definition of clinical deterioration is left to the discretion of the investigator but it 
is recommended that a decline in the Karnofsky Performance Score (KPS) from 100 or 90 to 
70 or less, a decline in KPS of at least 20 from 80 or less, or a decline in KPS from any 
baseline to 50 or less, for at least 7 days, be considered neurologic deterioration, unless 
attributable to co-morbid events or changes in corticosteroid dose. 
d) Failure to return for evaluation due to death or deteriorating condition 
 
Stable disease (SD). All of the following criteria must be met: 
a) Does not qualify for CR, PR, or progression. 
b) All measurable and non-measurable sites must be assessed using the same techniques as 
baseline. 
c) Stable clinically. 
 
Unknown response status. Progressive disease has not been documented and one or more 
measurable or non-measurable lesions have not been assessed. 
  
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed within 14 days prior 
to registration.  
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. 
  
Evaluation of Best Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 

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recorded since the treatment started). If a response recorded at one scheduled MRI does not 
persist at the next regular scheduled MRI, the response will still be recorded based on the 
prior scan, but will be designated as a non-sustained response. If the response is sustained, 
i.e. still present on the subsequent MRI at least four weeks later, it will be recorded as a 
sustained response, lasting until the time of tumor progression. Participants without 
measurable disease may only achieve SD or PD as their best “response.” 
  
Study Continuation Beyond Initial Progressive Disease 
RANO will be adapted to account for the potential tumor response characteristics seen with 
treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. Standard RANO may not 
provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. 
 
Therefore, the following adaptations of the RANO criteria will be used to assess response for 
patients treated on this study (Table 1): 
• If radiologic imaging shows initial PD, tumor assessment should be repeated 4 weeks later 
in order to confirm PD with the option of continuing treatment as described below while 
awaiting radiologic confirmation of progression. If repeat imaging shows a reduction in the 
tumor burden compared to the initial scan demonstrating PD, treatment may be continued / 
resumed. If repeat imaging confirms progressive disease, defined as a 25% increase from 
baseline or best response, then the date of disease progression will be the first date the 
subject met criteria for progression and subjects will be discontinued from study therapy. 
Subjects who have confirmed disease progression will discontinue study medication and 
enter the follow up/survival phase of the study. In determining whether or not the tumor 
burden has increased or decreased, investigators should consider all target lesions as well as 
non-target lesions. 
• Immune based therapies are expected to be associated with inflammatory changes that may 
include edema. RANO expanded the previously utilized Macdonald criteria to include the 
development of “significantly” increased T2 or FLAIR abnormality in the definition of 
progressive disease because such changes can be a major component defining radiographic 
progression following therapeutic use of VEGF/VEGFR-targeting therapeutics which are 
known to elicit potent anti-permeability changes that limit contrast uptake. Our study will 
define radiographic progressive disease by assessment of enhancing tumor burden and will 
not incorporate assessment of T2 or FLAIR changes as outlined in RANO because: 
(1) there is no expectation that immunotherapy agents will falsely diminish enhancing tumor 
burden as has been noted with anti-angiogenic therapies; and 
(2) immune based therapies may be associated with increased edema and associated 
T2/FLAIR changes which may inaccurately be interpreted to represent tumor progression 
(i.e. pseudoprogression). 
  
In subjects who have initial evidence of radiographic PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment until repeat imaging is obtained a 

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minimum of 4 weeks later. This clinical judgment decision should be based on the subject’s 
overall clinical condition, including performance status, clinical symptoms, and laboratory 
data. Subjects may receive study treatment while waiting for confirmation of PD if they are 
clinically stable as defined by the following criteria: 
• The subject is believed to demonstrate clinical benefit from the study regimen as 
determined by the treating physician; 
• The subject is adequately tolerating study therapy. 
  
When feasible, subjects should not be discontinued until radiographic progression is 
confirmed. This allowance to continue treatment despite initial radiologic progression takes 
into account the observation that some subjects can have a transient tumor flare in the first 
few months after the start of immunotherapy, but with subsequent disease response. Subjects 
that are exhibiting significant neurologic decline are not required to have repeat imaging for 
confirmation of progressive disease. 
 
Table.1  
Imaging and Treatment after 1st Radiologic Evidence of PD 
 
No Significant Neurologic Decline 
Significant Neurologic Decline 
 
Imaging 
Treatment 
Imaging  
Treatment 
1st 
radiologic 
evidence of PD 
Repeat imaging 
>4 weeks later 
to confirm PD 
May 
continue 
study treatment 
at 
the 
Investigator’s 
discretion while 
awaiting 
confirmatory 
scan 
Repeat imaging 
>4 weeks later 
to confirm PD 
Discontinue 
Treatment 
Repeat 
scan 
confirms PD 
No 
additional 
imaging 
required 
Discontinue 
Treatment 
No 
additional 
imaging 
required 
Not applicable 
Repeat 
scan 
confirms 
SD,PR, or CR 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 6  weeks 
Continue study 
treatment at the 
Investigator’s 
discretion 
Continue 
regularly 
scheduled 
imaging 
assessments 
every 6 weeks 
May 
restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per investigators 
discretion 
 
 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
All patients enrolled on this clinical trial must have unstained slides from their original tumor 
surgery to assess PD-L1 expression. In addition to the original tumor specimens, the 
recurrent surgical specimens will be sent for testing to compare the difference between PD-
L1 expressions in recurrent and primary untreated tumor in each patient enrolled on the trial.  
Pembrolizumab pharmacokinetics from the blood will be correlated with other tumor 
pharmacodynamics markers.  Tumor tissue from the surgical resection and peripheral blood 
will be evaluated longitudinally for pharmcodynamic effects. The evaluation of tissue PD 

2014-0820 
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biomarkers will be correlated with circulating biomarker effects following drug exposure and 
PFS6 to determine if treatment of recurrent glioblastoma with pembrolizumab monotherapy 
will result in an increase of the polyfunctional effector T cells:Treg ratio and improve the 
anti-tumor immune response. 
 
Biomarker 
Collection 
 
 
 
Specimen Type 
Lab Test 
Time of collection 
Lab Performing Test 
Blood 
 
 
 
 
Serum cytokines 
profile: CSF-1, IL-
6, TGF-β, VEGF, 
IL-10, IL-23 
(20mL - Heparin 
Tubes) 
Pre-dose 
Prior 
to 
cycle 1 (baseline), at 
the time of surgery, 
prior to cycle 3, 6, 
and 
9 
and 
at 
progression 
MDACC 
Core 
Immunotherapy lab 
 
Th1 vs Th2 
phenotyping: IL-2, 
IL4, IL-10, IL-13, 
INF-γ, TNF-α 
(20mL - Heparin 
Tubes) 
Pre-dose 
Prior 
to 
cycle 1 (baseline), at 
the time of surgery, 
prior to cycle 3, 6, 
and 
9 
and 
at 
progression 
MDACC 
Core 
Immunotherapy lab 
 
T-cell subtypes 
(CD3, CD4, CD8, 
FoxP3, CD25, 
etc.) including 
their functional  
status based on 
intracellular 
cytokines; effector 
to suppressor 
ratios (CD4:Treg; 
CD8:Treg)  
(20mL - Heparin 
Tubes)  
Pre-dose 
Prior 
to 
cycle 1 (baseline), at 
the time of surgery, 
prior to cycle 3, 6, 
and 
9 
and 
at 
progression 
MDACC 
Core 
Immunotherapy lab 
 
CD8+ CMV pp65 
specific tetramer 
positive cells 
(30mL - Heparin 
Tubes)  
Pre-dose 
Prior 
to 
cycle 1 (baseline), at 
the time of surgery, 
prior to cycle 3, 6, 
and 
9 
and 
at 
progression 
MDACC 
Amy 
Heimberger lab 
 
Future correlative 
analyses 20mLs – 
Heparin Tubes 
Pre-dose    Prior   
to 
cycle 
1 
(baseline), at the 
time 
of 
surgery, 
prior  to  cycle  3,  
6, and 9 and at 
MDACC Amy 
Heimberger lab 

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progression 
Tissue 
 
 
 
Fresh 
T-cell subtypes 
(CD3, CD4, CD8) 
including their 
functional status 
via intracellular 
cytokine profiling 
(IL-2, IFN-γ, 
TNF-α, perforin, 
granzyme)  
Day of Surgery  
MDACC 
Core 
Immunotherapy lab or 
Amy Heimberger Lab 
 
PD-L1 expression 
on tumor cells and 
immune cell 
subtypes (either 
using a 
commercial 
antibody or a 
proprietary 
antibody provided 
by Merck, as 
available) 
Day of Surgery 
MDACC 
Amy 
Heimberger 
Lab 
or 
Core 
Immunotherapy 
lab 
 
Formalin-fixed  
paraffin 
embedded 
tissue; 30 slides 
PD-L1 (CD 274) 
and PD-L2 (CD 
273 
Day of Surgery 
MDACC 
Amy 
Heimberger 
Lab 
or 
Wistuba Lab (PD-L2) 
QualTek 
Molecular 
Laboratories (PD-L1) 
Macrophages 
(CD68 and 
CSF1R) 
Day of Surgery 
MDACC 
Amy 
Heimberger 
Lab 
or 
Wistuba Lab 
Microvascular 
density (CD31) 
Day of Surgery 
MDACC 
Amy 
Heimberger Lab 
M2-skewed 
macrophage 
markers (CD163) 
Day of Surgery 
MDACC 
Amy 
Heimberger 
Lab 
or 
Wistuba Lab 
Hypoxia (carbonic 
anhydrase-9; CA9 
and HIF1-α) 
Day of Surgery 
MDACC 
Amy 
Heimberger 
Lab 
or 
Wistuba Lab 
Tregs (FoxP3+) 
Day of Surgery 
MDACC 
Amy 
Heimberger 
Lab 
or 
Wistuba Lab 
CMV viral antigen 
pp65 expression 
Day of Surgery 
MDACC 
Amy 
Heimberger 
Lab 
or 
Wistuba Lab 
Additional CMV 
Day of Surgery 
MDACC 
Amy 

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antigens may be 
assayed (i.e. gB, 
IE1) as well as 
non-viral related 
glioblastoma-
specific and 
tumor-associated 
antigens (i.e. 
EGFR, EGFRvIII, 
survivin, IL-13R) 
Heimberger 
Lab 
or 
Wistuba Lab 
 
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.   

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Table 9  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) 
 
  (CO2 or biocarbonate) 
 
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.  
 
 
 

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Laboratory tests for screening should be performed within 14 days prior to registration. 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.  
 
7.1.4 Other Procedures 
7.1.4.1 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 7.1.5.2.1.  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). 
7.1.4.2 Blinding/Unblinding 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered thus no blinding/unblinding is necessary. 
7.1.5 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. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
Any patient with recurrent glioblastoma at first or second relapse that is being considered for 
surgical resection will be eligible for screening.  Screening will include vital signs, physical 
exam, and determination of availability of archival tumor tissue for PD-L1 staining, and 
laboratory evaluations described in Table 1.  The window for screening will consist of 14  
days prior to registration. 
7.1.5.2 Treatment Period 
Patients will be treated with up to 2 doses of pembrolizumab prior to surgery (day -21 and 
day -1 prior to the surgery).   
During the presurgery phase, if, after one dose of pembrolizumab, a patient experiences 
progressive clinical symptoms, then the second dose of pembrolizumab will be deferred and 
the patient will proceed to surgery to correlate imaging changes with immunologic effects 
within the tumor. 
After recovery from surgery (approximately 2-3 weeks), patients will receive pembrolizumab 
until disease progression, the development of unacceptable toxicities, or until completion of 
24 months of treatment with pembrolizumab. Treatment will be administered every 3 weeks. 
Cycles are 42 days. Participants will remain on treatment until tumor progression, as long as 
there are no unacceptable toxicities until completion of 24 months of treatment with 
pembrolizumab. 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1  Safety Follow-Up Visit 

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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 
treatment should also be followed and recorded.   
7.1.5.4 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. 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.  Information regarding post-study anti-neoplastic 
treatment will be collected if new treatment is initiated. 
   
7.1.5.4.1 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 will 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.  
7.2 
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. Lab abnormalities will be considered an abnormal event if clinically 
significant. Clinically significant will be defined if requiring a holding of the treatment, a 
dose reduction of the treatment or a new prescription is given.  Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting condition 
that is temporally associated with the use of the Merck’s product, is also an adverse event. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Abnormal laboratory values or test results occurring after informed consent constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, require therapy (e.g., hematologic abnormality that requires transfusion or 
hematological stem cell support), or require changes in study medication(s). 
  
Adverse events that begin or worsen after informed consent should be recorded in the 
Adverse Events CRF. Conditions that were already present at the time of informed consent 
should be recorded in the Medical History page of the patient’s CRF. Adverse event 
monitoring should be continued for at least 30 days following the last dose of study 
treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 

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symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to grades 1 - 4, will be 
used. CTCAE grade 5 (death) will not be used in this study; rather, information about deaths 
will be collected though a Death form. 
 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient (subject) during the screening process after signing informed consent and at each visit 
during  the study. Adverse events also may be detected when they are volunteered by the 
patient (subject) during the screening process or between visits, or through physical 
examination, laboratory test, or other assessments. As far as possible, each adverse event 
should be evaluated to determine: 
1. The severity grade (CTCAE grade 1-4) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 7.2.3. 
 
Surgical resection of recurrent GBM is standard of care in the study and is not required to be 
reported as an AE. However medical complications related to this surgery must be reported 
as AE.  
 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. The PI or physician designee is responsible for providing source 
documentation and assigning attribution for all AEs. 
Adverse events will not be collected for subjects during the screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting. 
 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by 20% over the prescribed dose. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, 

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pembrolizumab should be discontinued and the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 2 working 
days hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
7.2.2 Reporting of Pregnancy and Lactation to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial or within 120 days of completing the trial completing the trial, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier.  All subjects and female partners of male subjects who become pregnant 
must be followed to the completion/termination of the pregnancy.  Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events).  If the pregnancy continues to term, the outcome (health of 
infant) must also be reported. 
Such events must be reported within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to Merck 
Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study that occurs to any subject from 
the time the consent is signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or not related to Merck 
product, must be reported within 2 working days to Merck Global Safety.  

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Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.1 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) 
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 Merck, 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. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to to Merck Global Safety within 2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.”  This document provides guidance 
regarding identification, evaluation and management of ECIs and irAEs.  Additional ECIs are 
identified in this guidance document and also need to be reported to Merck Global Safety 
within 2 working days of the event.   

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Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or 
not related to the Merck’s product, must be reported within 24 hours to Merck Global Safety 
within 2 working days. 
7.2.4 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. 

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Table 10  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; limiting 
self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product 
that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from 
the event as it occurred (Note: This does not include an adverse event that, had it occurred in a more 
severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to 
conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient 
admission, regardless of length of stay, even if the hospitalization is a precautionary measure for 
continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a 
preexisting condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to 
diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is 
considered a serious adverse event. An overdose that is not associated with an adverse event is considered 
a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical 
judgment, the event may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of 
time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck 
product caused the adverse event will be provided by an investigator who is a qualified physician. The 
investigator’s signed/dated initials on the source document or worksheet that supports the causality noted 
on the AE form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are intended as 
reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test 
drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and 
the AE; the greater the correlation with the components and their respective elements (in number and/or 
intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: 
reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the 
Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials 
with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, 
other drug(s)/vaccine(s), or other host or environmental factors 
 
 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: 
(continued) 

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to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Merck product; or (3) 
the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the trial is a single-dose drug trial); or (3) Merck product(s) is/are used 
only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE MERCK 
PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge 
regarding the Merck product or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified 
physician according to his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE 
onset relative to the administration of the Merck product is reasonable.  The AE is more 
likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative 
to administration of the Merck product is not reasonable OR there is another obvious cause 
of the AE.  (Also entered for a subject with overdose without an associated AE.) 

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7.2.5 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 
This will be an open label, single arm exploratory biomarker-driven Phase 2 clinical trial in 
patients with glioblastoma at first or second recurrence. Patients must have received prior 
radiation and/or temozolomide therapy.  A total of approximately 20 patients with recurrent 
glioblastoma who require reoperation for tumor progression will be treated and PFS6 will 
analyzed. 
Progression-free survival will be defined as the time from study enrollment until the time of 
first occurrence of disease progression, relapse, or death due to disease. Patients who are 
alive without progression or relapse will be censored at the time of last contact. Time to 
progression and overall survival will be evaluated using the Kaplan-Meier product-limit 
survival curve methodology. PFS6 will be estimated using Kaplan-Meier estimates and 
associated two-sided 95% confidence intervals. Cox proportional hazard regression will be 
employed for multivariate analysis on time-to-event outcomes. In addition, summary 
statistics and linear regression will be used to analyze continuous variables. Frequency tables 
will be used to summarize categorical variables. Logistic regression will be utilized to assess 
the effect of patient prognostic factors on the response rate and the toxicity rate. Given the 
sample size of 20 patients and a significant level of 10%, we have 74% power to detect the 
improvement of the PFS6 from 15% (i.e., the historical PFS rate) to 35% in a two-sided test.   
A Bayesian design will be used to conduct this single-arm phase II clinical trial, with an 
interim analysis performed after 10 patients are enrolled. Accrual will be halted, if needed, 
during the interim analysis. The interim analysis is based on co-primary endpoints: PFS6 and 
effector:Treg ratio measured at the time of surgery. We define effector:Treg ratio>=5% as a 
success (i.e., favorable outcome) and <5% as a failure (i.e., unfavorable outcome) and denote 
the success rate of Treg ratio as TRS. Historical data on similar patients show a PFS6 of 15% 
and TRS of 5% (Wong ET, 1999). Thus, we will early terminate the trial if, based on interim 
data, there is a high posterior probability that PFS6 <15% or/and TRS <10%. We assume that 
PFS6 and TRS marginally follow binomial distributions. Because our monitoring rule is 
based on the marginal distributions of PFS6 and TRS, we herein do not consider the joint 
distribution of PSF6 and TRS. As the sample size is small, we do not expect that this will 
cause noticeable loss of efficiency. We assign vague beta prior Beta (0.15, 0.85) to PFS6 and 
Beta (0.1, 0.9) to TRS. We will stop the trial if Pr (PFS6 <15%|Interim Data) >0.9 or/and Pr 
(TRS <10%|Interim Data)>0.9, which results in the following stopping boundary:  
 
Stop the trial if 10 out of 10 patients have disease progression within 6 months or/and  
10 out 10 patients have and effector:Treg ratio<5%. 
 
The following table provides the operating characteristics of the design, generated by 
MultcLean software based on 10,000 simulations. 
 

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True TRS Rate True PFS6 Rate Prob(stop the trial early) 
0.05 
0.05 
0.84 
 
0.15 
0.68 
 
0.25 
0.62 
 
0.35 
0.60 
0.10 
0.05 
0.74 
 
0.15 
0.48 
 
0.25 
0.39 
 
0.35 
0.36 
0.15 
0.05 
0.68 
 
0.15 
0.36 
 
0.25 
0.24 
 
0.35 
0.21 
 
 
We also monitor toxicity (TOX) using a Bayesian rule as follows: stop the trial if Pr (TOX > 
30%|Data)>0.8, where TOX is defined as any grade 3 or higher adverse event that is 
possibly, probably, or definitely related to any therapy received on this protocol and occur 
within the first 6 weeks of therapy with one exception. Any grade 3 or higher adverse event 
that is potentially treatable with steroids will only count as a TOX if it does not improve to 
grade 1 or better within 2 weeks of steroid therapy. Additionally, a delay of greater than 3 
months from the expected surgery date will count as a TOX. We monitor TOX based on 
cohort size of 5. Assuming a Beta prior Beta (0.3, 0.7) for the toxicity probability, this 
Bayesian rule translates into the following stopping boundary: stop the trial if the number of 
patients experienced TOX is 3-5/5, 5-10/10, or 7-15/15. The following table provides the 
operating characteristics of the design based on 1000 simulation. 
 
 
 
 
 
 
 
 
 
Baseline characteristics will be assessed by the use of tables and/or graphs. No statistical 
hypothesis will be performed on these characteristics. The number and percentage of subjects 
screened, the primary reasons for screening failure, and the primary reason for 
discontinuation will be displayed. Demographic variable (e.g., age, gender), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables. 
Longitudinal analyses of peripheral blood mononuclear cells immune response kinetics and 
circulating cytokines to pembrolizumab will be presented graphically and descriptively at 
each time point. Changes in the magnitude of the response relative to pretreatment after 
pembrolizumab therapy will be summarized descriptively. Changes in response between pre-
 
True TOX probability 
 
0.1 
0.2 
0.3 
0.4 
0.5 
Stopping 
probability 
1% 
7% 
26.4% 
54% 
77.6% 
Average 
sample size 
19.9 
19.0 
16.8 
13.3 
10.3 

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treatment and prior to initiation of cycle 3 of pembrolizumab, will be assessed using the 
Wilcoxon signed-rank test. 
 
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 11. 
Table 11  Product Descriptions 
Product Name & Potency 
Dosage Form 
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 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.  Pembrolizumab Solution for Infusion, 100 mg/vial:  
Pembrolizumab Solution for Infusion vials should be stored at refrigerated conditions (2 
– 8 °C) and protected from light. 
Note: vials should be stored in the original box to ensure the drug product is protected 
from light. 
 
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. 
 

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10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
The investigator will assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. The Informed Consent Form will 
incorporate (or, in some cases, be accompanied by a separate document incorporating) 
wording that complies with relevant data protection and privacy legislation. Pursuant to this 
wording, patients will authorize the collection, use and disclosure of their study data by the 
Investigator and by those persons who need that information for the purposes of the study. 
The use of the samples for research will be done in accordance with the guidelines defined by 
the FDA document “Guidance on Informed Consent for In Vitro Diagnostic Device Studies 
Using Leftover Human Specimens that are Not Individually Identifiable” (issued 25 April 
2006). The subject’s personal information will be removed before the research samples are 
used. The research samples will be de-identified by setting a study code /initials. If a subject 
requests destruction of their banked research tissue and blood samples, and the samples have 
not yet been de-identified, the investigator will destroy the samples as described in this FDA 
guidance. 
 
10.2 Compliance with Law, Audit and Debarment 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki.  The review of this protocol by the IRB/EC 
and the performance of all aspects of the study, including the methods used for obtaining 
informed consent, must also be in accordance with principles enunciated in the declaration, 
as well as ICH Guidelines, Title 21 of the Code of Federal Regulations (CFR), Part 50 
Protection of Human Subjects and Part 56 Institutional Review Boards. 
The Investigator will be responsible for preparing documents for submission to the relevant 
IRB/EC and obtaining written approval for this study.  The approval will be obtained prior to 
the initiation of the study. 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
Any amendments to the protocol after receipt of IRB/EC approval must be submitted by the 
Investigator to the IRB/EC for approval.  The Investigator is also responsible for notifying 
the IRB/EC of any serious deviations from the protocol, or anything else that may involve 
added risk to subjects. 
Any advertisements used to recruit subjects for the study must be reviewed and approved by 
the IRB/EC prior to use. 
10.3 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.     
10.4 Quality Management System 
Quality assurance measures are provided by three mechanisms: ongoing in-house monitoring 
of protocol compliance, on-site audits, and response reviews. Data monitoring will begin at 

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the time of patient registration and will continue during protocol performance and 
completion.  The Protocol Manager will perform the ongoing in-house protocol compliance 
monitoring with the support of the study investigators. 
10.5 Data Management 
All subjects will be registered in CORe and data will be entered in PDMS/CORe, the 
electronic CRF. Designated research staff will enter the data. All investigators will record 
information regarding on study, course (flowsheet), offstudy, survival, and toxicity data.   
All data will be monitored on an ongoing basis by the PI(s), the research study nurses, and 
data managers Institutional Review Board (IRB) will be notified of any adverse events and 
provided data to permit a safety review of the study treatment. The IRB may request 
additional meetings or safety reports as deemed necessary.  The IRB may also stop the trial 
following a review of results from such analysis. 
 
A data set from a completed clinical trial (N=15) of GBM patients that includes age, sex, 
KPS, IDH1 mutational status, MGMT methylation status, p38 reactivity, and pERK status, 
extent of resection, treatment, survival and timing of the drug to surgery will be consolidated 
with a dataset of patients treated at Northwestern University to determine genetic biomarkers 
of response to anti-PD-1. Dr. Adam M Sonabend is our collaborator at Northwestern 
Medicine/Northwestern University. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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12.0 APPENDICES 
12.1 Karnofsky Performance Status 
KPS  100 
Normal; no complaints; no evidence of disease 
KPS    90 
Able to carry on normal activity; minor signs or symptoms of disease 
KPS    80 
Normal activity with effort; some sign or symptoms of disease 
KPS    70 
Cares for self; unable to carry on normal activity or do active work 
KPS    60 
Requires occasional assistance, but is able to care for most personal needs 
KPS    50 
Requires considerable assistance and frequent medical care 
KPS    40 
Disabled; requires special care and assistance 
KPS    30 
Severely disabled; hospitalization is indicated, although death no imminent 
KPS    20 
Very sick; hospitalization necessary; active support treatment is necessary 
KPS    10 
Moribund; fatal processes progressing rapidly 
KPS     0 
Dead 
 
 

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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 Assessment in Neuro-Oncology (RANO) Criteria for Evaluating 
Response 
Definitions of Response (Based on RANO Criteria) 
 
RANO Criteria: 
 
 
 
Criterion                       
CR 
PR 
SD 
PD*** 
 
 
 
 
 
T1 gadolinium enhancing disease  
 None      > 50%  ↓ 
< 50% ↓ but  < 25% ↑ 
> 25%↑ 
T2/FLAIR 
Stable or  
↓  
Stable or  
↓  
Stable or  ↓  
↑* 
New Lesion 
None   
None   
None   
Present 
Corticosteroids 
None 
Stable or  
↓  
Stable or  ↓  
NA** 
Clinical Status 
Stable or  
↑  
Stable or  
↑  
Stable or  ↑  
↓* 
Requirement for Response 
All 
All 
All 
Any* 
 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR, complete response; PR, partial  
response; SD, stable disease; PD, progressive disease; FLAIR, fluid-attenuated inversion  
recovery; NA, not  applicable. 
* Progression occurs when this criterion is present. To be considered progressive disease, increase in 
T2/FLAIR should occur on stable or increasing doses of corticosteroids compared to baseline 
scan or best response following initiation of therapy, and should not be due to co-morbid 
events (e.g. radiation therapy, demyelination, ischemic injury, infection, seizures, post-
operative changes, or other treatment effects). 
**Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration. 
*** this criteria only pertains to assessment of progression >12 weeks following completion of 
chemoradiation. 
 
Progression is only diagnosed within the first 12 weeks following completion of  
chemoradiation in the context of new enhancement observed outside the radiation 
field and/or histological confirmation (biopsy-proven). (Wen, 2010) 
 
 
 

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Appendix 4: MD Anderson Form for reporting SAEs