Phase II Study of Pembrolizumab (MK-3475) in Combination With Standard Therapy for Newly Diagnosed Glioblastoma
Phase: PHASE2
Conditions: Glioblastoma, Gliosarcoma, Supratentorial Glioblastoma
Sponsor: Mayo Clinic

MC1572 
Protocol version: 24Feb2022 
Mayo Clinic Cancer Center 
MC1572 Phase II study of pembrolizumab (MK-3475) in combination with standard therapy for 
newly diagnosed glioblastoma 
Study Chair: 
 
 
 
Study Cochairs: 
 
 
 
Statistician: 
 
 
 
√Study contributor(s) not responsible for patient care 
 
Drug Availability  
Supplied Investigational Agents: MK-3475 (pembrolizumab) (IND# 131137)  
Commercial Agents: Temozolomide 
Drug Company Supplied: MK-3475 (pembrolizumab)  
 
 
Document History 
Effective Date 
Activation 
15Sep2017 
Amendment 1 
07Dec2017 
Amendment 2 
31Jul2018 
Amendment 3 
03Dec2019 
Amendment 4 
14Sep2020 
Amendment 5 
15Dec2020 
Amendment 6 
09Feb2021 
Amendment 7 
26Feb2021 
Amendment 8 
04Apr2022 
 
 
 
 

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Protocol Resources 
Questions: 
Contact Name: 
Patient eligibility*, test schedule, 
treatment delays/interruptions/adjustments, 
dose modifications, adverse events, 
forms completion and submission 
 
 
 
 
Forms completion and submission 
 
 
 
Protocol document, consent form, 
regulatory issues 
 
 
 
Paraffin-embedded tissue pathology  
TBD if sites other than Mayo Rochester 
Non-paraffin biospecimens  
 
 
 
 
Serious Adverse Event Reporting  
 
 
*No waivers of eligibility 
 
 

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Table of Contents 
MC1572 Phase II study of pembrolizumab (MK-3475) in combination with standard therapy for newly 
diagnosed glioblastoma .................................................................................................................... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema – Neoadjuvant Patients (Group 1) – Rochester only ....................................................................... 4 
Schema – Adjuvant Patients (Group 2)......................................................................................................... 5 
1.0 
Background ......................................................................................................................... 6 
2.0 
Goals ................................................................................................................................. 15 
3.0 
Patient Eligibility .............................................................................................................. 16 
4.0 
Study Calendars ................................................................................................................ 19 
5.0 
Grouping Factor ................................................................................................................ 23 
6.0 
Registration Procedures .................................................................................................... 23 
7.0 
Protocol Treatment ........................................................................................................... 26 
8.0 
Dosage Modification Based on Adverse Events ............................................................... 33 
9.0 
Ancillary Treatment/Supportive Care ............................................................................... 42 
10.0 
Adverse Event (AE) Reporting and Monitoring ............................................................... 51 
11.0 
Treatment Evaluation Using iRANO Guideline ............................................................... 69 
12.0 
Descriptive Factors ........................................................................................................... 75 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient .................................................. 75 
14.0 
Body Fluid Biospecimens ................................................................................................. 77 
15.0 
Drug Information .............................................................................................................. 81 
16.0 
Statistical Considerations and Methodology .................................................................... 88 
17.0 
Pathology Considerations / Tissue Specimen Submission ............................................... 94 
18.0 
Records and Data Collection Procedures .......................................................................... 96 
19.0  
Budget ............................................................................................................................... 97 
20.0 
References ......................................................................................................................... 98 
Appendix I 
ECOG Performance Status ............................................................................................. 101 
Appendix II 
Radiation Therapy Recommendations ............................................................................ 102 
Appendix III 
Pembrolizumab ECI Drug-Induced Liver Injury (DILI) ................................................ 106 
Appendix IV 
Presentation of Dermatologic Event ............................................................................... 108 
Appendix V 
Patient Medication Diary MC1572 ................................................................................. 110 
 

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Schema – Neoadjuvant Patients (Group 1) – Rochester only 
All Group 1 Patients: Prior to discussing protocol entry with the patient,  
call the MCCC Registration Office 
  
to ensure that a place on the protocol is open to the patient 
Registration 
↓ 
Neoadjuvant (Cycle 1) 
MK-3475 single dose 
4-7 days prior to craniotomy 
↓ 
Surgery (Cycle 2) 
Craniotomy/resection Day 1 
and recovery 21-35 days  
↓ 
Concurrent† (Cycle 3) 
MK-3475, Days 1, 22 and 43 
XRT and TMZ Days 8-54, plus 
rest period 21-35 days post RT 
↓ 
Adjuvant* (Cycles 4-8) 
MK-3475, Days 1, 22 and 43ᵠ 
TMZ Days 1-5, q 28 days 
up to 5 adjuvant cycles* 
↓ 
Observation 
↓ 
Event Monitoring 
 
PD at any time 
 
 
 
Intolerable adverse events 
 
→ 
Event Monitoring 
Patient refusal 
 
 (per Section 4.0) 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13 for follow-up information. 
†Cycle length = 7 weeks only during Concurrent stage, plus 21-35 day rest period post-RT 
*Cycle length = 63 days only during Adjuvant stage 
ᵠUp to maximum of 17 total doses of pembrolizumab 
Generic names: pembrolizumab, MK-3475 
Brand name(s): Keytruda® 
Mayo Abbreviation: MK-3475 
Availability: Mayo Research Pharmacy 
Generic name: temozolomide 
Brand name(s): Temodar® 
Mayo Abbreviation: TMZ 
Availability: commercial 
 
 

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Schema – Adjuvant Patients (Group 2) 
Safety Run-In Only (first 6 patients in Group 2): Prior to discussing protocol entry with the patient,  
call the MCCC Registration Office
 to ensure a place on the protocol is open to the 
patient 
Registration 
↓ 
Concurrent† (Cycle 1) 
MK-3475, Days 1, 22 and 43 
XRT and TMZ Days 8-54  
plus rest period up to 42 days 
post RT 
↓ 
Adjuvant* (Cycles 2-6) 
MK-3475, Days 1, 22 and 43ᵠ 
TMZ Days 1-5, q 28 days 
up to 5 adjuvant cycles* 
↓ 
Observation 
↓ 
Event Monitoring 
 
 
PD at any time 
 
 
 
Intolerable adverse events 
 
→ Event Monitoring 
Patient refusal 
 
 (per Section 4.0) 
 
If a patient is deemed ineligible or a cancel, please refer to Section 13.0 for follow-up information. 
†Cycle length = 7 weeks only during Concurrent stage, plus up to 42 day rest period post-RT 
*Cycle length = 63 days only during Adjuvant stage 
ᵠUp to maximum of 17 total doses of pembrolizumab 
Generic names: pembrolizumab, MK-3475 
Brand name(s): Keytruda® 
Mayo Abbreviation: MK-3475 
Availability: Mayo Clinic Research Pharmacy 
Generic name: temozolomide 
Brand name(s): Temodar® 
Mayo Abbreviation: TMZ 
Availability: commercial 

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1.0 
Background 
1.1 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades {Disis ML, 2010}. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells 
and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate 
with improved prognosis and long-term survival in many solid tumors {Dong , 2002; 
Sharpe, 2002; Brown 2003; Francisco, 2010; Thompson, 2007}. 
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){Talmadge 2007; Usubütün 1998}. The structure of murine PD-1 has been resolved. 
PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail 
which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition 
motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-
cell stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM 
motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules 
such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade 
{Talmadge 2007; Deschoolmeester 2010; Diez 1998; Galon 2006}. 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 {Hiraoka 
2010; Nobili 2008}. 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 {Hodi 2010; 
Kloor 2009}. Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells {Hillen 
2008}. 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 {Lee 2008; Leffers 2009; Nishimura 2000; Hiraoka 2010}. Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling 
motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through 
the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic 
tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably 
expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, 
whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues 
{Hiraoka 2010}. Although healthy organs express little (if any) PD-L1, a variety of 
cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma 
(MEL) {Liotta 2010}. This suggests that the PD-1/PD-L1 pathway plays a critical role in 
tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 

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Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2. Keytruda™ (pembrolizumab) has been approved in the 
United Stated for the treatment of: 
• 
Patients with unresectable or metastatic melanoma 
• 
Patients with metastatic NSCLC whose tumors have high PD-L1 expression 
[(Tumor Proportion Score (TPS) ≥50%)] as determined by an FDA-approved 
test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic 
chemotherapy treatment for metastatic NSCLC 
• 
Patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as 
determined by an FDA-approved test, with disease progression on or after 
platinum-containing chemotherapy 
• 
Patients with EGFR or ALK genomic tumor aberrations should have disease 
progression on FDA-approved therapy for these aberrations prior to receiving 
KEYTRUDA 
• 
Patients with recurrent or metastatic HNSCC with disease progression on or after 
platinum-containing chemotherapy 
1.2 
Rationale for the Trial and Selected Subject Population 
Glioblastoma multiforme (GBM), the most common primary brain tumor, is highly 
lethal despite aggressive therapy. Reported median survival is between 14 and 18 months. 
Immunotherapies such as tumor vaccines have shown promise in pre-clinical studies but 
more modest effects in clinical trials. This likely reflects tumor-mediated 
immunosuppression. Like many cancers, GBM’s are markedly immunosuppressive both 
within the tumor microenvironment and systemically. This immunosuppression is 
mediated both by tumor cells themselves and by immunosuppressive leukocytes such as 
myeloid-derived suppressor cells (MDSC’s) and regulatory T cells (TREG’s) {Parney 
2000; Rodrigues 2010; Gustafson 2010}. 
PD-L1 (B7-H1, CD274) is a particularly potent cancer immune checkpoint inhibitor that 
was originally cloned by a member of our group (Dong H et al, Nat Med 5: 1365-9). It 
exerts its immunosuppressive effects by binding its receptor PD-1 on T cells. In GBM’s, 
members of our group have shown that PD-L1 is expressed by both tumor cells {Parsa 
2006} and circulating MDSC’s {Rodrigues 2010} and is critical for inducing apoptosis in 
PD-1+ activated T cells that home to tumor and inducing MDSC expansion from naïve 
PD-1+ monocytes (Parney IF, unpublished). Cancer immunotherapy through PD-1/PDL1 
checkpoint blockade is the subject of intense investigation. MK-3475 (pembrolizumab) is 
a humanized anti-PD-1 monoclonal antibody developed for this purpose. In a dose 
escalation study of 135 patients with advanced melanoma, largely low grade adverse 
events (e.g. fatigue, rash, pruritis, diarrhea) were observed. Response rates ranged from 
35% (2 mg/kg every 3 weeks) to 56% (10 mg/kg every 2 weeks) {Hamid 2013}. Multiple 
other phase I, II, and III trials of MK-3475 alone or in combination with other agents are 
ongoing for a variety of advanced malignancies, including melanoma, non-small cell lung 
carcinoma, breast carcinoma, GI and urothelial cancers but not brain tumors. With that in 
mind, we plan a phase II of MK-3475 combined with standard therapy in newly 
diagnosed GBM patients. Standard therapy includes surgery, external beam radiotherapy 
(RT) with concurrent temozolomide (TMZ) chemotherapy, and adjuvant TMZ {Stupp 
2005}. Administration of RT to cancer patients undergoing active treatment with immune 
check point inhibitors has been associated with beneficial “abscopal” (off-target) 
responses of other unirradiated tumors. This is thought to be immune-mediated and 
reflects the release of tumor antigens by irradiated cancer cells upon a primed immune 

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system. This has been reported for ipilimumab in melanoma {Postow 2012} and 
demonstrated with PD-1 blockade in a pre-clinical melanoma model by members of our 
group (Park and Dong, unpublished). These findings underscore the rationale for 
combining MK-3475 treatment with standard RT and TMZ for glioblastoma. 
MK-3475’s ability to cross the blood-brain barrier is not well defined. GBM vasculature 
is relatively leaky as demonstrated by contrast-enhancement on magnetic resonance 
imaging (MRI). However, this does not always translate to blood-brain barrier 
penetration for therapeutic agents. To address this, we propose a window of opportunity 
component to the study wherein patients with newly diagnosed brain lesions compatible 
with GBM on MRI scans who have undergone stereotactic biopsy with histopathology 
confirming GBM, will receive MK-3475 IV once then undergo definitive craniotomy and 
resection one week later. Comparison will be made between intra-tumoral PD-L1/PD-1 
expression pre- and post-MK-3475. We will then re-initiate MK-3475 therapy one week 
prior to RT (~3 weeks post-op) to take advantage of potential abscopal RT effects on 
malignant cells beyond the radiation field. MK-3475 would then be continued with 
adjuvant TMZ. 
It is probable that blood-brain barrier penetration is not necessary for MK-3475 to have 
efficacy against GBM’s. GBM patients are systemically immunosuppressed and systemic 
immune modulation by MK-3475 may be therapeutic even if the agent itself does not 
reach the tumor directly. Monitoring systemic immunity will, therefore, be critical. Our 
research group has long-standing interests in monitoring systemic immune responses in 
GBM patients. We recently initiated a clinical trial of autologous dendritic cell / 
allogeneic tumor lysate vaccines for GBM patients (MC1272) that involves extensive 
immune monitoring including detailed immunophenotyping (flow cytometry analysis of 
>120 leukocyte surface markers on 5 mL of whole blood) and specific CD8 T cell 
response testing for a panel of 7 common GBM-associated antigens. We would propose a 
similar comprehensive immune monitoring in the present study. 
1.3 
Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated 
and no dose-limiting toxicities were observed. This first in human study of MK-3475 
showed evidence of target engagement and objective evidence of tumor size reduction at 
all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to 
date. Recent data from other clinical studies within the MK-3475 program has shown that 
a lower dose of MK-3475 and a less frequent schedule may be sufficient for target 
engagement and clinical activity. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to Investigator 
Brochure). Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days). This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q2W and Q3W dosing schedule.  
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 

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normalized dosing or a fixed dose across all body weights. MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication. The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication 
settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed 
at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 
mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on 
distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) 
the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. Based 
on data presented at the Society of Neuro-Oncology in November 2016, at least four 
patients have been treated with the combination of radiation therapy, temozolomide, and 
pembrolizumab followed by temozolomide and pembrolizumab without any Grade 3 or 
higher adverse events. {Dixit K, 2016} 
When used as a single agent, Q3W dosing is supported by the data above. This will be 
the approximate timing between the neoadjuvant dose and the first dose given concurrent 
with radiation and low dose temozolomide in this study. It will also be the timing 
between doses during the concurrent treatment phase. However, during the adjuvant 
phase treatment will be combined with higher dose temozolomide given on days 1-5 
every four weeks. Therefore, the cycle length will be 9 weeks (63 days) to harmonize the 
Q3W dosing and the clinical visits for typical MRI scans schedule at about every 8 
weeks.  
1.4 
Standard Treatment for Glioblastoma 
Standard treatment for patients with newly diagnosed glioblastoma has been defined for 
some time by the “Stupp regimen” {Stupp, 2005}. This includes maximal safe surgical 
resection, external beam radiation with concurrent temozolomide chemotherapy, and 
adjuvant temozolomide. Maximal safe resection is typically defined by the treating 
neurosurgeon. Practice patterns vary across the country regarding initial needle biopsy 

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followed by resection vs. proceeding directly with resection. At tertiary referral centers 
such as Mayo Clinic or MD Anderson, it is common to be referred patients who have 
undergone needle biopsy or subtotal resection elsewhere who subsequently undergo gross 
total resection at the tertiary center. In addition, a small set of patients have uncertain 
diagnosis based on imaging alone and confirming the diagnosis would potentially alter 
the need for resection (e.g. glioblastoma vs. metastasis, lymphoma, abscess, or 
inflammatory process). Radiation therapy is typically administered as approximately 
59.4 Gy delivered in daily fractions of 1.8 Gy five days per week for thirty-three 
fractions. Temozolomide is administered orally at 75 mg/m2 daily seven days per week 
from the first to last day of radiation. Patients typically have approximately 4 weeks of 
rest following radiation before initiating adjuvant temozolomide at 150 – 200 mg/m2 
daily for 5 days at the beginning of a 28 day cycle. Adjuvant temozolomide is frequently 
administered for up to twelve 28 day cycles. 
1.5 
Trial Design 
This is a phase II trial of MK-3475 (pembrolizumab) in combination with standard 
therapy in the treatment of newly diagnosed adult patients with glioblastoma amenable to 
surgical resection. There will be an initial safety lead-in phase. Treatment will be 
administered in three stages: neoadjuvant, concurrent with radiation therapy, and 
adjuvant following radiation therapy. Following completion of accrual to the safety lead 
in, an expansion cohort with the same treatment schema will be opened if the safety 
profile was satisfactory. If not, we will consider a dose de-escalation cohort. 
Update as of Amendment 3: Based on the Safety Run-In of 6 patients (1 patient replaced) 
in the Neoadjuvant design where 2 patients had dose limiting toxicities, we are altering 
the treatment schema. We will plan to enroll an additional 6 patients in the Neoadjuvant 
group (pilot phase/Safety Run-in/Group 1). In addition, because of uncertainty whether 
surgery is causing synergistic effects contributing to toxicities and because enrollment in 
the neoadjuvant protocol is limited by patient availability (need for biopsy or subtotal 
resection as part of their prior clinical care), we are adding an Adjuvant group (Group 2) 
to enroll patients who have already completed surgery and who could still benefit from 
the effects of pembrolizumab. We will have a Safety Run-In of 6 patients for this group 
(Group 2). This second group will enroll up to 33 patients. 
1.51 
Group 1 (Neoadjuvant) (Rochester Only)Neoadjuvant (Cycle 1):  
- 
Patients with newly diagnosed enhancing brain lesions on MRI compatible with 
glioblastoma amenable to resection will first undergo stereotactic needle biopsy 
to establish histology. If this proves to be any diagnosis other than glioblastoma, 
they will not be eligible for the study. If histology confirms glioblastoma (a.k.a. 
Grade IV astrocytoma, gliosarcoma), they will be enrolled and receive a single 
200 mg dose of MK-3475.  
- 
Resection/Surgery (Cycle 2): Patients will then undergo definitive craniotomy 
and resection 4 – 7 days later. Post-operative MRI will be obtained within 72 
hours of surgery to document extent of resection. Recovery period of 21-35 days 
is standard after surgical resection. 
- 
Concurrent (Cycle 3): Treatment will be initiated between 3 to 7 weeks after 
craniotomy and resection. This treatment phase will consist of a single 7 week 
cycle. Patients will receive MK-3475 (200 mg) on Days 1, 22 and 43. Radiation 
will be administered in a standard 30 fraction regimen (5 days per week) 
beginning Day 8, one week after first receiving MK-3475 to take advantage of 

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potential abscopal effects of radiation following MK-3475 administration. Low 
dose TMZ will be administered daily throughout while radiation is being 
administered. Patients will be assessed clinically prior to each MK-3475 infusion, 
on Day 1 (±2d), and Day 22 (±2d). They will undergo imaging (MRI) for 
radiation planning purposes prior to initiating this cycle. Recovery period of 21-
35 days is standard after radiation therapy. 
- 
Adjuvant (Cycles 4-8): Treatment will be initiated between 4 to 6 weeks after 
completing concurrent therapy. Treatment will be in 63 day cycles. Patients will 
receive MK-3475 (200 mg) on Days 1, 22, and 43 up to a maximum of 17 doses. 
TMZ will be administered on 5 consecutive days every 28 days per current 
clinical standard of care. Patients will be assessed clinically prior to initiating 
each round of MK-3475. They will undergo imaging (MRI) prior to Cycle 4 and 
every cycle thereafter. Treatment will be continued for up to 5 adjuvant cycles or 
until tumor progression, unacceptable toxic effects develop, or consent is 
withdrawn.  
- 
Safety Run-In: To ensure safety of treating patients with pembrolizumab in 
combination with standard therapy, an initial 6 patients will be enrolled and 
treated for adverse events assessment. Accrual of these patients will be in 
cohorts-of-3. Accrual will be temporarily suspended for evaluation of each 
cohort-of-3. If either of the two following criteria are met, accrual will be 
temporarily suspended and the study team will review toxicity data thoroughly 
and make decisions regarding changes to the protocol or permanently close the 
accrual to Group 1. 
 
If more than 1 patient of the first 3 evaluable patients experienced at least 
one dose-limiting toxicity (DLT, see definitions in Section 7.0) during 
Cycles 1-3 (before surgery, during surgery, and concurrent with external 
beam radiation therapy) 
 
If more than 1 patient of the first 6 evaluable patients experienced at least 
one dose-limiting toxicity (DLT, see definitions in Section 7.0) during 
Cycles 1-3 (before surgery, during surgery, and concurrent with external 
beam radiation therapy) 
Note: As of Amendment 3 the Group 1 Neoadjuvant study will reopen for at 
most an additional 6 DLT evaluable patients enrolled via the cohorts of 3+3 
design as described above including the following DLT stopping rules.  
 
The third cohort of 3 patients will receive pembrolizumab 200 mg 
intravenously (dose level 1). If less than 2 patients in this cohort experience a 
DLT (See Section 7.9a), the next cohort will be enrolled at the same 
pembrolizumab dose of 200 mg intravenously (dose level 1).  
 
If DLTs are observed in two or more patients in this third cohort of 3, or 
more than 1/6 patients in both cohorts 3 and 4, then accrual to Group 1 will 
be temporarily suspended. The study team will conduct a comprehensive 
review of all the adverse event data, investigate the specifics of each DLT, 
and after consulting with the FDA and the drug supplier, will consider 
possible actions including at least the following: 1) permanently suspend 
accrual to Group 1.  

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1.52 
Group 2 (Adjuvant) 
 
Concurrent (Cycle 1): Treatment will be initiated between 3 to 7 weeks after 
craniotomy and resection. This treatment phase will consist of a single 7 
week cycle. Patients will receive MK-3475 (200 mg) on Days 1, 22, and 43. 
Radiation will be administered in a standard 30 fraction regimen (5 days per 
week) beginning Day 8, one week after first receiving MK-3475 to take 
advantage of potential abscopal effects of radiation following MK-3475 
administration. Low dose TMZ will be administered daily throughout while 
radiation is being administered. Patients will be assessed clinically prior to 
each MK-3475 infusion, on Day 1 (±2d), and Day 22 (±2d). They will 
undergo imaging (MRI) for radiation planning purposes prior to initiating 
this cycle. Recovery period of 21-35 days is standard after radiation therapy. 
 
Adjuvant (Cycles 2-6): Treatment will be initiated between 4 to 6 weeks after 
completing concurrent therapy. Treatment will be in 63 day cycles. Patients 
will receive MK-3475 (200 mg) on Days 1, 22, and 43 up to a maximum of 
17 doses. TMZ will be administered on 5 consecutive days every 28 days per 
current clinical standard of care. Patients will be assessed clinically prior to 
initiating each round of MK-3475. They will undergo imaging (MRI) prior to 
Cycle 2 and every cycle thereafter. Treatment will be continued for up to 
5 adjuvant cycles or until tumor progression, unacceptable toxic effects 
develop, or consent is withdrawn.  
 
Safety Run-In: To ensure safety of treating patients with pembrolizumab in 
combination with standard adjuvant therapy, an initial 6 patients will be 
enrolled and treated for adverse events assessment. Enrollment to this group 
will be temporarily suspended for evaluating AEs in these 6 patients. If more 
than two patients of these first 6 evaluable patients experienced at least one 
dose-limiting toxicity (DLT, see definitions in Section 7.0) during Cycle 1 
(concurrent with external beam radiation therapy)  and attributable (possibly, 
probably, or definitely) to pembrolizumab, we will temporarily close the 
study and discuss options with the drug supplier and the FDA. 
1.6 
Rationale for Endpoints 
1.61 
Safety Endpoints 
Dose limiting toxicities (DLTs) are defined in Section 7.0. 
1.62 
Efficacy Endpoints 
The primary efficacy endpoint for this study will be 18 month overall survival. 
Stupp et al reported an 18 month overall survival rate (OS18) of 39% with 
standard surgery, radiation, and temozolomide {Stupp 2005}. This 39% is 
associated with a median overall survival of 14.6 months starting at the time of 
study registration, which for that study was within one week of starting 
concurrent RT+TMZ. Group 2 patients on this study will start treatment at the 
same time point; therefore this study will use this OS18 of 39% as the null 
hypothesis. A sample size of 33 evaluable Group 2 patients will provide a power 
of 85.3% to test the alternative hypothesis that the 18 month OS rate is at least 
59% against the null hypothesis that the 18 months OS rate is at most 39%, at a 
one-sided significance level of 0.099. Progression-free survival will also be 
recorded. 

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1.7 
Biomarker Research 
1.71 
Tumor PD-1/PD-L1 Expression and Inflammatory Microenvironment 
Tumor specimens will be available in all patients with histologically confirmed 
glioblastoma from stereotactic needle biopsy (pre-MK-3475) and definitive 
resection (post-MK-3475). PD-1 and PD-L1 expression will be determined by 
immunohistochemistry in pre- and post-treatment samples. Pre-treatment PD-L1 
expression has been associated with subsequent response to anti-PD-1 blockade 
in other tumors {Taube 2014}. The response of intra-tumoral PD-1 and PD-L1 
expression following anti-PD-1 blockade in GBM’s is unknown. We 
hypothesize that tumor PD-L1 expression will be unchanged but GBM-
infiltrating leukocyte PD-1 expression will be decreased following MK-3475 
administration, reflecting MK-3475’s effect on circulating leukocytes that 
subsequently infiltrate tumor but a relative inability to cross the blood-brain 
barrier itself. We will also perform immunohistochemical staining for CD3, CD4, 
CD8, and CD68 to assess inflammatory cell infiltrate in pre- and post-MK-3475 
specimens. We hypothesize that T lymphocyte (CD3+/CD4+, CD3+/CD8+) 
infiltrates will be increased but monocytic (CD68+) infiltrates will be 
decreased following MK-3475 administration, reflecting reduced PD-L1-
mediated apoptosis in tumor-infiltrating activated T cells and reduced PD-L1-
mediated immunosuppressive monocyte (myeloid-derived suppressor cell) 
expansion from tumor-infiltrating monocytes following systemic anti-PD-1 
blockade. 
1.72 
Immunomodulation 
Blood draws for immune assays will be obtained prior to definitive craniotomy 
and resection, prior to initiating concurrent therapy, prior to initiating cycle 1 of 
adjuvant therapy, prior to initiating every second cycle thereafter, and at 
progression. Assays will include: 
- 
Immunophenotyping: Our research group has developed methods for 
analyzing combinations of >120 leukocyte surface markers in small (5 mL) 
whole blood samples and pioneered interpretation of the resulting data with 
unbiased bioinformatics approaches. These methods allow for detailed 
immunophenotyping of leukocyte populations including normal T-cells, B-
cells, NK-cells, monocytes, neutrophils, and eosinophils as well as 
immunosuppressive populations such as regulatory T cells (Treg) and 
myeloid-derived suppressor cells (MDSC). This provides a comprehensive 
picture of patients’ systemic immune phenotype and has confirmed 
widespread systemic immunosuppression in GBM patients {Gustafson 
2010}. In prior studies of a GBM vaccine, immunophenotype determined 
using an earlier version of this technique predicted clinical responsiveness to 
tumor vaccines {Olin 2014}. We hypothesize that GBM patients with a 
systemically immunosuppressed phenotype at baseline will revert to a 
normal phenotype following MK-3475 treatment. 
- 
GBM-associated antigen-specific T cell responses: The frequency of CD8 
(killer) T cells specific for individual antigens can be detected by flow 
cytometry using fluorescently labeled multimers of class I major 
histocompatibility complexes (MHC) bound to antigen peptides. 
Commercially available dextramers designed for this purpose are particularly 
sensitive and reliable. These reagents are restricted to specific MHC 

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haplotypes. Most commonly, they are restricted to HLA-A*0201 which is 
present in ~60% of Caucasian North Americans. Patients’ peripheral blood 
will be screened for the HLA-A*0201+ haplotype by flow cytometry 
(anticipated to be >50% of our patient population), peripheral blood samples 
will be analyzed by flow cytometry for tumor-associated antigen (TAA)-
specific T cell frequencies using dextramers specific for a panel of common 
GBM-associated antigens (Her2/Neu, MAGE A3, gp100, p53, EGFR, and 
IL13Rα2) and controls (non-specific negative control; influenza peptide m). 
These TAAs meet criteria identified by the National Cancer Institute for 
targeting in immunotherapy trials {Cheever 2009} and are commonly and 
widely expressed in GBM’s. We have recently initiated testing with this 
panel in a pilot dendritic cell vaccine study in newly diagnosed GBM 
patients (MC1272; NCT01957956). Initial results suggest presence of TAA-
specific CD8 T cells at baseline ranges from 0% - 0.98% depending on the 
specific antigen with an overall frequency TAA-specific CD8 T cells of 
~1.5% {Parney and Dietz unpublished}. The presence of TAA-specific CD8 
T cells in measurable frequencies at baseline highlights the potential for 
expanding these anti-tumor T cells in GBM patients if immunosuppression is 
disrupted through immune checkpoint blockade with MK-3475. We 
hypothesize that GBM patients will undergo an increase in TAA-specific 
CD8 T cells following MK-3475 treatment. 
 

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2.0 
Goals 
2.1 
Primary 
2.11 
Neoadjuvant (Group 1) 
To assess the safety and tolerability of pembrolizumab in combination with 
standard therapy (surgery, external beam radiation therapy and TMZ 
chemotherapy) in patients with newly diagnosed glioblastoma multiforme 
(GBM). 
2.12 
Adjuvant (Group 2) 
To assess the 18 month overall survival rate of pembrolizumab in combination 
with standard therapy (surgery, external beam radiation therapy and TMZ 
chemotherapy) in patients with newly diagnosed glioblastoma multiforme 
(GBM). 
2.2 
Secondary  
2.21 
To assess adverse events (AE) and toxicity profile of pembrolizumab in 
combination with standard therapy in patients with newly diagnosed GBM. 
2.22 
To assess time to progression in patients treated with pembrolizumab in 
combination with standard therapy in patients with newly diagnosed GBM 
(Adjuvant only). 
2.23 
To assess progression-free survival in patients treated with pembrolizumab in 
combination with standard therapy in patients with newly diagnosed GBM 
(Adjuvant only). 
2.24 
To assess time to treatment failure in patients treated with pembrolizumab in 
combination with standard therapy in patients with newly diagnosed GBM 
(Adjuvant only). 
2.3 
Correlative Research 
2.31 
To assess the tumor PD-1/PD-L1 expression and inflammatory 
microenvironment profile by comparing PD-1/PD-L1 expression and T 
lymphocyte/monocytic infiltrates before and after administration of 
pembrolizumab treatment (Neoadjuvant only). 
2.32 
To assess the peripheral immunophenotype profile and GBM-associated antigen-
specific T cell responses before and after receiving pembrolizumab treatment in 
combination with standard therapy. 

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3.0 
Patient Eligibility 
3.1 
Registration – Inclusion Criteria 
3.11 
Age ≥18years. 
3.12 
Histological confirmation of supratentorial glioblastoma (also known as 
astrocytoma Grade IV, gliosarcoma) 
NOTE: Grade IV IDH-mutant astrocytoma is also allowed. 
3.13 
Neoadjuvant patients only:  
Have an enhancing mass on MRI amenable to >90% resection of contrast-
enhancing tumor (as determined by the neurosurgeon pre-operatively) and 
histological diagnosis of glioblastoma or astrocytoma (as defined in Section 3.12 
above) from a prior biopsy or surgery. 
NOTE: Biopsy or subtotal resection must have been ≤43 days prior to 
registration. 
3.14 
Prior Treatment 
3.141 Neoadjuvant patients only: Willing to undergo craniotomy and resection 
of their brain tumor at Mayo Clinic in Rochester, MN. 
3.142 Adjuvant patients only: Must have undergone craniotomy and resection 
of their brain tumor ≤6 weeks prior to registration. 
3.15 
ECOG Performance Status (PS) of 0 or 1 (see Appendix I). 
3.16 
The following laboratory values obtained ≤28 days prior to registration. 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Hemoglobin ≥9.0 g/dL without transfusion or EPO dependency (≤7 days 
prior to assessment) 
• 
Prothrombin Time (PT) ≤1.5 x ULN unless patient is receiving anticoagulant 
therapy and PT or PTT is within therapeutic range of intended use of 
coagulants 
• 
Activated Partial Thromboplastin Time (aPTT) ≤1.5 x ULN unless patient is 
receiving anticoagulant therapy and PT or PTT is within therapeutic range of 
intended use of coagulants 
• 
Albumin ≥2.5 mg/dL 
• 
Total bilirubin ≤1.5 x ULN OR Direct bilirubin ≤ULN for patients with total 
bilirubin levels >1.5 x ULN 
• 
Aspartate transaminase (AST) AND alanine transaminase (ALT) ≤2.5 x ULN 
• 
Creatinine ≤1.0 x ULN OR measured or calculated creatinine clearance (per 
institutional standard) must be ≥60 ml/min 
3.17 
Negative pregnancy test done ≤7 days prior to registration, for persons of 
childbearing potential only (POCBP). 
NOTE: Serum or urine pregnancy test allowed. If urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required. 
3.18 
POCBP must be willing to use adequate contraception starting with first dose 
through 120 days after last dose. (See Section 9.9c) 
3.19a 
Provide written informed consent. 

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3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
Note: During the Active Monitoring Phase of a study (i.e., active treatment and 
observation), participants must be willing to return to the consenting institution 
for follow-up. 
3.19c 
Willing to provide tissue and blood samples for correlative research purposes 
(see Sections 6, 14 and 17). 
3.2 
Registration – Exclusion Criteria  
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant persons 
• 
Nursing persons 
• 
Persons of childbearing potential who are unwilling to employ adequate 
contraception 
3.22 
Neoadjuvant patients only: Signs or symptoms of life-threatening raised 
intracranial pressure: as defined by the treating neurosurgeon, including severe 
headache, nausea, decreasing level of consciousness, precluding 4-7 day delay in 
scheduling neurosurgery. 
3.23 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
3.24 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy. 
3.25 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
3.26 
Receiving any other investigational agent which would be considered as a 
treatment for the primary neoplasm. 
3.27 
Other active malignancy ≤5 years prior to registration.  
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix. 
NOTE: If there is a history or prior malignancy, the patient must not be receiving 
other specific treatment for their cancer. 
3.28 
History of myocardial infarction ≤6 months prior to registration, or congestive 
heart failure requiring use of ongoing maintenance therapy for life-threatening 
ventricular arrhythmias. 
3.29a 
Active autoimmune disease that has required systemic treatment in the past 
2 years (i.e., with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs).  
NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is 
not considered a form of systemic treatment.  

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3.29b Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
3.29c 
Known history of active TB (Bacillus Tuberculosis). 
3.29d Received a live vaccine ≤30 days prior to registration. 
3.29e 
History of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
3.29f 
Hypersensitivity to pembrolizumab or any of its excipients. 
3.29g Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
3.29h Received or planning to receive Optune® device. 
 

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4.0 
Study Calendars 
4.1 
Test Schedule1 for Neoadjuvant Patients (Group 1) - Rochester only 
Trial Period Screening 
Active Treatment 
Post-Treatment 
Tests and Procedures2 
 
Neoadjuvant 
(Cycle 1) 
Surgery (C2) 
Prior to RT (C2)3 
Concurrent4 with 
RT5 (up to 54 days) 
 (Cycle 3) 
plus up to 42 day 
rest post RT 
Adjuvant 
(up to 5 cycles)6 
after RT 
(Cycles 4-8) 
 
Observation 
 
≤28 days 
End of 
Tx 
Safety 
follow up: 
30 days 
post-discon-
tinuation 
 
prior to 
registration 
D1 
D67 
 
 
D1 
D22 
D43 D1 D22 D43 
(for any 
reason) 
At time of 
progression 
Scheduling window (days) -28 to -1 
±3 
±2 
 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
 
Clinical Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and exam, weight, ECOG PS  
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event assessment 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Consultation with Radiation Oncologist  
(See Sect. 6.9d) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Surgical consultations (See Sect. 6.9b) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Oncology consultation (See Sect. 6.9c) 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Hematology: CBC/diff8 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry Panel9 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation PT, PTT, aPTT 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Thyroid panel: T3, Free T4, TSH 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Cycle length = 63 days during Adjuvant treatment only 
1 All tests and procedures are clinically indicated and can be performed more often at the treating physician’s discretion, unless noted with an R to indicate funding by research 
2 Each test or procedure should be obtained within ±3 business days of the designated date unless otherwise noted. 
3 Prior to RT items may overlap with Concurrent D1 items – in which case, separate assessments are not required 
4 Starting up to 42 days after surgery 
5 Recommendations for PJP/PCP prophylaxis are in Section 9.9f. 
6 Cycle length during adjuvant treatment = 63 days. 
7 Between Days 3-6, just prior to surgery 
8 Clinically indicated blood draws for monitoring temozolomide can be performed as needed by LMD and sent to Mayo Clinic. 
9 Complete metabolic panel (80053) or Hepatic function panel (80076) at treating physician discretion 

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Trial Period Screening 
Active Treatment 
Post-Treatment 
Tests and Procedures2 
 
Neoadjuvant 
(Cycle 1) 
Surgery (C2) 
Prior to RT (C2)3 
Concurrent4 with 
RT5 (up to 54 days) 
 (Cycle 3) 
plus up to 42 day 
rest post RT 
Adjuvant 
(up to 5 cycles)6 
after RT 
(Cycles 4-8) 
 
Observation 
 
≤28 days 
End of 
Tx 
Safety 
follow up: 
30 days 
post-discon-
tinuation 
 
prior to 
registration 
D1 
D67 
 
 
D1 
D22 
D43 D1 D22 D43 
(for any 
reason) 
At time of 
progression 
Urinalysis 10 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
Pregnancy test11 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Brain 12 
X 
 
X13 
 
X14 
 
 
 
X15 
 
 
 
 
 
Craniotomy and tumor resection 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Blood or Tissue- Analysis performed by Research Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for correlative studies (See Section 14.0) R 
 
X16 
 
 
X 
 
 
 
X17 
 
 
 
X 
X 
Mandatory tissue sample (see Section 17.0) 18R 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Optional follow up tissue sample19R 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MGMT and IDH testing20 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Cycle = 63 days during Adjuvant stage only; R = Research funded 
.
 
10 Urinalysis for protein, glucose, blood, and specific gravity.  
11 For persons of childbearing potential only. Serum or urine. Must be done ≤7 days prior to registration and must be done again ≤72 hours prior to first dose if first test was >72 
hours prior to first dose. 
12 Brain MRI as clinically indicated. MRI schedule may be adjusted at the discretion of the treating oncologist for clinical care at any time. Note: CT head is permissible instead of 
MRI Brain if patient is unable to undergo MRI (e.g. cardiac pacemaker). 
13 At the end of Cycle 1, just prior to surgery, typically this is the day prior to surgery or similar 
14 Post-surgery and prior to RT. This exam will be considered the starting baseline for measuring response and progression. 
15 Brain MRI as clinically indicated. Performed every cycle during adjuvant treatment unless indicated more frequently clinically at the treating oncologist’s discretion. 
16 Must be collected prior to treatment. 
17 During adjuvant treatment, research blood samples are only collected prior to treatment on Cycle 4, Day 1 (Day 1 of the first adjuvant cycle) 
18 Submission of adequate tissue from the primary tumor is mandatory. See Section 17.0. Note: Can be submitted before or during active treatment. 
19 An optional newly-obtained core, or excisional biopsy is requested at the time of recurrence or progressive disease if clinical biopsy or resection is done.  
20 MGMT and IDH testing is only required once as part of clinical care. Either based on the original diagnosis biopsy or from the surgical resection. 

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4.2 
Test Schedule21 for Adjuvant Patients 
Trial Period Screening 
Active Treatment 
Post-Treatment 
Tests and Procedures22 
 
Concurrent23 with RT24  
Adjuvant 
 
Observation 
 
≤28 days 
prior to 
(up to 54 days)  
(Cycle 1) 
plus up to 42 day rest post RT 
(up to 5 cycles) after 
RT 
(Cycles 2-6) 
End of Tx 
(for any 
Safety follow 
up: 30 days 
post- 
At time of 
registration 
D125 
D22 
D43 
D1 
D22 
D43 
reason) 
discontinuation progression 
Scheduling window (days) -28 to -1 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
 
Clinical Procedures 
 
 
 
 
 
 
 
 
 
 
History and exam, weight, ECOG PS  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Consultation with Radiation Oncologist (See Sect. 6.9d) 
X 
 
 
 
 
 
 
 
 
 
Medical Oncology consultation (See Sect. 6.9c) 
X 
 
 
 
X 
 
 
 
 
 
Hematology: CBC/diff26 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry Panel27 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation PT, PTT, aPTT 
X 
X 
 
 
X 
 
 
 
 
 
Thyroid panel: T3, Free T4, TSH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis28 
X 
X 
 
 
X 
 
 
X 
X 
 
Pregnancy test29 
X 
 
 
 
 
 
 
 
 
 
MRI Brain30 
X 
 
 
 
X 
 
 
 
 
 
 
Cycle length = 63 days during Adjuvant treatment only 
21 All tests and procedures are clinically indicated and can be performed more often at the treating physician’s discretion, unless noted with an R to indicate 
funding by research 
22 Each test or procedure should be obtained within ±3 business days of the designated date unless otherwise noted. 
23 Starting 21-35 days after surgery 
24 Recommendations for PJP/PCP prophylaxis are in Section 9.9f. 
25 May be waived if previous results ≤7 days prior to C1D1 
26 May be waived if previous results ≤7 days prior to C1D1 
27 Complete metabolic panel (80053) or Hepatic function panel (80076) at physician discretion  
28 Urinalysis for protein, glucose, blood, and specific gravity.  
29 For persons of childbearing potential only. Serum or urine. Must be done ≤7 days prior to registration and must be done again ≤72 hours prior to first dose, if 
previous test was >72 hours prior to first dose. 
30 Brain MRI as clinically indicated. MRI schedule may be adjusted at the discretion of the treating oncologist for clinical care at any time. Note: CT head is 
permissible instead of MRI Brain if patient is unable to undergo MRI (e.g. cardiac pacemaker). 

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Amendment 8 
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Trial Period Screening 
Active Treatment 
Post-Treatment 
Tests and Procedures22 
 
Concurrent23 with RT24  
Adjuvant 
 
Observation 
 
≤28 days 
prior to 
(up to 54 days)  
(Cycle 1) 
plus up to 42 day rest post RT 
(up to 5 cycles) after 
RT 
(Cycles 2-6) 
End of Tx 
(for any 
Safety follow 
up: 30 days 
post- 
At time of 
registration 
D125 
D22 
D43 
D1 
D22 
D43 
reason) 
discontinuation progression 
Blood or Tissue- Analysis performed by Research Lab 
 
 
 
 
 
 
 
 
 
 
Blood for correlative studies (See Section 14.0) R 
 
X31 
 
 
X32 
 
 
 
X 
X 
Mandatory tissue sample (see Section 17.0) 33R 
X 
 
 
 
 
 
 
 
 
 
Optional follow up tissue sample34R 
 
 
 
 
 
 
 
 
 
X 
MGMT and IDH testing35 
X 
 
 
 
 
 
 
 
 
 
Cycle = 63 days during Adjuvant treatment only; R = Research funded 
 
 
31 Baseline blood sample collected after registration and prior to treatment on Cycle 1, Day 1 (prior to radiation therapy) 
32 During adjuvant treatment, research blood samples are only collected prior to treatment on Cycle 2, Day 1 (Day 1 of the first adjuvant cycle) 
33 Submission of adequate tissue from the primary tumor (archived) is required if available. See Section 17.0. Note: Can be submitted before or during active 
treatment. 
34 An optional newly-obtained core, or excisional biopsy is requested at the time of recurrence or progressive disease if clinical biopsy or resection is done.  
35 MGMT and IDH testing is only required once as part of clinical care. Either based on the original diagnosis biopsy or from the surgical resection. 

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4.3 
Event Monitoring/Survival Follow-up 
 
Event Monitoring Phase1 
q. 3 
months 
until PD 
At PD 
After PD  
q. 6 months 
Death 
New Primary 
Event Monitoring 
X 
X 
X 
X 
At each occurrence 
1. Maximum follow-up time is 5 years after registration. No further follow-up is 
required after 5 years. 
5.0 
Grouping Factor  
Group 1: Neoadjuvant vs. Group 2: Adjuvant 
6.0 
Registration Procedures 
6.1 
Registration Procedures 
6.11 
Registration for Safety Run-in for Neoadjuvant Patients (Group 1) (Rochester 
only) and first six Adjuvant Patients (Group 2) (All sites)  
Prior to discussing protocol entry with the patient, call the Mayo Clinic 
Research Site Managment Office 
to ensure that a place on 
the protocol is open to the patient 
To register a patient, fax 
 a completed eligibility checklist to the 
Mayo Clinic Research Site Management Office between 8 a.m. and 4:30 p.m. 
Central Time Monday through Friday. 
6.12 
Registration for Adjuvant Patients (Group 2) after first 6 patients have been 
enrolled 
To register a patient, access the Research Registration Application at 
The Research Registration Application is available 
24 hours a day, 7 days a week. Back up and/or system support contact information 
is available on the website. If unable to access the website, call the Research Site 
Management Office at 
between the hours of 8 a.m. and 4:30 p.m. 
Central Time (Monday through Friday). 
The instructions for the Research Registration Application are available on the 
Office of Clinical Trials web page 
 and detail the process for completing and 
confirming patient registration. Prior to initiation of protocol treatment, this 
process must be completed in its entirety and a subject ID number must be 
available as noted in the instructions. It is the responsibility of the individual and 
institution registering the patient to confirm the process has been successfully 
completed prior to release of the study agent. Patient registration via the 
registration/randomization application can be confirmed in any of the following 
ways: 
• 
Contact Research Site Management 
 If the patient was fully 
registered, Research Site Management staff can access the information from 
the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 

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Amendment 8 
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6.2 
Correlative research 
6.21 
Mandatory correlative research (Group 1 and Group 2) 
A mandatory translational research component is part of this study; the patient 
will be automatically registered onto this component (Sections 3.0, 14.0, 17.0). 
6.22 
Optional correlative research (Adjuvant Group 2 ONLY) 
An optional correlative research component is part of this study. There will be an 
option to select whether the patient is to be registered onto this component (see 
Section 17.0). 
• 
Patient has/has not given permission to give his/her tissue samples for 
research testing. 
6.3 
Verification 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.4 
Documentation 
Documentation of IRB approval must be on file in the Research Site Management Office 
before an investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Research Site Management 
Office 
 If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the patient 
may not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Research Site Management Office is no longer necessary. 
6.5 
Optional tissue banking permissions 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research on cancer at Mayo Clinic. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.6 
Treatment location 
Treatment on this protocol must commence at Mayo Clinic under the supervision of a 
Mayo Clinic physician. 
6.7 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤7 days after registration. 

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6.8 
Pretreatment tests/procedures 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified in the test schedule. 
6.9a 
Baseline symptoms 
All required baseline symptoms (see Section 10.5) must be documented and graded. 
6.9b 
Neurosurgery consult (Neoadjuvant Group 1 ONLY) 
A neurosurgeon has seen the patient and confirms the patient is a suitable candidate for 
this trial. 
6.9c 
Medical oncology consult 
A medical oncologist has seen the patient and confirms the patient is a suitable candidate 
for this trial. 
6.9d 
Radiation oncology consult 
A radiation oncologist has seen the patient and confirms the patient is a suitable candidate 
for this trial. 
6.9e 
Study drug 
Study drug is available on site. 
6.9f 
Kits 
Blood draw kit availability checked (except Mayo Clinic in Rochester).  
 

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7.0 
Protocol Treatment 
7.1 
Group 1 Neoadjuvant Trial Treatments 
7.11 
Neoadjuvant treatment will be divided into four stages: 
1) Neoadjuvant (Cycle 1) prior to craniotomy 
Single dose given 4-7 days prior to definitive craniotomy/resection 
2) Surgery (Cycle 2) – Definitive craniotomy/resection and recovery. 
3) Concurrent (Cycle 3) with radiation therapy and temozolomide starting 21-
35 days after Surgery. Pembrolizumab initiated Day 1. Standard of care 
external beam RT and TMZ beginning Day 8 of Cycle 3 (See Appendix II 
for recommendations and Section 9.9f for PJP/PCP prophylaxis) plus 21-35 
day rest period post RT 
4) Adjuvant (Cycles 4-8) - Pembrolizumab with temozolomide following 
radiation therapy (63 day cycles, up to 5 adjuvant cycles) 
7.12 
Agents 
Agent 
Dose 
Route 
Day 
ReRx 
MK-3475 
(pembrolizumab)* 
200 mg 
IV 
Per stage 
Per stage 
Temozolomide**† 
75mg/m2 or 
150mg/m2 or 
200mg/m2 
PO 
Per stage 
Per stage 
* Pembrolizumab is given for 30 min -5 or +10 for a maximum total of 
17 doses. 
**Tablets should be taken once daily, as directed, with a glass (8 ounces) 
of water one hour before or after food. 
†Because this agent is known to produce nausea and/or vomiting, an 
appropriate anti-emetic should be used 30-60 minutes before each dose. 
 
Table 7.13 
Neoadjuvant Trial Treatment with Pembrolizumab (Cycle 1) 
Drug/Therapy 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
Pembrolizumab 
200 mg 
Once 
IV infusion 
Day 1 
Experimental 
 
Table 7.14 
Surgery (Cycle 2) and recovery 
Drug/Therapy 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
Craniotomy/ 
Resection 
N/A 
Once 
N/A 
Day 4 - 7 
Standard 
 
 
 

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Table 7.15 
Concurrent Trial Treatment with Pembrolizumab, TMZ, and RT (Cycle 3) 
Initiated 21-35 days post-op 
Single 54 day cycle plus 21-35 day rest period post RT 
Drug/Therapy Dose/Potency Dose Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Days 1, 22, 43 
Experimental 
External Beam 
Radiationa 
6000 cGy in 30 
fractions 
200 cGy/ 
fraction, 
5 days per week 
Standard or 
IMRT 
Beginning Day 8 
Standard 
Temozolomide 
75 mg/m2 
Daily 
Oral 
Day 8 – up 
through the end of 
radiation  
(Days 47-54) 
Standard 
a. Please see Appendix II for radiation therapy details 
Table 7.16 
Adjuvant Trial Treatment with Pembrolizumab and TMZ (Cycles 4-8) 
Initiated 3 - 5 weeks after completing radiation 
63 day cycle for up to 5 adjuvant cycles 
Drug/Therapy 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/  
Treatment Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Days 1, 22, 43* 
Experimental 
Temozolomide** 
150 mg/m2 – 
200 mg/m2 
Daily 
Oral 
Starting on Cycle 4 
Day 1, Days 1 – 5, 
then 5 consecutive 
days every 28 days 
Standard 
*Pembrolizumab will stop when patient has received a total of 17 doses. 
**Temozolomide must be stopped after completion of six (6) 5-day adjuvant “cycles” 
7.2 
Group 1: Neoadjuvant Treatment schedule (in order of occurrence) 
7.21 
Prior to study entry 
• 
Histological diagnosis of glioblastoma (based on prior biopsy or subtotal 
resection performed for clinical indications) 
7.22 
Neoadjuvant - Prior to craniotomy (Cycle 1) 
• 
Pembrolizumab single dose of 200 mg prior to definitive 
craniotomy/resection 
7.23 
Surgery (Cycle 2) 
• 
Craniotomy and maximal safe tumor resection 
• 
Recovery from surgery 21-35 days 
7.24 
Concurrent with standard of care RT and temozolomide (Cycle 3) 
• 
Pembrolizumab 200 mg on Days 1, 22, and 43 
• 
External beam RT beginning Day 8 (60.0 Gy in 30 equal fractions of 2.00 Gy 
administered 5 days per week) 
• 
Temozolomide 75mg/m2 daily during RT 
• 
Rest period up to 42 days post RT 

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7.25 
Adjuvant with standard of care temozolomide (63 day cycles up to 5 adjuvant 
cycles) (Cycles 4-8): 
• 
Pembrolizumab 200 mg on Days 1, 22, and 43 up to a maximum of 17 total 
doses 
• 
Temozolomide 150mg/m2 starts Cycle 4, Days 1-5. If no treatment related 
toxicity higher than Grade 2 is observed after the first 5-day round, the dose 
of temozolomide can be increased to 200mg/m2 for Cycle 4, Days 29-33, and 
subsequent 5-day rounds every 28 days.  
Note these rounds of TMZ will not be in sync with the Q3W frequency of 
pembrolizumab. With no delays in the treatment schedule, the following 
are the estimated start days of the 5-day rounds of TMZ within each cycle 
(see Table 7.251 below). 
NOTE: TMZ may be delayed for any number of reasons including TMZ 
treatment related AEs, time to mail the prescription, and others. There is no 
protocol violation for delays of TMZ dosing due to clinical need or for delays 
by less than or equal to 7 calendar days for administrative issues such as 
shipping. 
Table 7.251 
Approximate Timing of TMZ Doses during Adjuvant Treatment 
Cycle 
TMZ 
Round 1 
TMZ 
Round 2 
TMZ 
Round 3 
Pembrolizumab 
4 
Days 1-5 
Days 29-33 
Days 57-61 
Days 1, 22, 43 
5 
Days 22-26 Days 50-54 
No 3rd round this 
cycle 
Days 1, 22, 43 
6 
Days 15-19 
Days 43-
47** 
No 3rd round this 
cycle 
Days 1, 22, 43 
7** 
Days 8-12 Days 36-40 
No 3rd round this 
cycle 
Days 1, 22, 43 
8** 
Days 1-5 
Days 29-33 
Days 57-61 
Day 1* 
*Stop pembrolizumab when patient has received 17 total doses 
**Temozolomide must be stopped after completion of six (6) 5-day adjuvant 
“cycles” 
7.3 
Group 2: Adjuvant Trial Treatments 
7.31 
Adjuvant treatment will be divided into two stages: 
1) Concurrent (Cycle 1) with radiation therapy and temozolomide starting 21-
35 days after Surgery. Pembrolizumab initiated Day 1. Standard of care 
external beam RT and TMZ beginning Day 8 of Cycle 1 (See Appendix II 
for recommendations and Section 9.9f for PJP/PCP prophylaxis) plus up to 
42 day rest period post RT 
2) Adjuvant (Cycles 2-6) - Pembrolizumab with temozolomide following 
radiation therapy (63 day cycles, up to 5 adjuvant cycles) 
 
 

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7.32 
Agents 
Agent 
Dose 
Route 
Day 
ReRx 
MK-3475 
(pembrolizumab)* 
200 mg 
IV 
Per stage 
Per stage 
Temozolomide**† 
75mg/m2 or 
150mg/m2 or 
200mg/m2 
PO 
Per stage 
Per stage 
* Pembrolizumab is given for 30 min -5 or +10 for a maximum total of 
17 doses. 
**Tablets should be taken once daily, as directed, with a glass (8 ounces) 
of water one hour before or after food. 
†Because this agent is known to produce nausea and/or vomiting, an 
appropriate anti-emetic should be used 30-60 minutes before each dose. 
7.33 
Concurrent Trial Treatment with Pembrolizumab, TMZ, and RT (Cycle 1) 
Initiated 21-35 days post-op 
Single 54 day cycle plus up to 42 day rest period post RT 
Drug/Therapy Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Days 1, 22, 43 
Experimental 
External Beam 
Radiationa 
6000 cGy in 
30 fractions 
200 cGy/ 
fraction, 
5 days per week 
Standard or 
IMRT 
Beginning Day 8 
Standard 
Temozolomide 
75 mg/m2 
Daily 
Oral 
Day 8 – up through 
the end of radiation 
(Days 47-54) 
Standard 
a. Please see Appendix II for radiation therapy details 
7.34 
Adjuvant Trial Treatment with Pembrolizumab and TMZ (Cycles 2-6) 
Initiated 3 - 5 weeks after completing radiation 
63 day cycle for up to 5 adjuvant cycles 
Drug/Therapy 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/  
Treatment Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Days 1, 22, 43* 
Experimental 
Temozolomide** 
150 mg/m2 – 
200 mg/m2 
Daily 
Oral 
Starting on Cycle 2 
Day 1, Days 1 – 5, 
then 5 consecutive 
days every 28 days 
Standard 
*Pembrolizumab will be stopped when patient has received a maximum total of 17 doses. 
**Temozolomide must be stopped after completion of six (6) 5-day adjuvant “cycles” 
7.4 
Adjuvant Treatment Schedule (in order of occurrence) 
7.41 
Prior to study entry 
• 
Histological diagnosis of glioblastoma (based on prior biopsy or subtotal 
resection performed for clinical indications) 
• 
Craniotomy and maximal safe tumor resection 
• 
Recovery from surgery up to 42 days 

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7.42 
Concurrent with standard of care RT and temozolomide (Cycle 1) 
• 
Pembrolizumab 200 mg on Days 1, 22, and 43 
• 
External beam RT beginning Day 8 (60.0 Gy in 30 equal fractions of 2.00 Gy 
administered 5 days per week) 
• 
Temozolomide 75mg/m2 daily during RT beginning on Day 8 
• 
Rest period up to 42 days post RT 
7.43 
Adjuvant with standard of care temozolomide (63 day cycles up to 5 adjuvant 
cycles) (Cycles 2-6): 
• 
Pembrolizumab 200 mg on Days 1, 22, and 43 up to a maximum of 17 total 
doses 
• 
Temozolomide 150mg/m2 starts Cycle 2, Days 1-5. If no treatment related 
toxicity higher than Grade 2 is observed after the first 5-day round, the dose 
of temozolomide can be increased to 200mg/m2 for Cycle 2, Days 29-33, and 
subsequent 5-day rounds every 28 days.  
Note these rounds of TMZ will not be in sync with the Q3W frequency of 
pembrolizumab. With no delays in the treatment schedule, the following 
are the estimated start days of the 5-day rounds of TMZ within each cycle 
(see Table 7.431 below 
NOTE: TMZ may be delayed for any number of reasons including TMZ 
treatment related AEs, time to mail the prescription, and others. There is no 
protocol violation for delays of TMZ dosing by less than or equal to 7 
calendar days. 
Table 7.431 Approximate Timing of TMZ Doses during Adjuvant 
Treatment 
Cycle 
TMZ 
Round 1 
TMZ 
Round 2 
TMZ 
Round 3 
Pembrolizumab 
2 
Days 1-5 
Days 29-33 
Days 57-61 
Days 1, 22, 43 
3 
Days 22-26 Days 50-54 
No 3rd round this 
cycle 
Days 1, 22, 43 
4 
Days 15-19 
Days 43-
47** 
No 3rd round this 
cycle 
Days 1, 22, 43 
5** 
Days 8-12 Days 36-40 
No 3rd round this 
cycle 
Days 1, 22, 43 
6** 
Days 1-5 
Days 29-33 
Days 57-61 
Days 1, 22* 
*Pembrolizumab will be stopped when patient has received a maximum total 
of 17 doses. 
**Temozolomide must be stopped after completion of six (6) 5-day adjuvant 
“cycles” 
7.5 
Radiotherapy - Radiotherapy will be the same for all patients 
See Appendix II for Radiation Therapy Recommendations 
Questions regarding the radiotherapy section of this protocol should be directed to: 
 
 

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7.6 
Return to consenting institution 
7.61 
Neoadjuvant patients 
For this protocol, the patient must have craniotomy / resection and radiation 
therapy at the consenting institution and return to the consenting institution for 
evaluation at least every 21 days during adjuvant treatment, 30 days after the end 
of treatment . 
7.62 
Adjuvant patients 
For this protocol, the patient must have radiation therapy at the consenting 
institution and return to the consenting institution for evaluation at least every 
21 days during adjuvant treatment, and 30 days after the end of treatment. 
7.7 
Local medical doctor 
Treatment by a local medical doctor (LMD) is not allowed on this study, except for blood 
tests to monitor treatment with standard of care temozolomide. 
7.8 
IDH and MGMT testing of tumor 
Patient tumors will be tested for IDH and MGMT as part of standard clinical practice. A 
portion of the tumor will be submitted to the Department of Laboratory Medicine and  
Pathology at Mayo Clinic to test for the presence of these two markers.  
7.9a 
Dose-Limiting Toxicities for Safety Run-in (Group 1 and Group 2)  
Dose-limiting toxicity (DLT) will be defined as an adverse event attributed (definitely, 
probably, or possibly) to pembrolizumab, from start of treatment through the end of 
concurrent treatment and the associated rest period, and meeting the following criteria: 
Toxicity  
DLT Definition 
Cytopenias 
≥Grade 4 per NCI Common Terminology Criteria for 
Adverse Events v4.0 excluding the following: 
• 
Grade 4 neutropenia lasting ≤7 days 
Unspecified 
≥Grade 3 per NCI Common Terminology Criteria for 
Adverse Events v4.0, excluding the following:  
• 
Any Grade 3 electrolyte alteration that resolves to 
Grade ≤1 within 72 hours after it occurs. 
• 
Grade 3 nausea, vomiting, or diarrhea (lasting 
≤72 hours) which responds to maximal supportive 
treatment(s) 
Neurologic toxicity 
≥Grade 3 per NCI Common Terminology Criteria for 
Adverse Events v4.0 
Others not covered above 
See list below  
Other scenarios that will be considered DLTs if they are attributed (definitely, probably, 
or possibly) to pembrolizumab:  
• 
Toxicities leading to a delay of study treatment for ≥14 days.  
• 
The inability to proceed to planned surgical resection within 10 days following 
pembrolizumab administration (Neoadjuvant Group 1 only) 
• 
The inability to receive at least 75% of the cumulative radiation dose within 10 days 
of expected completion of radiation therapy.  

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Note: Any Grade 3 or greater adverse event common to treatment with standard of care 
RT and TMZ will be reviewed for relationship to pembrolizumab and will be defined as a 
DLT if it can be attributed (definitely, probably or possibly) to pembrolizumab as well. 
7.9b 
Safety Run-in (Adjuvant Group 2) 
The study will temporarily halt if 3 of the first 6 patients enrolled in the Adjuvant Group 
(Group 2) experience any of the following events attributed (definitely, probably, or 
possibly) to pembrolizumab: 
• 
Adverse events leading to a delay of planned treatment with RT and/or TMZ for 
≥14 days.  
• 
The inability to receive at least 75% of the cumulative radiation dose within 10 days 
of expected completion of radiation therapy.  
Note: Any Grade 3 or greater adverse event common to treatment with standard of care 
RT and TMZ will be reviewed for relationship to pembrolizumab and will result in 
temporary halt to the study if it can be attributed (definitely, probably or possibly) to 
pembrolizumab as well. 
 

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8.0 
Dosage Modification Based on Adverse Events  
These modifications should be regarded as guidelines to limit and/or reduce side effects.   
Providers may hold, delay, or reduce (as allowed in Section 8.1) doses, even in the absence of a 
requirement to do so in the tables (Section 8.2-8.4) per clinical judgement to maximize patient 
safety. For example, if the patient’s AE is Grade 2, and the tables do not indicate a change in 
action, if the provider determines that the patient’s Grade 2 AE is severe enough to warrant a 
change in the patient’s clinical care (i.e., for medically significant or intolerable Grade 2 AE 
despite appropriate (maximal) supportive care), then the provider may make that change, as long 
as the reason for the change is discussed with the PI, and documented in the medical record. 
ALERT: 
ADR reporting may be required for some adverse events (See Section 10) 
8.1 
Dose Levels Based on Adverse Events in Tables 8.2 and 8.3 
Dose 
Level 
Pembrolizumab** 
Temozolomide 
during 
Concurrent RT† 
Temozolomide 
during  
Adjuvant Tx† 
2 
-- 
 
 
1* 
200 mg 
75 mg/m2 
150-200 mg/m2 
-1 
-- 
 
 
-2 
-- 
 
 
*Dose level 1 refers to the starting dose. 
**There are no dose modifications for pembrolizumab 
†Dose modifications for temozolomide should follow institutional standard of care; 
suggested modifications are listed in Section 8.4 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0*  
unless otherwise specified   
8.2 
Treatment modifications for pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than on body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical 
to reduce complications. Based on existing clinical study data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests 
such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. 
Based on the severity of irAEs, withhold or permanently discontinue pembrolizumab and 
administer corticosteroids. Dose modification and toxicity management guidelines for 
irAEs associated with pembrolizumab are provided in the following tables. See Section 
9.0 for supportive care guidelines, including use of corticosteroids and management of 
symptoms. 
 

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8.21 
Treatment Modification Guidelines for Drug-Related Adverse Events for Pembrolizumab during Neoadjuvant and 
Concurrent treatment. 
NOTE: Permanently discontinue pembrolizumab for any severe or Grade 3 drug-related AE that recurs or any 
life-threatening event. 
CTCAE 
System/Organ/Class (SOC) 
Adverse Event 
Hold 
Treatment for 
Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Cardiac disorders 
Myocarditis 
Grade 1  
AE resolves to Grade 0 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose 
 
 
Grade 2, 3, or 4 
Permanently discontinue 
Permanently discontinue 
Endocrine disorders 
Endocrine disorders – 
Other, specify: 
Hypophysitis 
Grade 2 
AE resolves to Grade 0-1. 
Therapy with pembrolizumab can 
be continued while endocrine 
replacement therapy is instituted 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 
Grade 3 or4 
Withhold or permanently 
discontinue at investigator’s 
discretion 
Withhold or permanently 
discontinue at investigator’s 
discretion 
Endocrine disorders 
Hyperthyroidism 
Grade 3 or 4 
Withhold or permanently 
discontinue at investigator’s 
discretion 
Permanently discontinue at 
investigator’s discretion 
Endocrine disorders 
Hypothyroidism 
Grade 2-4 
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted 
 
Gastrointestinal disorders 
Diarrhea or  
Colitis 
Grade 2 or3 
AE resolves to Grade 0-1 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 
 
 
Grade 4  
Permanently discontinue 
Permanently discontinue 

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CTCAE 
System/Organ/Class (SOC) 
Adverse Event 
Hold 
Treatment for 
Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
General disorders and 
administration site conditions Infusion related reaction 
Grade 2 
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 
See Section 9.9b for more details. 
Permanently discontinue if AE 
develops despite adequate 
premedication 
 
 
Grade 3 or 4 
Permanently discontinue 
Permanently discontinue 
Investigations 
Alanine aminotransferase 
increased (ALT), or  
Aspartate aminotransferase 
increased (AST), or 
Grade 2 
AE resolves to Grade 0-1 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose 
 
Blood bilirubin increased 
Grade 3 or 4 
Permanently discontinue 
Permanently discontinue 
Metabolism and nutrition 
disorders 
Glucose intolerance (Type 1 
diabetes mellitus [if new 
onset]) or 
Hyperglycemia 
T1DM or 
Grade 3 or 4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus or 
Grade 3-4 hyperglycemia 
associated with evidence of beta 
cell failure 
Resume pembrolizumab when 
subjects are clinically and 
metabolically stable 
 
Renal and urinary disorders 
Acute kidney injury or 
Chronic kidney disease  
(e. g., Renal failure or 
Nephritis) 
Grade 2 
Withhold until AE resolves to 
Grade 0-1 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 
 
 
Grade 3 or 4 
Permanently discontinue 
Permanently discontinue 

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CTCAE 
System/Organ/Class (SOC) 
Adverse Event 
Hold 
Treatment for 
Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis 
Grade 2 
Withhold until AE resolves to 
Grade 0-1 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 
 
 
Grade 3 or 4, or 
recurrent 
Grade 2 
Permanently discontinue 
Permanently discontinue 
 
All Other Immune-Related 
Adverse Events 
Intolerable or 
persistent 
Grade 2 
Withhold at physician discretion 
until AE resolves to Grade 0-1 
Permanently discontinue study drug 
for persistent Grade 2 adverse 
reactions for which treatment with 
study drug has been held, that do not 
recover to Grade 0-1 within 
12 weeks of the last dose 
 
All Other Immune-Related 
Adverse Events 
Grade 3 
Withhold or discontinue based on the 
type of event.  
Events that require discontinuation 
include and are not limited to: 
Guillain-Barre Syndrome, 
encephalitis 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks. 
 
 
Grade 4 or 
recurrent 
Grade 3 
Permanently discontinue 
Permanently discontinue 
 
8.22 
Other instructions for pembrolizumab 
If pembrolizumab-related adverse event does not resolve to Grade 0-1 within 12 weeks after last administration of study 
drug, study therapy discontinuation is recommended. With Investigator agreement, patients with a laboratory adverse 
event still at Grade 2 may continue in the study only if asymptomatic and controlled. 
For patients who experience a recurrence of the same severe AEs listed above with rechallenge of pembrolizumab, a 
consultation with the Investigator will occur to determine whether the patient should continue in the study. A patient who 

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Amendment 8 
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experiences the same SAE of the same NCI CTCAE grade or higher with rechallenge of pembrolizumab must discontinue 
pembrolizumab immediately. 
Potential risks of adding pembrolizumab to TMZ and/or RT, include the possibility of increased radiation related toxicity, 
swelling in the brain and resulting neurological compromise that could lead to life threatening consequences and the risk 
of not being able to initiate or receive the full doses of RT and TMZ which have been shown to prolong survival in 
patients with newly diagnosed GBM. Although in an ongoing trial, this effect has not been seen as reported in Neuro-
Oncology Nov 2016 (Abstract ATIM-10, Dixit et al.). 
8.23 
Treatment Modifications for Adverse Events during Adjuvant Treatment with pembrolizumab 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
CTCAE System/Organ/ 
Class (SOC) 
Adverse Event 
Hold 
Treatment for 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Cardiac disorders 
Myocarditis 
Grade 1  
Withhold until AE resolves to Grade 0 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose 
 
 
Grade 2, 3, or 4 
Permanently discontinue 
Permanently discontinue 
Endocrine disorders 
Endocrine disorders – 
Other, specify: 
Hypophysitis 
Grade 2 
Withhold 
 
 
 
Grade 3 or 4 
Withhold or permanently discontinue at 
investigator’s discretion 
Withhold or permanently discontinue 
at investigator’s discretion 
Endocrine disorders 
Hyperthyroidism  
Grade 3 or 4 
Withhold or permanently discontinue at 
investigator’s discretion 
Withhold or permanently discontinue 
at investigator’s discretion 
Endocrine disorders 
Hypothyroidism 
Grade 2-4 
Therapy with pembrolizumab can be 
continued while treatment for the 
thyroid disorder is instituted 
 
Therapy with pembrolizumab can be 
continued while treatment for the 
thyroid disorder is instituted 
Gastrointestinal disorders 
Diarrhea or 
Colitis 
Grade 2 or 3 
Withhold until AE resolves to Grade 0-1 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 

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CTCAE System/Organ/ 
Class (SOC) 
Adverse Event 
Hold 
Treatment for 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
 
 
Grade 4 
Permanently discontinue 
Permanently discontinue 
General disorders and 
administration site 
conditions 
Infusion Reaction 
Grade 2 
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 
See Section 9.9b for more details 
Permanently discontinue if AE 
develops despite adequate 
premedication  
 
 
Grade 3 or 4 
Permanently discontinue 
Permanently discontinue 
Investigations 
Alanine aminotransferase 
(ALT) increased, or  
Aspartate 
aminotransferase (AST) 
increased 
Grade 2 
Withhold until AE resolves to Grade 0-1 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose 
 
or 
Blood bilirubin increased 
Grade 3 or 4 
Permanently discontinue 
Permanently discontinue 
Metabolism and nutrition 
disorders 
Glucose intolerance 
(Type 1 diabetes mellitus 
[if new onset]) or 
Hyperglycemia 
T1DM or 
Grade 3 or 4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence 
of beta cell failure 
Resume pembrolizumab when patients 
are clinically and metabolically stable 
 
 
Renal and urinary disorders 
Acute kidney injury or 
Chronic kidney disease  
(e.g. Renal Failure or 
Nephritis) 
Grade 2 
Withhold until AE resolves to Grade 0-1 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 
 
 
Grade 3 or 4 
Permanently discontinue 
Permanently discontinue 

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CTCAE System/Organ/ 
Class (SOC) 
Adverse Event 
Hold 
Treatment for 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Respiratory, thoracic and 
mediastinal disorders 
Pneumonitis 
Grade 2 
Withhold until AE resolves to Grade 0-1 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 
 
 
Grade 3 or  4, 
or recurrent 
Grade 2 
Permanently discontinue 
Permanently discontinue 
 
All Other Immune-
Related Adverse EventsC 
Intolerable/ 
persistent 
Grade 2 
Withhold at physician discretion 
Permanently discontinue study drug 
for persistent Grade 2 adverse 
reactions for which treatment with 
study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks 
of the last dose 
 
 
Grade 3  
Withhold or discontinue based on the type 
of event 
Events that require discontinuation 
include and not limited to: Guillain-Barre 
Syndrome, encephalitis 
Permanently discontinue if AE does 
not resolve within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or less of 
prednisone or equivalent per day 
within 12 weeks 
 
 
Grade 4 or 
recurrent 
Grade 3 
Permanently discontinue 
Permanently discontinue 

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8.3 
Radiotherapy Dose Modifications 
With the type and site of radiotherapy foreseen in this protocol, interruption due to acute 
radiation adverse events is unlikely. Individual reasons, such as major worsening of 
neurological or mental status or any other medical condition that would preclude the 
continuation of radiotherapy and conversely the decision to resume radiation therapy 
after interruption will be taken on an individual basis by the treating physician. 
For example, cranial irradiation can be withheld for CNS adverse events or toxicity 
≥Grade 3 attributable to radiotherapy. The overall time of interruption and overall time of 
radiotherapy must be recorded. If radiotherapy is interrupted, actions regarding dosing on 
concomitant temozolomide are described below: 
• 
If the administration of temozolomide is interrupted, the radiotherapy will 
proceed normally and no catch up days of temozolomide will be given after the 
end of radiotherapy. 
• 
If the course of RT extends beyond 42 days because of delays, the course of 
temozolomide may be extended to a maximum of 49 days. If RT is still not 
completed, additional temozolomide beyond 49 days is not permitted. 
• 
If radiotherapy definitely stopped for an adverse event felt clearly related to 
radiotherapy and not pembrolizumab/temozolomide, concomitant 
pembrolizumab/temozolomide should be continued per protocol unless PD 
occurs. 
8.4 
Suggested Temozolomide Dose Modifications 
Once a dose has been reduced, it should not be subsequently increased.  
NOTE: When switching from TMZ during RT to TMZ after RT, at that point (at the 
discretion of the treating physician) one can start with 150 or 200 mg/m2/day if there was 
a dose reduction for TMZ during RT. 
Patients with unresolved TMZ-related adverse event after 2 weeks should have TMZ 
dose reduction and/or discontinuation per Tables 8.41 and 8.42. If it is the treating 
physician’s opinion that the patient may benefit from continued treatment the patient may 
continue on study (even if TMZ is discontinued and the treating physician believes it is 
safe and reasonable to continue on study with pembrolizumab and radiation). Patients 
may have a second dose reduction of TMZ for adverse event; however, patients requiring 
a third dose reduction should have TMZ permanently discontinued unless, in the opinion 
of the treating physician, there is reason to believe the patient may benefit from continued 
treatment. The decision to proceed with treatment should be made in consultation with 
the Principal Investigator, 
 
See Tables 8.41 and 8.42 for suggested temozolomide dose modifications during and 
after RT. 
8.41 
Suggested Temozolomide (TMZ) Dose Modifications during treatment with 
RT 
CTCAE 
System/Organ/Category 
(SOC) 
Adverse Event 
Agent 
Action 
Gastrointestinal 
Nausea or vomiting  
(while on optimal antiemetic 
treatment) 
Grade 3 
TMZ 
Reduce TMZ dose by 25% 
If not successful reduce dose by 50% 
Discontinue TMZ if still Grade 3 
after second dose reduction 

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CTCAE 
System/Organ/Category 
(SOC) 
Adverse Event 
Agent 
Action 
Investigations 
Aspartate aminotransferase 
increased or  
Alkaline phosphatase 
increased or  
Blood bilirubin increased 
Grade 3 
 
Reduce TMZ dose by 50% 
 
Grade 4 
 
Discontinue TMZ 
 
Neutrophil count decreased 
Grade 2 
ANC <1500 1000/mm3 
OR 
Platelet count decreased 
PLT <75,000-50,000/mm3 
TMZ 
Reduce TMZ dose by 25% and 
check CBC weekly 
 
Neutrophil count decreased 
Grade 3 
ANC <1000 -500/mm3 
OR 
Platelet count decreased 
PLT <50,000-25,000/mm3 
 
Hold TMZ and check CBC weekly 
When ANC >1500 and PLTS 
>100,000, resume TMZ at 25% 
reduction from most recent dose  
If more than 2 dose reductions 
required, discontinue TMZ 
8.42 
Suggested Adjuvant Temozolomide (TMZ) Dose Modifications (after RT) 
CTCAE 
System/Organ/Category 
(SOC) 
Adverse Event 
Agent 
Action 
Investigations 
Interval: 
Neutrophil count decreased 
ANC <1000/mm3 
OR 
Platelet count decreased 
PLT <75,000/mm3 
TMZ 
If ANC 500 to 1000 or PLT 50,000 to 
75,000, reduce TMZ dose by 25% next 
cycle  
If ANC <500 or PLT <50,000, reduce TMZ 
dose by 50% next cycle 
 
At time of TMZ treatment 
Neutrophil count decreased 
ANC <1500/mm3 
OR 
Platelet count decreased 
PLT <75,000/mm3 
TMZ 
Hold TMZ and check CBC weekly  
When ANC ≥1500 and PLT >100,000 
begin TMZ based on interval results 
 
 
 

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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include 
the use of oral or intravenous treatment with corticosteroids as well as additional anti -
inflammatory agents if symptoms do not improve with administration of corticosteroids. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. For each disorder, attempts should be made to rule 
out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied 
when the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined below). Refer to Section 8.0 
for dose modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, 
or skin photography as part of evaluation of the event. 
9.2 
Immunotherapy-related toxicities 
9.21 
General Instructions for immune-related adverse events (iRAEs) associated with 
pembrolizumab: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or 
less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can 
be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE 
does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated 
first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids. 
9.22 
Patients should be monitored for signs and symptoms of immunotherapy-related 
toxicities, which include but are not limited to the following: 
• 
Pneumonitis 
Monitor participants for signs and symptoms of pneumonitis 
o Evaluate participants with suspected pneumonitis with radiographic 
imaging and initiate corticosteroid treatment 
o Administer corticosteroids (initial dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 

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• 
Diarrhea/colitis 
Patients should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with 
or without fever) and of bowel perforation (such as peritoneal signs and 
ileus). 
o All patients who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be substituted via IV infusion.  
o For Grade 2 or higher diarrhea, consider GI consultation and endoscopy 
to confirm or rule out colitis. 
o For Grade 2, 3 or 4 diarrhea/colitis, administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or equivalent) followed by taper. 
• 
Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥Grade 3 Hyperglycemia, if associated with ketosis 
(ketonuria) or metabolic acidosis (DKA) 
Monitor participants for hyperglycemia or other signs and symptoms of 
diabetes. 
For T1DM or Grade 3-4 Hyperglycemia: 
o Initiate insulin replacement therapy for Type I diabetes mellitus  
o Administer anti-hyperglycemic in participants with hyperglycemia 
• 
Hypophysitis 
Monitor for signs and symptoms of hypophysitis (including hypopituitarism 
and adrenal insufficiency)Administer corticosteroids and initate hormonal 
replacements as clinically indicated. 
• 
Hyperthyroidism or hypothyroidism 
Monitor patients for signs and symptoms of thyroid disorders. 
o In hyperthyroidism, treat with non-selective beta-blockers (e.g., 
propranolol) or thionamides as appropriate. 
o In hypothyroidism, initiate thyroid replacement hormones  (e.g., 
levothyroxine or liothyroinine) per standard of care. 
• 
Hepatic 
Monitor with liver function tests (consider weekly or more frequently until 
liver enzyme value returned to baseline or is stable 
o For Grade 2 events, administer corticosteroids (initial dose of 0.5- 1 
mg/kg prednisone or equivalent) followed by taper 
o For Grade 3-4 events, administer corticosteroids(initial dose of 1-2 
mg/kg prednisone or equivalent) followed by taper .  
• 
Renal failure or nephritis 
Monitor changes of renal function 
o Administer corticosteroids (prednisone 1-2 mg/kg or equivalent) 
followed by taper 
• 
Myocarditis 
Ensure adequate evaluation to confirm etiology and/or exclude other causes 
o Based on severity of AE administer corticosteroids  

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9.3 
Blood products and growth factors  
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Vol 33, No 28 (October 
1), 2015: pp. 3199-3212 AND Journal of Clinical Oncology, Volume 28, No 33 
(November 20), 2010: pp. 4955-5010 (darbepoetin/epoetin). 
9.31 
Neutropenia 
Prophylactic use of colony-stimulating factors including Granulocyte Colony-
Stimulating Factor (G-CSF), pegylated G-CSF or Granulocyte Macrophage 
Colony-Stimulating Factor GM-CSF is not allowed in this study. Therapeutic use 
of G-CSF is allowed in patients with Grade 3-4 febrile neutropenia. 
9.32 
Anemia 
Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia, but should be clearly noted as concurrent medications. 
9.33 
Thrombocytopenia 
Transfusion of platelets may be used if clinically indicated. ITP should be ruled 
out before initiation of platelet transfusion. 
9.4 
Anti-infectives 
Patients 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. 
9.5 
Cerebral Edema Management 
Patients requiring chronic steroid administration (excluding inhaled steroids) for 
conditions other than their glioblastoma are excluded from the trial. Patients may 
continue on inhalation therapy. Corticosteroids are known immunosuppressive agents 
that can mitigate the effects of pembrolizumab. However, corticosteroids are required at 
times to treat symptomatic cerebral edema in glioblastoma patients. This requirement will 
be particularly true in the perioperative (neoadjuvant) period of this study. All patients in 
this study will undergo or have undergone craniotomy and resection of their tumor, which 
should result in decrease or elimination of corticosteroid requirements. Dexamethasone 
should be administered for symptomatic cerebral edema as clinically indicated, but 
should be tapered off or to the lowest possible dose that controls symptoms as soon as is 
practical. Otherwise, corticosteroids should be generally reserved to treat side effects of 
pembrolizumab. Steroids can be used as primary prevention of nausea per institutional 
guidelines, but steroid doses should be reduced in subsequent cycles if nausea/vomiting is 
absent or very mild (see Section 9.6). 
Consider a short course of bevacizumab per standard treatment guidelines for cerebral 
edema if needed. 
9.6 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. Nausea and 
vomiting should be treated aggressively, and consideration should be given to the 
administration of prophylactic antiemetic therapy according to standard institutional 
practice. Patients should be strongly encouraged to maintain liberal oral fluid intake. 
Volume depletion should be corrected before initiation of study drug. 

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9.7 
Anti-diarrheals 
Patients should be 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 patients, infectious etiologies should 
be ruled out, and if symptoms are persistent and/or severe, endoscopic evaluation should 
be considered. (See Section 9.7 for management of treatment-related enterocolitis) 
All patients 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. 
NOTE: Loperamide/diphenoxylate/atropines should NOT be used for diarrhea symptoms 
unless: (1) it is believed that pembrolizumab-related enterocolitis is unlikely to be present 
after detailed evaluation by gastroenterology, including endoscopy; PLUS (2) approval is 
documented by a gastroenterology specialist. 
9.8 
Management of treatment related enterocolitis 
In patients with severe enterocolitis, MK-3475 will be held 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.  
In patients with moderate enterocolitis, MK-3475 should be withheld and antidiarrheal 
treatment should be started. If symptoms are 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. 
9.9a 
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 any medication or 
vaccination 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 patient’s primary physician.  
9.9a1 
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 in the case report forms (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 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs as defined in Section 10 and 
Appendix VI. 
9.9a2 
Prohibited Concomitant Medications  
Participants are prohibited from receiving the following therapies during the 
screening and treatment phase (including retreatment for post-complete response 
relapse) of this trial: 

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• 
Anti-neoplastic systemic chemotherapy or biological therapy  
NOTE: With exception of short course of bevacizumab for management of 
cerebral edema for this protocol only 
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab 
• 
Live vaccines within 30 days prior to the first dose of trial treatment and 
while participating in the trial. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, varicella/zoster, yellow 
fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killd virus vaccines and are allowed however 
intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines 
and are not allowed. 
o Systemic glucocorticoids for any purpose other than to reduce cerebral 
edema or to modulate symptoms from an event of clinical interest of 
suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the principal 
investigator. 
Patients 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. All 
treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community 
standards of medical care..  
Medications or vaccinations specifically prohibited in the Exclusion Criteria are not 
allowed during the ongoing study. If there is a clinical indication for any medication or 
vaccination specifically prohibited during the study, discontinuation from study therapy 
or vaccination may be required. The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the participant's primary physician. 
However, the decision to continue the participant on study treatment requires the mutual 
agreement of the investigator, Merck, and the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 

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9.9b 
Infusion Reaction 
Table 9.9b 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 participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but responds 
promptly to symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications indicated 
for ≤24 hrs 
Stop Infusion 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participatn is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
treatment 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 participant should 
be premedicated for the next scheduled dose. 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment. 
Participant may be premedicated 1.5h 
(±30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
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) 
Stop Infusion 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
No subsequent dosing 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent dosing 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Participant is permanently discontinued from 
further study drug treatment 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of study treatment 
administration. 
 

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9.9c 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male patients will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition). 
Female patients will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in female patients <45 years of age a high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal state 
in female patients not using hormonal contraception or hormonal replacement therapy. In 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR  
(3) have a congenital or acquired condition that prevents childbearing. 
All patients of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, as applicable, while receiving study drug and for 120 days after 
the last dose of study drug by complying with one of the following: 
(1) practice abstinence† from heterosexual activity; 
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female participant’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous female participants only) 
• 
contraceptive sponge (nulliparous female participants only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 

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it does not qualify as an acceptable method of contraception for patients participating at 
sites in this country/region. 
Patients 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, patients of childbearing potential must adhere to the 
contraception requirement (described above) from the day of study medication initiation 
(or 14 days prior to the initiation of study medication for oral contraception) throughout 
the study period up to 120 days after the last dose of trial therapy. If there is any question 
that a patient of childbearing potential will not reliably comply with the requirements for 
contraception, that patient should not be entered into the study. 
9.9d 
Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab, the 
patient will immediately be removed from the study. The site will contact the patient at 
least monthly and document the patient’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to Mayo Clinic and to 
Merck without delay and within 24 hours to Mayo Clinic and within 2 working days to 
Merck if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn). 
The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn. If a male subject 
impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Mayo Clinic and to Merck and followed as 
described above. 
9.9e 
Use in Nursing Patients 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, patients who are breast-feeding are not eligible for 
enrollment. Specific additional information follows for individual agents used in this 
trial. 
9.9d1 Pembrolizumab 
It is unknown whether pembrolizumab is excreted in human milk. 
9.9d2 Temozolomide 
It is unknown whether temozolomide is excreted in human milk. 
9.9f 
Pneumocystis jirovecii pneumonia [PJP (PCP)] prophylaxis 
Since low dose temozolomide is immunosuppressive and associated with an increased 
risk of PJP, all subjects must receive prophylaxis during RT with concomitant 
temozolomide and radiation therapy. Prophylaxis must be continued for at least two 
weeks after the completion of RT. The choice of prophylactic medications will be left to 
the discretion of the treating physician. Options include atovaquone and dapsone. 
Because, based on NABTC experience, trimethoprim-sulfamethoxazole appears to 
contribute to myelosuppression in patients on chemotherapy, this agent is not preferred. It 
may be used in patients who cannot tolerate other options listed above, although the final 
decision will be left to the discretion of the treating physician. The decision to continue 
PJP prophylaxis beyond the time points noted is left to the discretion of the treating 
physician. Subjects who continue to demonstrate lymphopenia after the continuous daily 
dosing of TMZ has been discontinued should be considered for ongoing prophylaxis.  

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10.0 
Adverse Event (AE) Reporting and Monitoring 
The site principal investigator is responsible for reporting any/all serious adverse events to the 
sponsor as described within the protocol, regardless of attribution to study agent or treatment 
procedure. 
The sponsor/sponsor-investigator is responsible for notifying FDA and all participating 
investigators in a written safety report of any of the following: 
• 
Any suspected adverse reaction that is both serious and unexpected. 
• 
Any findings from laboratory animal or in vitro testing that suggest a significant risk for 
human subjects, including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• 
Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND and whether or not conducted by 
the sponsor, that suggest a significant risk in humans exposed to the drug 
• 
Any clinically important increase in the rate of a serious suspected adverse reaction over 
the rate stated in the protocol or Investigator’s Brochure (IB). 
Summary of SAE Reporting for this study  
(please read entire section for specific instructions): 
WHO: 
WHAT form: 
WHERE to send: 
All sites 
Pregnancy Reporting 
 
Mayo Sites – attach to MCCC 
Electronic SAE Reporting Form 
Will automatically be sent to 
 
 
Mayo Clinic 
Sites 
Mayo Clinic Cancer Center SAE Reporting 
Form:
  
AND attach 
MedWatch 3500A: 
Will automatically be sent to 
 
  
 
 
Definitions 
Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  
Suspected Adverse Reaction 
Any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event. 

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Expedited Reporting 
Events reported to sponsor within 24 hours, 5 days or 10 days of study team becoming aware of 
the event. 
Routine Reporting 
Events reported to sponsor via case report forms 
Events of Interest 
Events that would not typically be considered to meet the criteria for expedited reporting, but that 
for a specific protocol are being reported via expedited means in order to facilitate the review of 
safety data (may be requested by the FDA or the sponsor).  
10.1 
Adverse Event Characteristics 
CTCAE term (AE description) and grade: The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting. All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web: 
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial. 
First, identify and grade the severity of the event using the CTCAE version 4.0. 
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3). With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4). Expedited reports are to be 
completed within the timeframes and via the mechanisms specified in Sections 
10.4. All AEs reported via expedited mechanisms must also be reported via the 
routine data reporting mechanisms defined by the protocol (see Sections 10.52 
and 18.0). 
10.12 Each CTCAE term in the current version is a unique representation of a specific 
event used for medical documentation and scientific analysis and is a single 
MedDRA Lowest Level Term (LLT). 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as 
serious AE, which is defined in the table in Section 10.4. 
10.2 
Expected vs. Unexpected Events  
Expected events - are those described within the Section 15.0 of the protocol, the study 
specific consent form, package insert (if applicable), and/or the investigator brochure, (if 
an investigator brochure is not required, otherwise described in the general 
investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in Section 
15.0 of the protocol, the study specific consent form, package insert (if applicable), or in 
the investigator brochure (or are not listed at the specificity or severity that has been 
observed); if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan. 
Unexpected also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator brochure as occurring with a class of drugs but have not 
been observed with the drug under investigation. 

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An investigational agent/intervention might exacerbate the expected AEs associated with a 
commercial agent. Therefore, if an expected AE (for the commercial agent) occurs with a 
higher degree of severity or specificity, expedited reporting is required. 
NOTE: *The consent form may contain study specific information at the discretion of the 
Principal Investigator; it is possible that this information may NOT be included in the 
protocol or the investigator brochure. Refer to protocol or IB for reporting needs. 
10.3 
Assessment of Attribution 
When assessing whether an adverse event is related to a medical treatment or procedure, 
the following attribution categories are utilized: 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
Events determined to be possibly, probably or definitely attributed to a medical 
treatment suggest there is evidence to indicate a causal relationship between the 
drug and the adverse event.  
10.31 AEs Experienced Utilizing Investigational Agents and Commercial Agent(s) 
on the SAME Arm 
NOTE: The combination of an investigational agent with a commercial agent is 
considered investigational. 
Routine Reporting 
• 
Routine AE reporting for Phase 1 and Phase 2 clinical studies using an 
investigational agent /intervention in combination with a commercial agent is 
stated in the protocol. See Section 10.52. 
NOTE: When a commercial agent(s) is (are) used on the same treatment arm as 
the investigational agent/intervention (also, investigational drug, 
biologic, cellular product, or other investigational therapy under an 
IND), the entire combination (arm) is then considered an 
investigational intervention for reporting. 
Expedited Reporting 
• 
An AE that occurs on a combination study must be assessed in accordance 
with the guidelines for CTEP investigational agents/interventions in Section 
10.4, and where indicated, an expedited report must be submitted. 
• 
An AE that occurs prior to administration of the investigational 
agent/intervention must be assessed as specified in the protocol. In general, 
only Grade 4 and 5 AEs that are unexpected with at least possible attribution 
to the commercial agent require an expedited report. Refer to Section 10.4 
for specific AE reporting requirements or exceptions. 
• 
Commercial agent expedited reports must be submitted to the FDA via 
MedWatch. 
• 
An investigational agent/intervention might exacerbate the expected AEs 
associated with a commercial agent. Therefore, if an expected AE (for the 
commercial agent) occurs with a higher degree of severity, expedited 
reporting is required. The clinical investigator must determine severity. 

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10.32 Special Situations for Expedited Reporting and Submission of Notification 
Forms 
Exceptions to Expedited Reporting and Submission of Notification Forms: 
EXPECTED Serious Adverse Events1 
 For this protocol only, the following Adverse Events/Grades are expected to 
occur within this population and do not require Expedited Reporting. These 
events must still be reported via Routine Reporting (see Section 10.6).* 
*Report any clinically important increase in the rate of a serious suspected 
adverse reaction (at your study site) over that which is listed in the protocol or 
investigator brochure as an expedited event.  
*Report an expected event that is greater in severity or specificity than expected 
as an expedited event. 
*Specific protocol exceptions to expedited reporting should be reported 
expeditiously by investigators ONLY if they exceed the expected grade of the 
event. 
System Organ Class (SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which 
the event will not be 
expeditedly reported1 
General disorders and 
administrations site conditions 
Fatigue  
Grade 3 
 
 
Gastrointestinal 
Vomiting 
Grade 3 
Nausea 
Grade 3 
Diarrhea 
Grade 3 
Investigations 
Neutrophil count decreased 
Grade 3 or 4 
White blood cell count decreased 
Grade 3 or 4 
Lymphocyte count decreased 
Grade 3 or 4 
Platelet count decreased 
Grade 3 or 4 
Blood and lymphatic system 
disorders 
Anemia 
Grade 3 or 4 
1These exceptions only apply if the adverse event does not result in hospitalization. If the 
adverse event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed.  
NOTE: Hospitalization related to convenience (e.g. transportation issues etc.) will not be 
considered an SAE for purposes of reporting to Merck. 
NOTE: The consent form may contain study specific information at the 
discretion of the Principal Investigator; it is possible that this information may 
NOT be included in the protocol or the investigator brochure. 
Efficacy endpoints as outlined in this section will not be reported to Merck, 
unless there is evidence suggesting a causal relationship between the drug and the 
event. Any such event will be submitted to the Sponsor (Mayo Clinic) within 24 
hours and to Merck Global Safety within 2 working days either by electronic or 
paper media. 
Specifically, the suspected/actual events covered in this exception include 
any event that is disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and 
safety data to ensure the safety of the subjects in the trial. Any suspected 
endpoint which upon review is not progression of the cancer under study will be 

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forwarded to Merck Global Safety as a SAE within 2 working days of 
determination that the event is not progression of the cancer under study. 
The following hospitalizations are not considered to be SAEs because there is no 
“adverse event” (i.e., there is no untoward medical occurrence) associated with 
the hospitalization: 
● Hospitalizations for respite care 
● Planned hospitalizations required by the protocol 
● Hospitalization planned before informed consent (where the condition 
requiring the hospitalization has not changed post study drug administration) 
● Hospitalization for elective procedures unrelated to the current disease and/or 
treatment on this trial 
● Hospitalization for administration of study drug or insertion of access for 
administration of study drug 
● Hospitalization for routine maintenance of a device (e.g., battery replacement) 
that was in place before study entry 
● Hospitalization, or other serious outcomes for signs and symptoms of 
progression of the cancer. 
10.321 
Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly 
referred to as disabilities), congenital abnormities or birth defects, must 
be reported immediately if they occur at any time following treatment 
with an agent under an IND/IDE since they are considered to be a 
serious AE and must be reported to the sponsor as specified in 21 CFR 
312.64(b). 
10.322 
Death 
• 
Any death occurring within 30 days of the last dose, regardless of 
attribution to an agent/intervention under an IND/IDE requires 
expedited reporting within 24-hours. 
• 
Any death occurring greater than 30 days with an attribution of 
possible, probable, or definite to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
Reportable categories of Death  
• 
Death attributable to a CTCAE term. 
• 
Death Neonatal: A disorder characterized by cessation of life 
during the first 28 days of life. 
• 
Death NOS: A cessation of life that cannot be attributed to a 
CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of 
life that cannot be attributed to a CTCAE term associated with 
Grade 5. 
• 
Death due to progressive disease should be reported as Grade 5 
“Neoplasms benign, malignant and unspecified (including 
cysts and polyps) – Other (Progressive Disease)” under the 
system organ class (SOC) of the same name. Evidence that the 
death was a manifestation of underlying disease (e.g., 

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radiological changes suggesting tumor growth or progression: 
clinical deterioration associated with a disease process) should 
be submitted. 
• 
Any death occurring within 30 days of the last dose, regardless 
of attribution to the investigational agent/intervention requires 
expedited reporting within 24 hours. 
• 
Any death occurring greater than 30 days after the last dose of 
the investigational agent/intervention requires expedited 
reporting within 24 hours only if it is possibly, probably, or 
definitely related to the investigational agent/intervention. 
10.323 
Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE must be reported. Three options are 
available to describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
10.324 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy). 
Second malignancies require ONLY routine reporting. 
10.4 
Expedited Reporting Requirements for IND/IDE Agents 
10.41  Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under an IND/IDE within 30 Days of 
the Last Administration of the Investigational Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they 
are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:  
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 

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ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported within the timeframes 
detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization ≥24 
hrs 
7 Calendar Days 
24-Hour 3 
Calendar Days 
Not resulting in 
Hospitalization ≥24 
hrs 
Not required 
7 Calendar Days 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 3 Calendar Days” - The AE must initially be reported within 24 hours of learning of the AE, 
followed by a complete expedited report within 3 calendar days of the initial 24-hour report. 
o 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above 
applies after this reporting period. 
Effective Date: May 5, 2011 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are 
found in Section 10.32 of the protocol. 
NOTE: Hospitalization related to convenience (e.g.transportation issues etc.) will 
not be considered an SAE for purposes of reporting to Merck. 
10.42 Additional instructions: 
Mayo Clinic Cancer Center (MCCC) Institutions: 
Complete online form at 
AND attach MedWatch 3500A: 
 
 
System will automatically email MCCC Regulatory Affairs Unit (RAU) Risk 
Information Specialist 
who will determine and 
complete IRB reporting. The RAU will submit to the MCCC SAE Coordinator 
and the MCCC IND Coordinator to determine if FDA submission is needed. 
10.5 
Other Required Reporting 
10.51 Adverse events to be graded at each evaluation and pretreatment 
symptoms/conditions to be evaluated at baseline  
(Per CTCAE v4.0 grading unless otherwise stated in the table below): 

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CTCAE SYSTEM/ORGAN/CLASS 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Investigations 
Creatinine increased 
X 
X 
Neutrophil count decreased 
X 
X 
Platelet count decreased 
X 
X 
General disorders and administration 
site conditions 
Fatigue  
X 
X 
Gastrointestinal Disorders 
Nausea 
X 
X 
Vomiting 
X 
X 
# of Stools 
X 
 
Diarrhea 
 
X 
Constipation 
 
X 
Infections and infestations 
Sepsis 
X 
X 
Blood and lymphatic system disorders 
Febrile neutropenia 
X 
X 
Skin and subcutaneous tissue disorders Rash, maculo-papular 
X 
X 
Nervous system disorders 
Ataxia 
X 
X 
 
Cognitive disturbance 
X 
X 
 
Dysarthria 
X 
X 
 
Dysphasia 
X 
X 
 
Edema, cerebral 
X 
X 
 
Facial muscle weakness 
X 
X 
 
Headache 
X 
X 
 
Pyramidal tract syndrome 
X 
X 
 
Seizure 
X 
X 
Nervous system disorders 
Central nervous system disorders – 
Other, specify: Hemisensory loss 
and/or Visual field cut 
X 
X 
10.52 Additional Considerations for this study 
10.521 Neoadjuvant Only 
Surgical outcomes will be recorded in the CRFs to ensure that there is no 
increase in incidence due to neoadjuvant pembrolizumab. 
The following items will be collected: 
- 
Neurological Outcome 
o Improved 
o Stable 
o Worse 
 
Temporary 
 
Permanent (> 6 weeks) 
 
New neurological symptoms 
• 
Seizures 
• 
Visual field cut 
• 
Facial droop 
• 
Hemiparesis 
• 
Hemisensory loss 
• 
Ataxia 
• 
Dysphasia 
• 
Dysarthria 

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• 
Cognitive impairment 
• 
Other 
- 
Regional Complications 
o Pseudomeningocele 
o CSF leak 
o Wound dehiscence 
o Superficial wound infection 
o Deep wound infection 
o Epidural hematoma 
o Subdural hematoma 
o Intraparenchymal hematoma 
o Other 
- 
Systemic complications 
o Deep venous thrombosis 
o Pulmonary embolism 
o Urinary tract infection 
o Pneumonia 
o Myocardial infarction 
o Other 
10.53 Submit via appropriate MCCC Case Report Forms (i.e., paper or electronic, as 
applicable) the following AEs experienced by a patient and not specified in 
Section 10.51: 
10.531 
Grade 2 AEs deemed possibly, probably, or definitely related to the 
study treatment or procedure. 
10.532 
Grade 3 and 4 AEs regardless of attribution to the study treatment or 
procedure. 
10.533 
Grade 5 AEs (Deaths) 
10.5331  Any death within 30 days of the patient’s last study 
treatment or procedure regardless of attribution to the study 
treatment or procedure. 
10.5332 Any death more than 30 days after the patient’s last study 
treatment or procedure that is felt to be at least possibly 
treatment related must also be submitted as a Grade 5 AE, 
with a CTCAE type and attribution assigned. 
10.54 Pregnancy, Fetal Death, and Death Neonatal  
If a female subject (or female partner of a male subject) taking investigational 
product becomes pregnant, the subject taking should notify the Investigator, and 
the pregnant female should be advised to call her healthcare provider 
immediately. The patient should have appropriate follow-up as deemed necessary 
by her physician. If the baby is born with a birth defect or anomaly, a second 
expedited report is required. 
Prior to obtaining private information about a pregnant woman and her infant, the 
investigator must obtain consent from the pregnant woman and the newborn 
infant’s parent or legal guardian before any data collection can occur. A consent 
form will need to be submitted to the IRB for these subjects if a pregnancy 
occurs. If informed consent is not obtained, no information may be collected. 

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In cases of fetal death, miscarriage or abortion, the mother is the patient. In cases 
where the child/fetus experiences a serious adverse event other than fetal death, 
the child/fetus is the patient. 
NOTE: When submitting Mayo Expedited Adverse Event Report reports for 
“Pregnancy”, “Pregnancy loss”, or “Neonatal loss”, the potential risk of exposure 
of the fetus to the investigational agent(s) or chemotherapy agent(s) should be 
documented in the “Description of Event” section. Include any available medical 
documentation. Include this form: 
10.541 
Pregnancy 
Pregnancy should be reported in an expedited manner as Grade 3 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC. Pregnancy should be followed until the outcome is 
known. 
10.542 
Fetal Death 
Fetal death is defined in CTCAE as “A disorder characterized by death 
in utero; failure of the product of conception to show evidence of 
respiration, heartbeat, or definite movement of a voluntary muscle after 
expulsion from the uterus, without possibility of resuscitation.” 
Any fetal death should be reported expeditiously, as Grade 4 
“Pregnancy, puerperium and perinatal conditions - Other 
(pregnancy loss)” under the Pregnancy, puerperium and perinatal 
conditions SOC. 
10.543 
Death Neonatal 
Neonatal death, defined in CTCAE as “A disorder characterized by 
cessation of life occurring during the first 28 days of life” that is felt by 
the investigator to be at least possibly due to the investigational 
agent/intervention, should be reported expeditiously.  
A neonatal death should be reported expeditiously as Grade 4 
“General disorders and administration - Other (neonatal loss)” 
under the General disorders and administration SOC.  
10.55 Events of Clinical Interest (ECIs) 
ECIs are selected non-serious and serious adverse experiences that must be 
reported (as described in Section 10.42) within 24 hours to Mayo Clinic via email 
and within 2 working days to Merck Global 
Safety 
 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any 
subject must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 90 
days following cessation of treatment, or 30 days following cessation of 

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treatment if the subject initiates new anticancer therapy, whichever is earlier, any 
ECI, or follow up to an ECI, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 24 hours to Merck Global 
Safety. 
Events of clinical interest for this trial include: 
1. A new cancer (that is not a condition of the study) 
2. An overdose of Merck product, as defined in Section 10.61, that is not 
associated with clinical symptoms or abnormal laboratory results.  
3. 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. 
10.56 Late occurring AEs 
Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion 
of the Active Monitoring Phase (i.e., compliance with Test Schedule in 
Section 4.0). 
10.57 Procedures for Reporting Drug Exposure during Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating 
in this study, she must inform the investigator immediately and permanently 
discontinue study drug. The sponsor-investigator must fax a completed 
Pregnancy Form to Regulatory Affairs Unit per instructions below. The 
pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a 
completed Pregnancy Form to the Regulatory Affairs Unit per instructions 
below. Every effort should be made to follow the pregnancy for the final 
pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
Use form available from the CTEP protocol development page: 
 
Mayo Clinic Cancer Center (MCCC) Institutions: Provide copies using Mayo 
Cancer Center automated system 
 which will automatically be 
routed to the MCCC Regulatory Affairs Unit (RAU) Risk Information Specialist 
who will determine and complete IRB reporting. The RAU will submit to the 
MCCC SAE Coordinator and the MCCC IND Coordinator to determine if FDA 
submission is needed. 

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10.6 
Additional Instructions for AE Reporting to Merck 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product or protocol-specified procedure, whether or not considered related to 
the medicinal product or protocol-specified procedure.  Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of the Merck’s product, is also an 
adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants 
and children and onset of menses or menopause occurring at a physiologically 
appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including 
placebo or active comparator medication) or marketed, manufactured by, licensed by, 
provided by or distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, 
or as prescribed in clinical practice, from overdose (whether accidental or intentional), 
from abuse and from withdrawal. 
All AEs, SAEs and other reportable safety events that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator 
if the participant is receiving placebo run-in or other run-in treatment, if the event cause 
the participant to be excluded from the study, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, or a procedure.  
● All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator.  
● All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier 
must be reported by the investigator.  
● All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 
days following cessation of study treatment if the participant initiates new anticancer 
therapy  must be reported by the investigator.  
● Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately by the investigator if the 
event is considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety 
events in former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the study, and 

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he/she considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify Merck. 
10.61 Definition of an Overdose for this Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any 
dose of 1,000 mg or greater (≥5 times the indicated dose). No specific 
information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant 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 (pembrolizumab), 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 (as 
described in Section 10.42) within 24 hours to Mayo Clinic 
(
and within 2 working days hours to Merck 
Global Safety. (
 
10.62 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered 
adverse events, it is the responsibility of investigators or their designees to report 
any pregnancy or lactation in a participant (spontaneously reported to them) that 
occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the 
consent form is signed but before treatment allocation/randomization must be 
reported by the investigator if they cause the participant to be excluded from the 
trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or 
a procedure.   
Pregnancies and infant exposures during breastfeeding that occur from the time 
of treatment allocation/randomization through 120 days following cessation of 
Sponsor’s product, or 30 days following cessation of treatment if the participant 
initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous 
abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 
working days to Merck Global Safety. 
  
 
10.63 Immediate Reporting of Adverse Events to the Sponsor and to Merck 

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Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any 
use of Merck’s product that: 
• 
Results in death; 
• 
Is life threatening; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in or prolongs an existing inpatient hospitalization; 
• 
Is a congenital anomaly/birth defect; 
• 
Is an other important medical event  
Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these 
events are considered serious by Merck for collection purposes. 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose. 
Refer to Table 7 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause that occurs to any participant 
must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety if it causes the participant to be excluded from the trial, or 
is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 90 
days following cessation of treatment, or 30 days following cessation of 
treatment if the participant initiates new anticancer therapy, whichever is earlier, 
any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause whether or not related to the Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to Merck product that is brought to the attention 
of the investigator at any time following consent through the end of the specified 
safety follow-up period specified in the paragraph above, or at any time outside 
of the time period specified in the previous paragraph also must be reported 
immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to 
the Merck Global Safety facsimile number:  
 
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. 
 

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at the time of submission to 
FDA. 
10.64 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of 
Clinical Interest (ECI) and must be reported within 2 working days to Merck 
Global Safety. 
 
For the time period beginning when the consent form is signed until 
treatment allocation/randomization, any ECI, or follow up to an ECI, that 
occurs to any participant must be reported within 2 working days to Merck 
Global Safety if it causes the participant to be excluded from the trial, or is 
the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization 
through 90 days following cessation of treatment, or 30 days following 
cessation of treatment if the participant initiates new anticancer therapy, 
whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 2 working days to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the 
upper limit of normal and an elevated total bilirubin lab value that is greater than 
or equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of abnormal 
hepatic tests that may require an additional evaluation for an underlying 
etiology.  
10.65 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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10.66 Table 7 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 participant, in the view of the investigator, at immediate risk of death from the event as it 
occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life 
functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless 
of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an 
elective procedure to treat a pre-existing condition that has not worsened is not a serious adverse event.  A pre-existing condition 
is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the patient’s medical history.); 
or 
 
†Is a congenital anomaly/birth defect (in offspring of participant taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 
24 hours and to Merck within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious 
adverse event for collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event 
of clinical interest and must be reported within 24 hours to the Sponsor and to Merck within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be 
considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the participant 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 Merck product to be discontinued? 

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Relationship 
to Merck 
Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event 
will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document 
or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was 
done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as 
reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse 
event based upon the available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely Merck product 
caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational 
medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors 
  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Sponsor’s product; or (3) the trial is a single-dose drug trial); or 
(4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the participant re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the 
trial is a single-dose drug trial); or (3) Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND 
WHICH MAY HAVE BEEN CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK 
PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT, THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 

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Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product 
or drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to 
his/her best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck 
product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the 
administration of Merck product is reasonable.  The AE is more likely explained by Merck product than by 
another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck product OR temporal sequence of the AE onset relative to administration 
of Merck product is not reasonable OR the AE is more likely explained by another cause than the Merck 
product.  (Also entered for a participant with overdose without an associated AE.) 
 

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11.0 
Treatment Evaluation Using iRANO Guideline 
Tumor response and regrowth can frequently be difficult to measure directly. Serial MRI/CT 
scans along with neurological exams will provide a guide for the effectiveness of therapy and the 
time-course of the disease.  
Time interval to progression will be measured from beginning of study therapy until deterioration 
is documented by the individual investigator using the guidelines in Section 11.4. The patient 
should use the same diagnostic imaging modality (MRI or CT) throughout the study. Ideally, 
patients should also be evaluated on the same physical imaging device throughout the length of 
the study to ensure the most accurate assessments of tumor response. (Note: The CT evaluation 
option should ONLY be used for patients unable to undergo MR imaging because of non-
compatible devices).  
Overall survival will be measured from beginning of study therapy to death. Progression-free 
survival will be measured from beginning of study therapy until the first occurrence of 
progression or death. The quality of survival will be measured by performance status.  
The primary measure of response will be by serial measures of the product of the two largest 
cross-sectional diameters (bidirectional product) using the RANO (Wen, et al 2010) and iRANO 
criteria (Okada, et al 2015).  
11.1 
Schedule of Evaluations: 
11.11 Baseline 
For the purposes of this study (for both treatment groups) the initial baseline 
measurement will be based on the post-surgery measurements obtained prior to 
RT. 
11.12 Follow-up Evaluations 
For the purposes of this study, patients should be reevaluated every 9 weeks 
while on therapy and then every 2 months until confirmed progression. 
11.2 
Definitions of Measurable and Non-Measurable Disease  
11.21 Measurable Disease 
We will define Measurable and Non-Measurable disease according to the 
updated RANO criteria. In short, measurable disease requires bidimensional 
contrast enhancing lesions with clearly defined margins on MRI (or CT scan) 
with two perpendicular diameters of at least 10mm, visible on two or more axial 
slices that are at most 5 mm in thickness (0-mm skip).  
11.22 Non-Measurable Disease 
We will define non-measurable disease as either unidimensionally measurable 
lesions, masses with indistinct margins, or lesions with maximal perpendicular 
diameters less than 10mm.  
11.3 
Guidelines for Evaluation of Measurable Disease 
11.31 Measurement Methods:  
• 
All measurements should be recorded in metric notation (i.e., decimal 
fractions of centimeters) using a ruler or calipers. We will measure all lesions 
in millimeters using standard ruler tools in the PACS system.  

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• 
The same method of assessment and the same technique must be used to 
characterize each identified and reported lesion at baseline and during 
follow-up.  
11.32 Acceptable Modalities for Measurable Disease: 
• 
Conventional MRI and CT: CT scan imaging is only acceptable if patients 
are medically unable to undergo MR evaluation. This guideline has defined 
measurability of lesions on MRI scan based on the assumption that MRI slice 
thickness is 5 mm or less. If MRI scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice 
thickness. 
As with MRI, if a CT scan is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the brain 
tumors. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. 
11.4 
Measurement of Treatment/Intervention Effect 
11.41 Target Lesions  
• 
Measurable lesions (as defined in Section 11.21) up to a maximum of 
5 lesions should be identified as “Target Lesions” and recorded and 
measured at baseline.  
Note: If fewer than 5 target lesions are identified (as there often will be), there is 
no reason to perform additional studies beyond those specified in the 
protocol to discover new lesions.  
• 
Target lesions should be selected on the basis of their size, be representative 
of all involved sites of disease, and should lend themselves to reproducible 
and repeated measurements.  
• 
Baseline Sum of Largest Bi-Dimensional Measurement (Baseline BDM): 
The sum of product of the largest bi-dimensional measurements for all target 
lesions will be calculated and reported as the baseline sum of bi-dimensional 
measurement. The baseline sum of the largest bi-dimensional measurement 
will be used as reference to further characterize any objective tumor response 
in the measurable dimension of the disease.  
• 
Post-Baseline Sum of Bi-Dimensional Measurement (Post-Baseline 
BDM): The sum of product of the largest bi-dimensional measurements for 
all target lesions will be calculated and reported as the post-baseline sum of 
bi-dimensional measurements (Post-Baseline BDM). If the radiologist is able 
to provide an actual measure on the target lesion, that should be recorded. If 
the target lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 0.5 cm2 should be assigned. If it is the opinion of 
the radiologist that the target lesion has likely disappeared, the measurement 
should be recorded as 0 cm2. 
• 
The minimum sum of the largest bi-directional measurements (Minimum 
BDM) is the minimum of the BDM of the baseline and post-baseline BDMs. 
11.42 Non-Target Lesions  
Non-measurable sites of disease (Section 11.22) are classified as non- target 
lesions and should also be recorded at baseline.  

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11.43 Response Criteria 
11.431 
Radiographic Response 
Radiographic response should be determined in comparison to the 
tumor measurements obtained at baseline for determination of 
response. Radiographic progression is to be determined using one of 
the following as the reference when comparing the current 
measurements: 1) the smallest sum of tumor measurements at either 
baseline or following initiation of therapy, or 2) the initial radiographic 
enhancement increased (IREI) new reference scan if treatment was 
continued under the iRANO criteria.  
Because the current treatment is likely to result in a higher than normal 
incidence of treatment-related contrast enhancement 
(“pseudoprogression”), patients should continue therapy with close 
observation (e.g. 4 to 8 week intervals) if there is a suspicion of 
pseudoprogression. If subsequent imaging studies and/or clinical 
observations demonstrate that progression in fact has occurred, the date 
of confirmed progression should be noted as the scan at which the 
potential progression was first identified. We will define complete 
response, partial response, progressive disease, and stable disease 
based on updated RANO criteria and in addition the iRANO criteria 
will apply if the patient has had less than or equal to 6 months of 
immunotherapy.  
11.432 
RANO Evaluation of Target Lesions 
Note: For patients with less than or equal to 6 months of 
immunotherapy these criteria apply along with the iRANO evaluation 
criteria listed in Section 11.433. 
• 
Pseudoprogression (PsP): All of the following must be true: 
a. Progression of contrast enhancing lesions and or T2/FLAIR is 
restricted to the initial radiation therapy volume. 
b. There are no new enhancing lesions outside of the initial 
radiation therapy volume. 
c. Patients are stable or improved clinically. 
Note: PsP may be diagnosed at any time during therapy (beyond the 
typical 12 week post-chemoradiotherapy window defined by 
RANO). 
• 
Complete Response (CR): All of the following must be true: 
a. Disappearance of all enhancing measurable and non-measurable 
disease (sustained for at least 4 weeks). 
b. No new enhancing lesions. 
c. Stable or improved non-enhancing (T2/FLAIR) lesions 
d.  Patients must be off corticosteroids (or on physiologic 
replacement doses only). 
e. Stable or improved clinically 
NOTE: Patients with non-measurable disease only cannot have CR; 
the best response possible is stable disease. 

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• 
Partial Response (PR): Requires all of the following: 
a. >50% decrease in sum of products of perpendicular diameters of 
all measurable enhancing lesions (sustained for at least 4 weeks) 
compared with baseline. 
b. No progression of non-measurable disease 
c. No new lesions 
d. Stable or improved non-enhancing (T2/FLAIR) lesions on same 
or lower dose of corticosteroids compared with baseline scan  
e. Steroid dose should be same or lower compared with baseline 
scan. 
f. 
Stable or improved clinically 
NOTE: Patients with non-measurable disease only cannot have PR; the 
best response possible is stable disease. 
• 
Progressive Disease (PD): Defined by any of the following: 
a. >25% increase in sum of products of perpendicular diameters of 
enhancing lesions, compared with the smallest tumor 
measurement obtained either at baseline (if no decrease) or best 
response (on stable or increasing steroid dose).  
 b.  Significant increase in T2/FLAIR non-enhancing lesion on 
stable or increasing doses of corticosteroids compared with 
baseline scan or best response after therapy initiation (stable 
doses of steroids include patient not on steroids) not caused by 
comorbid events (e.g., radiation therapy, demyelination, 
ischemic injury, infection, seizures, post-operative change).  
c. Any new lesion 
d. Clear clinical deterioration not attributable to other causes apart 
from tumor (e.g., seizures, medication adverse effect, therapy 
complication, stroke, infection) or change in corticosteroid dose 
e. Failure to return for evaluation as a result of death or 
deteriorating condition 
f. 
Clear progression of non-measurable disease 
• 
Stable Disease (SD): Requires all of the following: 
a. Does not qualify for complete response, partial response, or 
progression. 
b. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose 
of corticosteroids compared with baseline scan.  
c. In the event that corticosteroid dose was increased (for new 
symptoms/signs) without confirmation of disease progression on 
neuroimaging, and subsequent follow-up imaging shows that the 
steroid increase was required because of disease progression, the 
last scan considered to show stable disease will be the scan 
obtained when the corticosteroid dose was equivalent to the 
baseline dose. 

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11.433 
iRANO Evaluation of Target Lesions for patients with less than or 
equal to 6 months of immunotherapy. 
• 
CR, PR, and SD: All are the same as defined by the above RANO 
criteria 
• 
Progressive Disease (PD): All of the following must be true: 
a. Progessive Disease or PsP defined by RANO criteria. 
b. Less than or equal to 6 months from the start of immunotherapy. 
c. Significant clinical decline unrelated to comorbid events or 
concurrent medication; or, new or substantially worsened 
neurological deficits which are not due to comorbid events of 
concurrent medication. 
• 
Initial Radiographic Enhancement Increased (IREI): All of the 
following must be true: 
a. Progressive Disease or PsP defined by RANO criteria including 
new lesions. 
b. Less than or equal to 6 months from the start of immunotherapy. 
c. No new or substantially worsened neurological deficits which 
are not due to comorbid events of concurrent medication. 
d. No substantial clinical decline. 
NOTE: Patients with IREI that continue therapy will now use the IREI 
measurements as the “new reference scan” for evaluation of 
measurable disease for subsequent evaluations. 
• 
Confirmed Progressive Disease (PD): All of the following must 
be true: 
a. Previously considered IREI. 
b. Repeat imaging not less than 3 months after initial imaging 
shows progression from the IREI new reference scan. 
NOTE: Patients with confirmed progressive disease via iRANO 
criteria will have their date of progressive disease back-dated to the 
IREI date. The date of progressive disease is to be noted on the Event 
Monitoring Form. 
11.44 Overall Objective Status 
The overall objective status for an evaluation is determined by combining the 
patient’s status on target lesions, non-target lesions, new sites of disease, and 
symptomatic or neurologic deterioration as defined in the following table: 
NOTES: 
1) Patients with possible PsP should initially be given the Objective Status of 
Preliminary Progressive Disease.  
• 
If Progressive Disease is subsequently confirmed, the Objective Status is 
to be recorded for the current cycle as PD (confirmed) and the back-
dated date of the progressive disease (from the cycle with the initial 
Preliminary PD) is to be used as the date of progressive disease which is 
documented via the Event Monitoring Form.  
• 
If progressive disease is not confirmed the Objective Status for the 
current cycle can be documented as SD, PR, or CR as appropriate using 
the baseline scan measurement as the baseline for comparison with the 

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current measurements. The Objective Status for the cycle initially 
documented as Preliminary PD can be changed to PsP. 
2) Patients with IREI should be initially given the Objective Status of IREI. 
• 
If progressive disease is subsequently confirmed, the Objective Status is 
to be recorded for the current cycle as PD (confirmed) and the back-
dated date of progressive disease (from the cycle with the initial IREI) is 
to be used as the date of progressive disease which is documented via the 
Event Monitoring Form.  
• 
If progressive disease is not confirmed, the Objective Status for the 
current cycle can be documented as SD, PR, or CR as appropriate using 
the IREI new reference scan as the baseline for comparison with the 
current measurements. 
11.441 
Summary for Patients with Measurable and Non-measureable Disease  
Target Lesions 
 and/or 
 Non-Target Lesions 
via RANO Response 
Criteria 
New Sites of 
Disease 
Symptomatic 
or Neurologic 
Deterioration 
Pts with  
Treatment ≤6 mos 
iRANO1 
Overall Objective 
Status 
Pts with  
Treatment >6 mos 
RANO 
Overall Objective 
Status 
CR 
No 
No 
CR 
CR 
PR 
No 
No 
PR 
PR 
SD 
No 
No 
SD 
SD 
Not all Evaluated 
No 
No 
UNKN 
UNKN 
PD1 
Yes1 or No 
No 
IREI1 
PD (confirmed) 
CR/PR/SD/PD/Not all 
Evaluated 
Yes1 
No 
IREI1 
PD (confirmed) 
Possible PsP 
No 
No 
IREI1 
Preliminary PD 
PsP 
No 
No 
IREI1 
PsP 
Any status 
Any status 
Yes 
PD (confirmed) 
PD (confirmed) 
1) iRANO criteria to be used for initial radiographic enhancement increased (IREI) when 
patient has received ≤6 months of immunotherapy. 
11.45 Symptomatic Deterioration: Patients with global deterioration of health status or 
new or substantially worsened neurological deficits which are not due to comorbid 
events of concurrent medication, requiring discontinuation of treatment without 
objective evidence of disease progression at that time, and not either related to 
study treatment or other medical conditions, should be reported as PD due to 
“symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment due to symptomatic 
deterioration. 
11.5 
Definitions of analysis variables 
Formal definitions of variables used in analyses can be found in the Statistical 
Considerations section of the protocol. 
 
 

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12.0 
Descriptive Factors  
12.1 
Corticosteroid therapy at study entry: Yes vs. no 
12.2 
Extent of resection: Subtotal resection vs. gross total resection 
12.3 
MGMT promoter methylation: Yes vs. no vs unknown vs indeterminate 
12.4 
IDH mutation: Yes vs. no vs. unknown 
12.7 
Family history of brain tumor: Yes vs. no 
If yes, check all that apply: 
_____ Father  
_____ Mother  
_____ Brother/Sister 
_____ Child  
_____ Other (list: ________________________________________)  
13.0 
Treatment/Follow–up Decision at Evaluation of Patient 
13.1 
Continuation of treatment 
Patients who are CR, PR, SD, PsP or IREI will continue treatment per protocol. 
13.2 
PD during therapy 
Patients who develop PD while receiving therapy will go to the event-monitoring phase. 
13.3 
Follow-up 
After treatment completion patients will have one safety-observation visit at 30 days 
post-treatment and then be followed every 3-4 months for progression and survival per 
Section 4.0. 
13.4 
Off treatment for reasons other than PD 
Patients who go off protocol treatment for reasons other than PD (for example: 
pregnancy, unacceptable toxicity (See Section 8), start of new therapy, etc.) will be 
followed per observation schedule per Section 4.0. 
13.5 
Failure to complete treatment 
Inevaluable for either Safety Run-In (Group 1 or Group 2) Cohorts: 
If a patient fails to complete either of the following treatment steps for reasons other than 
toxicity considered at least possibly related to pembrolizumab, the patient will be 
regarded as inevaluable for a Safety Run-In Cohort and will be replaced 
• 
Neoadjuvant: fails to go on to craniotomy 
• 
Concurrent: fails to complete at least 75% of the chemoradiation treatment. 
13.6 
Ineligible 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry. 
The patient may continue treatment at the discretion of the physician as long as there are 
no safety concerns, and the patient was properly registered.  
If treatment is stopped, the patient will go directly to the event-monitoring phase of the 
study (or off study, if applicable).  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted. Event monitoring will be required per Section 4.0 of 
the protocol.  
• 
If the patient never received treatment, on-study material must be submitted. Event 

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monitoring will be required per Section 4.0 of the protocol. 
13.7 
Major violation 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
Cycles 1, 2, 3, or 4 of the therapy are severely violated that evaluability for primary end 
point is questionable. All data up until the point of confirmation of a major violation must 
be submitted. The patient will go directly to the event-monitoring phase of the study. The 
patient may continue treatment at the discretion of the physician as long as there are no 
safety concerns, and the patient was properly registered. Event monitoring will be 
required per Section 4.0 of the protocol. 
13.8 
Cancel 
A patient is deemed a cancel if he/she is removed from the study for any reason before 
any study treatment is given. On-study material and the End of Active Treatment/Cancel 
Notification Form must be submitted. No further data submission is necessary. 
13.9 
Off treatment for withdrawal of consent 
Patients who go off protocol treatment for withdrawal of all consent will be encouraged 
to have one final safety-observation visit at 30 days post-treatment. No further data 
submission is necessary. 
 

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14.0 
Body Fluid Biospecimens 
14.1 
Summary Tables of Research Blood and Body Fluid Specimens to be Collected for this Protocol 
14.11 Summary Table for Neoadjuvant Patients 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per 
tube (# of 
tubes to be 
collected) 
Prior to 
Cycle 1 
Prior 
to RT 
Prior to 
Tx 
(Adj) 
Cycle 4 
Day 1 
30 day 
Safety 
follow
up1  
At 
Time 
of PD1 
Process 
at site? 
(Yes or 
No) 
Temper-
ature 
Conditions 
for Storage 
/Shipping 
Tumor-associated 
antigen specific T cell 
frequency 
Mandatory 
Whole 
Blood 
EDTA 
(purple) 
10 mL (x 1) 
X 
X 
X 
X 
X 
Yes 
Ambient 
Treatment-induced T 
cell responses 
Mandatory 
Whole 
Blood 
ACD 
(yellow) 
6 mL (x 2) 
X 
X 
X 
X 
X 
Yes 
Ambient 
Immunophenotyping Mandatory 
Whole 
Blood 
EDTA 
(purple) 
10 mL (x 1) 
X 
X 
X 
X 
X 
Yes 
Ambient 
1Samples at time of safety follow-up and/or time of PD are requested, and if patient refuses, there is no protocol deviation. 
 
14.12 Summary Table for Adjuvant Patients 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Blood or 
Body Fluid 
being 
Collected 
Type of 
Collection 
Tube (color 
of tube top) 
Volume to 
collect per tube 
(# of tubes to be 
collected) 
Prior 
to RT 
Prior to Tx 
Cycle 2 
Day 1 after 
RT 
30 day 
Safety 
follow
up1  
At 
Time 
of PD1 
Process 
at site? 
(Yes or 
No) 
Temper-ature 
Conditions for 
Storage 
/Shipping 
Tumor-associated 
antigen specific T cell 
frequency 
Mandatory 
Whole 
Blood 
EDTA 
(purple) 
10 mL (x 1) 
X 
X 
X 
X 
Yes 
Ambient 
Treatment-induced T 
cell responses 
Mandatory 
Whole 
Blood 
ACD 
(yellow) 
6 mL (x 2) 
X 
X 
X 
X 
Yes 
Ambient 
Immunophenotyping Mandatory 
Whole 
Blood 
EDTA 
(purple) 
10 mL (x 1) 
X 
X 
X 
X 
Yes 
Ambient 
1Samples at time of safety follow-up and/or time of PD are requested, and if patient refuses, there is no protocol deviation. 
 
 

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14.2 
Collection and Processing  
All samples collected for ancillary studies will be collected on site at Mayo Clinic 
Rochester. All ancillary samples are derived from blood and will be collected by nurses 
or approved phlebotomists and delivered to Biospecimens Accessioning and Processing 
(BAP) Shared Resource. 
14.3 
Shipping and Handling 
No specimens will be shipped outside of Mayo Clinic Rochester Campus. Internal 
transport of specimens will be at room temperature and delivered to the Human Cell 
Therapy Lab within 24 hours of collection. After collection call 
for pick up. 
14.31 Kits will be used for this study (only for sites outside of Mayo Clinic in 
Rochester, MN) 
14.311 
Kits will be supplied by the Biospecimen Accessioning and Processing 
Shared Resource (BAP).  
14.312 
The kit contains supplies and instructions for collecting, processing 
and shipping specimens. 
14.313 
Participating institutions may obtain kits by faxing the Supply Order 
Form to the number listed on the form. Because we are charged for all 
outgoing kits, a small, but sufficient, supply of the specimen collection 
kits should be ordered prior to patient entry. Supply Order Forms 
must be filled in completely and legibly for quick processing. 
14.314 
Kits will be sent via FedEx Ground at no additional cost to the 
participating institutions. Allow at least two weeks to receive the kits. 
14.315 
Kits will not be sent via rush delivery service unless the participating 
institution provides their own Fed Ex account number or alternate 
billing number for express mail. Cost for rush delivery of kits will 
not be covered by the study. 
14.316 
All specimens must be collected and shipped Monday – Thursday 
ONLY. 
14.32 Shipping Specimens 
Specimens will be shipped by FedEx overnight to: 
 
 
14.33 Handling Specimens 
Specimens will be stored at 4°C after acquisition until packaged for shipping. 
They will be shipped the same day as they are acquired. For packaging, blood 
collection tubes will be placed in a plastic bag, then packed in a Styrofoam box 
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14.4 
Background and Methodology 
14.41 Measuring changes in treatment-induced frequency of tumor-associated antigen 
specific T cells 
Glioblastomas express and/or amplify multiple tumor-associated or tumor-
specific antigens, including EGVFviii, WT1, Her2/Neu, non-mutant p53, mutant 
p53, IL13Rα2, MAGE A3, MART-1, hTERT, gp100, tenascin, and others. 
Expression of these antigens varies between tumors and across different 
glioblastoma subtypes. The National Cancer Institute recently published a 
ranking of 75 tumor associated antigens appropriate for vaccine development 
based upon pre-determined criteria (therapeutic function, immunogenicity, 
specificity, oncogenicity, expression level, stem cell expression, percent of 
patients with antigen-positive tumors, number of epitopes, cellular location of 
expression). Two previously reported glioblastoma-associated antigens were 
ranked in the top five (WT1, EGFRviii), another three in the top ten (Her2/Neu, 
MAGE A3, non-mutant p53), and three further antigens in the top twenty 
(MART1, gp100, mutant p53). Of these, we found EGFRviii, ErbB2. gp100, 
MAGE A3, and p53 were commonly expressed in our Good Manufacturing 
Practices-grade human GBM cell lines. We additionally found common high 
levels of expression of EGFR and IL13Rα2. We therefore chose to focus our 
analysis of antigen-specific responses on these tumor-associated antigens. 
Antigen-specific responses can be measured in peripheral blood using 
commercially-available Dextramer technology (Immundex, Fairfax, VA). 
Fluorescently-labeled multimers of class I MHC molecules from common 
haplotypes (e.g. HLA-A*0201) bound to specific nonapeptide antigens will bind 
to HLA-matched CD8+ T cells with T cell receptors (TCR) that specifically 
recognize these antigens. Increased frequency of tetramer-positive CD8+ T cells 
in peripheral blood as determined by flow cytometry after therapy is an 
indication of positive changes in immune response. The source and specificity of 
HLA-A*0201 multimers to be used in this study are shown below. Antigen-
specific dextramer staining will only be performed in patients that are HLA-
A*0201 positive. 
 
Dextramer sStaining will be performed with whole blood samples according to 
standard protocols. Samples will be analyzed using FlowJo software (Treestar). 
14.42 Measuring treatment-induced T cell responses to vaccine 
We will measure vaccine-induced changes in the immune response by measuring 
using the following (or similar) assays prior to and after treatment. We will 
Tumor-Associated Antigen MHC 
Peptide 
Source 
Her-2/Neu (Erb-B2) 
HLA-A*0201 KIFGSLAFL 
Immudex (Fairfax, VA) 
MAGE A3 
HLA-A*0201 FLWGPRALV 
Immudex (Fairfax, VA) 
gp100 
HLA-A*0201 IMDQVPFSV 
Immudex (Fairfax, VA) 
p53 (wild type) 
HLA-A*0201 LLGRNSFEV 
Immudex (Fairfax, VA) 
EGFR 
HLA-A*0201 KLFGTSGQKT Immudex (Fairfax, VA) 
IL13Rα2 
HLA-A*0201 ALPFGFILV 
Immudex (Fairfax, VA) 
Negative control 
HLA-A*0201 ALIAPVHAV 
Immudex (Fairfax, VA) 
 
 
 
 

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measure changes in cytotoxic T lymphocyte (CTL) frequency after co-culturing 
autologous CD8+ or CD4+ T cells and autologous tumor lysate-pulsed 
autologous DC for 48 hours. Practical limitations in cell numbers will not allow 
us to test each individual TAA peptide listed in Section 14.41 but DC pulsed with 
EGFRviii nonapeptide (LEEKKGNYV) will be used as EGFRviii dextramers are 
not available and the reliability of EGFRviii tetramers (standard antigen-specific 
T cell detection reagents) has been questioned. In all cases, antigen specificity of 
the response (either to tumor lysate or EGFRviii peptide) will be determined by 
comparison to control T cell co-cultures with naïve DC. CTL frequency will be 
estimated by IFNγ ELISPOT assays. Naïve DC and pre-treatment T cells alone 
will be used as negative controls. DC pulsed with EGFRviii peptide and co-
cultured with autologous T cells pre-incubated with EGFRviii peptide-pulsed DC 
(5 days) will be used as positive controls. If for any reason this method of 
measuring induced T cell responses cannot be used, a similar method (e.g. 51Cr-
release or other cytotoxic T cell assays) using the same starting samples and 
measuring the same response will be used. 
14.43 Immunophenotyping. 
Glioblastoma patients have well-defined defects in circulating immune cells and 
are characterized by global reductions n T cell numbers and responsiveness 
combined with increases in circulating myeloid-derived suppressor cells and 
regulatory T cells. This has significant implications for response to 
immunotherapy. 
We have extensive experience in immunophenotyping whole blood samples from 
glioblastoma patients using flow cytometry. We routinely perform 24 panels of 
four-color FACS staining on 5 mL blood samples. This generates a detailed 
picture of patients’ peripheral blood immunophenotype, including lymphocyte, 
monocyte, and granulocyte subsets, regulatory T cells, and myeloid-derived 
suppressor cells. If for any reason this method of measuring immunophenotyping 
cannot be used a similar method using the same starting samples and measuring 
the same response will be used. 
14.44 Additional ancillary studies 
We will collect plasma at each blood collection point that may be used to 
measure changes in immune related cytokines and growth factors. We may also 
collect and store immune cell subtypes (such as T cells and monocytes) for 
transcriptome analysis or other global measures of the change in immune status. 
Finally, we may perform other molecular tests (including DNA sequencing) to 
identify changes in the behavior of the immune response during the course of 
therapy. 

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15.0 
Drug Information 
15.1 
Pembrolizumab (MK-3475, SCH 900475, Keytruda®) 
15.11 Background 
Pembrolizumab is a potent humanized IgG4 monoclonal antibody with high 
specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
PD-L1 and PD-L2. Based on preclinical in vitro data, pembrolizumab has high 
affinity and potent receptor blocking activity for PD-1. 
15.12 Formulation 
Pembrolizumab is available as a liquid 25 mg/mL, 100 mg/vial. 
15.13 Preparation and storage 
Vials should be stored in the refrigerator at temperatures between 2-8°C. 
Drug concentrate is further diluted with normal saline (or 5% dextrose in the 
concentration range of 1 to 10 mg/mL) in IV containers made of polyvinyl 
chloride (PVC) or non-PVC material. The infusion solution in the IV bag should 
be immediately administered. Diluted pembrolizumab solutions may be stored at 
room temperature for a cumulative period of up to 4 hours. This includes room 
temperature storage of admixture solutions in the IV bags and the duration of 
infusion. In addition, IV bags may be stored at 2-8°C for up to a cumulative time 
of 20 hours. This 24-hour total hold time from dilution may include up to 6 hours 
at room temperature 
15.14 Administration 
Pembrolizumab is administered by intravenous infusion over 30 minutes via a 
0.22 micron in-line filter. The final infusion volume must be between 1 and 10 
mg/mL. Maximum rate of infusion should not exceed 6.7 mL/minute through a 
peripheral or indwelling catheter. Flush the line with 0.9% NaCL following the 
completion of the infusion. 
15.15 Pharmacokinetic information 
a) Absorption – Because pembrolizumab is administered intravenously, it is 
immediately and completely bioavailable. Steady-state concentrations of 
pembrolizumab are reached by16 weeks of repeated dosing with a Q3W 
regimen, and the systemic accumulation is 2.1-fold. The peak concentration, 
trough concentration, and area under the plasma concentration versus time 
curve at steady state of pembrolizumab increased dose proportionally in the 
dose range of 2 to 10 mg/kg Q3W.  
b) Distribution – Pembrolizumab has a limited volume of distribution.  
c) Excretion – CL is approximately 23% lower after achieving maximal change 
at steady state compared with the first dose.  The terminal elimination half-
life (t½) is estimated to be 22 days at steady state. 
d) Metabolism - Pembrolizumab is catabolized through non-specific pathways; 
metabolism does not contribute to its CL. 
15.16 Potential Drug Interactions: There are no known significant drug interactions. 
15.17 Known potential adverse events:  
Very common known potential adverse events, ≥10%: 
Skin and subcutaneous tissue disorders: Pruritus, skin rash 
Gastrointestinal disorders: Diarrhea, nausea, abdominal pain 
General disorders and administration site conditions: fatigue 

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Common known potential adverse events, >10%: 
Blood and lymphatic system disorders: anemia 
Immune system disorders: infusion related reaction 
Endocrine disorders: hyperthyroidism, hypothyroidism 
Metabolism and nutrition disorders: decreased appetite 
Nervous system disorders: headache, dizziness, dysgeusia 
Respiratory, thoracic, and mediastinal disorders: pneumonitis, dyspnea, cough 
Gastrointestinal disorders: colitis, vomiting, constipation, dry mouth 
Skin and subcutaneous tissue disorders: severe skin reactions, vitiligo, dry skin, 
erythema 
Musculoskeletal and connective tissue disorders: arthralgia, myositis, 
musculoskeletal pain, arthritis, pain in extremity 
General disorders and administration site conditions: asthenia, edema, pyrexia, 
influenza like illness, chills 
Investigations: alanine aminotransferase increased, aspartate aminotransferase 
increased, blood alkaline phosphatase increased, blood creatinine increased 
Uncommon known potential adverse events, 1% - 10%: 
Infusion related reactions 
Blood and lymphatic system disorders: neutropenia, thrombocytopenia, 
leukopenia, lymphopenia, eosinophilia 
Endocrine disorders: hypophysitis, adrenal insufficiency, thyroiditis, 
hypopituitarism 
Metabolism and nutrition disorders: type I diabetes mellitus, hyponatremia, 
hypokalemia, hypocalcemia 
Psychiatric disorders: insomnia, confusional state 
Nervous system disorders: epilepsy, lethargy, peripheral neuropathy 
Eye disorders: uveitis, dry eye 
Cardiac disorders: myocarditis, atrial fibrillation 
Vascular disorders: hypertension 
Gastrointestinal disorders: pancreatitis 
Hepatobiliary disorders: hepatitis 
Skin and subcutaneous tissue disorders: lichenoid keratosis, psoriasis, alopecia, 
dermatitis, dermatitis acneiform, eczema, hair color changes, papule 
Musculoskeletal and connective tissue disorders: tenosynovitis 
Renal and urinary disorders: nephritis, acute kidney injury 
Investigations: blood bilirubin increased, amylase increased, hypercalcemia 
Rare known potential adverse events, <1% (Limited to important or life-
threatening): 
Blood and lymphatic system disorders: immune thrombocytopenic purpura, 
hemolytic anemia 
Immune system disorders: sarcoidosis 
Nervous system disorders: Guillain-Barre syndrome, myasthenic syndrome 
Gastrointestinal disorders: small intestinal perforation 
Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-
Johnson syndrome, erythema nodosum 
The risk profile for pembrolizumab also includes two important potential risks: a) 
myasthenic syndrome, and b) an increased risk of severe complications (such as 
early severe graft versus host disease and veno-occlusive disease) of allogeneic 
transplant in patients with hematologic malignancies who have previously been 
treated with PD-1 inhibitors. 

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15.18 Drug procurement 
Pembrolizumab will be provided free of charge to study participants by Merck. 
15.19 Nursing Guidelines 
15.191 
Pembrolizumab side effects vary greatly from those of traditional 
chemotherapy and can vary in severity from mild to life threatening. 
Instruct patients to report any side effects to the study team 
immediately. Side effects may be immediate or delayed up to months 
after discontinuation of therapy. Most side effects are reversible with 
prompt intervention of corticosteroids. 
15.192 
Diarrhea can be seen, however is less common than that seen with anti-
CTLA-4 agents. However it can be severe, leading to colonic 
perforation. Instruct patients to report ANY increase in the number of 
stools and/or change in baseline, blood in the stool, abdominal pain to 
the study team immediately.  
15.193 
Rash/pruritis/dermatitis is seen. Patients should report any rash to the 
study team. Treat per section 9.0 and monitor for effectiveness.  
15.194 
Monitor LFTs closely as elevations in these levels could indicate early 
onset autoimmune hepatitis. Patients should also be instructed to report 
any jaundice, or right upper quadrant pain to the study team 
immediately. 
15.195 
Pneumonitis can be seen and may be mild (only seen on imaging) to 
severe. Patients should be instructed to report any SOB, dyspnea, 
cough, chest pain, etc. to the study team immediately. Patients 
reporting these symptoms should have a pulse ox checked and consider 
immediate imaging per the treating MD. 
15.196 
Endocrinopathies (including hypopituitarism, hypothyroidism, 
hypophysitis, and adrenal insufficiency) are seen with this agent. 
Patients may present only with the vague sense of fatigue and “not 
feeling well.” Additional symptoms may be that of nausea, sweating 
and decreased activity tolerance. Instruct patients to report these signs 
or symptoms immediately and obtain appropriate labs as ordered by 
MD. 
15.197 
Patients who are started on steroid therapy for any side effects of 
pembrolizumab toxicity should be instructed to take the steroids as 
ordered, and not to discontinue abruptly as symptoms may return and 
be severe. Patients may be on steroid therapy for weeks. Instruct 
patients to report any increase or change in side effects with any 
dosage decrease as patients may need a slower taper. 
15.198 
Fatigue is common and may or may not be associated with immune 
related side effects. Assess patient’s fatigue level prior to each cycle of 
therapy and report any changes to the study team. 
15.199a Patients should avoid receiving live vaccines within 30 days of study 
drug administration or per other study guidelines.  
15.199b Patients who have undergone an allogenic bone marrow transplant, 
have an increased risk of severe complications including early GVHD, 
and veno-occlusive disease, if they have previously been treated with 
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15.199c Myocarditis has been reported and associated with pembrolizumab. 
Instruct patients to report chest pain, SOB, or dyspnea to study team 
immediately and/or seek emergency medical attention. 
15.199d Autoimmune hematologic disorders including ITP and hemolytic 
anemia have been reported. Monitor blood counts closely and report 
any abnormalities to the study team. 
15.199e Rare neurologic disorders including Guillain-Barre syndrome and 
myasthenia gravis have been reported. Instruct patients to report any 
neurologic symptoms including weakness, paresthesias or numbness, 
tingling to the study team immediately. 

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15.2 
Temozolomide for Oral Administration (Temodar®, TMZ) 
15.21 Background: Like dacarbazine, temozolomide is converted to the active 
alkylating metabolite MTIC [(methyl-triazene-1-yl)-imidazole-4-carboxamide]. 
Unlike dacarbazine, however, this conversion is spontaneous, nonenzymatic, and 
occurs under physiologic conditions in all tissues to which the drug distributes. 
15.22 Formulation: Commercially available for oral administration as:  
Capsules: 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, 250 mg  
15.23 Preparation, storage, and stability: Refer to package insert for complete 
dispensing instructions. Store capsules at room temperature of 15ºC to 
30ºC.  
15.24 Administration: Refer to the treatment section for specific administration 
instructions. Capsules should not be opened or chewed but swallowed whole with 
a glass of water. Temozolomide may be administered on an empty stomach to 
reduce nausea and vomiting. Bedtime administration may be advised. Do not 
repeat if vomiting occurs after dose is administered; wait until the next scheduled 
dose. 
15.25 Pharmacokinetic information: 
Absorption: Rapid and complete 
Distribution: Vd: Parent drug: 0.4 L/kg; penetrates blood brain barrier; 
CSF levels are ~35% to 39% of plasma levels 
Protein binding: 15% 
Bioavailability: 100% 
Time to peak, serum: Empty stomach: 1 hour; with food (high-fat meal): 
2.25 hours 
Metabolism: Prodrug, hydrolyzed to the active form, MTIC; MTIC is 
eventually eliminated as CO2 and 5-aminoimidazole-4-carboxamide 
(AID), a natural constituent of urine 
Half-life elimination: Mean: Parent drug: 1.8 hours 
Excretion: Urine (~38%; parent drug 6%); feces <1% 
15.26 Potential Drug Interactions: 
Ethanol/Nutrition/Herb Interactions: Food reduces rate and extent of 
absorption. 
15.27 Known potential adverse events: Consult the package insert for the most 
current and complete information. With CNS malignancies, it is difficult to 
distinguish between CNS adverse events caused by temozolomide versus 
the effects of progressive disease. 
Common known potential toxicities, >10%: 
Cardiovascular: Peripheral edema (11%) 
Central nervous system: Fatigue (34% to 61%), headache (23% to 41%), 
seizure (6% to 23%), hemiparesis (18%), fever (13%), dizziness (5% to 
12%), coordination abnormality (11%) 
Dermatologic: Alopecia (55%), rash (8% to 13%) 
Gastrointestinal: Nausea (49% to 53%; grades 3/4: 1% to 10%), vomiting 
(29% to 42%; grades 3/4: 2% to 6%), constipation (22% to 33%), anorexia 
(9% to 27%), diarrhea (10% to 16%) 

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Hematologic: Lymphopenia (grades 3/4: 55%), thrombocytopenia (grades 
3/4: adults: 4% to 19%), neutropenia (grades 3/4: adults: 8% to 14%), 
leukopenia (grades 3/4: 11%) 
Miscellaneous: Viral infection (11%) 
Less common known potential toxicities, 1% - 10%:  
Central nervous system: Amnesia (10%), insomnia (4% to 10%), 
somnolence (9%), ataxia (8%), paresis (8%), anxiety (7%), memory 
impairment (7%), depression (6%), confusion (5%) 
Dermatologic: Pruritus (5% to 8%), dry skin (5%), radiation injury (2% 
maintenance phase after radiotherapy), erythema (1%) 
Endocrine & metabolic: Hypercorticism (8%), breast pain (females 6%) 
Gastrointestinal: Stomatitis (9%), abdominal pain (5% to 9%), dysphagia 
(7%), taste perversion (5%), weight gain (5%) 
Genitourinary: Incontinence 98%), urinary tract infection (8%), urinary 
frequency (6%) 
Hematologic: Anemia (grades 3/4: 4%) 
Neuromuscular & skeletal: Paresthesia (9%), back pain (8%), abnormal 
gait (6%), arthralgia (6%), myalgia (5%) 
Ocular: Blurred vision (5% to 8%), diplopia (5%), vision abnormality 
(visual deficit/vision changes 5%) 
Respiratory: Pharyngitis (8%), upper respiratory tract infection (8%), 
cough (5% to 8%), sinusitis (6%), dyspnea (5%) 
Miscellaneous: Allergic reaction (up to 3%) 
Rare toxicities <1%:  
Alkaline phosphatase increased, alveolitis, anaphylaxis, aplastic anemia, 
emotional lability, erythema multiforme, febrile neutropenia, flu-like 
syndrome, hallucination, hematoma, hemorrhage, herpes simplex, herpes 
zoster, hyperglycemia, hypokalemia, interstitial pneumonia/pneumonitis, 
myelodysplastic syndrome, opportunistic infection (e.g., PCP), oral 
candidiasis, pancytopenia, peripheral neuropathy, petechiae, pneumonitis, 
pulmonary fibrosis, secondary malignancies (including myeloid leukemia), 
Stevens-Johnson syndrome, toxic epidermal necrolysis 
 
15.28 Drug procurement: Commercial supplies. Pharmacies or clinics shall obtain 
supplies from normal commercial supply chain or wholesaler. 
 
15.29 Nursing Guidelines 
15.291 
Myelosuppression has been found to be the dose-limiting toxicity. Gr 3 
thrombocytopenia occurred in 6% of patients and Gr 4 in 1%. Gr 3 and 
Gr 4 lymphopenia occurred in 55% of patients. Leukopenia, 
lymphopenia, thrombocytopenia and anemia usually occur 2-8 weeks 
after initiation of treatment. Monitor CBC carefully and report any 
significant changes to MD. Instruct patient to report signs/symptoms of 
infection, unusual bruising and bleeding to health care team. 
 
15.292 
In previous studies, patients have developed pneumocystis carinii 
pneumonia (PCP) when taking concomitant temozolomide and 
steroids. Instruct patient to report any fever, cough, chest pain, of other 

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signs of infection to the health care team. Counsel patients on the 
importance of taking PCP prophylaxis as prescribed if ordered. 
 
15.293 
Advise patient that a mild-moderate rash may be experienced.  
 
15.294 
Fatigue may be experienced. Work with patient in energy conserving 
lifestyle. 
 
15.295 
Remind patient that drug needs to be taken on an empty stomach with a 
full glass of water. Drug should not be crushed, chewed, opened, or 
dissolved. 
 
15.296 
Nausea and vomiting are common. Teach patient to self-medicate with 
anti-emetics one hour prior to dose. Assess for effectiveness. If 
vomiting occurs, do not repeat dose. Wait until next scheduled dose. 
 
15.297 
Temozolomide may interact with valproic acid by reducing the 
clearance of temozolomide by 5%. Assess concomitant medication use. 
 
15.298 
Constipation is common. Encourage patient to increase fluid intake. 
Administer stool softeners or laxatives as ordered and monitor for their 
effectiveness. 
 
15.299a  Monitor for cytopenia (i.e. CBC w/differential). Instruct patient to 
report any fever, signs or symptoms of infection, or any unusual 
bruising or bleeding to the study team. 
 
15.299b Headache may be seen. Assess for more serious condition (i.e. cerebral 
bleed, disease progression) first and then treat symptomatically and 
monitor for effectiveness. 
 

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16.0 
Statistical Considerations and Methodology 
16.1 
Study design 
This study is comprised of two separate treatment groups; Group 1 Neoadjuvant and 
Group 2 Adjuvant. Group 1 Neoadjuvant is a pilot study where patients begin treatment 
prior to surgery. These patients enter treatment at a different point in their treatment 
process and will be evaluated separately from the Group 2 patients. Group 2 Adjuvant is 
a single arm, one stage phase II study designed to evaluate the 18 month overall survival 
rate of pembrolizumab in combination with standard therapy after surgery (external beam 
radiation therapy plus concomitant TMZ and then adjuvant TMZ chemotherapy) in 
patients newly diagnosed glioblastoma. Group 1 has a safety run-in phase to conduct a 
thorough review of adverse event data within the initial 6 patients. Other endpoints are 
adverse event profile, time to progression, progression free survival, and time to 
treatment failure. 
16.11 Group 1 Neoadjuvant Safety Run-In Cohort: Early adverse event assessment 
(run-in phase) 
To ensure safety of treating patients with pembrolizumab in combination with 
standard therapy, an initial 6 patients will be enrolled and treated for adverse 
events assessment. These patients will be enrolled in cohorts of 3+3 design.  
The first cohort of 3 patients will receive pembrolizumab 200 mg intravenously 
(dose level 1). If less than 2 patients in this first cohort experience a DLT (See 
Section 7.9), the next cohort will be enrolled at a pembrolizumab dose of 200 mg 
intravenously (dose level 1).  
If DLTs are observed in two or more patients in the initial cohort of 3, or 
more than 1/6 patients in both cohorts, then accrual will be temporarily 
suspended. The study team will conduct a comprehensive review of all 
the adverse event data, investigate the specifics of each DLT, and after 
consulting with the FDA and the drug supplier, will consider possible 
actions including at least the following: permanently suspend accrual,  
Patients who have signed consent form, are deemed eligible, and have either 
completed the first 3 cycles (neoadjuvant, surgery, concurrent) of protocol 
treatment; or, are off protocol treatment due to toxicities, or other treatment 
related complications are evaluable for decision-making regarding early adverse 
event evaluation. If the pembrolizumab is deemed safe for the Group 1 study 
population, then these patients will be included in exploratory and hypothesis 
generating analysis of similar endpoints as listed for the Group 2 primary and 
secondary analysis. 
As of Amendment 3 the Group 1 Neoadjuvant study will reopen for at most an 
additional 6 DLT evaluable patients enrolled via the cohorts of 3+3 design as 
described above including the following DLT stopping rules. 
The third cohort of 3 patients will receive pembrolizumab 200 mg intravenously 
(dose level 1). If less than 2 patients in this cohort experience a DLT (See Section 
7.9), the next cohort will be enrolled.  
If DLTs are observed in two or more patients in this third cohort of 3, or more 
than 1/6 patients in both cohorts 3 and 4, then accrual to Group 1 will be 
temporarily suspended. The study team will conduct a comprehensive review of 
all the adverse event data, investigate the specifics of each DLT, and after 

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consulting with the FDA and the drug supplier, will consider possible actions 
including at least the following: permanently suspend accrual.  
16.12 Group 2 Adjuvant: Single arm, one-stage phase II design 
16.121 
Primary endpoint 
The primary endpoint of this study is the number of 18 month overall 
survival (OS18) successes. OS18 is defined as the number of patients 
who are alive at least 18 months after beginning study therapy divided 
by the total evaluable patients. All patients who have signed a consent 
form, are eligible, and have begun treatment in Cycle 3 (concurrent 
RT+TMZ+MK-3475) will be considered evaluable for the primary 
endpoint. The patients enrolled for early adverse events evaluation who 
meet this evaluable status will be included in the primary efficacy 
decision-making procedures and the analysis of the primary endpoint.  
Definition of Success: An evaluable patient will be classified as a 
“success” for the primary endpoint if the patient is alive at least 18 
months after beginning study therapy. 
16.122 
Decision Rule and Power Considerations 
Stupp et al. reported an 18 month OS rate (OS18) of 39.4% for newly 
diagnosed GBM received radiotherapy plus TMZ. This 39.4% is 
associated with a median overall survival of 14.6 months starting at the 
time of study registration, which for that study was within one week of 
starting concurrent RT+TMZ. This study starts at the same timepoint. 
A sample size of 33 evaluable patients will provide a power of 85.3% 
to test the alternative hypothesis that the 18 month OS rate is at least 
59.0% against the null hypothesis that the 18 months OS rate is at most 
39.0%, at a one-sided significance level of 0.099.  
At the conclusion of the trial, the regimen will be concluded that the 
combination of MK-3475 and standard therapy warrants the further 
investigation, if at least 17 patients are alive at least 18 months after 
beginning of study therapy. Otherwise, we will conclude that the 
proposed regimen does not warrant the further investigation. 
16.123 
Safety Run-In Cohort: Early adverse event assessment (run-in phase) 
To ensure safety of treating patients with pembrolizumab in 
combination with standard therapy, an initial cohort of 6 patients will 
be enrolled and treated for adverse events assessment. Enrollment will 
be temporarily suspended for the Safety Run-In AE assessment of 
these patients.  
If DLTs are observed in three or more patients in the initial cohort of 
6 DLT-evaluable patients, then accrual will be temporarily suspended. 
The study team will conduct a comprehensive review of all the adverse 
event data, investigate the specifics of each DLT, and after consulting 
with the FDA and the drug supplier, will consider possible actions 
including at least the following: permanently suspend accrual. 
Patients who have signed consent form, are deemed eligible, and have 
either completed the first cycle (concurrent) of protocol treatment; or, 
are off protocol treatment due to toxicities, or other treatment related 

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complications are evaluable for decision-making regarding early 
adverse event evaluation. 
16.13 Sample Size 
A total of 33 evaluable Group 2 patients are required for primary endpoint 
assessment per study design stated in Section 16.12. We anticipate accruing an 
additional 3 patients in Group 1 and 4 patients to Group 2 to account for 
ineligibilities, cancelations, major violations, and other reasons. Thus, the 
maximum accrual is 52 patients in total (15 patients in Group 1 and 37 in Group 
2. To account for patients that are consented and do not meet full eligibility 
criteria, we anticipate having to consent and screen 90 patients to achieve the 
maximum accrual of 52 patients. 
16.14 Accrual and Study Duration 
Given previous data from Mayo Clinic Cancer Center Phase I and Phase II 
clinical trials, it is expected that the accrual rate will be about 2 patients every 
month to this trial. Taking into account the minimal follow-up of 18 months after 
beginning of study therapy for the last enrolled patients, the overall study 
duration will be approximately 40 months. 
16.15 Primary Endpoint Completion Date for 
 Reporting 
For purposes of 
 reporting, the Primary Endpoint Completion 
Date for this study is the latest date all Group 2 patients have died or have been 
followed for at least 18 months whichever comes first. An initial Anticipated 
Primary Completion Data for this study is 40 months after the Group 2 study 
opens to accrual. 
16.2 
Analysis plans 
16.21 Primary Endpoints 
16.211 
Group 1: Dose-Limiting Toxicity Rate: The rate of DLTs within each 
dose-level cohort will be reported along with confidence intervals. All 
DLT evaluable patients will be included and DLT will be evaluated 
during all cycles of treatment. 
16.212 
Group 2: Overall Survival 18 month successes. OS18 successes will be 
measured as the number of evaluable patients classified as a “success” 
for the primary endpoint based on if the patient is alive at least 
18 months after beginning study therapy. The OS18 percentage will 
also be calculated in an exploratory manner as measured by the 
percentage of Group 2 evaluable patients alive at 18 months after 
beginning study treatment. The OS18 percentage and 95% confidence 
intervals will be calculated via the Kaplan-Meier method. 
16.22 Secondary Analysis 
16.221 
Adverse Events Profile (Group1 and Group 2)  
The number and severity of all adverse events will be tabulated and 
summarized in this patient population. Specifically, the overall toxicity 
percentages for Grade 3 or higher adverse events considered at least 
possibly related to treatment will also calculated and reported. All 
other adverse event analysis will be exploratory and hypothesis 
generating. This may include and not be limited to: a summary of non-
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ordinal CTCAE grading, measures of thrombocytopenia, neutropenia, 
and leukopenia will be assessed using continuous variables as the 
outcome measures (primarily nadir) as well as categorization via 
CTCAE grading, overall adverse event incidence as well as profiles by 
dose level and by tumor type will be explored and summarized, time 
until any treatment related adverse event, time until treatment related 
Grade 3+ adverse event, time until hematologic nadirs (WBC, ANC, 
platelets), and frequency distributions, graphical techniques and other 
descriptive measures will form the basis of these analyses.  
16.222 
Time to progression (Group 2 only) 
Time to Progression is defined as the length of time from start of study 
treatment to progression via the iRANO criteria listed in Section 11. 
The median and 95% confidence intervals will be calculated via the 
Kaplan-Meier method. 
16.223 
Progression Free Survival time (Group 2 only) 
Progression free survival (PFS) is defined as the time from the date of 
starting study treatment to the date of disease progression or death 
resulting from any cause, whichever comes first. Progression is defined 
according to iRANO criteria found in Section 11. The median and 95% 
confidence intervals will be estimated using the Kaplan-Meier 
estimator. 
16.224 
Time to Treatment Failure (TTF) (Group 2 only) TTFTime to 
treatment failure is defined as the time from beginning study therapy to 
documentation of progression, unacceptable adverse event(s), or 
refusal to continue participation by the patient. The median and 95% 
confidence intervals will be estimated using the Kaplan-Meier 
estimator. 
16.23 Translational Endpoints 
The biomarkers listed in Sections 14.0 and 17.0 will analyzed in an exploratory 
and hypothesis generating manner which may include and not be limited to:  
being examined at all defined time points and will be explored descriptively to 
detect patterns and substantial changes. In addition, differences between post-
baseline and baseline apoptotic scores will be analyzed using a paired-sample t-
test or the nonparametric equivalent. 
16.3 
Data & Safety Monitoring:  
16.31 The principal investigator(s) and the study statistician(s) will review the study at 
least twice a year to identify accrual, adverse event, and any endpoint problems 
that might be developing. The Mayo Clinic Cancer Center (MCCC) Data Safety 
Monitoring Board (DSMB) is responsible for reviewing accrual and safety data 
for this trial at least twice a year, based on reports provided by the MCCC 
Statistical Office.  
16.32 Adverse Event Stopping Rules:  
The stopping rules below will be assessed independently for Group 1 and 
Group 2. The stopping rules specified below are based on the knowledge 
available at study development. We note that the Adverse Event Stopping Rule 
may be adjusted in the event of either (1) the study re-opening to accrual or (2) at 
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information regarding the adverse event profile of the treatment(s) under 
investigation. The study team may choose to suspend accrual to either Group 1 or 
Group 2 independently because of unexpected adverse event profiles that have 
not crossed the specified rule below.  
Accrual will be temporarily suspended to Group 1 and/or Group 2 if at any time 
we observe events considered at least possibly related to study treatment (i.e. an 
adverse event with attribution to pembrolizumab specified as “possible”, 
“probable”, or “definite”) that satisfy either of the following:  
• 
In addition to the stopping rules associated with the safety run-in cohort 
(see Section 16.11), if at any time >1/3rd of patients experience a DLT as 
specified in Section 7.0.  
• 
If there is one patient death that is considered related to pembrolizumab 
any time during the study 
Any group closed to accrual will not be re-opened without proper protocol 
modification. If no modifications are possible then accrual to the group will close 
i.e. accrual to the appropriate group will be permanently stopped. We note that 
we will review Grade 4 and 5 adverse events deemed “unrelated” or “unlikely to 
be related”, to verify their attribution and to monitor the emergence of a 
previously unrecognized treatment-related adverse event. 
16.4 
Inclusion of Minorities  
16.41 Availability 
This study will be available to all eligible patients, regardless of race or ethnic 
origin. 
16.42 Power for Subset Analyses 
Although the planned analysis will, as always, look for differences in treatment 
effect based on racial groupings the sample size is not increased in order to 
provide additional power for subset analyses.  
16.43 Population 
Based on prior studies involving similar disease sites conducted at Mayo Clinic 
in Rochester, MN, we expect about 7% of patients will be classified as minorities 
by race/ethnicity and about 40% of patients will be women. Expected sizes of 
racial subsets are shown in the following table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
1 
1 
2 
Not Hispanic or Latino 
20 
30 
50 
Ethnic Category: Total of all subjects 
21 
31 
52 
Racial Category 
American Indian or Alaskan Native 
1 
1 
2 
Asian 
1 
0 
1 
Black or African American 
1 
2 
3 
Native Hawaiian or other Pacific Islander 
0 
1 
1 
White 
18 
27 
45 
Racial Category: Total of all subjects 
21 
31 
52 

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Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 
 

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17.0 
Pathology Considerations / Tissue Specimen Submission  
17.1 
Summary Table of Research Tissue Specimens to be Collected for this Protocol 
Correlative Study 
(Section for more 
information) 
Mandatory 
or Optional 
Type of 
Tissue to 
Collect 
Block, Slides, 
Core, etc.  
(# of each to 
submit) 
Tissue from 
Pre-
treatment 
Biopsy 
(Group 1) or 
Surgery 
(Group 2) 
Craniotomy/ 
tumor 
resection at 
Mayo Clinic 
(Group 1) 
At Time of 
Progressive 
Disease 
(Group 1 
and 2) 
Process at 
site?  
(Yes or No) 
Temperature 
Conditions for 
Storage 
/Shipping 
Antigen 
Mandatory* 
Formalin fixed 
and paraffin 
embedded 
(FFPE) 
1 block  
or 5 slides at 
5 microns 
+1 H&E 
X 
 
 
Yes 
Ambient 
Antigen 
Mandatory 
FFPE 
1 block  
or 5 slides at 
5 microns 
+1 H&E 
 
X** 
 
Yes 
Ambient 
Antigen 
Mandatory* 
FFPE 
1 block  
or 5 slides at 
5 microns 
+1 H&E 
 
 
X 
Yes 
Ambient 
*Only if available 
** Neoadjuvant patients (Group 1) only 
 
 

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17.2 
Diagnostic Slides from Original and /or Recurrent Tissue 
Along with original diagnostic slides, include the surgical pathology report. Send slides 
to the
 
 
17.3 
Correlative Tissue Collection  
17.31 Tissue kits will not be provided for this protocol. 
17.32 Paraffin Embedded Tissue 
17.321 Provision of a single block of tumor tissue each from the biopsy prior to 
enrollment and the subsequent craniotomy and resection is mandatory. If 
available, provision a single block of tumor tissue obtained at time of 
progression is optional. NOTE: For biopsy prior to enrollment, if block is 
not available, then submit 5 unstained slides at 5 microns plus one H&E 
slide. 
17.322 Label slides with the study number, the patient study ID number, patient 
initials, and the date of the operative procedure. 
17.323 Samples are to be sent to the
 
17.324 Samples can be stored at room temperature.  
17.4 
Background and Methodology 
17.41 Immunohistochemistry 
Immunohistochemical techniques have been validated on paraffin-embedded 
tissues and appropriate specific antibodies are available for CD4, CD8, CD68, 
PD-1, and PD-L1. Accordingly, we will be obtaining immunohistochemical 
stains for these antigens on glioblastoma tissue from initial diagnostic biopsy and 
subsequent craniotomy and resection as well as at recurrence when such tissue 
slides are availability. This may be limited if the initial diagnosis was based on 
needle biopsy (not resection) or if further resection is not clinically indicated at 
time of recurrence. Tissue availability for these ancillary studies will not be an 
entrance criteria and this testing, while highly desirable, will be considered 
optional. 
 

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18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
18.11 Initial Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
On-Study 
 
Adverse Event - Baseline 
 
Measurement – On Study 
 
Baseline Research Blood Submission  
(see Section 14.0) 
≤2 weeks after registration 
Concurrent Steroids and Anticonvulsants 
 
OP and Path Reports (see Section 17.0) 
 
End of Active Treatment/Cancel 
Notification 
Submit ≤2 weeks after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
18.12 Pathology and Research Tissue Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
Baseline Research Tissue Submission (See Section 17.0) 
Can be submitted before or during active 
treatment. (see Section 17.0) 
Pathology Materials  
Pathology Reporting Brain Tumor GBM Trials 
18.13 Test Schedule Material(s) 
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each evaluation during treatment 
At end of 
treatment Observation 
Evaluation/Treatment 
X1 
X 
 
Evaluation/Observation 
 
 
X 
Adverse Event 
X 
X 
X 
Measurement3 
X 
X 
 
Research Blood Submission 
X (see Section 14.0) 
 
X 
Research Tissue Submission 
X (see Section 17.0) 
 
 
Concurrent Steroids and Anticonvulsants 
X 
X 
X 
Surgery 
X2 
 
 
Radiation Therapy Reporting Brain 
X4 
 
 
Pathology Reporting Brain Tumor GBM Trials 
X2 
 
 
End of Active Treatment/Cancel Notification 
 
X 
 
ADR/AER 
At each occurrence (see Section 10.0) 
 
 
Dose Limiting Toxicity 
At each occurrence 
 
 
1. Complete at each evaluation during Active Treatment (see Section 4.0). 
2. Complete following Craniotomy/tumor resection. 
3. Cycle 1 form is at the end of Cycle 1 and just Prior to Surgery, and Cycle 2 form is Post Surgery, pre-RT. 
4. Submit following completion of radiation therapy 

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18.14 Follow-up Material(s) 
CRF 
Event Monitoring Phase1 
q. 2 
months 
until PD2 
At PD2 
After 
PD q. 6 
mos. 
Death 
New Primary 
Event Monitoring 
X3 
X3 
X 
X 
At each occurrence 
1. If a patient is still alive 3 years after registration, no further follow-up is required. 
2. If PD is determined at site outside of Mayo Clinic that does not use Epic Clinical Systems: 
Submit relevant radiographic images as a digital image with a viewing tool free of marks that 
may obscure the lesions or bias the evaluation of the independent reviewer(s) of tumor 
response at baseline and tumor response and/or progression to address in note below. 
3. Submit copy of documentation of response or progression to the
 
  
18.2 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
18.3 
Site responsibilities 
Each site will be responsible for insuring that all materials contain the patient’s 
initials, MCCC registration number, and MCCC protocol number. Patient’s name 
must be removed. 
18.5 
Supporting Documentation 
This study requires supporting documentation for evidence of response to study therapy 
and progression after study therapy. Pathology and operative reports for pre-treatment 
biopsy and surgery are also required. 
18.6 
Incomplete materials 
Any data entered into a form will result in that form being marked as “received.” 
However, missing data will be flagged by edit checks in the database. 
18.7 
Overdue lists 
A list of overdue materials and forms for study patients will be generated 
monthly. The listings will be sorted by location and will include the patient study 
registration number. The appropriate site will be responsible to obtain the 
overdue material. 
19.0  
Budget 
19.1 
Costs charged to patient: routine clinical care 
19.2 
Tests to be research funded: Correlative studies and research analyses of blood and tissue 
samples 
19.3 
Other budget concerns: Pembrolizumab will be provided by Merck. 

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20.0 
References 
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of programmed 
death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 
2003;170:1257-66. 
Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, et al. The prioritization of cancer 
antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer 
Res. 2009; 15:5323-37. 
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. Tumor infiltrating 
lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol 2010; 
11:19. 
Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. Histopathologic prognostic 
score in colorectal adenocarcinomas. Anticancer Res 1998; 18:689-94. 
Disis ML. Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8. 
Dixit K, Kumthekar P, et al. Phase I/II trial of radiation therapy, temozolomide, and pembrolizumab 
followed by temozolomide and pembrolizumab in patients with newly diagnosed glioblastoma. Abstract 
#42692 http://neuro-oncology.oxfordjournals.org/content/18/suppl_6/vi19.4.short.  
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumorassociated B7-H1 
promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8(8):793-800. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther 
S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan; 
45(2):228-47. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 
2010; 236:219-42. 
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, density, and 
location of immune cells within human colorectal tumors predict clinical outcome. Science 2006; 
313:1960-4. 
Gustafson MP, Lin Y, New KC, Bulur PA, O'Neill BP, Gastineau DA, et al. Systemic immune 
suppression in glioblastoma: the interplay between CD14+HLA-DRlo/neg monocytes, tumor factors, and 
dexamethasone. Neuro-oncology. 2010. 
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber 
JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, 
Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, and Ribas A. 
Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma. NEJM 2013; 369: 134-44 
Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, Winnepenninckx V, et al. 
Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous 
melanoma. Cancer Immunol Immunother 2008; 57:97-106. 
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. Int J Clin 
Oncol 2010; 15:544-51. 
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan Pathol 2010; 
37(Suppl 1):48-53. 

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Ji, YA, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for dose-finding trials. 
Clinical Trials. 2010 Dec; 7(6):653-663. 
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 2009; 10:840-841. 
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of type and density 
of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 2008; 99(10):1704-11. 
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. Prognostic 
significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage 
ovarian cancer. Cancer Immunol Immunother 2009; 58:449-59. 
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory T cells in 
peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell 
carcinoma. BJU Intern 2010; 107:1500-6. 
Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive selection in the 
thymus of PD-1-deficient mice. J Exp Med 2000; 191(5):891-7. 
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival of a patient 
affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic cell infiltration after 
interleukin-2 immunotherapy. Report of a case. Tumori 2008; 94:426-30. 
Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-oncology: a report for 
the RANO working group. Lancet Oncology, 16(15) 2015 e534-e542  
Olin MR, Low W, McKenna DH, Haines SJ, Dahlheimer T, Nascene D, Gustafson MP, Dietz AB, Clark 
HB, Chen W, Blazar b, Ohlfest JR, Moertel C. Vaccination with dendritic cells loaded with allogeneic 
brain tumor cells for recurrent malignant brain tumors induces a CD4+ IL17+ response. J Immunother 
Cancer 2014; 2:4 
Park S, H. Dong H, unpublished 
Parney IF, Farr-Jones MA; Change LJ; Petruk, KC, Human Glioma Immunobiology in Vitro: 
Implications for Immunogene Therapy, Neurosurgery 2000; 46(5): 1169-77  
Parney IF, Dietz AB unpublished 
Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, 
Jensen MC, Mischel PAS, Sokoe D, and Pieper RO. Loss of tumor suppressor PTEN function increases 
B7-H1 expression and immunoresistance in glioma. Nat Med 2006; 13: 84-8 
Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, 
Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Alison JP, 
Lesokhin AM, Gnjatic S, Wolchok JD. Immunologic Correlates of the Abscopal Effect in a Patient with 
Melanoma, NEJM 2012; 366: 925-31 
Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, et al. Normal human 
monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro-
oncology. 2010; 12:351-65. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002; 2:116-26. 
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus 
concomitant and adjuvant temozolomide for glioblastoma. The New England journal of medicine. 2005; 
352:987-96. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer 
Metastasis Rev 2007; 26:373-400. 

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Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL and Anders 
RA. Association of PD-1, PD-1 Ligands, and Other Features of the Tumor Immune Microenvironment 
with Response to Anti–PD-1 Therapy. Clin Cancer Res, 2014; 20:5064. 
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 expressed by 
tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell 
carcinoma. Clin Caner Res 2007; 13(6):1757-61. 
Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998; 17(1):77-81. 
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response 
assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin 
Oncol. 2010; 28:1963-72. 
 
 

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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 

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Appendix II 
Radiation Therapy Recommendations 
II.1 
Certification: 
Standard conformal techniques will be allowed in this study along with IMRT.  
 
II.2 
Radiation Energy: 
Minimum photon energy of 4MV with multiple ports designed and verified by simulation. If IMRT is 
utilized, 6 MV is preferred. Minimum SSD or SAD of 80 cm. 
 
II.3 
Treatment Volumes 
II.3.1 Gross Tumor Volume 1 (GTV1):  
A postoperative MRI must be used for tumor localization, with the exception of 1) patient in 
whom MRI is contraindicated (e.g., pacemaker, claustrophobia, etc.) in which case a CT scan can 
be used, and 2) patients who underwent biopsy only; in which case the preoperative MRI scan 
can be used. For purposes of the protocol, the GTV1 will be the so-called “edema volume” which 
is best visualized on the FLAIR or T2-weighted MR images. The GTV1 should also include the 
surgical resection cavity and any FLAIR or T2 abnormalities beyond the edges of the cavity. The 
GTV1 should also encompass all of GTV2, which is defined by regions of contrast enhancement. 
In the case of a gross total resection without any residual FLAIR/T2 abnormalities, then the 
surgical cavity will be considered the GTV1. In cases where a partial or complete lobectomy has 
been performed, the region distal to the edge of the resection (i.e., where no brain tissue is 
present) does not need to be included in the GTV1 (or the CTV1). For example, if a patient has an 
anterior temporal lobectomy, the anterior middle cranial fossa does not need to be included in the 
tumor volume. In this situation, the GTV1 should encompass the resection margin and any 
FLAIR to T2-weighted abnormalities and areas of tumor enhancement.  
II.3.2 Clinical Target Volume 1 (CTV1):  
The CTV1 is the GTV1 plus a margin of 1.0 cm in all directions. However, the CTV1 must not 
extend outside the brain. The CTV1 may also be modified to meet critical dose constraints (e.g., 
optic nerves) but should never be less than the GTV1. In cases where a partial or complete 
lobectomy has been performed, the region distal to the edge of the resection (i.e., where no brain 
tissue is present) does not need to be included in the CTV1. For example, if a patient has an 
anterior temporal lobectomy, the anterior middle cranial fossa does not need to be included in the 
tumor volume. In this situation, the CTV1 should be an expansion of the GTV1 in all directions, 
but not into the resection cavity. 
II.3.3 Planning Target Volume 1 (PTV1): 
The PTV expansion is institution dependent to account for set-up uncertainty. Typically, the 
PTV1 expansion is 3 to 5 mm in all directions to account for daily setup variation and patient 
movement, but not beam penumbra or buildup. Generally another 5-7 mm is added to block edge 
in 3D planning to account for penumbra. 
 
 

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II.3.4 GTV2 
The region of contrast enhancement on T1 imaging should be contoured to define GTV2. In the 
case of a resection, the resection margin should be included in the GTV2 even if there is no 
residual contrast enhancement. 
II.3.5 CTV2 
CTV2 is defined by a 1 cm expansion of GTV2. 
11.3.6 PTV2 
The PTV expansion is institution dependent to account for set-up uncertainty. Typically, the 
PTV2 expansion is 3 to 5 mm in all directions to account for daily setup variation and patient 
movement, but not beam penumbra or buildup. 
II.3.6 Internal Margin (IM), Set-Up Margin (SM): 
There will be no IM or SM. 
II.4 
Prescription Isodose: 
The prescription isodose (i.e. the isodose that is 100% of the prescription dose) should be the isodose 
surface (i.e. curve) that encompasses 95% of the PTV. In addition, the goal of the treatment plan is to 
encompass the entire PTV within the 95% isodose surface. The dose uniformity guidelines below should 
be met for both the PTV1 and the PTV2. If IMRT is used, the PTV and the PTV boost should be treated 
concomitantly. 
II.5 
Tissue Heterogeneity: 
Calculations are required for IMRT and strongly recommended for 3D treatment planning to take into 
account the effect of tissue heterogeneities whenever CT-based planning is used. 
II.6 
Total Dose: 
II.6.1 3D Total Dose: 
The dose to the prescription isodose for the PTV1 (derived from the GTV1 – see above) will be 
5000 cGy in 25 daily fractions of 200 cGy each. The dose will be delivered to the treatment 
volumes as previously described. The dose to the prescription isodose for the PTV2 (derived from 
the GTV2 – see above) will be 1000 cGy in 5 daily fractions of 200 cGy each. The dose will be 
delivered to the treatment volumes as previously described. Therefore, the total dose will be 6000 
cGy in 30 daily fractions of 200 cGy each. 
II.6.2 IMRT Total Dose: 
The dose to the prescription isodose for the PTV1 (derived from the GTV1 – see above) will be 
5400 cGy in 30 daily fractions of 180 cGy each. The dose to the prescription isodose for the 
PTV2 (derived from the GTV2 – see above) will be 6000 cGy in 30 daily fractions of 200 cGy 
each. The dose should be delivered concurrently to the treatment volumes as previously 
described. Alternatively, use of 2 sequential IMRT plans to deliver 5000 cGy in 25 fractions to 
PTV1 followed by an additional 1000 cGy to PTV2 is acceptable  
 
 

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II.7 
Dose Uniformity: 
The entire PTV should be encompassed within the 95% isodose surface as evaluated by dose volume 
histogram. Please note it is preferable that 95% or more of the PTV receives the prescribed dose. The 
uniformity guidelines should be met for both the PTV 1 and the PTV boost. In addition, none of the PTV 
boost should receive more than 110% of the prescription dose. 
II.8 
Time Considerations: 
Patients will receive one treatment per day, five days per week (Monday through Friday with the 
exception of holidays). All fields will be treated each day. At least two fractions must be given during the 
first week of treatment. 
II.8.1 Interruptions: 
No special considerations need to be made for treatment delays of 1 week or less. Treatment may 
be given on weekends to make up for treatment interruptions. If treatment is delayed more than 1 
week, notify the Study Chair. 
II.9 
Simulation: 
Simulation will be performed using either a conventional CT or MRI simulator. 
II.9.1 Patient Position and Immobilization:  
The patient shall be treated in the supine or other appropriate position, depending on the location 
of the lesion. A head-holding device that is transparent to x-rays (thermoplast masks, bit-block, 
etc) must be used to ensure adequate immobilization during therapy of reproducible treatment 
setups. 
II.10 
Organs at Risk (OAR): 
When possible, without shielding GTV/CTV/PTV, no more than 1% of the volume or 1 cc of each of the 
following OAR should receive more than the following doses: brainstem 5500 cGy, optic nerves and 
optic chiasm 5400 cGy, retina 4500 cGy, cervical spinal cord 5000 cGy, and lens 1000 cGy. These 
constraints may have a higher priority than the target volumes at the treating physician’s discretion. If 
possible, no more than 1% or 1 cc of the contralateral uninvolved brain should receive more than 3000 
cGy. Also, no more than 1% or 1 cc of unspecified tissue outside of the PTV to receive >110% of the 
prescribed dose. Planning organ at risk volumes (PRVs) are recommended such that the spinal cord 
should have 3-dimensional expansion by 5 mm while the optic nerves, optic chiasm, and brainstem 
should have a 3 dimensional expansion by at least 1 mm. The dose constraints to the PRVs will be the 
same as for their respective OARs as outlined above. Lower priority (lower priority than PTV coverage) 
include: Parotids (entire volume) ≤10 Gy, oral cavity/lips/nasal cavity mean dose 20 Gy and <1% >40 
Gy; inner/middle ear mean dose 30 Gy and <1% >50 Gy; lens as low as reasonable possible. Typically 
100% of the parotids should receive <10 Gy, but tumor coverage is of higher priority in cases where this 
dose will exceed 10 Gy. 
II.11 
Dose Calculation and Reporting: 
Not applicable for this study 
 
 

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II.12 
Dose Volume Histograms: 
Dose volume histograms must include GTVs, CTVs, PTVs, and OARs as noted above. A DVH in 
absolute dose must also be submitted for so called “unspecified tissue,” i.e., tissue contained within the 
skin, but not included with the GTV, CTV, PTV, or OAR. 
II.13 
IMRT Plan Verification: 
If IMRT is used, the monitor units generated by the IMRT planning system must be independently 
checked prior to the patient’s first treatment. Measurements in a QA phantom can suffice for a check as 
long as the plan’s fluence distribution can be re-computed for a phantom geometry. 
II.14 
Quality Control and Definitions of Deviations:  
This will be done according to standard guidelines. All plans and associated materials as per Mayo Clinic 
standard will be reviewed by 2 radiation oncologists. 
II.15 
Verification of treatment set-up:  
Port films of each field will be obtained and compared with initial simulation films at least weekly. 
Alternatively, after initial ports are taken of all fields (excluding vertex), an orthogonal pair of reference 
ports may be taken on a weekly basis. For IMRT, orthogonal pair of reference films is sufficient for the 
initial and subsequent ports. 
 
Questions regarding the radiotherapy section of this protocol should be directed to: 
 
 
 
 
 
 

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Appendix III Pembrolizumab ECI Drug-Induced Liver Injury (DILI) 
Hepatotoxicity is injury or damage to the liver that may be associated with impaired liver 
function (Navarro and Senior 2006). Drug-induced hepatotoxicity is one of the most common 
causes of termination of drug development, a major reason for refusal of market authorization 
and for restricted use, and the single most important cause of the withdrawal of market 
authorization for products (Björnsson 2006). Thus, drug-induced hepatotoxicity is a major 
concern during the discovery, development to postauthorization phases of the product life cycle 
(excerpted from Draft Guidance Document, Hepatotoxicity of Health Products, Ministry of 
Public Health, Canada, December 2010). 
As stated in the United States Food and Drug Administration (FDA) Guidance for Industry - 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation; hepatocellular injury (usually 
detected by serum aminotransferase elevations [AT]) can be caused by drugs that rarely, if ever, 
cause severe DILI (e.g. aspirin, tacrine, statins, and heparin) as well as by drugs that do cause 
such injury. The frequency of serum AT elevations also is not a good indicator of a potential for 
severe DILI, because drugs such as tacrine (not a cause of severe DILI) can cause AT elevations 
in as many as 50 percent of patients. Very high levels of observed ATs may be a somewhat 
better indicator of potential for severe DILI, but the most specific indicator is evidence of altered 
liver function accompanying or promptly following evidence of hepatocellular injury. 
The single clearest (most specific) predictor found to date of a drug’s potential for severe 
hepatotoxicity, is the occurrence of hepatocellular injury (AT elevation) accompanied by 
increased serum total bilirubin (TBL), not explained by any other cause, such as viral hepatitis or 
exposure to other hepatotoxins, and without evidence of cholestasis, together with an increased 
incidence of AT elevations in the overall trial population compared to control. Increased plasma 
prothrombin time, or its international normalized ratio (INR), a consequence of reduced hepatic 
production of Vitamin K dependent clotting factors, is another potentially useful measure of liver 
function that might suggest the potential for severe liver injury. 
Recognition of the importance of altered liver function, in addition to liver injury, began with 
Hyman Zimmerman’s observation that drug-induced hepatocellular injury (i.e. AT elevation) 
accompanied by jaundice (i.e. TBL elevation) had a poor prognosis, with a 10 to 50 percent 
mortality from acute liver failure (in pretransplantation days) (Zimmerman 1978, 1999). This 
became known as "Hy's Law". This document describes the recommended process for 
monitoring and evaluation of subjects meeting the laboratory criteria for potential DILI defined 
as: 
• 
an elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater 
than or equal to three times (3X) the upper limit of normal (ULN)  
and 
• 
an elevated total bilirubin (TBL) lab value that is greater than or equal to two times (2X) ULN 
and 
• 
at the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
as a result of within-protocol-specific testing or unscheduled testing. 
The protocol identifies these laboratory criteria for potential DILI as ECIs. ECIs are selected adverse 
experiences that must be reported within 24 hours. 
Initiate close observation as defined below and continue follow-up until resolution. 

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• 
Repeat liver enzyme and serum bilirubin tests two (2) or three (3) times weekly. Frequency of 
retesting can decrease to once a week or less if abnormalities stabilize or study drug has been 
discontinued and the subject is asymptomatic. 
• 
Obtain a more detailed history of symptoms and prior or concurrent diseases. 
• 
Obtain a history of concomitant medication use (including prescription and nonprescription 
medications, herbal and other dietary supplements), alcohol use, recreational drug use and special 
diets. (See Section 5 for details.) 
• 
Obtain a history of exposure to chemical agents or other environmental toxins. 
• 
Obtain additional history and complete Stage 1 workup to attempt to rule out other potential 
causes of the transaminase elevation, including but not limited to the following: acute viral 
hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; non-alcoholic steatohepatitis 
(NASH); hypoxic/ischemic hepatopathy; and biliary tract disease 
• 
Consider gastroenterology or hepatology consultation 
 

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Appendix IV Presentation of Dermatologic Event 
Collect information on clinical presentation and potential contributing factors. Key information should be 
summarized and entered on the Adverse Experience CRF. Any treatments administered should be entered 
on the Concomitant Medication CRF. Scan and forward this form to Principal Investigator. 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
____________________________________________________________________________ 
2. Has the subject contacted any known allergens? □ Yes □ No 
If so what kind? _______________________________________ 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, 
personal care product, poison ivy, etc.)? □ Yes □ No 
If so what kind? _______________________________________ 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and supplement)? 
□ Yes □ No 
If so what kind? _______________________________________ 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
If so what kind? _______________________________________ 
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
If so what kind? _______________________________________ 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No 
If so what kind? _______________________________________ 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g. 
Molluscum Contagiosum)? □ Yes □ No 
9. Has the subject had recent sun exposure? □ Yes □ No 
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 
If so what kind? _______________________________________ 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No  
iii. Signs of dyspnea? □ Yes □ No 

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iv. Fever, night sweats, chills? □ Yes □ No 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine 
therapy? □ Yes □ No 
If so what kind? _______________________________________ 
 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No 
List medication(s) and dose(s): _______________________________________ 
13. Is the rash pruritic (itchy)? □ Yes □ No 
 
Focused Skin Examination 
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience CRF. 
 
Primary Skin Lesions Description 
Color: _______________________________________ 
 
General description: 
_________________________________________________________________ 
_________________________________________________________________ 
 
Describe the distribution of skin reaction, skin eruption, or rash on the body: 
_________________________________________________________________ 
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
_________________________________________________________________ 
 
Any associated signs on physical examination? 
_________________________________________________________________ 
 
 
Scan this form and forward by email to the Principal Investigator listed on the cover page of the protocol. 

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Appendix V 
Patient Medication Diary MC1572 
MC1572 Patient Medication Diary during Concurrent Radiation Therapy (RT) 
Please record the time you take your temozolomide (Temodar®) medication and number of pills 
taken. Return this diary at your next clinic visit and make sure you get another diary.  
If steroids are taken on any day, please record the time and number of pills.  
If an area is shaded gray, that means you are NOT scheduled to take that drug on that day. 
{Pembrolizumab  
given in clinic} 
Temozolomide  
Taken daily during RT 
Steroid dose (if applicable) 
Day 
Date 
(mm/dd/yy) 
Time taken 
(please circle 
am or pm): 
Number of tablets: 
Time taken 
(please circle 
am or pm): 
Number of 
capsules: 
1  
am/pm 
am/pm 
2  
am/pm 
am/pm 
3  
am/pm 
am/pm 
4  
am/pm 
am/pm 
5  
am/pm 
am/pm 
6  
am/pm 
am/pm 
7  
am/pm 
am/pm 
8  
am/pm 
am/pm 
9  
am/pm 
am/pm 
10  
am/pm 
am/pm 
11  
am/pm 
am/pm 
12  
am/pm 
am/pm 
13  
am/pm 
am/pm 
14  
am/pm 
am/pm 
15  
am/pm 
am/pm 
16  
am/pm 
am/pm 
17  
am/pm 
am/pm 
18  
am/pm 
am/pm 
19  
am/pm 
am/pm 
20  
am/pm 
am/pm 
21  
am/pm 
am/pm 
22  
am/pm 
am/pm 
23  
am/pm 
am/pm 
24  
am/pm 
am/pm 
25  
am/pm 
am/pm 
26  
am/pm 
am/pm 
27  
am/pm 
am/pm 
28  
am/pm 
am/pm 
29  
am/pm 
am/pm 
30  
am/pm 
am/pm 
31  
am/pm 
am/pm 
32  
am/pm 
am/pm 
33  
am/pm 
am/pm 

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{Pembrolizumab  
given in clinic} 
Temozolomide  
Taken daily during RT 
Steroid dose (if applicable) 
Day 
Date 
(mm/dd/yy) 
Time taken 
(please circle 
am or pm): 
Number of tablets: 
Time taken 
(please circle 
am or pm): 
Number of 
capsules: 
34  
am/pm 
am/pm 
35  
am/pm 
am/pm 
36  
am/pm 
am/pm 
37  
am/pm 
am/pm 
38  
am/pm 
am/pm 
39  
am/pm 
am/pm 
40  
am/pm 
am/pm 
41  
am/pm 
am/pm 
42  
am/pm 
am/pm 
43  
am/pm 
am/pm 
44  
am/pm 
am/pm 
45  
am/pm 
am/pm 
46  
am/pm 
am/pm 
47  
am/pm 
am/pm 
48  
am/pm 
am/pm 
49  
am/pm 
am/pm 
50  
am/pm 
am/pm 
51  
am/pm 
am/pm 
52  
am/pm 
am/pm 
53  
am/pm 
am/pm 
54  
am/pm 
am/pm 
55  
am/pm 
am/pm 
56  
am/pm 
am/pm 
57  
am/pm 
am/pm 
__________________________ 
_______________ 
Participant Signature 
Date 
__________________________ 
_______________ 
Medical Personnel Signature 
Date 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________ 
Bring all bottles and any unused study medication along with this diary when you return for your 
next appointment. 
 
Study Coordinator Use Only 
Number of pills returned ______ 
Number of vials returned: _______ 
 
Discrepancy Yes____/No____ 
Verified by __________________ 
Date_______________ 
 

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MC1572 Patient Medication Diary during Adjuvant Treatment 
Please record the time and date that you take your study medications. Return this diary, the 
medication bottles (even if empty or unopened), and any unused tablets or capsules at your next 
clinic visit and make sure you get another diary. If an area is shaded gray, that means you are not 
scheduled to take that particular drug on that day. 
Day 
Temozolomide 
# of tablets 
Date taken (mm/dd/yy) 
Time taken (circle a.m. or p.m.) 
1 
 
a.m./ p.m. 
 
2 
 
a.m./ p.m. 
 
3 
 
a.m./ p.m. 
 
4 
 
a.m./ p.m. 
 
5 
 
a.m./ p.m. 
 
6 
No temozolomide taken 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
__________________________ 
______________ 
Participant Signature 
Date 
__________________________ 
_______________ 
Medical Personnel Signature 
Date 
My next scheduled visit is: _______________________________ 
If you have any questions, please call: ______________________ 
Bring all bottles and any unused study medication along with this diary when you return for your 
next appointment. 
 
Study Coordinator Use Only 
Number of pills returned ______ 
Number of vials returned: _______ 
 
Discrepancy Yes____/No____ 
Verified by __________________ 
Date_______________