Neoadjuvant Pembrolizumab for Patients With Mismatch Repair Deficient Locally Advanced Solid Cancers
Phase: PHASE2
Conditions: Locally Advanced Malignant Solid Neoplasm
Sponsor: M.D. Anderson Cancer Center

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SPONSOR: Michael Overman, MD Anderson Cancer Center 
TITLE: Neoadjuvant Pembrolizumab for Patients with Mismatch Repair Deficient Locally 
Advanced Solid Cancers 
IND exempt 
NCT number: NCT04082572 
Coordinating Center: University of Texas MD Anderson Cancer Center 
PI: Michael Overman (moverman@mdanderson.org) 
Co-PI: Kaysia Ludford 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Neoadjuvant Pembrolizumab for Patients with Mismatch Repair Deficient 
Locally Advanced Solid Cancers 
Trial Phase 
II 
Clinical Indication 
Treatment of MSI high locally advanced solid tumors in the neoadjuvant 
setting 
Trial Type 
Interventional 
Type of control 
None 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded, open-label 
Treatment Groups  
All patients will receive pembrolizumab 200mg every 3 weeks 
Number of trial participants 
35 patients 
Estimated enrollment period 
We estimate that the trial will require approximately 17 months from the 
first patient enrolling until the final patient signs informed consent. 
Estimated duration of trial 
We estimate that the trial will require approximately 24 months to allow 
full accrual and at least the first 6 cycles of pembrolizumab. 
Duration of Participation 
Until disease progression, drug intolerance, or 24 months of 
pembrolizumab therapy. 
Estimated average length of 
treatment per patient 
One year 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This study is a Phase II open-label, single center trial assessing the safety and efficacy of pembrolizumab 
given pre-operatively for 6 months in patients with locally advanced (unresectable primary cancer or a 
resectable primary cancer with a high chance of recurrence) dMMR solid organ tumors. High risk will be 
defined by the treating physician as patients with an estimated risk of recurrence of greater than or equal 
to 20%. Given the variety of cancer types and variety of factors within each tumor type this decision will 
be based on an expert treating physician estimation for that specific disease type.  As an example, for 
colon cancer, clinoco-radiographic  factors have been incorporated into risk recurrence estimation include: 
age, CEA level, MRI identified perineural or lymphovascular invasion, radiographic T stage, presence of 
enlarged lymph nodes on radiographic imaging, and involvement of neighboring structures34.  
Unresectable versus resectable status will be defined at the time of study enrollment, as patients with 
resectable cancers will be monitored to ensure an adequate rate of surgical resection.  All tumor types are 
eligible and prior radiation or chemotherapy is allowed. Based on epidemiological distribution of dMMR 
we anticipate 70% of tumors will be colorectal, endometrial, gastric and adrenocortical carcinomas.   
To ensure safety, interim safety monitoring will be conducted to ensure the consequent resection in 
resectable patients who do not respond to therapy.  In addition, Bayesian toxicity stopping boundaries will 
be applied using the approach of Thall, Simon, Estey (1995, 1996) for the total of 35 patients throughout 

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the study.  In addition early use of ctDNA will be utilized in addition to radiographic RECIST v1.1 data 
to help determine treatment benefit at the early time point of 6 weeks.  Patients will have pre-treatment 
and cycle 2 day 1 (3weeks) ctDNA sampling via an MD Anderson CLIA certified 70 gene liquid biopsy 
panel.  After two cycles of pembrolizumab (6weeks) patients will be assessed for a benefit from therapy.  
Patients with clinical benefit will continue therapy on clinical trial and those that are not benefiting will 
discontinue the clinical trial.  Clinical benefit will be defined if a patient meets any of the following 
criteria: 
(i) 
Patients with PR/CR per RECIST v1.1 
(ii) 
SD per RECISTv1.1 with either a decrease in total tumor measurement (-1% to -19%), or a 
stable or decreases in ctDNA tumor mutation from baseline.  If there are no mutations on 
baseline ctDNA then elevated tumor marker can be utilized, such as CEA, CA 19-9, or PSA 
for example. 
(iii) 
Patients who are felt to have clinical benefit (such as improvement in pain, reduction in 
bleeding, improved bowel function…).   
 
Patients meeting these criteria will continue therapy with per protocol restaging imaging studies.  
Stable or decrease in ctDNA tumor mutation will be defined as ctDNA that is declining or the same 
as pretreatment and if multiple mutations exist then dominant clone will be utilized.  Patients with 
PR/CR/SD will continue therapy for a total of 6 months. At the 6-month time point all participants are 
recommended to proceed to surgery. However, due to the potential for extremely high risk surgeries 
to be needed on this clinical trial (for example brain resection for dMMR glioblastoma multiforme) 
the patient and physician can opt to forego surgery and continue pembrolizumab for a total of one 
year. Post-operatively after surgical resection following pembrolizumab patients will be monitored for 
complications (Clavien-Dindo classification for severity1) for up to 30 days.  
 
Prior radiation, surgery, or chemotherapy is allowed.  Locally recurrent disease is allowed.  Disease 
that is not RECIST measurable maybe allowed after discussions with study PI as long as disease is 
evaluable by another modality or blood tumor marker/ctDNA is measurable. 
 
2.2 
Trial Diagram 
     

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OBJECTIVES & ENDPOINTS & HYPOTHESISES 
2.3 
Primary Objective & Endpoints & Hypothesis 
(1) Hypothesis 
We hypothesize that neoadjuvant pembrolizumab will be safe and result in a high pathological complete 
response rate.  
(2) Primary Objectives 
(i) 
To assess the safety of neo-adjuvant pembrolizumab in patients with locally advanced 
(unresectable primary cancer or  resectable primary cancer with a high chance of recurrence)) 
dMMR solid organ tumors by CTCAE assessed toxicity and post-surgical complication 
assessment by the Clavien-Dindo classification1 
(ii)  
To assess the rate of complete pathological response for patients who undergo surgical 
resection following at least 3 doses of neoadjuvant pembrolizumab. The primary endpoint is 
pCR after 3 doses. 
 

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2.4 
Secondary Objective 
(i) 
To quantify the rate of organ sparing at 1 year for all patients treated with one dose of 
pembrolizumab (intent to treat) and those patients who receive at least 3 doses of neoadjuvant 
pembrolizumab and decline to undergo surgical resection and opt to continue receiving 
pembrolizumab for a total of 1 year.  
(ii) 
To assess radiographic tumor response to neoadjuvant pembrolizumab  
(iii) 
To estimate the relapse-free survival and overall survival in all enrolled participants 
(iv) 
To determine the overall rates of pathological response to neoadjuvant pembrolizumab 
(v) 
To assess the rate of complete pathological response (intent to treat) for patients who undergo 
surgical resection following at least 1 dose of neoadjuvant pembrolizumab. 
2.5 
Exploratory Objective: 
(i) 
To explore the predictive ability of changes in ctDNA for efficacy endpoints.  
(ii) 
To determine if total mutational burden correlate with response and extent of benefit from 
pembrolizumab 
(iii) 
To correlate pre-treatment tumor samples tumor-immune microenvironment (for example T-
effector cell populations; CD4 subsets; T-regulatory populations; B cell populations; 
dendritic and macrophage populations) with efficacy endpoints. 
 
(iv) 
To compare targeted gene expression profiles of immune related genes and genes pertaining 
to common cancer signaling pathways in pre-treatment samples and also the change in these 
factors for cases with both pre and on-treatment (i.e. at time of resection) tumor samples of 
responders (stable disease or radiographic response prior to resection) versus non-responders 
(progression prior to resection). 
 
3.0 BACKGROUND & RATIONALE 
3.1 
Background 
PEMBROLIZUMAB 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with 
high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction 
with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an 
intravenous (IV) immunotherapy for advanced malignancies.  Keytruda® (pembrolizumab) is indicated 

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for the treatment of patients across a number of indications because of its mechanism of action to bind 
the PD-1 receptor on the T cell.  For more details on specific indications refer to the Investigator 
brochure. 
MSI-HIGH CANCER 
Microsatellites are short tracts of DNA in which there are multiple repeats (on the order of 5-50) of 1 to 5 
base pair motifs. They occur at thousands of locations within the genome. Many microsatellites are located 
in non-coding DNA regions and thus are biologically silent. Others are located in regulatory or coding 
DNA – which can affect biological activity and lead to disease. The mismatch repair (MMR) system is 
one of several cellular DNA repair mechanisms that functions to maintain the count and integrity of 
microsatellites during cell division. Deficiencies in the MMR system lead to cells being unable to regulate 
the length of their microsatellites during cell division, a term called microsatellite instability (MSI). This 
leads to hypermutability and disease states such as cancers2. Mismatch repair deficiencies typically occur 
through inherited germline mutations in mismatch repair genes such as the case in Lynch syndrome or 
through somatic hypermutation of mismatch repair genes such as MLH1. The most common tumor types 
harboring defects in MMR and thus MSI are colorectal, endometrial and gastric adenocarcinomas. MSI is 
routinely tested in all colorectal cancer patients in accordance with the National Comprehensive Cancer 
Network (NCCN) guidelines and in selected patients with endometrial and gastric tumors. Little is known 
about the true prevalence in other cancer types. In order to perform a more comprehensive surveillance of 
the landscape of MSI across a wide range of tumors, Bonneville and Crook et al3 examined paired whole-
exome sequencing data primarily from the The Cancer Genome Atlas (TCGA) database in 39 distinct 
cancer types representing 11,139 tumors in 11,080 patients. As shown in figure 1 below, MSI was detected 
in 27 distinct tumor types with approximately 
30% 
prevalence 
in 
endometrial 
carcinomas and just over 15% in 
colon and gastric adenocarcinomas 
consistent with previously published 
data by Hause4 which had examined 
MSI prevalence in 17 distinct tumor 
types. Interestingly, this study by Bonneville et 
al.3 showed significant MSI representation in 
other tumor types not previously associated with 
microsatellite 
instability 
including 
adrenocortical carcinoma (~4%), uterine carcino-sarcoma cervical squamous cell carcinoma, Wilms 
tumor and mesothelioma. MSI status has been shown to be predictive of response to chemotherapy and 
immunotherapy in colorectal cancers in addition to having prognostic value. Less is known about its 
predictive and prognostic value in non-colorectal cancers. 
LIMITATION OF STANDARD CHEMOTHERAPY IN dMMR CANCER 
Figure 1. Prevalence of microsatellite 
instability (MSI) across 39 human cancer 
types. (A) MSI prevalence was detected 
across 39 tumor types 

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In colorectal cancer (CRC) the standard treatment for Stage III and high risk Stage II disease is adjuvant 
5-fluorouracil (5-FU) based chemotherapy which confers survival advantage of 10%5. However, pre-
clinical and clinical studies have demonstrated that this advantage does not apply to patients whose tumors 
express microsatellite instability (MSI-H). Several in vitro studies have shown that MSI-H tumors are 
resistant to many commonly used chemotherapeutic agents including 5-FU6-8. Meyers et al8 found that 
MSI-H CRC cell lines with mismatch repair (MMR) deficiency secondary to hMLH1 dysfunction were 
two-fold more resistant to 5-FU compared to the same cell line with a mismatch repair (MMR) proficient 
system (restored by chromosome 3 transfer) as shown in figure 2 below. 5-FU is cytotoxic to cancer cells 
via its active metabolites: fluorodeoxyuridine triphosphate (FdUTP) and fluoridine triphosphate (FUTP) 
which disrupt DNA and RNA synthesis and disrupt the action of 
thymidylate synthase leading to nucleotide pool imbalance. The 
mechanism of 5-FU resistance in MSI-H tumors is thought to be 
secondary to inability of MMR deficient genes to bind DNA modified 
by incorporation of 5-FU and its metabolites and by reduced 
thymidylate synthase activity in MSI-H tumors9-10. Similarly, clinical 
studies have shown that the clinical benefit derived from adjuvant 5-
FU based therapies is observed only in MSS patients but not MSI-H 
patients11-12. In an analysis of 570 tissue specimens of patients with 
Stage II and III CRC from pooled randomized control trials in which 
patients were randomized either to adjuvant 5-FU or no 5-FU, Ribic 
et al11  highlighted two important findings: 1) there was a trend 
towards reduced survival in patients with MSI-H CRCs receiving 5-
FU chemotherapy compared to patients with MSI-H CRCs who did 
not and 2) patients with MSI-H tumors who did not receive 5-FU had 
increased 5 year survival rate compared to patients with MSS tumors 
who did not receive adjuvant 5-FU. Like CRC 5-FU is used in 
neoadjuvant and adjuvant therapy for gastric cancer.  Data for 
chemotherapy resistance in other solid tumors with microsatellite instability is limited, however 
preclinical data suggests this effect is also observed with alkylating agents in endometrial carcinoma cell 
lines known to have mismatch repair deficiency13. For Stage II and III endometrial carcinomas with high 
risk features, the standard of care is systemic adjuvant therapy which includes chemotherapeutic agents 
such as platinum. There are no clinical studies outlining whether patients with MSI-H endometrial 
carcinomas respond equivalently to adjuvant chemotherapy as patients with MSS endometrial carcinomas. 
Given the pre-clinical and clinical data demonstrating that standard chemotherapy may have limited role 
in the adjuvant treatment of resectable MSI-H tumors, there is a need to explore alternative therapeutic 
options.   
 
 
IMMUNOTHERAPY IN METASTATIC dMMR CANCER 
Mismatch-repair deficiency (dMMR) occurs in a number of solid cancers including colorectal, 
endometrial, gastric, uterine, biliary tract, pancreatic, ovarian and small intestinal cancer, with 70% of 
cases occurring among the first three. Key studies have shown that mismatch-repair status predicts clinical 
Figure 2. Cytotoxicity of MMR-
deficient HCT116 (circle) and MMR-
proficient HCT116 3-6 (square) colon 
cell lines caused by 5-FU. The cell lines 
were treated with various concentrations 
of 5-FU continuously for 10 days and 
colony forming ability was assessed.  

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benefit of immune checkpoint blockade. In a landmark trial to assess the clinical activity of 
pembrolizumab in patients with progressive metastatic carcinoma with and without mismatch-repair 
deficiency, Le et al14 showed immune-related objective response rate and immune-related progression free 
survival rate of 71% and 67% in patients with mismatch-repair deficient non-colorectal cancers. The 
immune-related objective response rate and immune-related progression free survival rates for mismatch 
deficient colorectal cancers were 40% and 78% respectively compared to 0% and 11% respectively for 
mismatch-repair proficient colorectal cancers (see figures 2 and 3 below) 14-15.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Our group has similarly shown high response rates of 31% and progression free survival of 69% at 12 
weeks or more in patients with metastatic colorectal cancer with dMMR, treated with nivolumab. Median 
duration of response was not yet reached at median follow up of one year16.. 
This activity level has also been demonstrated by Le et al14 as the pembrolizumab study for dMMR solid 
tumors provided therapy for a maximum of 2 years.  At the time of the publication 18 patients had reached 
2 years and stopped therapy.  At a median follow-up of 8 months, none of these 18 patients has had disease 
progression/recurrence. 
 
NEOADJUVANT AND ADJUVANT IMMUNOHERAPY 
Figure 3. Radiographic responses to 
treatment with pembrolizumab based 
on RECIST criteria. 
Figure 4. Overall survival among 
patients with patients with mismatch 
repair deficient and proficient CRC 
after pembrolizumab. 

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Treatment with PD1 inhibitors represents a major advancement in the treatment of Stage IV MSI-H 
colorectal and non-colorectal cancers. For patients with resectable MSI-H colorectal cancer, surgical 
resection ± chemotherapy is the standard of care. Despite treatment with curative intent many patients 
subsequently relapse and develop distant disease. Given that immune checkpoint blockade against 
programmed cell death-1 (PD-1) is associated with significant improvement in progression free survival 
in stage IV disease and given that MSI-H tumors do not respond well to standard chemotherapy, there is 
a need to evaluate PD1 inhibitors in earlier-stage disease. Neoadjuvant immunotherapy is appealing since 
the primary tumor can serve as a source of antigens against which expanded and activated tumor-specific 
T-cells are produced by the host to effect systemic surveillance of micrometastases. In addition, 
neoadjuvant utilization of PD1 blockade offers the opportunity to investigate the in vivo effects of  PD1 
inhibition on the tumor micro environment and how that correlates with the periphery such as release of 
ctDNA. 
Recently presented data from the NICHE trial at ESMO 201835 highlights the impressive response 
neoadjuvant immune checkpoint inhibition can elicit in early stage dMMR colon adenocarcinomas. In this 
study, combination checkpoint inhibition with ipilimumab 1mg/kg (day 1) and nivolumab 3mg/kg (days 
1 and 15) was administered neoadjuvantly to a cohort of 19 patients stages I-III colon adenocarcinoma, 
15 of whom were evaluated for response. Of those, 7 patients had dMMR while 8 harbored pMMR tumors. 
4 of the 7 patients with dMMR tumors has complete pathological response at time of definitive resection 
after 1 cycle of combination checkpoint inhibition. The remaining 3 had 1-2% viable residual tumor. In 
contrast, among the 8 patients with pMMR, 2 had 100% viable residual tumor at resection and the 
remaining 6 had 85-95% viable residual tumor. Importantly, there were only 5 cases of grade 3 toxicity 
and these did not result in delays in surgery.This data confirms that neoadjuvant immune checkpoint 
inhibition can be safely given and significantly, can generate complete pathological response in early stage 
dMMR colon cancers.  
Likelwise, preliminary data from ongoing trials in other checkpoint sensitive tumor types such as non-
small cell lung cancer (NSCLC) have demonstrated that the integration of checkpoint blockage into the 
treatment of early-stage and locally advanced NSCLC is safe, tolerable, and has the potential to improve 
outcomes without adding substantial toxicity17. As an example, Forde et al18 performed a pilot study to 
examine the safety and feasibility of the use of neoadjuvant nivolumab in 21 Stage I-IIIA resectable 
NSCLC. The study was designed such that treatment would not be considered feasible if the probability 
that surgery would be delayed was 90% or more for more than 25% of the patient. Of 21 planned 
resections, 20 were completed and there were no surgical delays thus feasibility endpoint was met. 
Similarly safety end point was satisfied with minor grade 3-4 events.  
Additional data suggests there may be superior efficacy of neoadjuvant compared to adjuvant immune 
checkpoint blockade in immune responsive disease such as non-small cell lung cancer19. Preclinical 
models of resectable NSCLC were generated and immune response after neoadjuvant or adjuvant 
immunotherapy investigated. Mice with established tumor were randomized to either 3 doses of 
neoadjuvant anti-PD1, anti-CTLA4, the combination of both or to observation followed by resection of 
primary tumor 2 days after immunotherapy. On post-operative day 2, mice in the observation group were 
treated with 3 doses of anti-PD1, anti-CTLA-4 or both and survival and subsequent lung metastases 
quantified.  Notably, combined therapy in the neoadjuvant setting significantly prolonged survival 
compared to adjuvant combined treatment with more profound reduction in lung metastases compared to 
adjuvant combined treatment. 

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Anecdotally at MD Anderson Cancer Center, we have treated two patients with locally advanced dMMR 
colon adenocarcinoma with anti-PD1 therapy prior to surgical resection of the primary and observed near 
pathological response in 1 and complete pathological response in the other. As an example patient YH is 
a 34-year-old man with dMMR locally advanced colorectal adenocarcinoma with abdominal 
lymphadenopathy who was treated initially with capecitabine/oxliplatin/bevacizumab with stable disease. 
He subsequently received 3 cycles of pembrolizumab followed by right colectomy one month later. 
Pathology of the surgical specimen revealed near pathological complete response with “residual 
adenocarcinoma almost exclusively acellular mucin with rare cluster of well-differentiated 
adenocarcinoma cells”. Eighty of eighty resected lymph nodes were negative for adenocarcinoma. The 
second patient, a 71-year-old woman with dMMR locally advanced cecal adenocarcinoma with invasion 
of right lower quadrant mesentery and abdominal lymphadenopathy received 4 cycles of FOLFOX 
terminated prematurely secondary to poor tolerance. She subsequently received 5 cycles of nivolumab 
followed by resection of primary 3 months later. Pathology of resected specimen revealed complete 
pathological response.  Though anecdotal in nature this experience appears to demonstrate activity similar 
to what is seen in metastatic patients and suggests this approach is safe in the locally advanced setting. 
NEOADJUVANT CHEMOTHERAPY AS A STANDARD CANCER APPROACH  
Neoadjuvant therapy represents a standard of care for multiple cancer types due to the ability to downstage 
cancer to enhance surgical resection and the ability to provide earlier therapy to micrometastatic disease, 
which represents the site of greatest post-surgical failure for most cancer types.  In particular neoadjuvant 
therapy is standard for locally advanced gastroesophageal cancers, rectal cancer, T4b colon cancers, and 
endometrial cancers with cervical involvement.  In particular for colon cancer in 2016, the NCCN 
guidelines included neoadjuvant chemotherapy as a treatment option for patients with clinical T4b colon 
cancer. The FOxTROT Collaborative Group20 examined the feasibility, safety and efficacy of preoperative 
chemotherapy for colon cancer in a pilot randomized controlled trial comparing neoadjuvant 
chemotherapy followed by surgery and adjuvant chemotherapy to standard of care treatment: surgery 
followed by adjuvant chemotherapy. The results demonstrated that neoadjuvant chemotherapy resulted in 
significant TNM downstaging, reduction in resection margin involvement and reduction in tumor 
regression grading. The Phase III trial to assess long term oncological outcome is ongoing. Retrospective 
analysis of 921 patients, 3% of adult patients with non-metastatic T3 or T4 colon cancer identified in the 
National Cancer Database between 2006 and 2014, who received neoadjuvant chemotherapy prior to 
surgical resection of their colon cancer showed patients with T4b colon cancer treated with neoadjuvant 
chemotherapy had a 23% lower risk of death at 3 years compared to patients that had adjuvant 
chemotherapy21.  
 
3.1.1 Pembrolizumab Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades22.  Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes 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 (T-regs) correlates with improved prognosis and long-term survival in solid malignancies, such as 
ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal 

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cell carcinoma.  Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing 
durable objective tumor responses in cancers such as melanoma 23-24. 
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 immunoglobulin (Ig) superfamily member related to 
cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has 
been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 
and/or PD-L2) 25-26. 
The structure of murine PD-1 has been resolved27.  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for ligand 
binding and a cytoplasmic tail 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, 
and an immunoreceptor tyrosine-based switch motif.  Following T-cell stimulation, PD-1 recruits the 
tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based switch motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), 
protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in 
the CD3 T-cell signaling cascade26,28-30. The mechanism by which PD-1 down-modulates T-cell 
responses is similar to, but distinct from, that of CTLA-4, because both molecules regulate an 
overlapping set of signaling proteins31-32. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in mismatch repair deficient solid organ tumors.  
3.1.2 Preclinical and Clinical Trial Data for Pembrolizumab 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
3.2 
Rationale 
3.2.1 Rationale for the Trial 
While several studies have shown outstanding efficacy of immune checkpoint blockade in metastatic 
dMMR cancers, there is a dearth of data in a key clinical setting. There are no reports to date testing this 
mechanism in the preoperative setting for resectable dMMR solid organ cancers. In both metastatic 
melanoma and dMMR solid cancers, pembrolizumab has demonstrated the ability to eradicate all areas of 
disease suggesting the potential for a high rate of pathological complete responses and possibly cure from 
this therapy33.  
Neoadjuvant treatment in the presence of an intact primary tumor maximizes antigen availability for 
immune priming and could potentially lead to complete pathologic response reducing risk of recurrence 
post resection of involved organ and ultimately leading to the possibility of organ sparing. As these 
examples, highlight this study has the potential to bring about a paradigm shift in the treatment of patients 
with dMMR solid organ tumor through harnessing the immune response through checkpoint blockade in 
the frontline curative intent setting. This could possibly obviate the need for adjuvant therapy as well as 
potentiate the possibility of organ sparing while maintaining curative intent.   

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3.2.2 Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose of 
pembrolizumab for adults across all indications and regardless of tumor type.  As outlined below, this 
dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival at 200 
mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] 
analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment naïve, 
previously treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy).  Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006).  All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied representing an 
approximate 5- to 7.5-fold difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided 
similar responses to the highest doses studied.  Subsequently, flat dose-exposure-response relationships 
were also observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer 
and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, which acts 
by interaction with immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation of 
PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a PBPK analysis was 
conducted to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 
expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 
saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body weight 
and other participant covariates on exposure, has shown that the fixed-dosing provides similar control of 
PK variability as weight based dosing, with considerable overlap in the distribution of exposures from 
the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported by these PK characteristics, and given 
that fixed-dose has advantages of reduced dosing complexity and reduced potential of dosing errors, the 
200 mg Q3W fixed-dose was selected for evaluation across all pembrolizumab protocols. 

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To date, pembrolizumab (2 mg/kg Q3W) has been evaluated in 85 pediatric participants (aged 1 to 18 
years) with advanced melanoma, PD-L1 positive advanced, relapsed, or refractory solid tumors, or 
lymphoma.  The exposures in pediatric participants following the 2 mg/kg Q3W regimen were found to 
be similar to that observed in adult participants.  Pediatric data has also been incorporated in an 
integrated population PK analysis, which confirmed that a pembrolizumab dose of 2 mg/kg Q3W (up to 
a maximum of 200 mg Q3W) in pediatric participants renders exposures similar to adults.  Based on 
these results, the pediatric dose for evaluation in this trial is 2 mg/kg Q3W (up to a maximum of 200 mg 
Q3W). 
 
 
4.0 METHODOLOGY 
4.1 
Study Population 
4.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Male/female participants who are at least 18 years of age on the day of signing informed consent 
with histologically confirmed diagnosis of solid cancer 
 
2.  Solid cancer that is deficient in mismatch repair (dMMR) or microsatellite instability high (MSI-
H) as determined by one of three methods: 
a.  Immunohistochemistry determined dMMR by complete loss of MLH1, PMS2, MSH2 or 
MSH6 
b. PCR determined microsatellite instability at >30% of tested microsatellites 
c. Next-generation determined MSI-H based upon instability at multiple microsatellites as 
determined by the specific next generation sequencing panel 
3. Locally advanced cancer defined as either an unresectable primary cancer or a resectable primary 
cancer with a high chance of recurrence (defined as an estimated greater or equal to 20% chance 
of recurrence by the treating physician).  A resectable primary may include locoregional disease, 
as long as all disease is felt by the treating physician to be in a resectable distribution.  
 
4. The participant (or legally acceptable representative if applicable) provides written informed 
consent for the trial.   
 
5. Have measurable disease based on RECIST v1.1 (unless discussed and approved by study PI). 
 
6. Have available archival tumor tissue.  Availability will be met as long as a request to obtain 
formalin-fixed, paraffin embedded (FFPE) tissue blocks (preferred) or slides has been made  
(unless discussed and approved by study PI). 

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7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation 
of ECOG is to be performed within 7 days prior to the date of signing study consent.   
 
8. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies:  
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least [120 days (corresponding to time needed to eliminate any study 
treatment(s) plus 30 days (a menstruation cycle) for risk of genotoxicity]  after the last dose of 
study treatment. 
9. Have adequate organ function as defined in the following table (Table 1).  Specimens must be 
collected within 14 days prior to the start of study treatment. 
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥ 8.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN  
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 

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4.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to enrollment (see 
Appendix 3).  If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. Note: in the event that 72 hours have elapsed between the screening 
pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must 
be performed and must be negative in order for subject to start receiving study medication. 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137). 
 
3. Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks 
of study treatment.  Note: Participants must have recovered from all AEs due to previous 
therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. 
 
4. If participant received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting study treatment. 
 
5. Has received prior radiotherapy within 2 weeks of start of study treatment.  Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not have had 
radiation pneumonitis.  A 1-week washout is permitted for palliative radiation (≤2 weeks of 
radiotherapy) to non-CNS disease. 
 
6. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of live 
vaccines include, but are not limited to, the following:  measles, mumps, rubella, varicella/zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) =aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 

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however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not 
allowed. 
 
7. Is currently participating in or has participated in a study of an investigational agent or has used 
an investigational device within 4 weeks prior to the first dose of study treatment. 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous investigational agent. 
 
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy 
within 7 days prior to the first dose of study drug. 
 
9. Has a known additional malignancy that is progressing or has required active treatment within the 
past 1 year.  Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) or other similar good 
prognosis cancer with recurrence rates expected to be <10% that have undergone potentially 
curative therapy are not excluded. 
10. Known metastatic sites of disease. Note: locoregional lymph nodes or tumor deposits are not 
considered metastatic disease. 
11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
12. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
13. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. 
14. Has an active infection requiring systemic therapy. 
15. Has a known history of Human Immunodeficiency Virus (HIV).   
16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or 
known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: 
no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.  
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the subject’s participation for the full duration of 
the study, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator.   
18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the trial. 

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19. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose of trial 
treatment. 
 
4.1.3 Lifestyle Restrictions 
4.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
4.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception. 
For this study, male participants 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).   
4.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the participant 
will be immediately discontinued from study treatment.  The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has been completed or terminated.  
The outcome of the pregnancy will be reported to Merck within 2 working days if the outcome is a 
serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-
threatening complication to the mother or newborn).  The study Investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or 
newborn to Merck.  If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to Merck and followed as described 
in Section 7.2.2. 
4.1.5 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, participants 
who are breast-feeding are not eligible for enrollment. 
4.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 

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Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
 
 
Trial treatment should begin as close as possible to signing study consent considering appropriate time for 
screening procedures to be completed. 
4.2.1 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments have been 
completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be administered up to 3 
days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given the 
variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
The current label for pembrolizumab contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
4.2.2 Dose Modification and toxicity management for immune-related AEs associated with 
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 Table 3. 

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Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (i.e., diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(i.e., peritoneal signs and ileus). 

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Grade 4 
Permanently 
discontinue 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 

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Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 

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Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 
4.  
 
Table 4 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 

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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 therapy or 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 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 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 participant should be premedicated for the next scheduled dose. 
Participants 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 with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 

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Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
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. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 
 

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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the patient's study record. 
 
4.2.3 Second Course * 
4.3 
Participants who stop study treatment with SD or better will not be eligible for a 
second course of pembrolizumab. The intent of the study is to treat with maximum 
of 1 year of pembrolizumab. Concomitant Medications/Vaccinations (allowed & 
prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participants’ primary physician.  
4.3.1 Acceptable Concomitant Medications 
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.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
4.3.2 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: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 

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• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are 
live attenuated vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than 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 Sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  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, the 
Sponsor and the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
4.3.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, [Table 3].  Where appropriate, these guidelines include the use of oral or IV 
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 

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guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 
5.2.2 for guidelines regarding dose modification and supportive care.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
4.4 
Participant Withdrawal/Discontinuation Criteria 
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
• The participant  or participant’s legally acceptable representative requests to 
discontinue study treatment 
• Confirmed radiographic disease progression outlined in Section 7.1.2.6 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse experiences as described in Section 5.2.2. 
• The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or sponsor, placed the participant at unnecessary risk 
from continued administration of study treatment. 
• The participant  has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 6 cycles (at 
least 24 weeks), receiving at least 2 doses of pembrolizumab beyond the date when 
the initial CR was declared. These participants may be eligible for second course 
treatment described in Section 5.2.3. 

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• The participant is lost to follow-up 
• Completion of 17 treatments (approximately 1 year) with pembrolizumab 
• Note: The number of treatments is calculated starting with the first dose.  Participants 
who stop pembrolizumab after receiving 17 doses are not eligible for retreatment if 
they progress after stopping study treatment.  Administrative reasons 
4.5 
Participant Replacement Strategy 
A participant that discontinues from the study after receiving a dose of pembrolizumab will 
not be replaced.  Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made. 
 

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5.0 TRIAL FLOW CHART 
5.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 a 
2  
3 
4 
To be repeated beyond 8 
cycles (max 16 cycles, 
[1yr]) 
6m 
(surgery) 
or 12m (no 
surgery) 
Safety 
Follow-up 
Follow Up 
Visitsb 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-14 to  
C1D1 
± 2 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
6m 
(surgery) 
or 12m (no 
surgery) 
30 days 
post +/- 
7d 
Every  4 
months +/- 
31d 
Every 
24 
weeks 
+/-56d  
Administrative Procedures 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administration 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Full Physical Examination 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Vital Signs and Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
ECOG Performance Status 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCG 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT, HIV, hepatitis* 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 

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Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 a 
2  
3 
4 
To be repeated beyond 8 
cycles (max 16 cycles, 
[1yr]) 
6m 
(surgery) 
or 12m (no 
surgery) 
Safety 
Follow-up 
Follow Up 
Visitsb 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-14 to  
C1D1 
± 2 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
6m 
(surgery) 
or 12m (no 
surgery) 
30 days 
post +/- 
7d 
Every  4 
months +/- 
31d 
Every 
24 
weeks 
+/-56d  
Comprehensive Serum Chemistry Panel 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Urinalysis 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
FT4 and TSH 
 
x 
 
x 
 
x 
 
x 
 
x 
 
 
 
 
Tumor marker (e.g. CEA, PSA…)** 
 
x 
 
x 
x 
 
 
x 
 
x 
 
 
x 
 
ctDNA--MD Anderson CLIA validated 70-
Gene Liquid Biopsy Panel (LBP-70) 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
 
Optional tumor biopsies 
 
X 
 
X (may 
be done 
betwee
n 
weeks 
3-9) 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging (on-tx +/-14 days)*** 
 
x 
 
 
x 
 
 
x 
 
X**
** 
 
 
x 
 
Archival Tissue Collection/Correlative Studies Blood 
Archival Tissue Collection 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
Correlative Studies Blood Collection 
 
x 
 
x 
x 
 
 
x 
 
x 
x 
 
 
 

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Trial Period: 
Screening Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 a 
2  
3 
4 
To be repeated beyond 8 
cycles (max 16 cycles, 
[1yr]) 
6m 
(surgery) 
or 12m (no 
surgery) 
Safety 
Follow-up 
Follow Up 
Visitsb 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-14 to  
C1D1 
± 2 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
6m 
(surgery) 
or 12m (no 
surgery) 
30 days 
post +/- 
7d 
Every  4 
months +/- 
31d 
Every 
24 
weeks 
+/-56d  
*can be up to 28days prior to first dose 
**if standard of care for that tumor type 
***baseline tumor imaging may be up to 28d prior (required imaging based on standard of care for that tumor type) 
**** = Cycle 9, 12, and 15. Imaging is not needed on Cycle 8.  
a If screening labs are done within 3 days of Cycle 1, labs for C1D1 do not need to be repeated 
b The interval is a recommendation. Given the various tumor types, the follow up should be according to the standard of care approach for each tumor type. 
Note: For luminal tumors, endoscopic evaluation prior to and at approximately 3 weeks or first restaging should be considered to help guide disease response 
assessment. 
 
 
 
 

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6.0 TRIAL PROCEDURES 
6.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to participant safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the participant.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
6.1.1 Administrative Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant prior to 
participating in a clinical trial. 
6.1.1.1.1 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s dated signature 
or by the participant’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 

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6.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.  
6.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the participant has enrolled in this study will be recorded separately and not listed as 
medical history.   
6.1.1.4 Prior and Concomitant Medications Review 
6.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
6.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
6.1.1.5 Disease Details and Treatments 
6.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
6.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 

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6.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 
days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before 
the first dose of the new therapy.  Once new anti-cancer therapy has been initiated the 
participant will move into survival follow-up.  
6.1.2 Clinical Procedures/Assessments 
6.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Appendix 2).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
6.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
6.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
6.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 

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6.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation 
of trial treatment as specified in the Trial Flow Chart.   
 
6.1.2.6 Tumor Imaging and Assessment of Disease 
This trial will utilize iRECIST upon initial progression at any time point after the first 
restaging study at 6weeks.  At this initial restaging study, iRECIST will not be utilized but 
the criteria specified in the protocol will be used to guide subsequent treatment at this time 
point. 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  For the 
abdomen and pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used 
when CT with iodinated contrast is contraindicated, or when local practice mandates it.  MRI 
is the strongly preferred modality for imaging the brain.  The same imaging technique 
regarding modality, ideally the same scanner, and the use of contrast should be used in a 
participant throughout the study to optimize the reproducibility of the assessment of existing 
and new tumor burden and improve the accuracy of the assessment of response or 
progression based on imaging. For participants with primary brain tumor, brain imaging is 
required at screening. MRI is preferred; however CT imaging will be acceptable, if MRI is 
medically contraindicated. For luminal tumors, endoscopic evaluation prior to and at first 
restaging should be considered to help guide disease response assessment. Expedited 
confirmation of measurable disease based on RECIST 1.1 at screening should be used to 
determine participant eligibility.  Confirmation that the participant’s imaging shows at least 1 
lesion that is appropriate for selection as a target lesion per RECIST 1.1 is highly 
recommended prior to participant allocation. Participant eligibility will be determined using 
local assessment (Investigator assessment) based on RECIST 1.1.  In addition, images 
(including via other modalities) that are obtained at an unscheduled time point to determine 
disease progression, as well as imaging obtained for other reasons, but which demonstrate 
radiologic progression, should also be used to determine progression. 
When the Investigator identifies radiographic progression per RECIST 1.1, efforts should be 
made to verify radiologic PD. Treatment should continue until PD has been verified.  
Regardless of whether PD is verified, if the Investigator considers the participant has 
progressed, but elects to implement iRECIST, the Investigator will assess for confirmation of 
progression by iRECIST at subsequent time points.   
Expedited confirmation of measurable disease based on RECIST 1.1 at Screening should be 
used to determine participant eligibility.  Confirmation that the participant’s imaging shows 
at least 1 lesion that is appropriate for selection as a target lesion per RECIST 1.1 is highly 
recommended prior to participant enrollment   

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7.1.2.6.1 Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within [28] days prior to the date of 
pembrolizumab. The site study team must review screening images to confirm the participant 
has measurable disease per RECIST 1.1. Tumor imaging performed as part of routine clinical 
management is acceptable for use as screening tumor imaging if they are of diagnostic 
quality and performed within 28 days prior to the date of first pembrolizumab.  Need for 
additional imaging aside from standard cross-sectional imaging will be determined by the 
standard of care imaging performed for that tumor type. 
6.1.2.6.1 Tumor Imaging During the Study 
The first on-study imaging assessment should be performed at approximately 6 weeks (42 
days ±7 days]) from the date of first pembrolizumab.  Subsequent tumor imaging should be 
performed every 9 weeks (63 days ±7 days) or more frequently if clinically indicated.  .  It is 
highly recommended that imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts.  Imaging should continue to be performed until disease 
progression is identified by the Investigator or completion of planned treatment duration per 
protocol.  
Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed.  Participants will then return to regular scheduled imaging every 9 
weeks, starting with the next scheduled imaging time point.  Participants who receive 
additional imaging for confirmation do not need to undergo the next scheduled tumor 
imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point.   
Per iRECIST (Section 9.2.1.6), disease progression should be confirmed 4 to 8 weeks after 
first radiologic evidence of PD in clinically stable participants.  Participants who have 
unconfirmed disease progression may continue on treatment at the discretion of the 
Investigator until progression is confirmed by the site provided they have met the conditions 
detailed in Section 9.2.1.6.  Participants who receive confirmatory imaging do not need to 
undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point, if clinically stable.  Participants who 
have confirmed disease progression by iRECIST, as assessed by the site, will discontinue 
study treatment.  Exceptions are detailed in Section 9.2.1.6. 
6.1.2.6.2 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window).  If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory.  In participants who discontinue study treatment due to documented disease 

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progression and the Investigator elects not to implement iRECIST, this is the final required 
tumor imaging. 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every 9 weeks in Year 1 or every 
16 weeks after Year 1) to monitor disease status until the start of a new anticancer treatment, 
disease progression, pregnancy, death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
6.1.2.6.3 Second Course (Retreatment) Tumor Imaging 
Tumor imaging must be performed within 28 days prior to restarting treatment with 
pembrolizumab.  Local reading (Investigator assessment with site radiology reading) will be 
used to determine eligibility. 
The first on-study imaging assessment should be performed at 6 weeks (24 days ±7 days) 
after the restart of treatment.  Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±7 days) or more frequently, if clinically indicated. 
Per RECIST 1.1 (Section 9.1.2.6), if tumor imaging shows initial PD, tumor assessment 
should be repeated 4 to 8 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression.  Participants who obtain 
confirmatory imaging do not need to undergo scheduled tumor imaging if it is less than 
4 weeks later and may wait until the next scheduled imaging time point, if clinically stable. 
Imaging should continue to be performed until disease progression, the start of a new 
anticancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first.  Disease progression may be confirmed 4 to 8 weeks after the first tumor 
imaging indicating PD, by the Investigator using iRECIST, in clinically stable participants. 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window).  If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory.  In participants who discontinue study treatment due to documented disease 
progression, this is the final required tumor imaging. 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging 
every 9 weeks (63 days ±7 days) until either the start of a new anticancer treatment, disease 
progression, pregnancy, death, or the end of the study, whichever occurs first. 

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6.1.2.6.4 RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status (e.g., 
discontinuation of study treatment).  Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total 
and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.  
6.1.2.6.5 iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs.  When clinically stable, participants should not be 
discontinued until progression is confirmed by the Investigator, working with local 
radiology, according to the rules below.  This allowance to continue treatment despite initial 
radiologic PD takes into account the observation that some participants can have a transient 
tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response. 
A description of the adaptations and iRECIST process is provided in Appendix 4, with 
additional detail in the iRECIST publication [Seymour et al, 2017].  iRECIST will be used by 
the Investigator to assess tumor response and progression, and make treatment decisions.   
 
 

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Table 5 Imaging and Treatment after First Radiologic Evidence of Progressive Disease (first restaging evaluation at approximately 
6weeks excluded) 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic evidence of 
PD by RECIST 1.1  
Repeat imaging at 4 to 
8 weeks to confirm PD. 
May continue study treatment at 
the Investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion 
only. 
Discontinue treatment 
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per Investigator 
assessment 
No additional imaging 
required. 
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor). 
No additional imaging 
required. 
Not applicable 
Repeat tumor imaging shows 
iUPD by iRECIST per 
Investigator assessment 
Repeat imaging at 4 to 
8 weeks to confirm PD.  May 
occur at next regularly 
scheduled imaging visit. 
Continue study treatment at the 
Investigator’s discretion. 
Repeat imaging at 4 to 
8 weeks to confirm PD per 
Investigator’s discretion 
only. 
Discontinue treatment 
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per Investigator assessment. 
Continue regularly scheduled 
imaging assessments. 
Continue study treatment at the 
Investigator’s discretion. 
Continue regularly scheduled 
imaging assessments. 
May restart study treatment if 
condition has improved and/or 
clinically stable per Investigator’s 
discretion.  Next tumor image should 
occur according to the regular imaging 
schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1.. 

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Figure 5: Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
 
 

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6.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Submit at least one formalin fixed paraffin-embedded (FFPE) archived tumor tissue block from 
biopsy of the primary cancer at time of enrollment and from the resected surgical specimen at 
the time of primary tumor resection. A corresponding H&E slide from the submitted block 
must be provided to permit quality assessment (QA) of tissue block. If patient has tissue 
collected for reasons other than the protocol, study will also acquire surplus tissue remaining. 
The FFPE tissue block is preferred; however, if unable to provide a tissue block, cut 20 five-
micron unstained slides and mount on charged glass slides and 10 ten-micron unstained slides 
mounted on uncharged slides. Label the slides with the patient ID number, accession number, 
and order of sections (i.e., 1-11).  H&E stain the first cut slide (i.e., slide labeled 1). Please do 
not re-label over the original label.  For samples containing less than 7 square millimeters of 
tumor tissue, multiple sections should be mounted onto each slide to ensure that the appropriate 
amount of tumor tissue is available. Ideally, each slide must have a minimum of 75% tumor 
tissue on the slide to be deemed adequate for study. Do not bake or place cover slips on the 
slides.  
The following materials below are mandatory (unless indicated otherwise), though: 
• 
Paraffin embedded tissue blocks with corresponding H&E (or 30 slides), if limited 
tissue is available exceptions to the amount of tissue will be made. 
• 
Surgical Pathology Report 
Correlative blood sampling will be performed at screening, prior to second cycle of 
pembrolizumab and subsequently corresponding to restaging frequency 
6.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 6.   

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Table 6 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Free thyroxine (T4) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Thyroid stimulating hormone (TSH) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Blood for correlative studies 
 
Uric Acid 
 
Tumor markers (per tumor type) 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus* 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
* Not performed during screening. 
 
 
 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 14 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
 
6.1.4 Other Procedures 
6.1.4.1 Withdrawal/Discontinuation 
When a participant discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Participants who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 5.2.3.  After discontinuing treatment following assessment of 
CR, these participants should return to the site for a Safety Follow-up Visit (described in 
Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 
7.1.5.3.2). 
6.1.4.2 Blinding/Unblinding 
This is an open-label unblinded study 
6.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
6.1.5.1 Screening 
6.1.5.1.1 Screening Period 
If a patient is thought to be a potential candidate for the trial then he/she can be offered 
participation and, if agreeable, will undergo screening procedure outlined below from D-14 
to C1D1.  Previously conducted HIV, PT/PTT, and hepatitis testing within 30 days does not 
need to be repeated and will be acceptable for screening purposes (results performed at 
outside laboratories as standard of care testing will be accepted).  
 

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Table 6.1.5.1-1: 
Screening Procedural Outline 
Procedure 
Screening 
Visit 
From D-14 
to C1D1* 
Notes 
 
Eligibility 
Assessments 
 
 
Informed Consent 
X 
Original IC in screening for protocol participation; 
 
Inclusion/Exclusion 
Criteria 
X 
All inclusion/exclusion criteria should be assessed at 
screening and confirmed prior to first dose. 
Determination of 
resectable or 
unresectable 
X 
 
Medical History 
X 
 
Tumor Tissue Sample  
X 
Confirm diagnosis of solid organ cancer 
Paraffin Tissue 
X 
Determine availability and order prior collected 
tumor tissue  
Prior Medications 
X 
Prior exposure to checkpoint inhibitor therapy 
excluded 
ECOG Performance 
Status 
X 
Within 14 days prior to first dose 
Safety Assessments 
 
 
Physical Examination 
X 
 
Vital Signs & Oxygen 
Saturation 
X 
Including BP, HR, temperature and oxygen saturation 
by pulse oximetry (at rest). Obtain vital signs at the 
screening 
 visit and within 72 hours prior to first dose. 
Physical 
Measurements 
X 
Height and Weight. Within 14 days prior to first dose 
Assessment of Signs 
and Symptoms 
X 
Within 14 days prior to first dose 
Concomitant 
Medication Collection 
X 
Within 14 days prior to first dose 

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Table 6.1.5.1-1: 
Screening Procedural Outline 
Procedure 
Screening 
Visit 
From D-14 
to C1D1* 
Notes 
 
Laboratory Tests 
X 
CBC w/differential and platelet count, 
Chemistry panel including: LDH, AST, ALT, ALP, T.Bili, 
BUN or serum urea level, creatinine, Ca, Mg, Na, K, 
Cl, Glucose, CEA, amylase, lipase, TSH, Free T4, 
appropriate tumor markers per primary site (for 
example CEA, PSA, CA19-9, CA125…),within 14 days 
prior to first dose 
Research Blood Test 
x 
correlative blood sample (60ml of blood: 
approximately 3 10ml Streck cell-free DNA BCT 
gold/black top tubes) within 14 days prior to first 
dose. (for full details related to blood collection 
please see laboratory collection manual and note 
exact tube types may be adjusted during study) 
HIV, hepatitis, PT/PTT 
laboratory tests 
X 
HIV Ab, Hepatitis B surface antigen (HBV sAg), and 
hepatitis C antibody (HCV Ab) or Hepatitis C RNA 
(HCV RNA)  or PT/PTT within 28 days prior to first 
dose 
Pregnancy Test 
(WOCBP only) 
X 
Serum or urine to be done at screening visit and 
repeated within 72hours of first dose of study 
therapy 
Efficacy Assessment 
 
 
Baseline Tumor 
Imaging Assessment 
X 
CT of the C/A/P or or PET/CT or MRI brain or 
appropriate standard of care imaging per that 
disease type as indicated within 28 days of first 
treatment dose. 
* If screening labs are done within 3 days of Cycle 1, labs for C1D1 do not need to be 
repeated. 
 
6.1.5.2 Treatment Period 
Once enrolled on trial, each participant will have the visits/events outlined in the study flow 
chart in section 5.1.  Treatment will not commence until at least 2 weeks from prior systemic 

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chemotherapy or radiation therapy.  Patients may undergo screening during this time or after 
two weeks.  There is no maximum time from prior chemotherapy until pembrolizumab 
treatment. Any resectable patient confirmed to have disease progression on restaging visit 
should be evaluated for and proceed to surgical resection. Each clinic visit while on active 
therapy will include targeted physical examination, vital signs, adverse events assessment and 
routine labs. Thyroid function testing should be done every 6 weeks.  
 
Post-Treatment Visits 
Follow-up will be done as per standard of care guidelines and decision-making by the treating 
physician 
The research team will conduct chart reviews or patient calls approximately every six months 
to assess survival and disease recurrence status for up to 2 years following surgery or last dose 
of drug. 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Participants with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment 
should also be followed and recorded.  Participants who are eligible for retreatment with 
pembrolizumab (as described in Section 5.2.3) may have up to two safety follow-up visits, one 
after the Initial Treatment Period and one after the Second Course Treatment. 
7.1.5.3.2 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 6 weeks (42 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 9 weeks (± 7 days). Every effort should be made to collect information regarding disease 
status until the start of new anti-cancer therapy, disease progression, death, end of the study or 
if the participant begins retreatment with pembrolizumab as detailed in Section 5.2.3.  
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated. 
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 5.2.3 will move from the follow-up phase to the Second Course Phase when 
they experience disease progression.   
7.1.5.3.3 Survival Follow-up 
Participants who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 

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12 weeks to assess for survival status until death, withdrawal of consent, or the end of the trial, 
whichever occurs first.  
 
6.2 
Assessing and Recording Adverse Events 
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 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 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 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 
through 120 days following cessation of study treatment, or 30 days following cessation of 

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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 he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify Merck. 
6.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this study, 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, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229) 
6.2.2 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 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, 

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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 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. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
6.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
6.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 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, 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. 

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For the time period beginning at treatment allocation 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:  +1-215-661-6229 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
6.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
For the time period beginning when the consent form is signed until treatment allocation, any 
ECI, or follow up to an ECI, that occurs to any 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 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.  

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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.  
 
6.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

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Table 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.. 

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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? 
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 
 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was 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. 
 
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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6.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
7.0 STATISTICAL ANALYSIS PLAN 
7.1 
Statistical Analysis Plan Summary 
Statistical Consideration: 
Efficacy: 
1) 
The primary endpoint is Pathological complete response (pCR) after 3 doses. 
Pathological complete response will also be  estimated for all patients who receive at least 1 
dose of pembrolizumab (intent to treat). Those who do not undergo surgical resection will be 
classified as non-pCR for the intention to treat analysis. We will estimate the pCR rate among 
the group of patients who receive at least 3 doses of pembrolizumab and undergo surgical 
resection (the primary endpoint).  Assuming the pCR is 80%, with 20 patients, the 95% 
confidence interval is (0.56, 0.94).  
 
2) 
Rate of organ sparing at 1 year (primary tumor control and no metastatic disease) will 
be assessed for all patients who receive at least 1 doses of neoadjuvant pembrolizumab for the 
intention to treat analysis.  In addition we will estimate the organ sparing rate at 1 year among 
the group of patients who receive at least 3 doses of neoadjuvant pembrolizumab and do not 
undergo surgical resection. Assuming the organ sparing rate of 0.7, with 10 patients, the 95% 
confidence interval is (0.35, 0.93) . 
 
Safety monitoring: 
Toxicity will be monitored using the Bayesian approach of Thall, Simon, Estey (1995, 1996) 
and the extension by Thall and Sung (1998). Multc Lean Desktop (version 2.1) was used to 
generate the stopping boundaries and the OC tables for toxicity monitoring. Toxicity 
monitoring will be performed (n=35 patients) throughout the study. Unacceptable toxicities 
are defined as any Grade 3 or higher probably or definite treatment-related CTCAE toxicity 
that occurs during the first 6 months of therapy. Denote the probability of toxicity by PT. We 
assume as a priori, PT ~ beta (0.5, 1.5). Our stopping rule is given by the following probability 
statement:  
Pr (PT > 0.25 | data)>0.85. 

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That is, we will stop the trial for new patient enrollment if at any time during the study, we 
determine that there is more than 85% chance that the unacceptable toxicity rate is more than 
25%. This toxicity monitoring rule will be applied after the first 5 patients have been enrolled 
and evaluated, and then will be monitored by cohort of 5. Stopping boundaries corresponding 
to this stopping rule are listed in Table 8.  
Table 8.  Early stopping boundaries for toxicity monitoring 
# of patients (in cohort size of 5, starting from the 5th patient) 
Stop this cohort if there 
are this many patients with toxicities:  
# of patients ( in cohort size of 
5, starting from the 5th  patient) 
Stop this cohort if there are this 
many patients with toxicities:  
5 
3-5 
10 
5-10 
15 
6-15 
20 
8-20 
25 
9-25 
30 
11-30 
35 
Always  stop with this many 
patients 
 
 
Table 9. Operating characteristic for toxicity monitoring 
True toxicity rate 
Prob(stop the 
trial early) 
Average number 
of patients treated 
0.15 
0.04 
33.87 
0.25 
0.27 
29.02 
0.35 
0.66 
20.46 
0.45 
0.93 
12.94 
 
If patients do not respond to pembrolizumab, they would stop the treatment after two doses. In 
case the patients have resectable tumors, the subsequent surgical resection will be monitored.  
Patients will be allowed up to 6 months to have surgery. We expect that 80% of these patients 
with resectable tumors would undergo surgery.   After 5 patients falling into this category, the 

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Bayesian stopping rule: Pr (surgery rate> 0.8|data) < 0.01 will be continuously implemented 
assuming the surgery rate follows a Beta prior (0.8,0.2). That is, if at any time after enrolling 
5 patients who have resectable tumor and don’t respond to  pembrolizumab, we determine that 
there is a less than 1% chance that the surgery rate is more than 80%, we will stop enrollment 
of the study. Assuming there are 20 patients, the surgery rate monitoring rule will be applied 
after the first 5 patients have been enrolled and evaluated, and then will be monitored by cohort 
of 5. Stopping boundaries corresponding to this stopping rule are listed in Table 10 (operating 
characteristic in table 11). For example, if there is none or only 1 patient out of the 1st 5 patients 
undergo surgery, the study will be stopped. Table 10.  Early stopping boundaries for surgery 
rate monitoring for patients who do not respond to pembrolizumab but with resectable tumor 
# of patients ( in cohort size of 
5, starting from the 5th  patient) 
Stop the study if there are this 
many patients with surgery 
5 
0-1 
10 
0-4 
15 
0-7 
20 
                       0-11 
 
Table 11. Operating characteristic for surgery rate monitoring for patients who do not respond 
to pembrolizumab but with resectable tumor 
 
True surgery rate 
Prob(stop the 
trial early) 
0.5 
0.56 
0.6 
0.27 
0.7 
0.08 
0.8 
0.01 
 
7.2 
Statistical Analysis Plan 
Analysis Plan: 
All patients who received any dose of the study agent, pembrolizumab, will be included in the 
analysis for efficacy and safety.  Demographic/clinical characteristics and safety data of the 
patients will be summarized using descriptive statistics such as frequency, mean, standard 

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deviation, median and range. We will follow standard reporting guidelines for adverse events. 
Safety data will be summarized by category, severity and frequency.  
Safety will be recorded according to CTCAE toxicity and also post-operative complications 
will be classified according to Clavien-Dindo classification1. 
For the efficacy analysis, we will estimate the pathological complete response and rate of organ 
sparing at 1 year along with the 95% confidence interval.   
For each subject, relapse-free survival and overall survival will be calculated. Relapse-free 
survival is defined as the number of days from the date of response to the date of documented 
treatment failure, relapses or death from any cause, whichever occurs first, and will be 
calculated for all patients. The overall survival is defined as the time from treatment start till 
death or last follow-up.  The distribution of time-to-event endpoints including overall survival 
(OS) and event free survival (RFS) will be estimated using the method of Kaplan and Meier. 
Comparisons of time-to-event endpoints by important subgroups will be made using the log-
rank tests. The association between response (e.g. pathological complete response) and 
patient’s clinical characteristics, such as changes in ct DNA, mutation burden, T-effector cell 
populations, gene expression profiles, etc.  will be examined by Wilcoxon’s rank sum test or 
Fisher’s exact test, as appropriate.  
 
8.0 TRANSLATIONAL PLAN 
The following are part of efforts to further exploratory objectives:  
Patient ctDNA levels may be tracked at various time-points during the study to identify 
patterns of change and it association to treatment benefit for patients.  
Optional paired tumor biopsies may be performed at baseline and while on treatment. 
Biomarkers evaluated from the biopsies will include the following: pre-treatment indel 
mutation score, which is potentially predictive of MSI-H cancer outcomes (Mandal et al., 
Science. 2019); correlation of CD8 infiltration changes with efficacy; and relationship of 
protein and RNA expression of immune resistance with tumor response and progression. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Pembrolizumab will be provided by Merck as summarized in Table 8. 

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Table 12 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
The investigator’s or site’s designated investigational product manager is required to maintain 
accurate investigational product accountability records. Upon completion of the study, copies 
of investigational product accountability records will be returned to Merck. All unused 
investigational product will be returned to Merck- authorized depot or disposed of upon 
authorization by Merck. 

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10.1 Patient confidentiality  
In order to maintain patient confidentiality, we will protect participants’ privacy by coding 
samples and keeping the master list of identifiers accessible to only key project staff.  Patient 
data will be kept on secure computers and Samples will be kept in freezers in locked 
laboratories and buildings.  Additionally in some other cases, samples may be provided from 
outside collaborators or institutions for discovery and research purposes. In such cases, the 
samples should be obtained under IRB-approved protocols at these outside collaborators and 
institutions to allow them for participation in this protocol and under a specific grant/ contract 
or Material Transfer Agreement (MTA) with MD Anderson Cancer Center. 
 
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10. Peters GJ, van der Wilt CL, van Groeningen CJ, Smid K, Meijer S, Pinedo HM. 
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12. Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera 
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15. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling 
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Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, 
Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler 
D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, 
Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors 
to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413 
16. Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, Desai J, Hill 
A, Axelson M, Moss RA, Goldberg MV, Cao ZA, Ledeine JM, Maglinte GA, Kopetz 
S, André T. Nivolumab in patients with metastatic DNA mismatch repair-deficient or 
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multicentre, phase 2 study. Lancet Oncol. 2017 Sep; 18(9):1182-1191. 
17. Puri S, Shafique M, Gray JE. Immune Checkpoint Inhibitors in Early-Stage and 
Locally Advanced Non-Small Cell Lung Cancer. Curr Treat Options Oncol. 2018 Jun 
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M, Yang SC, Jones DR, Broderick S, Battafarano RJ, Velez MJ, Rekhtman N, Olah 
Z, Naidoo J, Marrone KA, Verde F, Guo H, Zhang J, Caushi JX, Chan HY, Sidhom 
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Merghoub T, Taube JM, Velculescu VE, Topalian SL, Brahmer JR, Pardoll DM. 
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer. N Engl J Med. 2018 May 
24; 378(21):1976-1986.  
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Hudgens, Leila J. Williams, Qiuyu Wu, Jayanthi Gudikote, Weiyi Peng, Patrick Hwu, 
Jing Wang, Michael Tetzlaff, William N. William, and John V. Heymach. Superior 
efficacy of neoadjuvant compared to adjuvant immune checkpoint blockade in non-
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advanced, operable colon cancer: the pilot phase of a randomized controlled trial. 
Lancet Oncol. 2012 Nov;13(11):1152-60. 
21. Dehal A, Graff-Baker AN, Vuong B, Fischer T, Klempner SJ, Chang SC, 
Grunkemeier GL, Bilchik AJ, Goldfarb M. Neoadjuvant Chemotherapy Improves 
Survival in Patients with Clinical T4b Colon Cancer. J Gastrointest Surg. 2018 Feb; 
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chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
Clin Oncol 2005;23(10):2346-57. 
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment 
of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J 
Med 2008; 358(25):2698-703. 
25. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005; 23:515-48. 
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 2001; 
98(24):13866-71. 
27. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory receptor programmed death-1. Immunity 
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28. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate 
with immunoreceptor tyrosine-based switch motif of programmed death 1 upon 
primary human T cell stimulation, but only receptor ligation prevents T cell 
activation. J Immunol 2004; 173:945-54. 
29. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 
inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome 
and downstream signaling to PKCtheta. FEBS Lett. 2004; 574:37-41. 
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31. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, 
et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. 
Mol Cell Biol 2005; 25(21):9543-53. 
32. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010; 236:219-42. 
33. Robert C, Ribas A, Hamid O, Daud A, Wolchok JD, Joshua AM, Hwu WJ, Weber JS, 
Gangadhar TC, Joseph RW, Dronca R, Patnaik A, Zarour H, Kefford R, Hersey P, 
Zhang J, Anderson J, Diede SJ, Ebbinghaus S, Hodi FS. Durable Complete Response 
After Discontinuation of Pembrolizumab in Patients With Metastatic Melanoma. J 
Clin Oncol. 2018 Jun 10; 36(17):1668-1674. 
34. Weiser MR, Landmann RG, Kattan MW, Gonen M, Shia J, Chou J, Paty PB, Guillem 
JG, Temple LK, Schrag D, Saltz LB, Wong WD. Individualized prediction of colon 
cancer recurrence using a nomogram. J Clin Oncol. 2008 Jan 20; 26(3):380-5. 
35. Chalabi M, Fanchi, L, van den Berg J, Beets G, Aalbers A, Snaebjornsson P, 
Grootscholten C, Mertz M, Lopez M, Nuijtn E, Kuiper M, Kok M, can Leerdam M, 
Shumacher T, Voest E, Hannen J. Neoadjuvant ipilimumab plus nivolumab in early 
stage colon cancer. ESMO. 2018. Abstract number: LBA37_PR. 
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37.  
 

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12.0 APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
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 Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 

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Appendix 2: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Requirements 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 11 consistently and correctly during the 
protocol-defined time frame in Section X. 
 
Table 11 
Contraceptive Methods 
 
Acceptable Contraceptive Methods   

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Failure rate of >1% per year when used consistently and correctly.  
● Male or female condom with or without spermicide 
● Cervical cap, diaphragm or sponge with spermicide 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least [X days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential]  after the last dose of study treatment . 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 

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Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
 

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Appendix 4:  Description of the iRECIST Process for Assessment of Disease 
Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST 
assessment. 
Assessment and Decision at RECIST 1.1 Progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will 
decide whether to continue a participant on study treatment until repeat imaging is obtained 
(using iRECIST for participant management (see Table 5 and Figures 1 and 3).  This decision 
by the Investigator should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of 
disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per Investigator assessment.  I 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of 
measurements”, but “sum of diameters” will be used in this protocol, consistent 
with the original RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, 

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the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of 
≥ 5 mm, compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD 
time point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 

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• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on 
which iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”.  This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule.  If PD is confirmed, participants will be discontinued from study 
treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered.  In this case, if study treatment is continued, tumor imaging 
should continue to be performed following the intervals as outlined in Section 6. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression.  
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression. 

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• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except 
in one respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
scan the burden of new lesions has increased from its smallest value (for new target lesions, 
their sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD 
or iPR. It will remain iUPD until either a decrease in the new lesion burden allows resolution 
to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication [Seymour et al, 
2017].