Single Arm Phase II Study to Assess the Efficacy of Pembrolizumab Plus Radiotherapy or Ablation in Metastatic Colorectal Cancer Patients
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
Page 1 of 46 
 
 
 
 
Single Arm Phase II Study to Assess the Efficacy of Pembrolizumab Plus 
Radiotherapy or Ablation in Metastatic Colorectal Cancer Patients 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
Principal Investigator/Department: 
Neil H. Segal, MD, PhD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Leonard B. Saltz, MD 
Josh Yamada, MD 
Stephen Solomon, MD 
Medicine 
Radiation Oncology 
Interventional Radiology 
Investigator(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Medicine 
Medicine 
Andrew Epstein, MD 
James Harding, MD 
David Ilson, MD, PhD 
Medicine 
Medicine 
Medicine 
Yelena Janjigian, MD 
David Kelsen, MD 
Medicine 
Medicine 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Diane Reidy-Lagunes, MD 
Medicine 
Medicine 
Medicine 
Eileen O‟ Reilly, MD 
Armin Shahrokni, MD 
Medicine 
Medicine 
Zsofia K. Stadler, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Medicine 
Medicine 
Medicine 
Kenneth Yu, MD 
Nitya Raj, MD 
Abraham Wu, MD 
Medicine 
Medicine 
Radiation Oncology 
Constantinos Sofocleous, MD 
Joseph P. Erinjeri, MD 
Interventional Radiology 
Interventional Radiology 
Jill Gluskin, MD 
Vaios Hatzoglou, MD 
Ellen Hollywood, NP 
Radiology 
Radiology 
Nursing 
Erica Kaufman, NP 
Patricia Gabriel, NP 
Nursing 
Nursing 
Jinru Shia, MD 
Marinela Capanu, PhD 
Pathology 
Epidemiology and 
Biostatistics 
Consenting 
Professional(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Medicine 
Medicine 
Andrew Epstein, MD 
James Harding, MD 
David Ilson, MD, PhD 
Medicine 
Medicine 
Medicine 
Yelena Janjigian, MD 
David Kelsen, MD 
Medicine 
Medicine 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Medicine 
Medicine 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
Page 2 of 46 
 
 
 
 
Diane Reidy-Lagunes, MD 
Eileen O‟ Reilly, MD 
Armin Shahrokni, MD 
Leonard B. Saltz, MD 
Neil H. Segal, MD, PhD 
Zsofia K. Stadler, MD 
Anna Varghese, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
Nitya Raj, MD 
Ellen Hollywood, NP 
Erica Kaufman, NP 
Patricia Gabriel, NP 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 
Nursing 
Nursing 
Nursing 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
3 
 
 
 
 
Table of Contents 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ...................................................................... 7 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ............................................................................. 10 
3.0 
BACKGROUND AND RATIONALE .................................................................................. 10 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................................... 16 
4.1 
Design ........................................................................................................................... 16 
4.2 
Intervention .................................................................................................................... 16 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS .......................................................................... 17 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY .......................................................................... 17 
6.1 
Subject Inclusion Criteria ................................................................................................ 17 
6.2 
Subject Exclusion Criteria .............................................................................................. 19 
7.0 
RECRUITMENT PLAN ...................................................................................................... 20 
8.0 
PRETREATMENT EVALUATION ..................................................................................... 21 
9.0 
TREATMENT/INTERVENTION PLAN............................................................................... 21 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION ................................................... 28 
11.0 
TOXICITIES/SIDE EFFECTS ............................................................................................ 29 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....................... 32 
13.0 
CRITERIA FOR REMOVAL FROM STUDY ...................................................................... 35 
14.0 
BIOSTATISTICS ............................................................................................................... 36 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES37 
15.1 
Research Participant Registration .................................................................................. 37 
15.2 
Randomization ............................................................................................................... 38 
16.0 
DAT A M ANAGEMENT ISSUES ....................................................................................... 38 
16.1 
Quality Assurance .......................................................................................................... 38 
16.2 
Data and Safety Monitoring ............................................................................................ 38 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................................ 38 
17.1 
Privacy ........................................................................................................................... 39 
17.2 
Serious Adverse Event (SAE) Reporting ........................................................................ 40 
17.2.1 
 40 
18.0 
INFORMED CONSENT PROCEDURES ........................................................................... 42 
19.0 
REFERENCES .................................................................................................................. 43 
20.0 
APPENDICES ................................................................................................................... 44 

Memorial Sloan Kettering Cancer Center 
4 
 
 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
List of Abbreviations 
Abbreviation or 
Specialized Term 
Definition 
ADA 
anti-drug antibody 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
ALT 
alanine aminotransferase 
APC 
antigen presenting cells 
AST 
aspartate aminotransferase 
CD 
cluster of differentiation 
CI 
confidence interval 
CIS 
carcinoma in situ 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CRF 
case report form 
CT 
computed tomography 
CTC 
circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte antigen 4 
DC 
disease control 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ELISA 
enzyme-linked immunosorbent assays 
EMA 
European Medicines Agency 
EOI 
end of infusion 
EU 
European Union 
Fc 
fragment crystallizable 
FFPE 
formalin fixed paraffin embedded 
FTIH 
First-time-in-human 

5 
 
 
Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
Abbreviation or 
Specialized Term 
Definition 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HCl 
hydrochloride 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN 
interferon 
IgG1κ 
immunoglobulin G1 kappa 
IHC 
immunohistochemistry 
IL 
interleukin 
IM 
immunogenicity 
IRB 
Institutional Review Board 
irAE 
immune-related adverse event 
irRC 
immune-related response criteria 
IV 
intravenous(ly) 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
MAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDSC 
Myeloid derived suppressor cell 
miRNA 
micro ribonucleic acid 
MMR 
mismatch repair 
mRNA 
messenger ribonucleic acid 
MRI 
magnetic resonance imaging 
MRSD 
maximum recommended starting dose 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
no-observed adverse-effect-level 
NSCLC 
non-small cell lung cancer 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
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Abbreviation or 
Specialized Term 
Definition 
OBD 
optimal biological dose 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cell 
PD 
progressive disease 
PD-1 
programmed death 1 
PD-L1 
programmed death ligand 1 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
Q2W 
every 2 weeks 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RFA 
Radiofrequency ablation 
RT 
Radiation therapy 
SAE 
serious adverse event 
SD 
stable disease 
SID 
subject identification 
SMC 
Safety Monitoring Committee 
SPD 
sum of products of diameters 
SRT 
Safety Review Team 
SUSAR 
suspected unexpected serious adverse reaction 
TIL 
tumor infiltrating lymphocyte 
TNF-α 
tumor necrosis factor alpha 
TSH 
thyroid-stimulating hormone 
ULN 
upper limit of normal 
US FDA 
United States Food and Drug Administration 
USA 
United States of America 
WFI 
water for injection 
WHO 
World Health Organization 
w/ v 
weight/ volume 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
7 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Name of Investigational drug: Pembrolizumab 
Title of Study:  Single Arm Phase II Study to Assess the Efficacy of Pembrolizumab Plus Radiotherapy 
or Ablation in Metastatic Colorectal Cancer Patients 
Study Centers: MSKCC 
Study Period: 24 months 
Phase of Development: II 
Objectives: 
The primary objective is Overall Response Rate in disease that is not ablated or radiated (Complete 
Response and Partial Response). 
The secondary objectives are: 
1. 
Safety and tolerability of Pembrolizumab plus radiotherapy (RT) or ablation 
2. 
Overall Survival of pembrolizumab plus RT or ablation 
3. 
Progression free survival rate at 1 year 
4. 
Progression free survival rate at 2 years 
The exploratory objectives are to evaluate biomarkers that may correlate with activity of pembrolizumab 
plus RT or pembrolizumab plus ablation in colorectal cancer (CRC), or prospectively identify CRC 
patients likely to respond to treatment. 
Study De sign: This will be a Simon two-stage design, phase II study. It will be conducted to determine 
the efficacy and safety of (1) pembrolizumab plus RT in subjects with metastatic CRC who are 
undergoing RT as standard therapy; and, (2) pembrolizumab plus ablation in subjects with metast atic 
CRC who are undergoing ablation as standard therapy. Eligible patients will have metastatic colorectal 
cancer and received at least two prior standard therapy for metastatic disease. Patients will be stratified 
according to eligibility for RT (cohort 1) or ablation (cohort 2). Patients in cohort 1 will have at least one 
locally advanced or metastatic lesion for which palliative RT is considered appropriate standard therapy, 
and at least one other measurable index lesion that will not undergo RT. Patients in cohort 2 will have at 
least one metastatic lesion for which palliative ablation is considered appropriate standard therapy, and at 
least one other measurable index lesion that will not undergo ablation. All subjects will undergo ablation 
or begin RT within 1 week prior to dose 1 of pembrolizumab. Subjects will receive pembrolizumab via IV 
infusion at 200 mg every three weeks (Q3W), and continue treatment Q3W until progression of disease, 
initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to discontinue treatment 
occur, up to 24 months. Patients who had a prior response or stable disease without another reason to 
discontinue therapy may resume treatment for an additional 12 months upon disease progression. 
Repeat palliative RT in cohort 1, or ablation in cohort 2, will be permitted in select cases for the treatment 
of isolated lesions, provided a target lesion remains. Patients will be evaluated by physical exam and 
routine blood tests every three weeks during the study period. CT or MRI will be performed during 
screening, and then at 9 week intervals. Tumor measurements and deter mination of tumor responses will 
be performed according to RECIST 1.1. Subjects may continue to receive pembrolizumab beyond 
radiographic progression in the absence of clinical deterioration, and after discussion with the Principal 
Investigator. All subjects will be followed up to 2 years for survival or until the study closes. The primary 
endpoint of this trial is the response rate in CRC treated with RT plus pembrolizumab (cohort 1) or 
ablation plus pembrolizumab (cohort 2). A two-stage Simon‟s optimal design will be employed to test the 
null hypothesis that the true response rate is ≤5% versus the alternative hypothesis that the true response 
rate is at least 25% with type I and II error rates of 10% each. Each cohort will be evaluated separately for 
this purpose. In the first stage, we will accrue 9 patients in each cohort. If 0 objective tumor responses 
(PR or CR) are observed among the 9 subjects treated in a cohort, then subject enrollment will be 
terminated in that cohort. If at least 1 response is observed among the 9 subjects treated in a cohort, 
then the study will be expanded to enroll a total of 24 treated subjects in that cohort. At the end of the 
study, if 2 or less objective tumor responses are observed in a cohort, then the study will be considered 
not worthy of further investigation in that particular cohort. If at the end of the study ≥3 tumor responses 
per RECIST 1.1 are observed in a cohort, then further investigation of pembrolizumab plus RT and/or 
pembrolizumab plus ablation will be considered worthwhile. The study will complete when all subjects 
have either progressed or discontinued from the study for other reasons. This study requires accrual of a 
minimum of 18 subjects and up to a maximum of 48 subjects if both cohorts are expanded to the second 
stage. The accrual time is estimated to be 2 years. Tumor biopsies for research purposes will be 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
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mandatory in all patients. Pre-treatment biopsies will be obtained during fiducial placement for RT, at the 
time of ablation, or during a separate procedure. On treatment biopsies will be performed,1 week after 
completing RT or undergoing ablation (of the radiated/ ablated lesion) and then 4 weeks after dose #1 of 
pembrolizumab (of a non-radiated/ ablated lesion). Tumor immunohistochemistry may be performed for 
PD-L1 expression and quantification of tumor infiltrating lymphocyte (TIL) subtypes, including CD8+ T- 
cells, CD4+ T-cells, Regulatory T-cells (Treg), and Myeloid Derived Suppressor Cells (MDSCs). 
Peripheral blood samples will be obtained in all patients at baseline then weeks 3, 6, and 9 for all 
patients. 
Additional 
blood 
draws 
beyond 
week 
9 
are 
permitted 
based 
upon 
interesting 
clinic/immunological findings. Plasma may be analyzed for change in antibody responses to a broad 
panel of antigens (seromics). Flow cytometry may be performed for peripheral blood immune cell 
phenotype and their activation status, including CD8+ T-cells, CD4+ T-cells, Tregs, and MDSCs. The 
amount of PDL-1 expression, changes in immune cell repertoire and activation status within the tumor 
and peripheral blood as well as immune responses against specific tumor antigens will be correlated with 
clinical outcome in an exploratory manner in order to identify predictive makers for response, and to 
further our understanding of pembrolizumab plus RT, and pembrolizumab plus ablation in CRC. 
Diagnosis and Main Criteria for Inclusion in the Study: 
Inclusion Criteria 
1. 
Willing and able to provide written informed consent. 
2. 
Histologically- or cytologically- confirmed CRC. 
3. 
Locally advanced or metastatic CRC. 
4. 
Subjects have received at least two standard available therapies. 
5. 
At least one tumor for which palliative RT is considered appropriate standard therapy (cohort 
1); or, at least one tumor for which palliative ablation is considered appropriate standard 
therapy (cohort 2). 
6. 
At least one index lesion that will not undergo RT or ablation, and is measurable based on 
RECIST 1.1. 
7. 
≥ 18 years of age on day of signing informed consent. 
8. 
Consent for tumor biopsies and blood draws for research purposes. 
9. 
Consent for use of available archived tissue for research purposes. 
10. 
Performance status of ECOG 0 or 1. 
11. 
Adequate organ function, defined as: 
• 
Absolute Neutrophil Count ≥ 1,500/mm3. 
• 
Platelet count ≥ 100,000/mm3. 
• 
Serum creatinine ≤ 1.5 x ULN or CrCl ≥60 mL/min. 
• 
AST and ALT ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with liver metastases. 
• 
Bilirubin ≤ 1.5 × ULN or Direct bilirubin ≤ ULN. 
• 
INR/PT and PTT ≤1.5 X ULN unless on anticoagulant therapy and PT/PTT within 
therapeutic range. 
12. 
Adequate method of contraception. 
 
Exclusion Criteria 
1. 
Currently participating in/ has participated in an investigational study within 4 weeks. 
2. 
Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial t reatment. 
3. 
Prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered (i.e., 
≤ Grade 1 or at baseline) from adverse events due to agents administered > 4 weeks earlier. 
4. 
Prior chemotherapy, targeted small molecule therapy, within 2 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent (exc. Grade 2 neuropathy). 
5. 
If subject received major surgery, they must have recovered adequately from the t oxicity 
and/or complications from the intervention prior to starting therapy. 
6. 
Known additional malignancy that is progressing or requires active treatment. Exceptions 
include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in s itu 
cervical cancer that has undergone potentially curative therapy. 
7. 
Known CNS metastases and/or carcinomatous meningitis.  Subjects with previously treated 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
9 
 
 
 
 
brain metastases may participate provided they are stable without evidence of new or 
enlarging brain metastases, and are not using steroids for at least 7 days prior to trial 
treatment. 
8. 
Active autoimmune disease requiring systemic treatment within the past 3 months or a 
documented history of clinically severe autoimmune disease, or a syndrome that requires 
systemic steroids or immunosuppressive agents. 
9. 
Interstitial lung disease or active, non-infectious pneumonitis. 
10. 
Active infection requiring systemic therapy. 
11. 
History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject‟s participation for the full duration of 
the trial, or is not in the best interest of the subject to p articipate, in the opinion of the treating 
investigator. 
12. 
Known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
13. 
Pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the trial, starting with the pre-screening or screening visit through 120 days after 
the last dose of trial treatment. 
14. 
Prior therapy with an anti-P D-1, anti-P D-L1, anti-P D-L2, anti-CD137, or anti-Cytotoxic T- 
lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 
15. 
Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. 
Known active Hepatitis B or C. 
17. 
Live vaccine within 30 days prior to the first dose of trial treatment. 
Number of Subjects: 18 to 48, including patients in cohort 1 (n= 9 to 24) and cohort 2 (n=9 to 24). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
10 
 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
• 
The primary objective is Overall Response Rate in disease that is not ablated or radiated 
of pembrolizumab plus RT or pembrolizumab plus ablation in subjects locally 
advanced/metastatic CRC, according to RECIST v1.1. 
• 
The secondary objectives are to determine: 
o Safety and tolerability of pembrolizumab plus RT or ablation 
o Overall Survival of pembrolizumab plus RT or ablation 
o Progression free survival rate at 1 year 
o Progression free survival rate at 2 years 
• 
The exploratory objectives are to evaluate biomarkers that may correlate with activity of 
pembrolizumab plus RT or ablation in CRC, or prospectively identify CRC patients likely 
to respond to treatment. 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 
Colorectal cancer 
Worldwide, CRC is the third most common form of cancer in men, with 663,000 cases (10% of 
the total) and second most common in women, with 571,000 cases (9.4% of the total) per year. 
Each year there are about 608,000 deaths from colon cancer which is approximately 8% of all 
cancer deaths making colorectal cancer the fourth most common cause of cancer death [1]. In 
2012 in the U.S. an estimated 103,170 new cases were diagnosed with 51,690 deaths [2]. 
Treatment of CRC depends largely on the stage of the disease, which is most commonly rated 
according to tumor, nodes, and metastasis (TNM) criteria. The initial treatment is surgery. 
However, post-surgery metastatic disease occurs in 40%-60% of patients and the prognosis for 
patients who develop advanced metastatic disease is poor. Over the past decade, progress has 
been made in the role of systemic therapy for the palliation of advanced colorectal cancer. With 
the introduction of oxaliplatin, irinotecan, anti-VEGF therapies, and anti-EGFR therapies, the 
median life expectancy of patients has been increased to about 29 months [3]. Despite these 
therapeutic advances, patients with unresectable, metastatic and/or recurrent CRC, remain 
incurable. There is a substantial unmet medical need for more effective and less toxic therapies, 
especially for those patients with advanced disease that have not responded or have become 
resistant to the existing standard treatments. The development of novel approaches to 
treatment is greatly needed in order to improve outcomes in such patients. 
 
3.2 Immune Augmentation in Colorectal Cancer 
Immune augmentation, including checkpoint-directed therapies, has been studied in patients 
with CRC, and isolated tumor responses have been observed. Our group performed a study of 
CTLA-4 blockade with tremelimumab (15 mg/kg every 90 days) in 47 patients with previously 
treated CRC. Grade 3/4 treatment-related adverse events (AEs) included diarrhea (n = 5; 11%), 
ulcerative colitis (n = 1; 2%), fatigue (n = 1; 2%), autoimmune thrombocytopenia (n = 1; 2%), 
and hypokalemia (n = 1; 2%). Of 45 response-evaluable patients, 44 did not reach second dose 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
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(43 progressive disease; one discontinuation). Twenty-one patients (45%) lived ≥ 180 days after 
enrollment. One patient (2%; 90% CI, < 1% to 10%) had a stable pelvic mass and substantial 
regression in an adrenal mass (partial response) [4]. Another study was a dose escalation study 
of PDL-1 blockade with MPDL3280A (0.01-20 mg/kg every three weeks) in 20 patients with 
solid tumors and lymphoma. Tumor regression was observed in 1 of 4 patients with CRC 
(partial response). In a first-in-human single-dose, dose-escalation (0.3 to 10 mg/ kg) study of 
PD-1 blockade with nivolumab in solid tumors, 14 patients with CRC were enrolled. In the phase 
I multi-dose, dose escalation (1 to 10 mg/kg every 2 weeks) study, 19 patients with CRC were 
enrolled. Treatment was reasonably well tolerated in both studies. Durable tumor regression 
(complete response) beyond 3 years was observed in one patient [5-7]. 
3.3 Rationale for immune therapy plus radiotherapy or ablation in colorectal 
cancer 
RT and ablation, such as cryoablation or radiofrequency ablation, are both standard therapies in 
patients with metastatic colorectal cancer. Ablation results in tumor destruction by direct heat or 
cold, and RT results in tumor destruction by ionizing radiation. Either ablation or RT alone is not 
expected to result in objective systemic benefit alone. However, each modality has been 
associated with induction of systemic immunity that can be augmented by co-stimulatory 
blockade with PD-1 leading to potential for tumor shrinkage. 
The phenomenon of tumor destruction by RT or ablation leading to shrinking of tumors away 
from the site of initial treatment has been termed the abscopal effect. Albeit rare, when the 
abscopal effect occurs, the clinical implications can be profound. 
The rationale of the abscopal effect is that in situ tumor destruction releases a large amount of 
tumor antigens. Antigen-presenting cells, such as dendritic cells, then take up these antigens in 
the periphery and migrate to lymph nodes where they activate CD4+ and CD8+ T-lymphocytes 
that recognize these tumor-antigens. Immune augmentation via immune co-stimulatory 
molecules then permits the ensuing immune response to strengthen and destroy cancer. 
The combination of tumor cryoablation and immunomodulation has been shown in animal 
models, by our colleagues, to generate such a systemic anti-tumor response [8]. Specifically, 
local tumor destruction with cryoablation can lead to exposure of DCs with sufficient quantities 
of tumor antigens to ultimately lead to DC maturation and activation. Recently, our collaborators 
(Dr. James Allison‟s group at MSKCC) showed that combination therapy with cryoablation and 
CTLA4 blockade successfully mediated rejection of metastatic prostate cancer lesions and 
prevented the growth of secondary tumors in preclinical murine models [8]. Levy et al. from 
MSKCC showed in a BALB/c mouse model of metastatic colon cancer that cryoablation of a 
solitary tumor mass plus cyclophosphamide, to selectively depletes regulatory T cells (Tregs), 
leads to regression of established tumors and protection against tumor rechallenge [9]. Den 
Brok et al. have also demonstrated this effect in vivo using the well-defined murine B16-OVA 
melanoma cell line using RFA. They demonstrated that RFA alone results in a weak but 
detectable immune response against OVA, as well as other B16 antigens. Whereas, the 
combination of co-stimulatory blockade by anti-CTLA-4 together with RFA approximately 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
12 
 
 
 
 
doubled the number of mice alive at 70 days post-tumor rechallenge compared with mice that 
received control antibody plus ablation alone [10]. 
A similar effect has been shown with RT and blockade of PD-1/PDL-1 interaction. Deng et al. 
showed that anti-PDL-1 enhanced the effect of RT in a MC38 colorectal tumor model, with 
substantial delay in tumor growth 34 days after treatment with combination therapy. Tumors 
measured 27.85 (± 27.85) mm after combination therapy, compared to 278.6 (± 94.20) mm and 
457.6 (± 44.24) mm after RT alone, or anti-PDL-1 alone, respectively. A similar benefit was 
shown in the TUBO breast cancer cell line, with reduced TUBO tumor growth after mice were 
re-challenged in the opposite flank, implying systemic immunity. This immunological effect was 
associated with activation of CD8+ T-cells and reduced tumor-infiltrating myeloid-derived 
suppressor cells (MDSC) [11]. 
More recently, Dr. Postow from our group reported this abscopal effect in a patient who 
developed a systemic response to localized RT after having had disease progression while 
receiving CTLA-4 blockade (ipilimumab). Specifically, a right hilar lymph-node and spleen 
metastases, which were not the target of RT, showed regression only after the patient received 
palliative RT after several months of CTLA-4 blockade. A delayed response to the ipilimumab 
was considered unlikely [12]. 
The preclinical models and the clinical observation provide compelling rationale to further study 
tumor ablation and RT in combination with immune augmentation by co-stimulatory blockade. 
Pembrolizumab is an excellent choice, as this agent has already demonstrated activity in 
cancer. CRC is an appropriate target for such a study because this disease is (1) frequently 
associated with Tumor Infiltrating Lymphocytes (TILs), is (2) routinely treated with combination 
therapies including RT or ablation, and (3) there is substantial unmet need for novel therapies 
beyond the currently available systemic therapies. 
3.3 
Pembrolizumab 
3.3.1 Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decade. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [13-16]. In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2). The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
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glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and 
a cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic 
tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based 
inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T- 
cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by 
which PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as 
both molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells. Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells. 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors. Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs. 
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably 
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen- 
presenting cells found in lymphoid tissue or chronic inflammatory environments. PD -L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues [13]. Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this 
T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in 
subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role 
in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
Pembrolizumab (previously known as MK-3475 or SCH 900475) is a potent and highly selective 
humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. 
3.3.2 Preclinical and Clinical Trial Data 
 
3.3.2.1 Non-Clinical Toxicology Summary of results 
In the 1-month and 6-month toxicology study in cynomolgus monkeys, pembrolizumab 
administered once a week and once every other week respectively, intravenously up to 
200 mg/kg resulted in no adverse treatment related effects. The exposure multiple based on 
a predicted AUC 0-tau of 4464 µg/day/mL at the maximum anticipated human clinical dose 
of 10 mg/kg Q2W or Q3W is 15-fold at 200 mg/kg, the NOAEL for the 6-month monkey 
study. Additionally, in the tissue cross-reactivity study of pembrolizumab with human and 
monkey tissues demonstrated the expected on-target staining of the membranes of 
mononuclear leukocytes in both species.  Off-target cross-reactivity staining was also 
noted in both species but was limited to cytoplasm of various cell types/tissues and the 
stroma (extracellular  connective  tissue  matrix), and  was  considered  related  to  the 

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experimental method artifacts, i.e. tissue processing for IHC, that are well recognized 
limitations of tissue cross-reactivity studies and, thus not considered toxicologically 
relevant. 
No reproductive or developmental toxicity studies are planned with pembrolizumab. 
Therefore, inclusion of women of childbearing potential in clinical trials should be in 
accordance with the study protocol and applicable regulatory guidance (e.g., ICH 
M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals). 
3.3.2.2 Clinical Summary of results 
 
As of 18-Oct-2013, 1,000 patients have been treated with pembrolizumab at several 
dose- schedules, including 10 mg/kg every 2 weeks. Pembrolizumab has been 
generally well tolerated, as expected based on preclinical findings and other anti-PD-1 
monoclonal antibodies.  As of 18-Oct-2013 no serious infusions reactions have been 
reported in PN001, however, since the potential exists in anti-PD-1 monoclonal 
antibodies, investigators should be vigilant to this possibility. Less than 1% of patients 
thus far assayed had confirmed positive ADA samples and among these, no or no clear 
impact on exposure has been observed. There is no contraindication to further clinical 
investigation with pembrolizumab. Pharmacokinetics were as expected, based on 
pembrolizumab being an IgG mAb and based on preclinical data, which support dosing 
once every 2 or 3 weeks. pembrolizumab monotherapy induces an ORR of 25%/27% 
in patients with ipilimumab- exposed melanoma by central independent RECIST and 
oncology review/investigator assessed irRC, respectively. Pembrolizumab monotherapy 
induces an ORR of 39%/43% in patients with ipilimumab-naive melanoma by central 
independent RECIST and oncology review/investigator assessed irRC, respectively. These 
responses are remarkably durable. The preliminary 1-year survival rate for patients, many 
of whom have had multiple therapies, including ipilimumab, who receive pembrolizumab is 
81%. Pembrolizumab monotherapy induces an ORR of 21%/24% in patients with 
previously-treated NSCLC by central independent RECIST/investigator assessed irRC, 
respectively, with these responses also remarkably durable.  Preliminary data suggest 
higher levels of PD-L1 expression in tumors of NSCLC are associated with increased 
activity (ORR 67% by investigator assessed irRC/57% by central independent RECIST); 
additional data are required to define the optimal PD-L1 cut point. 
 
The most commonly reported treatment emergent AEs experienced are fatigue (43.8%), 
nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhea (22.3%) and rash (21.5%). 
Immune-related adverse events were reported in 21.4% of melanoma patients; most of 
these events (15.8%) were considered drug-related by the investigator. The most commonly 
reported, immune-related adverse events across the dose-schedules are rash (3.2%), 
pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), diarrhea (2.2%), 
and pneumonitis (1.9%). Review of the overall benefit:risk ratio of pembrolizumab favors 
enrollment of eligible patients into clinical trials of pembrolizumab. 

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3.3.2.3 Rationale for Dose Selection/Regimen/Modification 
 
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab. The dose escalation portion of that trial evaluated three 
dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects 
with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting 
toxicities were observed. This first in human study of pembrolizumab showed evidence of target 
engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg 
and 10 mg/kg Q2W). No MTD was identified. Recent data from other clinical studies within the 
pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). 
This early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule. 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight norm alized dosing or a fixed 
dose across all body weights. Pembrolizumab has been found to have a wide therapeutic range 
based on the melanoma indication. 
MK-3475 has been found to have a wide therapeutic range based on the melanoma indication. 
The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body 
weight based regimen are anticipated to remain well within the established exposure margins of 
0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose 
regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different indication settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with 

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those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established in 
melanoma that are well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
4.1 
Design 
This will be a Simon two-stage design, phase II study. It will be conducted to determine the 
efficacy and safety of (1) pembrolizumab plus RT in subjects with metastatic CRC who are 
undergoing RT as standard therapy; and, (2) pembrolizumab plus ablation in subjects with 
metastatic CRC who are undergoing ablation as standard therapy. 
4.2 
Intervention 
Patients will be stratified according to eligibility for RT (cohort 1) or ablation (cohort 2). Patients 
in cohort 1 will have at least one locally advanced or metastatic lesion for which palliative RT is 
considered appropriate standard therapy, and at least one other measurable index lesion that 
will not undergo RT. Patients in cohort 2 will have at least one metastatic lesion for which 
palliative ablation is considered appropriate standard therapy, and at least one other 
measurable index lesion that will not undergo ablation. Subjects in cohort 2 will undergo ablation 
of one or more lesions. The ablation method is at the discretion of the interventional radiologist. 
All subjects will undergo ablation or begin RT within 7 days prior to starting pembrolizumab. 
Pembrolizumab dosing may continue during RT. Subjects will receive pembrolizumab via IV 
infusion at 200 mg every three weeks (Q3W), and continue treatment Q3W until progression of 
disease, initiation of alternative cancer therapy, unacceptable toxicity, or other reasons to 
discontinue treatment occur, up to 24 months. Patients who had a prior response without 
another reason to discontinue therapy after 24 months will continue clinic visits, routine blood 
work (CBC, COMP, CEA) and CT/MRI every 9 weeks, and may resume treatment for an 
additional 12 months upon disease progression. Repeat palliative RT in cohort 1, or ablation in 
cohort 2, will be permitted in select cases for the treatment of isolated, non-target lesions. 
Patients will be evaluated by physical exam and routine blood tests every three weeks during 
the study period. CT or MRI will be performed during screening, and then at 9 week intervals. 
Tumor measurements and determination of tumor responses will be performed according to 
RECIST 1.1. 
Subjects may continue to receive pembrolizumab beyond radiographic disease progression in 
the absence of clinical deterioration, and after discussion with the Principal Investigator. 
All subjects will be followed up to 2 years for survival or until the study closes. Exploratory 
research studies to evaluate the effect of this therapy will be performed in patients using 

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research blood draws, and tumor biopsy at baseline, 1 week after completing RT or undergoing 
ablation (from the radiated/ablated lesion), and then 4 weeks after dose #1 of pembrolizumab 
(from a non-radiated/ablated lesion),for research purposes. 
4.3 Estimated Duration of Subject Participation 
Subjects may be treated for up to 24 months, with the option to resume treatment for an 
additional 12 months upon disease progression, unless there is anot her reason to discontinue 
treatment. All subjects will be followed for survival for up to 2 years unless the Principal 
Investigator or Merck decides to end the study. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
5.1 
Cryoablation 
The cryoablation will be performed percutaneously under image guidance as standard therapy 
in accordance with institutional standard practice. 
5.2 
Radiofrequency ablation 
The radiofrequency ablation (RFA) will be performed percutaneously under image guidance as 
standard therapy in accordance with institutional standard practice. 
5.3 
Radiotherapy 
Radiotherapy will be performed using external beam ionizing radiation or by brachytherapy as 
standard therapy in accordance with institutional standard practice. 
5.4 
Pembrolizumab 
Pembrolizumab will be provided by Merck. Pembrolizumab will be prepared and administered 
as per MSKCC guidelines. Please refer to investigator brochure for additional information 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and regulations. 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
6.1 
Subject Inclusion Criteria 
 
1. Be willing and able to provide written informed consent/assent for the trial. 
 
2. Histologically- or cytologically- confirmed CRC. 
3. Metastatic or recurrent CRC. 

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4. Subjects have received two or more standard available therapies known to prolong 
survival and for which they would be considered eligible. Such therapies should include 
regimens containing oxaliplatin and irinotecan in combination with a fluoropyrimidine if 
appropriate (e.g., FOLFOX and FOLFIRI or their variants). 
 
5. At least one tumor for which palliative RT is considered appropriate standard therapy 
(cohort 1); or, at least one tumor for which palliative ablation is considered appropriate 
standard therapy (cohort 2). 
6. At least one index lesion that will not undergo RT or ablation, and which is measurable 
based on RECIST 1.1. 
 
7. Be ≥ 18 years of age on day of signing informed consent. 
 
8. Consent for tumor biopsies and blood draws for research purposes. 
9. Consent for use of available archived tissue for research purposes. 
 
10. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
11. Demonstrate adequate organ function as defined in Table 6.1, all screening labs should 
be performed within 6 weeks of treatment initiation. 
Table 6.1 Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Renal 
Serum creatinine 
OR 
Measured or calculateda creatinine 
clearance (GFR can also be used in 
place of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) 
OR 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant the rapy 
as long as PT or PTT is within therapeutic range of intended 
use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 

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12. Female subject of childbearing potential should have a negative serum pregnancy within 
2 weeks prior to starting radiation therapy or undergoing ablation. 
 
13. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 120 days after the last dose of study medication (Reference Section 
9.5.2). Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year. 
 
14. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
 
6.2 
Subject Exclusion Criteria 
1. Is currently participating in or has participated in a study of an investigational agent or 
using an investigational device within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
4. Has had prior chemotherapy, targeted small molecule therapy within 2 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. 
• 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
5. If subject received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy. 
6. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy. 
7. Has known active central nervous system (CNS) metastases and/or carcinom atous 
meningitis. Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks prior 
to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment. 
8. Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a syndrome 
that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or 
resolved childhood asthma/atopy would be an exception to this rule.  Subjects that 

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require intermittent use of bronchodilators or local steroid injections would not be 
excluded from the study. Subjects with hypothyroidism stable on hormone replacement 
or Sjorgen‟s syndrome will not be excluded from the study. 
9. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
10. Has an active infection requiring systemic therapy. 
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject‟s participation for the 
full duration of the trial, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator. 
12. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic 
T-lymphocyte-associated 
antigen-4 
(CTLA-4) 
antibody 
(including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways). 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
17. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
 
7.0 
RECRUITMENT PLAN 
This study will be available to all patients seen at Memorial Hospital, who meet the eligibility 
criteria outlined in section 6.0. 
Memorial Hospital is a referral center for CRC. In addition, the study may be placed on the 
institutional Website to maximize patient recruitment. Patients will be identified from medical 
oncology clinics for treatment of their disease. 
The investigators take due notice of the NIH policy concerning inclusion of women and minorities 
in clinical research populations. There will be no limitation to access with regard to race or 
gender. Patients will be required to read, agree to, and sign an IRB-approved informed consent 
form prior to registration on this trial. The registration procedure will be conducted as described 
in section 15.0. Patients will not receive payment for their participation on this study. 

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8.0 
PRETREATMENT EVALUATION 
To be completed prior to starting RT or ablation and within 6 weeks of starting pembrolizumab: 
• 
CT scan with contrast (chest, abdomen and pelvis). If patient is unable to receive CT 
contrast, or the abdominal/pelvic target lesion is indeterminate on CT scan then MRI with 
contrast (abdomen and pelvis) plus CT chest without contrast may be perfromed. Non- 
contrast CT CAP may be used if the target lesion(s) do not require contrast for accurate 
measurements. 
• 
12-lead Electrocardiogram (EKG). 
• 
Signed informed consent for study participation. 
• 
History and physical examination, including height, weight, vital signs (temperature, pulse 
rate, respiration rate, blood pressure), and performance status (ECOG). 
• 
Serum pregnancy test for all women of childbearing potential (within two weeks of starting 
RT or ablation). If the test result is positive related to pregnancy, the patient will not be 
allowed to participate in this study. 
• 
CBC with differential and platelet count, serum chemistries (Na, Cl, BUN, Creatinine, K, 
CO2, and glucose), LFTs (AST, ALT, alkaline phosphatase, total bilirubin), calcium, albumin, 
total protein, and CEA 
• 
Serology for HepBsAg, HepBcAb and hepatitis C antibody (negative test acceptable prior to 
screening period) 
• 
Blood test for research purposes. 
• 
Perform baseline tumor biopsy for research purposes at the time of fiducial placement or 
ablation or during a separate procedure. 
9.0 
TREATMENT/INTERVENTION PLAN 
9.1 
Dosing Instructions and Schedule 
 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
n/a 
Experimental 
 
The first day of dosing is considered Day 1. Subjects will receive pembrolizumab as an 
IV infusion. Refer to „MK-3475 Drug Preparation Instructions‟ manual. 

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Trial treatment should be administered on Day 1 of each cycle. 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 will be administered as a 30 minute IV infusion (every effort should be made 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). 
9.2 
Monitoring of Dose Administration 
Subjects will be monitored during and after infusion with assessment of vital signs per 
institutional practice. 
In the event of an infusion-related reaction, refer to See appendix C for guidance. 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit subjects to an intensive care unit if necessary. 
9.3 
Concomitant Medications 
9.3.1 
Permitted Concomitant Medication 
Investigators may prescribe concomitant medications or treatments (e.g., acetaminophen, 
diphenhydramine) deemed necessary to provide adequate prophylactic or supportive care 
except for those medications identified as “excluded” as listed in Section 9.3.2. 
9.3.2 
Excluded Concomitant Medications 
 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
The following medications are considered exclusionary during the study. The Principal 
Investigator must be notified if a subject receives any of these during the study. 
• 
Any investigational anticancer therapy. 
• 
Any concurrent chemotherapy (except as permitted above), immunotherapy, or biologic 
therapy. Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for 
diabetes and hormone replacement therapy) is acceptable. 
• 
Immunosuppressive medications including, but not limited to systemic corticosteroids 
(>10 mg/day prednisone or equivalent), methotrexate, azathioprine, and tumor necrosis 
factor alpha (TNF-α) blockers. Use of immunosuppressive medications for the 
management of investigational product-related AEs, in subjects with contrast allergies is 
acceptable. In addition, use of inhaled and intranasal corticosteroids is permitted. 

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9.4 
Dose Modification 
 
Refer to APPENDIX C for guidance in the event of a drug-related adverse event. 
Pembrolizumab dosing may continue in the event of an unrelated, grade 1 or tolerable grade 2 
adverse event. 
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from trial 
treatment. 
9.4.1 
Supportive Care Guidelines 
 
• 
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of prophylactic 
antiemetic therapy according to standard institutional practice. Subjects should be 
strongly encouraged to maintain liberal oral fluid intake. 
• 
Anti-infectives: Subjects with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 
9.5 Diet/Activity/Other Considerations 
9.5.1 
Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
9.5.2 
Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. Non-pregnant, non- 
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive. Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study. The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of 

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the study and during the follow-up period defined in section 11.1.2 - Pregnancies. If there is any 
question that a subject will not reliably comply with the requirements for contraception, that 
subject should not be entered into the study. 
9.5.3 
Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study. The site will contact the subject at least monthly 
and document the subject‟s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to Merck without delay and within 24 hours if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn). 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 subject impregnates his female partner 
the study personnel at the site must be informed immediately and the pregnancy reported to 
Merck and followed as described above and in Section 11.1.2. 
9.5.4 
Use in Nursing Women 
 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
9.6 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial 
plan is violated, or for administrative and/or other safety reasons. 
A subject must be discontinued from the trial for any of the following reasons: 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• 
Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved. 
• 
Unacceptable adverse experiences 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator‟s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The subject is lost to follow-up 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
25 
 
 
 
 
• 
Completed 24 months of treatment with pembrolizumab 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of additional 
study treatment at the discretion of the PI if they responded during the initial 24 months 
and then progressed after stopping study treatment. 
• 
Administrative reasons 
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events will be collected for 90 days after the end of treatment). 
Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up, for up to 2 years. After documented disease 
progression each subject will be followed by telephone (if not otherwise following up at Memorial 
Hospital) for overall survival until death, withdrawal of consent, the end of the study, or 2 years, 
whichever occurs first. 
9.7 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made. 
9.8 
RESEARCH BLOOD AND BIOPSY SPECIMENS 
9.8.1 Research blood 
 
For all patients, blood specimens will be obtained for research purposes during screening or on 
day 1, then at weeks 3, 6 and 9 (± 3 days). Additional blood draws beyond week 9 are 
permitted based upon interesting clinic/immunological findings. 
Specimens should be collected prior to drug administration. Four (4) tubes of blood are to be 
collected in BD Vacutainer® CPT™ Cell Preparation Tubes with Sodium Heparin. Each tube 
should contain approximately 10 cc of blood. Peripheral blood mononuclear cells and plasma 
will then be isolated per institutional practice in the Immune Monitoring Facility (IMF). 
9.8.2 Research biopsy 
A pre-treatment tumor biopsy will be obtained at the time of ablation or fiducial placement or 
during a separate procedure. On treatment biopsies will be performed 1 week (±3 days) after 
completing RT or undergoing ablation (from the radiated/ ablated lesion), and then 4 weeks (±1 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
26 
 
 
 
 
week) after dose #1 of pembrolizumab (from a non-radiated/ ablated lesion). For patients that 
are unable to have biopsy 4 weeks after dose #1 of pembrolizumab, the procedure may be 
delayed up until Week 9. 
Patients will be permitted to continue enrollment and treatment on protocol in the event that 
insufficient material was obtained from the biopsy. The on treatment biopsy will not be required 
if this is no longer considered appropriate at the time of the planned procedure, for example, if 
the tumor is no longer accessible or the procedure is deemed to be unsafe. Tumor lesion 
planned for on-treatment biopsy may be an index lesion if ≥ 2 cm in at least one diameter. 
If clinically practical, subjects will undergo up to 5 core biopsies. Three core biopsies will be 
placed in formalin and processed for FFPE, 2 core biopsies will be immediately frozen in liquid 
nitrogen and then stored at -80°C (appendix B). All tissue obtained during biopsy procedures 
will be sent to the IMF facility for analysis under this study as indicated below. If the patient 
undergoes a routine procedure, tissue may be obtained for future correlative analyses. Up to 20 
x 5µm slides (unstained) may be obtained from each routine procedure where tissue was 
extracted. Tissue from routine procedures may be sent directly to the IMF facility for immediate 
processing (e.g. isolation of Tumor Infiltrating Lymphocytes). 
9.8.3 
Correlative studies 
Pharmacodynamic changes may be evaluated for associations with clinical activity, and safety 
(adverse event) data. Tissue may be used for correlative studies such as IHC, tumor mutation 
analysis, proteomic analysis, and immunodiversity. PDL-1 immunohistochemistry will be done 
by a Merck designated laboratory. Other assessment will be done at MSKCC. 
9.8.3.1 
Whole Blood 
Flow cytometry will be performed at baseline and during treatment to assess baseline and 
changes in composition/activation status of lymphocyte subsets present in peripheral blood 
mononuclear cell preparations (PBMCs). Lymphocyte subsets to be assayed may include, but 
are not limited to CD8+ and CD4+ T-cell subsets (activated; effector/memory; regulatory) and 
populations of those cells as defined by the expression of activation, exhaustion, or signaling 
markers such as ICOS, HLA-DR, PD-1, CTLA-4, and/or intracellular IFNγ. NK cell populations 
may be monitored in a similar fashion with a focus on characterizing subsets defined by the 
expression of activation markers (e.g. NKG2D; IL-21R) and/or by markers that are associated 
with the potential of NK cells to lyse target cells (e.g., CD107a, granzyme, perforin). Additional 
flow cytometry-based assays will focus on defining and monitoring the abundance of myeloid- 
derived suppressor cells (MDSCs), a cell type which appears to negatively impact anti-tumor 
activity and which has been shown to promote immune escape by limiting activated CD8 T-cell 
infiltration into the tumor microenvironment [17]. Immune cells may be evaluated using HLA-A2- 
restricted tetramer assays to detect and quantify the presence of T cells directed against 
specific antigens which are anticipated to be presented to the immune system due to study 
treatment. Detecting on-treatment increases in these T cell populations may be considered 
evidence of adaptive immune responses in CRC. 
9.8.3.2 Plasma 
To understand the prevalence of circulating proteins and the impact they may have on the 
clinical activity and/or safety of pembrolizumab treatment, the protein concentrations of a panel 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
27 
 
 
 
 
of cytokines, chemokines, and other relevant immunomodulatory, soluble factors may be 
investigated by ELISA and/or other relevant multiplex-based protein assay methods. Examples 
of analytes to be assessed may include but are not limited to factors induced by IFNγ signaling 
(e.g., T cell chemoattractants CXCL9; CXCL10) and other factors generally involved in 
inflammatory processes. Plasma may be used also to assess the presence and/or concentration 
of anti-tumor antibodies using a mulitplex platform such as Invitrogen‟s Protoarray platform(c). 
Levels of sPD-L1 in peripheral blood may also be assessed. 
9.8.3.3 Tissue Biopsies and/or archived tissue 
The presence of TILs within tumors in response to pembrolizumab treatment will be evaluated 
baseline and on-treatment biopsies and, when feasible, tissue acquired from routine 
procedures. Archived tissue (up to 20 x 5 µm slides), tissue acquired from routine procedures 
(up to 20 x 5 µm slides per procedure), and biopsy tissue may be analyzed using 
immunohistochemistry for PD-L1 expression and other immune-related genes, and gene 
expression (microarray and/or RT- QPCR) research platforms. Laser Capture Microdissection 
may be utilized to enrich specific regions of tumor material for use in similar or additional 
downstream applications, which may include in-situ hybridization, flow cytometry, ELISA, and/or 
assessment of miRNA. In all cases, the goal may be to determine the abundance of a battery of 
immunoregulatory genes or proteins associated with cancer cells and/or cancer-interacting 
lymphocytes derived from biopsied material. Other biomarkers may be evaluated as determined 
by additional data. Remaining specimens may be stored for future studies related to CRC 
immunity. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
28 
 
 
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
Study Calendar 
Period 
Screening 
Treatment 
End of 
study 
visit15 
Cycle1 
<6 weeks2 
1 
1 
2 
2 
3 
4 
5 
6 
7+ 
Week 
0 
1 
3 
4 
6 
9 
12 
15 
18+ 
Informed consent 
x 
Medical history 
x 
EKG 
x 
CT/MRI3 
x 
x 
x 
x 
Height4 
x 
Physical examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vital signs/ Performance status 4 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Report medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pulse oximetry 
x 
x 
x 
x 
x 
x 
x 
x 
Report side effects 
x 
x 
x 
x 
x 
x 
x 
CBC5,6 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Comp5,7 
x 
x 
x 
x 
x 
x 
x 
x 
Thyroid function (TSH, fT3,fT4) 
x 
x 
x 
odd 
cycles 
CEA8 
x 
x 
x 
x 
x 
Hepatitis B and C9 
x 
Pregnancy test if female (Serum)10 
x 
Research blood tests 5,11 
x 
x 
x 
x 
Obtain archived tissue 12 
x 
Research tumor biopsy 13 
x 
x 
x 
RT (Cohort 1) 14 
x 
Ablation (Cohort 2) 14 
x 
Pembrolizumab 
x 
x 
x 
x 
x 
x 
x 
1. 
Each cycle is approximately 3 weeks in duration, corresponds to 1 completed treatment. 
2. 
Procedures must be performed within 6 weeks prior to dose 1 of Pembrolizumab on Day 1. 
3. 
CT or MRI will be performed during screening, then at 9 week (±1 wk) intervals and at final visit if more than 4 
weeks from prior imaging. If patient is unable to receive CT contrast or the abdominal/ pelvic target lesion is 
indeterminate on CT then MRI with contrast (abdomen and pelvis) plus CT without contrast (chest) may be 
performed. Imaging may be delayed up to 2 weeks if patient is receiving additional RT or ablation. 
4. 
Vital signs to include heart rate, respiratory rate, blood pressure, and weight. 
5. 
Blood to be collected prior to dosing any study medications. 
6. 
Hematology to include standard complete blood cell (CBC) panel. 
7. 
Comprehensive metabolic panel included sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, 
total protein, albumin, bilirubin, alkaline phosphatase, AST, ALT, calcium. 
8. 
CEA to be obtained during screening, day 1 and then within two weeks (or on day) of subsequent imaging. 
9. 
Serology for HepBsAg, HepBcAb and hepatitis C antibody (unless previously tested negative). 
10. Serum pregnancy test is required within 2 weeks of starting radiation or ablation 
11. Blood draws for research purposes performed during screening or day 1, then weeks 3, 6 and 9 for all patients. 
Additional blood draws beyond week 9 are permitted based upon interesting clinic/immunological findings for all 
patients. 

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IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
29 
 
 
 
 
 
12. Up to 20 x 5µm slides (unstained) of archived tissue will be requested on all patients for research purposes. For 
patients undergoing routine procedures during the study, additional tissue (up to 20 x 5µm slides (unstained)) 
may be obtained from each routine procedure. for research purposes. 
13. Research tumor biopsy will be performed during fiducal placement or ablation or during a separate procedure, 
then 1 week (±3 days) after completing RT or ablation (from the radiated/ablated lesion) and 4 weeks 
after dose #1 of pembrolizumab (±1 week) from a non-ablated/radiated lesion. For patients that are unable to 
have biopsy 4 weeks after dose #1 of pembrolizumab, the procedure may be delayed up until Week 9. 
14. RT begins or ablation is performed during cycle 1, within one week prior to dose 1 of Pembrolizumab. 
15. EOS visit occurs 4(±1 wk) weeks after last dose of pembrolizumab. CT scan or MRI to be done only if last 
imaging was conducted greater than four weeks prior to the date of the Final Visit. 
11.0 
TOXICITIES/SIDE EFFECTS 
The most commonly reported treatment emergent AEs related to pembrolizumab are fatigue 
(43.8%), nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhea (22.3%) and rash 
(21.5%).  Immune-related adverse events were reported in 21.4% of melanoma patients; 
most of these events (15.8%) were considered drug-related by the investigator. The most 
commonly reported, immune-related adverse events across the dose-schedules are rash 
(3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), diarrhea 
(2.2%), and pneumonitis (1.9%). 
 
11.1 
SAFETY MONITORING 
Subjects will be evaluated for occurrence of AEs at each visit. Events will be characterized and 
reported as described below. Safety will also be monitored by performing physical exams and 
routine laboratory procedures. 
11.1.1 
Adverse Events and Serious Adverse Events 
Definitions of AEs, non-serious AE, and serious adverse events (SAEs) are provided in this 
section. Additionally, provided in the sections below are reporting guidelines for any AE or SAE 
occurring during this study. 
Definition of Adverse Event and Non-Serious Adverse Event 
The following definition of AE will be used for the study: “Any untoward medical occurrence in a 
subject or clinical investigation subject administered a pharmaceutical product and which does 
not necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to medicinal (investigational) product.” 
This definition includes any abnormalities or anomalies that were not seen at baseline or which 
worsened during the course of the study, if present at baseline. 
A “non-serious” adverse event is any event that does not meet the definition of “serious adverse 
event” as presented, below. 
Reporting and Treating Non-Serious Events 
It is the responsibility of the investigator to perform regular assessments for AEs. Subjects will 
be regularly queried about the occurrence of any AEs and will be monitored throughout the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
30 
 
 
 
 
study for reactions to study drug and/or study procedures. The investigator and clinical staff will 
record all AEs, whether volunteered by or elicited from the subject, at any time during a 
subject‟s participation in the study. Abnormal laboratory findings (e.g., hematology, 
comprehensive metabolic panel) or other abnormal assessments (e.g., vital signs) will be 
recorded as AEs if they are judged as clinically significant by the investigator. 
All subjects experiencing an AE will be evaluated by the investigator and monitored until 
resolution of the events or until the investigator deems the event clinically stable and/or at an 
acceptable level. Unless the event requires hospitalization (SAE), medical treatment will be 
provided to the subjects at the unit and treatment medication and/or medical procedures will be 
provided per the treating-investigator‟s clinical discretion. All clinically significant AEs, including 
clinically significant laboratory abnormalities, will be followed until resolution. AEs meeting the 
definition of SAEs require special reporting in addition to documentation in the CRDB as 
described below. 
All AEs, including clinically significant laboratory and assessment abnormalities will be recorded 
according to “Common Terminology Criteria for Adverse Events” V4.0 (CTCAE) and must be 
recorded in the CRDB. Events occurring prior to initiation of first dose should be recorded on 
the Medical History page of the CRDB. Any AE occurring after initiation of first dose of study 
drug should be recorded on the Adverse Event page of the CRDB. AEs should be recorded in 
the CRDB using the medical terminology found in the source documentation. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology. 
It is the investigator‟s responsibility to provide his/her assessment of the relationship of the 
event to the study drug and the severity of the event using the following scales: 
• 
Relationship 
 Unrelated: The AE is clearly attributable to a concurrent illness, concurrent medication, 
clinical state, or environmental factor other than the investigative agent. 
 Unlikely: The occurrence of the AE does not follow the study in a temporal sequence and/or 
based upon available subject information, e.g., medical history, disease process, known 
pharmacology of drug, a relationship between the drug and AE is unlikely. 
 Possible: The AE follows a reasonable temporal sequence from the time of study drug 
administration, but it is possible that other factors; e.g., subject‟s clinical state or concomitant 
mediations, environmental factors, or the drug‟s pharmacology may have caused the AE. 
 Probable: The AE follows a reasonable temporal sequence from the time of study drug 
administration, follows a known response pattern of the medication class, and cannot be 
reasonably explained by other factors. 
• 
Severity 
The severity of all adverse events should be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) V4.0. For those adverse events not listed in the CTCAE, 
the following grading system should be employed: 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
31 
 
 
 
 
 Mild (CTCAE Grade 1): Transient symptoms, awareness of sign/symptom, but easily 
tolerated and no interference with subject‟s daily activities 
 Moderate (CTCAE Grade 2): Marked signs/symptoms that interfere with subject‟s usual 
activities, but still acceptable 
 Severe (CTCAE Grade 3): Incapacitating signs/symptoms which cause considerable 
interference with the subject‟s daily activities, unacceptable 
 Life-threatening (CTCAE Grade 4): Life-threatening of disabling AE 
 Death (CTCAE Grade 5): Death-related AE. See CTCAE Guidelines for assigning Grade 5. 
 
Definition of Serious Adverse Event 
The following definition of SAE applies for the study: “A serious AE means any AE occurring at 
any dose that results in any of the following outcomes: death, a life-threatening AE, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, a congenital anomaly/birth defect, or overdose of study drug. Important 
medical events that may not result in death, be life threatening, or require hospitalization may be 
considered a serious AE when, based upon appropriate medical judgment, they may jeopardize 
the subject or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. A life-threatening AE is any AE that places the subject or 
subject, in the view of the investigator, at immediate risk of death from the reaction as it 
occurred (e.g., it does not include a reaction that, had it occurred in a more severe form, might 
have caused death).” Reporting and Treating Serious Adverse Events as per section 17.2. 
Pregnancies 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 5 calendar days to the MSKCC Safety Office and within 2 
working days to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
11.1.3 
Other Events of Special Interest 
Hepatic Function Abnormality 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
32 
 
 
 
 
 
Hepatic function abnormality is defined as any increase in ALT or AST to greater than 3 × ULN 
and concurrent increase in bilirubin to greater than 2 × ULN. Concurrent findings are those that 
derive from a single blood draw or from separate blood draws taken within 8 days of each other. 
Follow-up investigations and inquiries will be initiated promptly by the investigational site to 
determine whether the findings are reproducible and/or whether there is objective evidence that 
clearly supports causation by a disease (e.g., cholelithiasis and bile duct obstruction with 
distended gallbladder) or an agent other than the investigational product. 
Events of hepatic function abnormality (as defined above) should be recorded according to the 
definitions of AE and SAE: 
• 
If an event of hepatic function abnormality is considered to be related to a pre-existing 
condition and does not represent a worsening of this condition and/or is considered to be 
within the range of normal physiological fluctuation for the subject, the event does not meet 
the definition of an AE and does not need to be recorded as such. 
• 
If a definitive diagnosis for an underlying condition unrelated to the investigational product is 
established for an event of hepatic function abnormality, the diagnosis should be recorded 
as an AE/SAE. 
• 
If no definitive diagnosis is determined for an event of hepatic function abnormality, the term 
“hepatic function abnormal” should be used to report the AE/SAE. 
Definition of an Overdose for This Protocol and Reporting of Overdose to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by 20% over the prescribed dose. No specific information is available 
on the treatment of overdose of pembrolizumab. In the event of overdose, subject should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. Pembrolizumab does not need to be discontinued in case of overdose, but it 
does need to be reported. 
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 5 calendar 
days to the MSKCC Safety Office and within 2 working days to Merck Global Safety . (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
33 
 
 
 
 
For the purposes of this study, patients will be evaluated for response every 3 cycles 
(approximately 9 weeks), or as clincially indicated if interim toxicity occurs mandating cancer 
staging re-assessment. RECIST 1.1 criteria will be used. 
CT scan with contrast of the chest, abdomen, and pelvis 
• 
CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. 
Spiral CT should be performed using a 5-mm contiguous reconstruction algorithm. 
MRI scans 
• 
MRI of the abdomen and pelvis is acceptable for measurement of lesions provided that 
the same anatomical plane is used for serial assessments. If possible, the same imaging 
device should be used for serial evaluations. In case of MRI, measurements will be 
preferably performed in the axial (transverse) plane on contrast-enhanced T1-weighted 
images. However, there are no specific sequence recommendations. 
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows: 
• 
Measurable Lesions - Must be accurately measured in at least one dimension (longest 
diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double 
the slice thickness and a minimum of 10 mm) 
• 
10 mm caliper measurement by clinical exam (when superficial) 
• 
Malignant lymph nodes are considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). 
• 
Nonmeasurable Lesions - Nonmeasurable lesions are defined as all other lesions (or 
sites of disease), including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis). Lesions considered truly nonmeasurable 
include the following: leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
• 
Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 2 
lesions per organ) representative of all involved organs should be identified as target 
lesions. It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
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34 
 
 
 
 
• 
Non-target Lesions - It is possible to record multiple nontarget lesions involving the 
same organ as a single item on the case record form (e.g., “multiple enlarged pelvic 
lymph nodes” or “multiple liver metastases”) 
Response 
Criteria 
Evaluation of Target Lesions 
• 
Complete Response - Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm (the 
sum may not be “0” if there are target nodes). 
• 
Partial Response - At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
• 
Progressive Disease - At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new lesions is also considered progression.) 
• 
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
Evaluation of Non-target Lesions 
• 
Complete Response - Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
• 
Non-complete response/Non-progressive disease - Persistence of 1 or more non- 
target lesion(s) and/or maintenance of tumor marker level above the normal limits. 
• 
Progressive Disease - Unequivocal progression of existing non-target lesions will be 
defined as the overall level of substantial worsening in non-target disease such that, 
even in presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. In the absence of measurable disease, 
change in non-measurable disease comparable in magnitude to the increase that would 
be required to declare PD for measurable disease. Examples include an increase in a 
pleural effusion from „trace‟ to „large,‟ an increase in lymphangitic disease from localized 
to widespread. 
Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. 
Considering the unique response kinetics that have been observed with immunotherapy, new 
lesions may not represent true disease progression. In the absence of rapid clinic al 
deterioration, subjects may continue to receive treatment with pembrolizumab. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
35 
 
 
 
 
Evaluation of Overall Response 
Table 12 provides overall responses for all possible combinations of tumor responses in target 
and non-target lesions with or without the appearance of new lesions. 
 
Table 12 
Evaluation of Overall Response 
 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete response 
Complete response 
No 
Complete response 
Complete response 
Not evaluable 
No 
Partial response 
Complete response 
Non-complete response / 
non-progressive disease 
No 
Partial response 
Partial response 
Non-progressive disease and 
not evaluable a 
No 
Partial response 
Stable disease 
Non-progressive disease and 
not evaluable a 
No 
Stable disease 
Not all evaluated 
Non-progressive disease 
No 
Not evaluable 
Progressive disease 
Any 
Yes/No 
Progressive disease 
Any 
Progressive disease 
Yes/No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
a Not evaluable is defined as either when no or only a subset of lesion measurements are made at an assessment. 
 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
In the absence of serious toxicity or complications, all patients will continue treatment for up to 2 
years. In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
• 
Disease progression (unless the patient continues treatment beyond progression). 
• 
Development of an intercurrent medical condition or need for concomitant treatment that 
precludes further participation in the trial. 
• 
Unacceptable toxicity or any adverse event that precludes further participation in the 
trial. 
• 
The investigator removes the patient from the trial in the best interests of the patient. 
• 
Patient death. 
• 
Study completion or discontinuation for any reason. 
• 
Patient withdraws consent to continued participation in the trial or is lost to follow up. 
 
Subjects who are permanently discontinued from receiving investigational product will return for 
end of study visit, unless consent is withdrawn, the subject is lost to follow-up or begins another 
treatment. All subjects will be followed for survival every 3 months for up to 2 years. If not 
otherwise following up at Memorial Hospital, patient‟s will be contacted by phone for survival 
follow up. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
36 
 
 
 
 
If consent is withdrawn, the subject will not receive any further investigational product or further 
study observation. 
 
14.0 
BIOSTATISTICS 
 
The primary endpoint of this trial is the response rate in CRC treated with RT plus 
pembrolizumab (cohort 1) or ablation plus pembrolizumab (cohort 2). No response is expected 
in a non-radiated or non-ablated lesion with these current therapies and we consider a response 
rate ≤5% as unacceptable. A two-stage Simon‟s optimal design will be employed to test the null 
hypothesis that the true response rate is ≤5% versus the alternative hypothesis that the true 
response rate is at least 25% with type I and II error rates of 10% each. Each cohort will be 
evaluated separately for this purpose. In the first stage, we will accrue 9 patients in each 
cohort. If 0 objective tumor responses (PR or CR) are observed among the 9 subjects treated in 
a cohort, then subject enrollment will be terminated in that cohort. If at least 1 response is 
observed among the 9 subjects treated in a cohort, then the study will be expanded to enroll a 
total of 24 treated subjects in that cohort. At the end of the study, if 2 or less objective tumor 
responses are observed in a cohort, then the study will be considered not worthy of further 
investigation in that particular cohort. If at the end of the study ≥3 tumor responses per RECIST 
1.1 are observed in a cohort, then further investigation of pembrolizumab plus RT and/or 
pembrolizumab plus ablation will be considered worthwhile. 
Secondary outcomes, including toxicity, the additional measures of efficacy and exploratory 
objectives will be summarized by cohort. 
The study will complete when all subjects have either progressed or discontinued from the study 
for other reasons. This study requires accrual of a minimum of 18 subjects and up to a 
maximum of 48 subjects if both cohorts are expanded to the second stage. The accrual time is 
estimated to be 9 months to 2 years for both cohorts. 
Antitumor Activity 
 
Assessments of antitumor activity will be based on the ORR, PFS, and OS. Response 
Evaluation Criteria in Solid Tumors guidelines (v1.1) [18] with modifications to account for the 
unique response patterns observed with immunotherapy will be used to determine tumor 
response. 
The ORR is defined as the proportion of subjects CR or PR based on RECIST criteria. The 
exact 95% CI of ORR will be estimated using the binomial distribution. Progression-free survival 
will be measured from the start of treatment with pembrolizumab until the documentation of 
disease progression or death due to any cause, whichever occurs first. Progression-free 
survival will be censored on the date of last tumor assessment documenting absence of tumor 
progression for subjects who are still alive prior to data cutoff, dropout, or the initiation of 
alternate anticancer treatment. Subjects having no tumor assessments after the start of 
treatment with pembrolizumab will have PFS censored on the first date of treatment with 
pembrolizumab. Progression-free survival will be evaluated using the Kaplan-Meier method 
(Kaplan and Meier, 1958). Overall survival will be determined as the time from the start of 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
37 
 
 
 
 
treatment with pembrolizumab until death. For subjects who are alive at the end of study or lost 
to follow-up, OS will be censored on the last date when subjects are known to be alive. The OS 
will be evaluated using the Kaplan-Meier method. 
Safety and Tolerability Analyses 
All recorded adverse events will be listed and tabulated by system organ class, preferred term 
and treatment. Any significant vital signs and clinical laboratory test results will be listed and 
summarized. Any significant physical examination findings, and clinical laboratory results will be 
listed. 
Biomarker Analysis 
 
Exploratory research studies will be done to evaluate the effect of this therapy will be performed 
using research blood draws and tumor biopsies at baseline, 1 week after completing RT or 
undergoing ablation (from the radiated/ablated lesion), and then 4 weeks after dose #1 of 
pembrolizumab (from a non-radiated/ablated lesion). 
The pharmacodynamic effect of pembrolizumab and RT or ablation on Tumor Infiltrating 
Lymphocytes (TILs), such as CD4+ and CD8+ T-cells, and expression of tumor markers, such 
as PD-L1, will be assessed by summary statistics, and investigated graphically to explore 
patterns of change from pre-treatment to post-treatment specimens. 
 
The pharmacodynamic effect of pembrolizumab and RT or ablation on markers in peripheral 
blood, such as ICOS, HLA-DR, PD-1, CTLA-4; and, serum proteins, such as CXCL9; CXCL10, 
will be assessed by summary statistics, and investigated graphically to explore patterns of 
change over time, i.e.: pretreatment, then week 3, and week 9. 
In addition, the relationship of TIL changes and tumor marker expression with measures of 
peripheral blood markers will be summarized descriptively. 
 
Associations between the markers and response by RECIST will be explored. 
 
Fisher‟s exact test will be employed to assess associations between categorical variables while 
Spearman's rank correlation will be used for continuous variables. Wilcoxon signed rank test will 
be used to test for differences in continuous expression tumor markers between pre- and post- 
treatment specimens while McNemar‟s test will be used to assess these relationships for binary 
markers. Fisher‟s exact test will be employed to assess associations between categorical 
variables. 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
38 
 
 
 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the 
PPR Electronic Registration System (http://ppr/). The completed signature page of the 
written consent/RA or verbal script/RA, a completed Eligibility Checklist and other 
relevant documents must be uploaded via the PPR Electronic Registration System. 
15.2 
Randomization 
 
n/a 
16.0 
DAT A M ANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of 
the RSA include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate the 
activities of the protocol study team. 
The data collected for this study will be entered into a secured database (Clinical 
Research Database, CRDB) at Memorial Sloan-Kettering Cancer Center. Source 
documentation will be available to support the computerized patient record. 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and 
completeness of registration data. Routine data quality reports will be generated to 
assess missing data and inconsistencies. Accrual rates and extent and accuracy of 
evaluations and follow-up will be monitored periodically throughout the study period and 
potential problems will be brought to the attention of the study team for discussion and 
action. Random-sample data quality and protocol compliance audits may be conducted 
by the study team, at a minimum of two times per year, more frequently if indicated. 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer 
Center were approved by the National Cancer Institute in September 2001. The plans 
address the new policies set forth by the NCI in the document entitled “Policy of the 
National Cancer Institute for Data and Safety Monitoring of Clinical Trials”, which can be 
found at http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC DSM Plans 
can 
be 
found 
on 
the 
MSKCC 
Intranet 
at 
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359689/Data_safety%20Mon 
itoring07.pdf 
17.0 
PROTECTION OF HUMAN SUBJECTS 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
39 
 
 
 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of 
informed consent, which must conform to IRB guidelines. 
Inclusion of Women and Minorities: Memorial Sloan-Kettering Cancer Center has filed 
forms HHS 441 (civil rights), HHS (handicapped individual), 639-A (sex discrimination), 
and 680 (age discrimination); we also take due notice of the NIH policy concerning 
inclusion of women and minorities in clinical research populations. Patients of all races, 
both male and female, will be accepted into the protocol. The proposed study population 
is as described in section 7.0. 
Exclusion of Lactating or Pregnant Women: Children have been excluded from this 
study. Colorectal adenocarcinoma is an adult cancer. Thus, the relevance of these drug 
to the pediatric population has not been established. Lactating and pregnant women are 
also excluded because of potential anti-proliferative effects of chemotherapy that may be 
harmful to the developing fetus or nursing infant. 
Benefits: It is possible that this treatment will result in shrinkage of colorectal cancer or in 
a stabilization of an otherwise progressing disease. It is not known, of course, whether 
these or any other favorable events will occur. It is not known whether this treatment will 
affect the overall survival of the patients. 
Costs: The patient will be responsible for the costs of standard medical care, including, 
CT scans, all drug administration fees and all hospitalizations, even for complications of 
treatment. Pembrolizumab will be supplied to patients by Merck at no cost. Patients will 
not be responsible for the costs of blood procurement obtained for research purposes , 
the cost of special testing of any tissue for research purposes, or the cost for obtaining 
the tumor biopsy for research purposes. 
Incentives: No incentives will be offered to patients/subjects for participation in the 
study. 
Alternatives: Patients may be eligible for other investigational studies, or focus on 
palliative care options. 
Confidentiality: Every effort will be made to maintain patient confidentiality. Research 
and hospital records are confidential. Patient‟s name or any other personally identifying 
information will not be used in reports or publications resulting from this study. The Food 
and Drug Administration or other authorized agencies (e.g., qualified monitors) may 
review patients records and pathology slides, as required. 
17.1 
Privacy 
 
MSKCC‟s Privacy Office may allow the use and disclosure of protected health 
information pursuant to a completed and signed Research Authorization form. The use 
and disclosure of protected health information will be limited to the individuals described 
in the Research Authorization form. A Research Authorization form must be completed 
by the Principal Investigator and approved by the IRB and Privacy Board (IRB/PB). 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
40 
 
 
 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 
calendar days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report 
be submitted electronically to the SAE Office at sae@mskcc.org. The report should 
contain the following information: 
Fields populated from CRDB: 
• 
Subject‟s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject‟s condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent 
form. 
The PI‟s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: The CRDB AE report should be completed as above and the 
FDA assigned IND/IDE number written at the top of the report. If appropriate, the report 
will be forwarded to the FDA by the SAE staff through the IND Office. 
17.2.1 Any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause other than progression of the cancer under study that occurs to 
any subject from the time the consent is signed through 90 days following cessation of 
treatment, or the initiation of new anti-cancer therapy, whichever is earlier, whether or 
not related to Merck product, must be reported within 5 calendar days to the MSKCC 
Safety Office and within 2 working days to Merck Global Safety unless specified in the 
ECI reporting guidance (APPENDIX C). 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
41 
 
 
 
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the 
Merck Global Safety facsimile number: +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by 
FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or 
other local regulators. Investigators will cross reference this submission according to 
local regulations to the Merck Investigational Compound Number (IND, CSA, etc.) at the 
time of submission. Additionally investigators will submit a copy of these reports to 
Merck & Co., Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) at the time of 
submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) (see APPENDIX C) and must be recorded as such on the Adverse Event 
case report forms/worksheets and reported within 5 calendar days to the MSKCC Safety 
Office and to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
according to the ECI reporting guidance (APPENDIX C). 
Events of clinical interest for this trial include: 
1. 
an overdose of Merck product, as defined in Section 11.1.3 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing. 
**Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
3. In the event a subject develops any of the following AEs, a detailed narrative of the 
event should be reported as an ECI to the Sponsor within 5 calendar days to the 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
42 
 
 
 
 
MSKCC Safety Office and to Merck Global Safety according to the ECI reporting 
guidance (APPENDIX C): 
a. Grade ≥ 3 diarrhea 
b. Grade ≥ 3 colitis 
c. Grade ≥ 2 pneumonitis 
d. Grade ≥ 3 hypo- or hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.” This document provides 
guidance regarding identification, evaluation and management of ECIs and irAEs. 
Additional ECIs are identified in this guidance document and also need to be reported to 
the Sponsor within 5 calendar days to the MSKCC Safety Office and to Merck Global 
Safety according to the ECI reporting guidance (APPENDIX C). 
Subjects should be assessed for possible ECIs prior to each dose. Lab results should 
be evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event. Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes. If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes. If no other cause is found, then it is 
assumed to be immune-related. 
ECIs that occur in any subject from the date of first dose through 90 days following 
cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the Merck‟s product, must be reported within 5 calendar days to 
the MSKCC Safety Office and to Merck Global Safety according to the ECI reporting 
guidance (APPENDIX C). 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 
meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
43 
 
 
 
 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
19.0 
REFERENCES 
 
1. 
Ferlay, J., et al., Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. 
Int J Cancer, 2010. 127(12): p. 2893-917. 
2. 
American Cancer Society. Cancer Facts and Figures 2011. 
3. 
Meyerhardt, J.A. and R.J. Mayer, Systemic therapy for colorectal cancer. N Engl J Med, 
2005. 352(5): p. 476-87. 
4. 
Chung, K.Y., et al., Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 
4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal 
cancer. J Clin Oncol, 2010. 28(21): p. 3485-90. 
5. 
Lipson, E.J., et al., Durable Cancer Regression Off-Treatment and Effective Reinduction 
Therapy with an Anti-PD-1 Antibody. Clin Cancer Res, 2013. 19(2): p. 462-8. 
6. 
Brahmer, J.R., et al., Phase I study of single-agent anti-programmed death-1 (MDX- 
1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and 
immunologic correlates. J Clin Oncol, 2010. 28(19): p. 3167-75. 
7. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
8. 
Waitz, R., M. Fasso, and J.P. Allison, CTLA-4 blockade synergizes with cryoablation to 
mediate tumor rejection. Oncoimmunology, 2012. 1(4): p. 544-546. 
9. 
Levy, M.Y., et al., Cyclophosphamide unmasks an antimetastatic effect of local tumor 
cryoablation. J Pharmacol Exp Ther, 2009. 330(2): p. 596-601. 
10. 
den Brok, M.H., et al., In situ tumor ablation creates an antigen source for the generation 
of antitumor immunity. Cancer Res, 2004. 64(11): p. 4024-9. 
11. 
Deng, L., et al., Irradiation and anti-PD-L1 treatment synergistically promote antitumor 
immunity in mice. J Clin Invest, 2014. 124(2): p. 687-95. 
12. 
Postow, M.A., et al., Immunologic correlates of the abscopal effect in a patient with 
melanoma. N Engl J Med, 2012. 366(10): p. 925-31. 
13. 
Sharpe, A.H. and G.J. Freeman, The B7-CD28 superfamily. Nat Rev Immunol, 2002. 
2(2): p. 116-26. 
14. 
Dong, H., et al., Tumor-associated B7-H1 promotes T-cell apoptosis: a potential 
mechanism of immune evasion. Nat Med, 2002. 8(8): p. 793-800. 
15. 
Brown, J.A., et al., Blockade of programmed death-1 ligands on dendritic cells enhances 
T cell activation and cytokine production. J Immunol, 2003. 170(3): p. 1257-66. 
16. 
Francisco, L.M., P.T. Sage, and A.H. Sharpe, The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev, 2010. 236: p. 219-42. 
17. 
Lesokhin, A.M., et al., Monocytic CCR2(+) myeloid-derived suppressor cells promote 
immune escape by limiting activated CD8 T-cell infiltration into the tumor 
microenvironment. Cancer Res, 2012. 72(4): p. 876-86. 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
44 
 
 
 
 
18. 
Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47. 
20.0 
APPENDICES 
 
APPENDIX A: 
Requisition For Blood Specimens 
APPENDIX B: 
Requisition For Biopsy Specimens 
APPENDIX C: 
PEMBROLIZUMAB PROGRAM (MK-3475) EVENT OF CLINICAL 
INTEREST GUIDANCE DOCUMENT, Version 5.0 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
45 
 
 
 
 
APPENDIX A: REQUISITION FOR BLOOD SPECIMENS 
Single Arm Phase II Study to Assess the Efficacy of Pembrolizumab Plus Radiotherapy 
or Ablation in Metastatic Colorectal Cancer Patients 
A) Section A: Patient information 
(To be completed by RSA) 
Patient initials:  
  
Patient study ID#:  
 
Site:  
 
B) Section B: Sample information 
(To be checked off by RSA) 
4 CPT tubes (10 cc) will be collected at the 
following time points 
[ ]Baseline 
[ ]Week 3 
[ ]Week 6 
[ ]Week 9 
[ ]Week  
 
C) Section C: Sample Collection information 
(To be completed by phlebotomy) 
Drawn By: 
 
Date/ Time: 
  
Sample Collection Instructions: 
1. Gently invert all tubes 8-10 times at room 
temperature immediately after collection 
2. Write patient initials, date, and time of 
collection on each tube 
3. Place all collected tubes in biohazard ziplock 
bag 
4. Send all specimens at room temperature via 
Stat Messengers to  
 
D) Section D: Sample Processing information 
(To be completed by laboratory personnel) 
Lab ID#:  
 
Received by:  
 
Date/Time:  
 
E) Section E: Sample shipping information 
(To be completed by laboratory personnel) 
Sent by:  
 
Date/Time:  
  
Received by:  
 
Date/Time:  
  
Sample shipping Instructions 
Ship samples on dry ice to: 
Dr. Jianda Yuan 
Memorial Sloan-Kettering Cancer Center 
Zuckerman Research Building 
425 East 66th street, Z1545 
New York, NY 10065 

Memorial Sloan Kettering Cancer Center 
IRB Number: 15-069 A(5) 
Approval date: 04-Apr-2018 
46 
 
 
 
 
APPENDIX B: REQUISITION FOR BIOPSY SPECIMENS OR LEFT OVER TISSUE 
OBTAINED DURING A ROUTINE PROCEDURE 
Single Arm Phase II Study to Assess the Efficacy of Pembrolizumab Plus Radiotherapy 
or Ablation in Metastatic Colorectal Cancer Patients 
A) Section A: Patient information 
(To be completed by RSA) 
Patient initials:  
  
Patient study ID#:  
 
Site:  
  
B) Section B: Sample information 
(To be checked off by RSA) 
[ ] Baseline: 5 Core Biopsies 
[ ] Week 1: 
 5 Core Biopsies 
[ ] Week 4: 
 5 Core Biopsies 
[ ] Routine Procedure: 5 Cores or divided tumor 
C) Section C: Sample Collection information 
(To be completed by physician or designee) 
Obtained By: 
 
Procedure:  
 
Date/ Time: 
 
Sample Collection Instructions: 
1. Cores # 1, 2, 5: Place into formalin (3-5 cc) 
2. Cores # 3, 4: Place in sterile Nunc tube and snap 
freeze in liquid nitrogen 
3. Core #  : Place in RPMI (5 cc) 
[If tissue remains, collect/ process as for core #5] 
D) Section D: Storage/Processing information 
(To be completed by laboratory personnel) 
Lab ID#:  
 
Received by:  
 
Date/Time:  
  
Sample Storage/ Processing Instructions 
1. Cores # 1, 2, 5: Store at 4-8oC 
2. Cores # 3, 4: Store at -70 to -80oC 
3. Core # 
: Process immediately for isolation of 
tumor infiltrating lymphocytes. 
E) Section E: Sample shipping information 
(To be completed by laboratory personnel) 
Sent by:  
 
Date/Time:  
  
Received by:  
 
Date/Time:  
  
Sample shipping Instructions 
Ship samples 1, 2, and 5 at room temperature; 
samples 3 and 4 on dry ice, attention: 
Dr. Jianda Yuan 
Memorial Sloan-Kettering Cancer Center 
Zuckerman Research Building 
425 East 66th street, Z1545 
New York, NY 10065