Clinical trial NCT02971956
Conditions: Esophageal Cancer Squamous Cell Esophagus Cancer Adenocarcinoma Esophagus
Keywords: Esophageal Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2017-01-18; Completion date: 2020-05-13
Enrollment: 49 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a targeted therapy as a possible treatment for advanced esophageal cancer.

The study intervention involved in this study is:

-Pembrolizumab

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for the participant specific disease but it has been approved for other uses.

Pembrolizumab, also known as KEYTRUDA or MK-3475, is approved in the USA and several other countries to treat other types of diseases.

The goal of this research study is to

-Evaluate the safety and efficacy of pembrolizumab in participants with advanced esophageal cancer that have not responded to standard treatment.

Arms: arm 1: Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Immune checkpoint inhibitor

Protocol documents:
Prot_SAP_000.pdf: 
Status Page 
 
 
 
PROTOCOL 16-293 
 
 
 
 
  
Closed to New Accrual  
 
 
 
 
 
 
 
 
 
 
 
Closure Effective Date: 10/11/2018 
No new subjects may be enrolled in the study as described above.  
Any questions regarding this closure should be directed to the 
study’s Principal Investigator 
 
 
 
 


DF/HCC Protocol #: 16-293 
Protocol Version Date: 02/26/2019 
 
 
1 
 
 
NCI Protocol #:  NCT02971956 
 
DF/HCC Protocol #: 16-293 
 
 
TITLE:  A Phase II Study of Pembrolizumab in Refractory Advanced Esophageal Cancer 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Center 
 
Principal Investigator (PI): 
Peter C. Enzinger MD 
 
Dana-Farber Cancer Institute 
 
Peter_Enzinger@dfci.harvard.edu 
 
Other Investigators: 
 
Justin Gainor, MD 
 
Massachusetts General Hospital 
 
JGainor@partners.org 
 
 
Eirini Pectasides, MD 
 
Beth Israel Deaconess Medical Center 
 
epectasi@bidmc.harvard.edu 
 
 
Statistician:  
Hui Zheng, PhD 
 
Massachusetts General Hospital 
 
HZheng1@partners.org 
 
Study Coordinator: 
Bridget Fitzpatrick  
 
Dana-Farber Cancer Institute 
 
Bridget_Fitzpatrick@dfci.harvard.edu 
 
 
 
 
Agent(s): Pembrolizumab (MK-3475) (NSC 776864) 
 
 
 
IND #:  130810 
IND Sponsor:  Peter Enzinger, MD 
 
 
 
Protocol Version Date: 02/26/2019 
 


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2 
 
 
Registration 
 
Eligibility 
Screening and 
Pretreatment 
Biopsy 
SCHEMA 
 
 
 
 
      
 
Pembrolizumab 
every 3 weeks 
(one cycle = 3 
weeks) 
 
Mandatory 
Biopsy at 56 
Days (20 
patients) 
 
Continue 
Treatment until 
Progression 
 


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TABLE OF CONTENTS 
1. 
TRIAL DESIGN .................................................................................................................. 5 
1.1 
Trial Design ............................................................................................................. 5 
2. 
OBJECTIVE(S) & HYPOTHESIS(ES) .............................................................................. 5 
2.1 
Primary Objective(s) & Hypothesis(es) .................................................................. 5 
2.2 
Secondary Objective(s) & Hypothesis(es) .............................................................. 5 
2.3 
Exploratory Objective ............................................................................................. 6 
3. 
BACKGROUND & RATIONALE ..................................................................................... 6 
3.1 
Background ............................................................................................................. 6 
3.2 
Pharmaceutical and Therapeutic Background ......................................................... 7 
3.3 
Rationale .................................................................................................................. 8 
4. 
PARTICIPANT SELECTION .......................................................................................... 11 
4.1 
Eligibility Criteria .................................................................................................. 11 
4.2 
Subject Exclusion Criteria ..................................................................................... 13 
4.3 
Inclusion of Women and Minorities ...................................................................... 15 
5. 
REGISTRATION PROCEDURES ................................................................................... 15 
5.1 
General Guidelines for DF/HCC Institutions ........................................................ 15 
5.2 
Registration Process for DF/HCC Institutions ...................................................... 15 
6. 
TREATMENT PLAN ....................................................................................................... 15 
6.1 
Trial Treatment ...................................................................................................... 15 
6.2 
Concomitant Medications/Vaccinations ................................................................ 16 
6.3 
Diet/Activity/Other Considerations ....................................................................... 17 
6.4 
Criteria for Taking a Participant Off Protocol Therapy ........................................ 18 
6.5 
Clinical Criteria for Early Trial Termination ........................................................ 20 
6.6 
Duration of Follow Up .......................................................................................... 20 
6.7 
Criteria for Taking a Participant Off Study ........................................................... 20 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ............................................................... 20 
7.1 
Dose Modification ................................................................................................. 20 
7.2 
Rescue Medications & Supportive Care ................................................................. 1 
8. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .............................. 4 
8.1 
Adverse Event Characteristics ................................................................................. 4 
8.2 
Expedited Adverse Event Reporting ....................................................................... 5 
8.3 
Expedited Reporting to the Food and Drug Administration (FDA) ........................ 5 
8.4 
Expedited Reporting to Hospital Risk Management ............................................... 5 
8.5 
Routine Adverse Event Reporting ........................................................................... 5 
8.6 
Definition of an Adverse Event and Reporting of Adverse Events to Merck ......... 5 
8.7 
Definition of an Overdose and Reporting to the Sponsor and to Merck ................. 6 
8.8 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck ..................... 7 


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8.9 
Immediate Reporting of Adverse Events to the Sponsor and to Merck .................. 7 
9. 
PHARMACEUTICAL  INFORMATION ........................................................................ 11 
9.1 
Investigational Product .......................................................................................... 11 
9.2 
Packaging and Labeling Information .................................................................... 12 
9.3 
Clinical Supplies Disclosure ................................................................................. 12 
9.4 
Storage and Handling Requirements ..................................................................... 12 
9.5 
Ordering ................................................................................................................. 12 
9.6 
Returns and Reconciliation ................................................................................... 12 
10. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................ 13 
10.1 
Biomarker Studies ................................................................................................. 13 
11. 
STUDY CALENDAR and Visit requirements ................................................................. 17 
11.1 
Survival Follow-up ................................................................................................ 18 
12. 
MEASUREMENT OF EFFECT ....................................................................................... 19 
12.1 
Antitumor Effect – Solid Tumors .......................................................................... 19 
13. 
DATA REPORTING / REGULATORY REQUIREMENTS .......................................... 20 
13.1 
Data Reporting ...................................................................................................... 20 
13.2 
Data Safety Monitoring ......................................................................................... 21 
14. 
STATISTICAL CONSIDERATIONS .............................................................................. 21 
14.1 
Study Design/Endpoints ........................................................................................ 21 
15. 
PUBLICATION PLAN ..................................................................................................... 22 
REFERENCES .............................................................................................................................. 23 
APPENDIX A 
PERFORMANCE STATUS CRITERIA .................................................. 25 
APPENDIX B 
Events of Clinical Interest ......................................................................... 26 
1. OVERVIEW .............................................................................................................................. 26 
2. ECI REPORTING GUIDELINES ............................................................................................ 28 
3. ECI CATEGORIES AND TERMS ........................................................................................... 29 
4. APPENDIX B REFERENCES ................................................................................................. 44 
APPENDIX C – Past Medical History Related to Dermatologic Event ....................................... 45 
APPENDIX D – Presentation of the Dermatologic Event ............................................................ 46 
APPENDIX E – Focused Skin Examination ................................................................................. 48 


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1. TRIAL DESIGN 
 
1.1 
Trial Design 
 
This is an open label, single arm phase 2 clinical trial of pembrolizumab in advanced, refractory 
esophageal cancer.  Advanced esophageal cancer patients who have progressed on a prior regimen 
are eligible to participate. All 50 patients enrolled on the study will receive pembrolizumab 200 
mg administered every three weeks. 
Patients will continue on the trial until they suffer intolerable toxicity or are found to have disease 
progression by Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST). [19] 
Toxicity will be graded according to CTCAE 4.0. Mandatory day 56 (+/- 5 days) tumor biopsies 
will be performed on 20 patients and optional post-treatment tumor biopsies will be performed on 
patients who initially respond to pembrolizumab and then develop acquired resistance. 
 
 
2. OBJECTIVE(S) & HYPOTHESIS(ES) 
 
2.1 
Primary Objective(s) & Hypothesis(es) 
 
(1) Objective:  
Evaluate the response rate, by irRECIST, of pembrolizumab in refractory, advanced 
esophageal adenocarcinoma patients. 
 
Hypothesis:   
• Pembrolizumab will show a response rate of ≥ 10% in refractory, advanced esophageal 
adenocarcinoma patients 
 
2.2 
Secondary Objective(s) & Hypothesis(es) 
 
(1) Objective: 
Evaluate the response rate, by irRECIST, of pembrolizumab in refractory, advanced 
esophageal adenocarcinoma patients who are PD-L1 positive and negative.  
 
Hypothesis:   
• Pembrolizumab will have anti-cancer activity in both PD-L1 positive and negative 
refractory, advanced esophageal cancer. 
 
(2)  Objective: 
Evaluate the Progression-free Survival (PFS) and Overall Survival (OS) as measured by the 
Method of Kaplan and Meier in patients with refractory, advanced esophageal 
adenocarcinoma. 
 
 
 


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Hypothesis:   
• Pembrolizumab will have similar PFS and OS as seen in the KEYNOTE-059 study. 
 
(3) Objective 
Evaluate the durability of pembrolizumab response in advanced esophageal cancer patients by 
measuring median overall survival and median progression free survival. 
 
Hypothesis: 
• The response to pembrolizumab in metastatic esophageal cancer will be durable and will 
significantly increase progression free survival. 
 
(4) Objective 
Evaluate the safety and tolerability of pembrolizumab 200 mg, administered every three 
weeks, in advanced esophageal cancer. 
 
Hypothesis: 
• Pembrolizumab 200mg every 3 weeks will be well tolerated in the advanced esophageal 
cancer patient population. 
 
2.3 
Exploratory Objective 
 
(1) Objective:  
Evaluate relationship between response rate, by irRECIST, and potential predictive 
biomarkers.  
 
Hypothesis: 
• Molecular analysis of pre-treatment tumor biopsy samples as well as serially collected 
PBMCs and plasma samples will enable us to identify biomarkers predictive of 
pembrolizumab response. 
 
(2) 
Objective:  
Evaluate the response rate, by irRECIST, of pembrolizumab in refractory, advanced, Western 
esophageal squamous cell carcinoma patients. 
 
Hypothesis: 
• Pembrolizumab will show activity in refractory, advanced, Western esophageal squamous 
cell carcinoma patients. 
 
 
3. BACKGROUND & RATIONALE 
3.1 
Background 
Esophageal cancer is one of the most rapidly increasing cancers in the United States.  In 2014, it 
is predicted that 18,170 cases will be diagnosed and 15,450 patients will die of this disease. [1] 


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Globally, esophageal cancer was diagnosed in 482,300 persons and 406,800 individuals died of 
this cancer in 2008.[2]  Therapy remains inadequate, as these numbers show, and few definitive 
trials have been conducted in esophageal cancer specifically.  Based on a few large randomized 
trials that have included esophageal cancer in addition to gastroesophageal junction cancer and 
gastric cancer, it is believed that esophageal cancer responds similarly to standard chemotherapy 
as these lower GI malignancy sites.[3]  Thus, the standard of care is a platinum-fluoropyrimidine 
doublet (+ trastuzumab for HER2/neu positive tumors) upfront and recently, 2nd line therapy has 
become established in this disease through a sequence of 3 trails, Cougar 02, REGARD, and 
RAINBOW, as the combination of Paclitaxel and Ramucirumab.[4-6]  There are, however, no 
other established lines of therapy beyond this and the treatment algorithm remains wide open to 
additional new effective drugs in this disease. 
 
Recently, immunotherapies directed against the immune checkpoint molecules CTLA-4 and PD-1 
have shown very great promise in the treatment of metastatic melanoma. Ipilimumab, a fully 
humanized antibody directed against CTLA-4, was FDA approved for the treatment of melanoma 
after two randomized phase 3 clinical trials showed a significant survival benefit.[7,8] 
Monoclonal antibodies directed against PD-1, pembrolizumab and nivolumab, have also shown 
promising results in metastatic melanoma, non-small cell lung cancer, and renal cancer.[9-12] 
Importantly, in melanoma the majority of responses to both CTLA-4 and PD-1 directed-therapies 
appear to be durable and last for greater than one year.[12,13] Pembrolizumab was granted FDA 
approval in 2014 on the basis of a phase 1 clinical trial expansion cohort of 173 patients with 
refractory metastatic melanoma (Robert et al.). Refractory melanoma patients receiving 
pembrolizumab had an overall response rate of 26% and 88% of the responding patients were still 
benefitting from the drug after 6 months.[7] Pembrolizumab was generally well tolerated and 
drug-related grade 3 and 4 toxicity occurred in only 13% of patients. 
 
A large, multicenter phase 1 clinical trial testing pembrolizumab in several disease cohorts is 
currently underway (MK-3475-028, NCT02054806). This trial is molecularly prescreening 
patients for PD-L1 positivity. Preliminary data generated by this prescreening effort showed that 
33% of 89 metastatic esophageal cancers patients were PD-L1 positive.  
 
3.2 
Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors. 
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 


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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 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.  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 is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United Stated for 
the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
3.3 
Rationale 
3.3.1 Rationale for the Trial and Selected Subject Population 
 
Data on the expression and prognostic impact of PD-L1 and PD-L2 in human esophageal cancer 
is limited.  One study by Ohigashi and colleagues sought to define the clinical significance PD-L1 
and PD-L2 expression after esophagectomy.[14] They evaluated 41 esophagectomy patients by 
real-time quantitative PCR, using newly generated monoclonal antibodies that recognize human 
PD-L1 (MIH1) and PD-L2 (MIH18).  They demonstrated that PD-L positive patients had a 
significantly poorer prognosis than negative patients.  This was more pronounced in advanced 


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stage tumors. Multivariate analysis indicated that PD-L status was an independent prognostic 
factor. Although there was no significant correlation between PD-L1 expression and tumor-
infiltrating T lymphocytes.  PD-L2 expression was inversely correlated with tumor-infiltrating 
CD8+ Tcells. 
 
Until recently, there was limited clinical experience with immune checkpoints inhibitor in 
gastroesophageal cancer. A phase 2 trial of tremelimumab, a CTLA4 inhibitor, in metastatic 
gastric cancer showed a low overall response rate but did have one patient who had a durable, 
over 2.5 years, partial response.[15]  
 
Recently, the gastric cancer results of Keynote- 012 were presented at GI Cancers Symposium in 
San Francisco, California by Muro and colleagues.[16] This Merck phase 2 clinical trial screened 
162 patients with recurrent of metastatic adenocarcinoma of the stomach or GE junction and 
found that 65 (40%) were PD-L1 positive.  PD-L1 expression was assessed in archival tumor 
samples using a prototype IHC assay and the 22C3 antibody.  Patients with PD-L1 staining in the 
stroma or in > 1% of tumor cells were eligible for enrollment.  Of these 65 patients, 39 patients 
received Pembrolizumab at 10mg/kg every 2 weeks.  Nine (23%) had received < 1 prior therapy 
and 26 (67%) had received two or more prior therapies for metastatic disease.  The treatment was 
well tolerated and grade 3-5 adverse events occurred in only 4 patients (10%), including grade 3 
decreased appetite, grade 3 fatigue, grade 5 hypoxia, grade 3 peripheral sensory neuropathy and 
grade 4 pneumonitis.  Best overall response by investigator review (N=39) was 33% (95%CI: 
19.1-50.2) with 13 partial responses, 5 stable disease, and 21 progressive disease.  Best overall 
response by central review (N=36) was 22% (95% CI:  10.1-39.2) with 8 partial responses, 5 
stable disease, and 19 progressive disease.  Overall, 53.1% of patients showed at least some 
improvement from baseline in the measurement of their tumor size by central review.  Of the 
patients with response, 10 have had responses of 24 weeks or longer and many responses are 
ongoing.  Six month progression-free survival is 24% and median overall survival has not yet 
been reached.  A trend toward an association between higher levels of PD-L1 expression and 
response, progression-free survival, and overall survival was observed. 
 
A second study in esophageal carcinoma, the Keynote -028 study, was recently presented by Doi 
and colleagues at the ASCO conference in Chicago, IL on May 31st, 2015.[17]  This study 
screened 83 patients for PD-L1.  Of these, 37 were deemed PD-L1 positive by the same criteria 
used in Keynote -012.  Of these, 23 patients (17 with squamous cell carcinoma and 5 with 
adenocarcinoma and 1 with mucoepidermoid carcinoma) were enrolled.  Two patients (8.7%) had 
one prior therapy for advanced disease, nine patients (39.1%) had two prior therapies for 
advanced disease, and 11 (47.8%) had three or more prior lines of therapy for advanced disease.  
Treatment-related adverse events occurred in only four (17.4%) patients, including one decreased 
lymphocyte count, one decreased appetite, one liver disorder, and one pruritic rash.  There were 
no treatment-related deaths or discontinuations due to treatment-related adverse events.  
Pembrolizumab-specific toxicity included 2 patients with grade 2 hypothyroidism and 2 patients 
with grade 2 adrenal insufficiency, neither requiring pembrolizumab discontinuation.  Of 23 
patients, a partial response rate was documented in 30% (95% CI:  13.2-52.9) of patients by 
investigator review.  Five of 17 squamous cell carcinoma patients had a major response and two 
of five adenocarcinoma patients had a major response.  Overall, 52.2% of patients showed a 


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decrease in target lesion burden.  To date, responses have been 24 weeks or longer in 7 patients, 
including 2 adenocarcinoma patients.  The median time to response was 16 weeks and the median 
duration of response was 40 weeks. 
 
Data from KEYNOTE -059 (DFCI Protocol 15-073) have recently become available to co-
authors and is embargoed (strictly confidential) until the presentation at the ASCO Meeting on 
June 4th, 2017.  A manuscript has been submitted to Lancet.  KEYNOTE – 059 enrolled 259 
patients with measurable gastric and gastroesophageal junction adenocarcinoma with disease 
progression after at least 2 prior lines of treatment.  Patients received 200mg of pembrolizumab 
every 3 weeks.  Primary endpoint was objective response rate by RECIST 1.1.  Important points 
of this study relevant to this protocol are:  1)  the study enrolled 259 patients, of whom 51.4% 
were gastroesophageal junction cancers; 2)  the study enrolled both PD-L1 positive and negative 
patients, of whom 42.1% were PD-L1 negative; 3) Objective response was 15.5% for PD-L1 
positive patients and 6.4% for PD-L1 negative patients; 4) Patients with PD-L1 negative tumors 
who received pembrolizumab as a third-line treatment for metastatic disease had an objective 
response rate of 8.6% with 3.4% achieving complete response; 5) Median duration of response 
was 16.3 months in PD-L1 positive patients and 6.9 months in PD-L1 negative patients. 
 
This trial is being performed to further characterize pembrolizumab’s activity in esophageal 
carcinoma, particularly in the esophageal adenocarcinoma population that is less common in East 
Asia (with only 5 patients reported in the Keynote -028 study).  However, we would also like to 
perform an exploratory analysis of North American squamous cell carcinoma patients, which may 
have a different pathophysiology from East Asian patients.  This is based on the fact that North 
American squamous cell carcinoma patients are HPV negative [18] and these patients typically do 
not have the other risk factors seen in East Asia. 
 
3.3.2 Rationale for Dose Selection/Regimen/Modification  
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg 
Q2W).  No MTD has been identified to date.  Recent data from other clinical studies within the 
MK-3475 program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to 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 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 


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MK-3475 were found to be dependent on body weight. The relationship between clearance and 
body weight, with an allometric exponent of 0.59, is within the range observed for other 
antibodies and would support both body weight normalized dosing or a fixed dose across all body 
weights.  MK-3475 has been found to have a wide therapeutic range based on the melanoma 
indication.  The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg 
Q3W body weight based regimen are anticipated to remain well within the established exposure 
margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based 
on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed dose 
regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. In addition, exposure 
was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated 
changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid 
tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg 
or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that are 
well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
 
4. PARTICIPANT SELECTION 
 
4.1 
Eligibility Criteria  
 
In order to be eligible for participation in this trial, the subject must have: 
 
1. Histologically confirmed, measurable, unresectable adenocarcinoma or squamous cell 
carcinoma of the esophagus.  For the purposes of this study, undifferentiated carcinomas 
or adenosquamous carcinomas will be categorized as adenocarcinomas. 


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2. The primary tumor must originate in the esophagus.  Tumors that involve the GE junction 
must meet Sievert Type 1 criteria: “Adenocarcinoma of the distal oesophagus which 
usually arises from an area with specialized intestinal metaplasia of the oesophagus (i.e. 
Barrett’s oesophagus) and which may infiltrate the oesophagogastric junction from 
above.”  For the purposes of this protocol, this will be interpreted as:  greater than 50% of 
the tumor must be above the GE junction or, alternatively, the tumor must involve the GE 
junction and arise in the setting of biopsy-documented Barrett’s esophagus (specialized 
intestinal metaplasia). 
3. Patients must have received at least one prior therapy for unresectable disease.  Patients 
with recurrence within 6 months of completion of neoadjuvant or adjuvant therapy may be 
considered as having received one prior therapy for unresectable disease. 
4. Be willing and able to provide written informed consent for the trial. 
5. Be ≥ 18 years of age on day of signing informed consent. 
6. Have measurable disease based on irRECIST. 
7. Be willing to provide tissue from a newly obtained biopsy of a tumor lesion, most 
commonly an EGD biopsy from the esophagus.  Newly-obtained is defined as a specimen 
obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1.  Subjects for 
whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety 
concern) may submit an archived specimen only upon agreement from the Sponsor.  
Please note, patients may not initiate therapy until the biopsy specimen is received at the 
Dana-Farber Cancer Institute.  
8. The first 15 patients with adenocarcinoma will be offered an optional tumor biopsy 
(typically EGD biopsy) at 8 weeks.  Starting with adenocarcinoma patient #16, patients 
must have an accessible tumor and must agree to tumor biopsy at 8 weeks; this will 
continue to be mandatory until a total of 20 patients have undergone biopsy at 8 weeks. 
9. Have a performance status of 0 or 1 on the ECOG Performance Scale (Appendix A). 
10. Female subject of childbearing potential must have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
11. Female subjects of childbearing potential must 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 6.3.2).  
Subjects of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for > 1 year.  
12. Male subjects must 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. 


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13. Demonstrate adequate organ function as defined below, all screening labs should be 
performed within 10 days of treatment initiation. 
Hematological 
• Absolute neutrophil count (ANC) ≥1,500 /mcL 
• Platelets ≥80,000 / mcL 
• Hemoglobin ≥8.5 g/dL or ≥5.6 mmol/L 
 
Renal 
• Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured creatinine 
clearance ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN 
(GFR can also be used in place of creatinine or CrCL) Creatinine clearance should be 
calculated per institutional standard. 
 
Hepatic 
• Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
• AST (SGOT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases 
• ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases 
• Albumin > 2.8 mg/dL 
 
Coagulation  
 
• International Normalized Ratio (INR) OR Prothrombin Time (PT) ≤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 
• 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 
 
4.2 
Subject Exclusion Criteria 
 
The subject must be excluded from participating in the trial if the subject: 
1. 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. 
Subjects requiring systemic steroids are excluded from the trial. The use of physiologic 
doses of corticosteroids may be approved after discussion with the sponsor. 
2. Has a known history of active TB  (Bacillus Tuberculosis) 
 
3. Hypersensitivity to pembrolizumab or any of its excipients. 
4. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 
1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to 
agents administered more than 4 weeks earlier. 


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5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy and alopecia are an exception to this 
criterion and may qualify for the study. 
- 
Note:  If subject received major surgery, they must wait ≥ 3 weeks prior to starting 
study treatment. 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 or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
7. Has known active central nervous system (CNS) metastases and/or carcinomatous 
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.  This exception does not include carcinomatous 
meningitis which is excluded regardless of clinical stability.   
8. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
9. Has an active infection requiring systemic therapy. 
10. Patients that require supplemental oxygen are excluded. 
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, or anti-PD-L2 agent. 
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 


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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 of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
 
18. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
5. REGISTRATION PROCEDURES 
 
5.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause treatment 
delays should be discussed with the Overall Principal Investigator (PI). If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled. Registration cancellations must be made in OnCore as soon as possible.  
 
5.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 
6. TREATMENT PLAN 
 
6.1 
Trial Treatment 
The treatment to be used in this trial is outlined below in Table 1. Treatment must begin within 5 


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days of registration. 
 
Table 1  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3-
week cycle 
Experimental 
 
6.1.1 Timing of Dose Administration 
 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 11).  Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
 
All trial treatments will be administered on an outpatient basis. 
 
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
6.2 
Concomitant Medications/Vaccinations 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Merck Clinical team.  The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician. 
  
6.2.1 Acceptable Concomitant Medications 
 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
 


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All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
Events of Clinical Interest (ECIs)  as defined in Section 8.3.1.1. 
6.2.2 Prohibited Concomitant Medications 
 
Subjects are prohibited from receiving the following therapies during the Treatment Phase 
(including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Intranasal influenza vaccines 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.3 
Diet/Activity/Other Considerations 
 
6.3.1 Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
 
6.3.2 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 


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considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period defined in section 8.2-Reporting of Pregnancy and 
Lactation to the Sponsor and to Merck.  If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
6.3.3 Use in Pregnancy 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and within 
24 hours to the Sponsor and within 2 working days to Merck if the outcome is a serious adverse 
experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male subject 
impregnates his female partner, the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as described above and in 
Section 8.2. 
6.3.4 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. 
6.4 
Criteria for Taking a Participant Off Protocol Therapy 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 


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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 as described in Section 7.1 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of additional 
study treatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 11.1.1.1. 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 11 (Protocol Flow 
Chart). After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events will be collected for 90 days after the end of treatment as 
described in Section 8.9).  Subjects who discontinue for reasons other than progressive disease 
will have post-treatment follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented 
disease progression each subject will be followed by telephone for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
 
Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR 
that have been treated for at least 24 weeks with pembrolizumab and had at least two treatments 
with pembrolizumab beyond the date when the initial CR was declared.  Subjects who then 
experience radiographic disease progression may be eligible for up to one year of additional 
treatment with pembrolizumab via the Second Course Phase at the discretion of the investigator if 
no cancer treatment was administered since the last dose of pembrolizumab, the subject meets the 
safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will 
resume therapy at the same dose and schedule at the time of initial discontinuation.  Additional 
details are provided in Section 11.1.1.1. 


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6.5 
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. 
 
6.6 
Duration of Follow Up 
 
Participants will be followed until 30 days after last study treatment or death, whichever occurs 
later.  Participants removed from protocol therapy for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
6.7 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Decentralized Subject Registrations, the research team updates the relevant Off Treatment/Off 
Study information in OnCore.  
 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
 
7.1 
Dose Modification  
 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 3 below. See Section 7.2.1 and Events 


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of Clinical Interest Guidance Document for supportive care guidelines, including use of corticosteroids. Please also refer to the Events 
of Clinical Interest Guidance Document (Appendix B). 
 
 
Table 3 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated with 
Pembrolizumab 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
Grade 4 
Permanently 
discontinue 


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substituted via IV infusion. 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
Grade 2 
Withhold  
• Administer corticosteroids 
• 
Monitor changes of renal function 


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


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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient's study record. 
 
7.2 
Rescue Medications & Supportive Care 
7.2.1 Supportive Care Guidelines 
 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below and in greater detail in the Event of Clinical 
Interest (ECI) guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be related to 
pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator is instructed 
to follow the ECI reporting guidance but does not need to follow the treatment guidance (as 
outlined in the ECI guidance document). Refer to Section 7.1 for dose modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Suggested conditional procedures, as appropriate, 
can be found in the ECI guidance document. 
 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 


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2 
perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In 
hypothyroidism, 
thyroid 
hormone 
replacement 
therapy, 
with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 


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should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion 
of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Stop Infusion. 
Additional appropriate medical therapy may 
No subsequent dosing 


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4 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilator 
support indicated 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
8. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 9.1) and the characteristics of an observed 
AE (Section 9.2) will determine whether the event requires expedited reporting in addition to 
routine reporting. 
 
 
8.1 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which is 
provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 


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- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
8.2 
Expedited Adverse Event Reporting  
 
8.2.1 All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators 
in accordance with all applicable global laws and regulations. 
 
8.2.2 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 90 days of the last 
dose of treatment or 30 days of starting a new treatment (whichever is earlier), on the local 
institutional SAE form.  
 
8.2.3 
DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
8.3 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
8.4 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy.  
 
8.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
8.6 
Definition of an Adverse Event and Reporting of Adverse Events to Merck 
 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 


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6 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic agent 
or protocol-specified procedure, whether investigational (including placebo or active comparator 
medication) or marketed, manufactured by, licensed by, provided by or distributed by Merck for 
human use. 
 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as a 
result of a protocol-specified intervention, including washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
 
Progression of the cancer under study is not considered an adverse event unless it is considered to 
be drug related by the investigator. 
 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in Section 8. 
 
8.7 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 


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7 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Sponsor and within 24 hours to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 
993-1220) 
 
 
 
8.8 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of 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 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
 
8.9 
Immediate Reporting of Adverse Events to the Sponsor and to Merck 
 
8.9.1.1 
Serious Adverse Events 
 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck’s 
product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is an other important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious 
by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 


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Refer to Table 6 for additional details regarding each of the above criteria. 
 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 8.9.1.3 for additional details) that occurs to any subject must be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety if it causes the subject to be 
excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under study 
(reference Section 8.9.1.3 for additional details), whether or not related to the Merck product, 
must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
8.9.1.2 
Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) Events of clinical interest for this trial include: 
 
1.  An overdose of Merck product, as defined in Section 8.1 - Definition of an Overdose for This 
Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms 
or abnormal laboratory results.  


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9 
 
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.  Additional adverse events: 
 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document” (previously entitled, “Event of Clinical Interest and Immune-Related 
Adverse Event Guidance Document”).  This document can be found in Appendix 4 and 
provides guidance regarding identification, evaluation and management of ECIs and irAEs.   
 
 
ECIs (both non-serious and serious adverse events) identified in this guidance document from 
the date of first dose through 90 days following cessation of treatment, or 30 days after the 
initiation of a new anticancer therapy, whichever is earlier, need to be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220), regardless of attribution to study treatment, consistent 
with standard SAE reporting guidelines. 
 
 
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. 
 
8.9.1.3 
Protocol-Specific Exceptions to Serious Adverse Event Reporting  
 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless there 
is evidence suggesting a causal relationship between the drug and the event. Any such event will 
be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 working days 
either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to ensure 
the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE within 


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10 
2 working days of determination that the event is not progression of the cancer under study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE. 
 
 
8.9.2 Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
Table 6 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: 
This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length 
of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization 
for an elective procedure] for a preexisting condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. 
An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 
24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a 
serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action 
taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship 
to test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will 
be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet 
that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the 
investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely the Merck product caused the 
adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in 
bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  


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11 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal 
product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other 
host or environmental factors 
 
 
 
 
 
9. PHARMACEUTICAL  INFORMATION 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7. 
 
9.1 
Investigational Product  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of investigational 
product in accordance with the protocol and any applicable laws and regulations. 
 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
 
Table 7  Product Descriptions 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck 
product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT 
POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST 
BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or 
drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her 
best clinical judgment, including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product 
relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the 
administration of the Merck product is reasonable.  The AE is more likely explained by the Merck product than by 
another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck 
product is not reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose 
without an associated AE.) 


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12 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
9.2 
Packaging and Labeling Information 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
9.3 
Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
 
9.4 
Storage and Handling Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
9.5 
Ordering 
 
Participating Institutions will order their own investigational agent (Pembrolizumab) directly 
from Merck using the Drug Supply Request Form. Please allow for 3 weeks for drug to arrive 
after the order is submitted. The Participating Institution will ensure that the pharmacy will be 
able to receive and store the agent according to state and federal guidelines. The IRB should be 
kept informed of who will supply the agent (i.e., Merck pharmaceuticals Inc.) so that any 
regulatory responsibilities can be met in a timely fashion. 
 
9.6 
Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal have 
been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 


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10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
10.1 
Biomarker Studies 
 
10.1.1 Pre-treatment Tumor Biopsies 
 
Through the biopsies of pre-treatment disease, we will test hypotheses regarding predictors of 
response to PD-1 inhibition based upon the inflammatory state of the tumor.  At this time, our 
understanding of the etiology of response and de novo resistance to these drugs are still 
emerging.  However, increasing evidence points to the potential for a 6-10 gene mRNA 
expression signature of interferon γ-related genes as predictive.  This signature was recently 
identified in melanoma samples as being significantly associated with response to 
pembrolizumab [20]. A recent assessment of pembrolizumab activity in PD-L1 positive 
advanced stomach and gastroesophageal junction tumors [21] also showed a trend between 
an interferon γ gene signature and response to pembrolizumab (P= 0.07).  
 
Based upon pre-clinical research within the Bass laboratory at Dana-Farber, the estimated 
prevalence of the interferon γ-gene signature in an unselected group of esophageal 
adenocarcinoma is 43% (unpublished data).  Based upon these preliminary data, we 
anticipate this signature being significantly more prevalent in responders than non-
responders.   Assuming that we are unable to get good quality biopsies for RNA extraction in 
75% of patients (small biopsies, technical problems with RNA extraction), we anticipate that 
we will have 30 samples of baseline tumors prior to treatment with PD-1 inhibitor.  With 
n=30, we have > 90% power to detect a difference between 40% vs. 70% in the prevalence of 
interferon γ-gene signature the using one sided test with 5% type 1 error. 
 
All patients with tumors that can be safely biopsied are required to undergo a pretreatment 
biopsy.  For patients with a primary tumor intact, this will typically be an endoscopic biopsy 
of the primary tumor. Among other studies (below), the fresh pretreatment tumor biopsy will 
allow us to analyze immunohistochemically the tumor and surrounding immune-infiltrate for 
PD-L1, PD-L2 and PD1 expression.  
 
Biopsy tissues will be collected and fixed by 10% neutral buffered formalin overnight, 
dehydrated and paraffin embedded. The paraffin blocks will be stored at room temperature. 
IHC staining for immunological markers will be performed in the Center for Immuno-
Oncology Pathology Core at Dana-Farber/Harvard Cancer Center Specialized 
Histopathology Core. 
 
PD-L1 testing will be performed by QualTek Molecular Laboratories. Biopsies tissues must 
be sent to the Dana-Farber Cancer Institute study team as soon as possible. DFCI study team 


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14 
will prepare batch shipments of tissue to QualTek for testing. 
 
 
 
 
 
The tissue samples should be sent to the following address: 
 
 
Bridget Fitzpatrick 
Gastrointestinal Cancer Center 
 
Dana-Farber Cancer Institute 
 
450 Brookline Avenue, DA1B16 
 
Boston, MA 02215 
 
Ph: 617-632-6565 
 
Please alert the Study Coordinator via email and provide a tracking number for the 
shipment: Bridget_Fitzpatrick@dfci.harvard.edu 
 
We will also collect additional pre-treatment tissue to attempt immune cell characterization 
in collaboration with the Belfer Center for Applied Science.  Biopsy tissue will be placed 
immediately into DMEM+10%FBS, placed on ice and delivered immediately to the Belfer 
Center for disaggregation and flow cytometry characterization to define the specific cellular 
composition of the CD3+ immune cell population (e.g. percent of cells which are CD4, CD8, 
FOXP3, CD45RO, CD45RA, CXCR7, CD19-positive), the presence of T-cell exhaustion 
markers (e.g. PD-1, LAG3, TIM3), the composition of the myeloid population (macrophages, 
MDSCs) and for flow cytometric evidence of PD-L1 and/or PD-L2 on the EPCAM-positive 
cell population.  If material is available, additional material will be stored for possible later 
gene expression profiling. 
 
If sufficient cell material is available from pre-treatment biopsies, these may be utilized as 
part of ongoing cancer modeling whereby residual tumor is utilized for generation of in vitro 
cultures and/or implantation into immunocompromised mice for xenograft generation. 
 
Furthermore, additional testing of samples will be done to explore genomic sequencing, RNA 
expression patterns, and somatic alterations with existing next generation testing, for 
example, OncoPanel.  
 
10.1.2 Analysis of Circulating Peripheral Blood Mononuclear Cells (PBMCs):   
 
We will isolate PBMCs at initiation of pembrolizumab therapy and at serial time points 
during pembrolizumab therapy.  PBMCs will be isolated prior to the administration of 
pembrolizumab on day 1 of the first three cycles. Following cycle 3, PBMCs will be 
collected at the time of restaging. PBMCs will also be collected, if possible, on the visit when 
the patient is taken off the trial. 
 


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15 
Blood samples collected at Massachusetts General Hospital and Beth Israel Deaconess 
Medical Center will be delivered to the Dana-Farber Cancer Institute. All samples will be 
processed and stored by the DFCI Hodi Lab. 
 
PBMCs will be processed and frozen for later batched flow cytometric analysis.  Peripheral 
blood mononuclear cells (PBMCs) will be collected from whole blood to assess immune cell 
populations. Surface staining with a panel of antibodies (CD3, CD4, CD8, CD25, FoxP3, 
CD11c, CD83, CD86, CD56) and intracytoplasmatic cytokine staining, followed by flow 
cytometry will be performed in order to identify different T cell populations, their activation 
status, and the production of different cytokines as well as other immune cell populations as 
described below: 
 
 
 
10.1.3 Analysis of Circulating Immune Markers:  
 
In parallel to PBMC isolation, we will also collect plasma at multiple time points through the 
course of pembrolizumab therapy. Plasma samples will be isolated prior to the administration of 
pembrolizumab on day 1 of the first three cycles. Following cycle 3, plasma samples will be 
collected at the time of restaging. A plasma sample will also be collected, if possible, on the visit 
when the patient is taken off the trial. 
 
Blood samples collected at Massachusetts General Hospital and Beth Israel Deaconess Medical 
Center will be delivered to the DFCI Hodi Lab. All samples will be processed and stored by the 
DFCI Hodi Lab. 
 


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16 
Plasma will be frozen and then analyzed in batches by DFCI’s immune-oncology core laboratory 
(led by Dr. Steve Hodi). A panel of cytokines and chemokines will be tested in serum using 
Luminex cytokine assay. Changes in cytokine production in immune cell subsets as a function of 
treatment will be determined by ELISA and intracellular cytokine staining. Absolute lymphocyte 
count (ALC) will be monitored. 
 
10.1.4 Post-treatment Tumor Biopsies in Patients with Acquired Resistance to 
Pembrolizumab 
 
Post-treatment biopsies will be obtained at 56 days (+/- 5days) after the first dose of 
pembrolizumab.  Patients that develop acquired resistance to pembrolizumab will be encouraged 
to undergo an optional post-treatment biopsy but this is not mandatory. This biopsy will allow us 
to study mechanisms of resistance to pembrolizumab. To do this, we utilize the immune 
characterization techniques described above.  Furthermore, at time of acquired resistance, 
additional testing of the sampled tumor may include genomic analysis to identify novel somatic 
alterations which could contribute to resistance. 
 
Additionally, further testing of samples will be done to explore genomic sequencing, RNA 
expression patterns, and somatic alterations with existing next generation testing, for example, 
OncoPanel 
 
The tissue samples should be sent to the following address: 
 
 
Bridget Fitzpatrick 
Gastrointestinal Cancer Center 
 
Dana-Farber Cancer Institute 
 
450 Brookline Avenue, DA1B16 
 
Boston, MA 02215 
 
Ph: 617-632-6565 
 
Please alert the Study Coordinator via email and provide a tracking number for the shipment: 
Bridget_Fitzpatrick@dfci.harvard.edu 
 


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17 
11. STUDY CALENDAR AND VISIT REQUIREMENTS 
 
Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treatment 
Post-
Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post discon 
Every 12 
weeks  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum b-HCGf 
Xi 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
Xh 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
Xh 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
 
 
 
Comprehensive Serum Chemistry Panelg 
Xh 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
 
 
 
Urinalysis 
Xh 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
Xh 
 
X 
 
X 
 
X 
 
Xa 
 
 
 
Efficacy Measurements 
Tumor Imaging 
Xb 
 
 
Xc 
 
 
Xc 
 
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
X 
 
 
Xd 
 
 
 
 
 
Xe 
 
 
Correlative Studies Blood Collection 
 
Xl 
X 
Xj 
 
 
Xj 
 
 
X 
 
 
a: Beyond the 8th cycle TSH can be checked every 2-3 cycles at the treating investigators discretion 
b: Baseline scans need to be obtained within 21 days of the start of pembrolizumab 
c:. Scans are obtained every 9 weeks (-7 day window), approximately every 3 cycles.  After cycle 18, restaging scans can be 
performed every 4 cycles at the discretion of the treating investigator.  
d:  For the first 15 adenocarcinoma patients, biopsy at 56 days (+/- 5 days is optional).  Starting with adenocarcinoma patient #16, 
biopsy at 56 days is mandatory until tumor biopsies have been obtained on 20 individuals.  Biopsy at 56 days is optional for 
squamous cell carcinoma patients. 
e: All patients that initially responded to pembrolizumab can undergo an optional tumor biopsy on progression of disease at the 
end of the trial. 
f: Only for women of child-bearing potential 
g: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium. 


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h: Labs for screening are to be performed within 10 days prior to the first dose of trial treatment. Labs do not need to re-meet 
eligibility criteria if performed within 7 days of C1D1. 
i: For women of reproductive potential, a serum pregnancy test must be performed within 72 hours prior to each cycle of trial 
treatment and 30 days post treatment. Pregnancy tests should be repeated if required by local guidelines. 
j: After Cycle 3, Correlative Studies Blood Collection will be collected at the time of restaging. 
k: Labs must be reviewed prior to treatment 
l: Baseline blood sample can be collected within 7 days prior to C1D1. Must be collected prior to treatment on C1D1. 
 
11.1 
Survival Follow-up 
 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first, up to a maximum of 5 years.  
11.1.1.1 
Second Course Phase (Retreatment Period) 
 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to irRECIST, and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 Received at least two treatments with pembrolizumab beyond the date when the 
initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression after 
stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 4.1 


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19 
• Female subject of childbearing potential should have a negative serum or urine pregnancy 
test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of the 
study through 120 days after the last dose of study medication (Reference Section 6.3.2).  
Subjects of child bearing potential are those who have not been surgically sterilized or 
have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of the 
trial or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when they 
last received pembrolizumab.  Treatment will be administered for up to one additional year. 
Visit requirements are outlined in Section 11 – Trial Flow Chart. 
 
 
12. MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 9 weeks (3 
cycles) up to cycle 18. After cycle 18, restaging scans can be performed every 4 cycles at the 
discretion of the treating investigator. 
Response and progression will be evaluated in this study using the new Immune-related Response 
Evaluation Criteria In Solid Tumors (irRECIST) criteria. [Wolchok et al. Clin Cancer Res 
2009;15(23):7412-20] as administered by the Dana-Farber/Harvard Cancer Center Tumor 
Imaging Metrics Core.[19]. 
 
12.1.1 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started, or 
death due to any cause. Participants without events reported are censored at the last 
disease evaluation). 
 


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Duration of overall complete response: The duration of overall CR is measured from the 
time measurement criteria are first met for CR until the first date that progressive disease 
is objectively documented, or death due to any cause. Participants without events reported 
are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
12.1.2 Progression-Free Survival 
 
Overall Survival: Overall Survival (OS) is defined as the time from registration to death 
due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
registration to the earlier of progression or death due to any cause. Participants alive 
without disease progression are censored at date of last disease evaluation. 
 
Time to Progression: Time to Progression (TTP) is defined as the time from registration to 
progression, or censored at date of last disease evaluation for those without progression 
reported. 
 
12.1.3 Response Review 
 
Central review of baseline and restaging scans will be performed by the DF/HCC Tumor 
Imaging Metrics Core. 
 
 
13. DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
13.1 
Data Reporting 
 
13.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
13.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the ODQ according to the schedule set by the ODQ. 
 
 


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21 
13.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that raises 
any questions about participant safety will be addressed with the Overall PI and study team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 days 
of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths while 
being treated and during active follow-up; any response information; audit results, and a summary 
provided by the study team. Other information (e.g. scans, laboratory values) will be provided 
upon request.  
 
 
14. STATISTICAL CONSIDERATIONS 
 
14.1 
Study Design/Endpoints 
 
14.1.1 Primary Objective 
 
The primary endpoint of this study is to determine the major response rate (CR + PR) of patients 
with refractory esophageal adenocarcinoma to pembrolizumab.  We expect a response rate of 
approximately 10-15% for patients with refractory metastatic esophageal adenocarcinoma, similar 
to what was seen in the Keynote– - 059 study (DFCI Protocol 15-073).   
 
 
We propose a one-stage study (n=40) including both PD-L1 positive and PD-L1 negative patients.  
With this sample size, we will have 80% power to reject the null hypothesis that the response rate 
is 7% or lower if the true response rate is 22% or higher, using a one-sided binomial test with 5% 
type 1 error.  The null hypothesis is rejected if there are 7 or more responses. 
 
We will also perform an exploratory analysis in patients with esophageal squamous cell 
carcinoma, a cancer that accounts for only approximately 10-20% of the patients seen in our 
practice.  We will enroll no more than 10 patients of this histologic subtype. 
 
Overall survival and progression-free survival will include all evaluable adenocarcinoma 
patients, will be measured from the date of registration, and will be calculated using the 
method of Kaplan and Meier. 
 
14.1.2 Analyses of Correlative Endpoints 
 
Subpopulations of PBMCs will be isolated, including but not limited to dendritic cells, 


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22 
T cells, and B cells. Phenotype changes in these cell populations by flow cytometry will be 
determined as a function of treatment. These include regulatory and effector immune panels, 
naïve and memory CD4, CD8 and NK lymphocyte populations. Given its importance in immune 
regulation and association, we will evaluate Tie-2 expressing monocytes (TEM).  
 
For the analysis of cytokines, chemokines, and immune cell populations from serum or blood, 
data will be analyzed in longitudinal measurements for all patients. Serum marker levels will be 
summarized descriptively and graphically. The time course of expression levels will also be 
summarized graphically by patient and time of disease progression. 
 
A pretreatment tumor biopsy will be utilized for analysis of tissue biomarkers. Pre-treatment 
biomarker expression, using appropriate IHC, Aperio scoring, or H-score will be reported and 
summarized using descriptive methods. We will also summarize descriptively pre-treatment 
biomarker levels according to response (PD vs. non-PD). For a sample size of 32 patients, formal 
statistical inference relating pre-treatment biomarker levels to response will be of low power and 
will be capable of detecting only a strong signal. However, we will explore the prognostic ability 
of biomarker scoring by retrospectively dividing the patient sample according to PD vs. non-PD.  
 
Pre-treatment immune cell infiltration and biomarker changes will be summarized graphically and 
using descriptive methods. Immune cell infiltration sub-populations will also be dichotomized 
into positive and negative at 10% (negative: < 10%, positive: ≥ 10%).  
 
 
15. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome data 
are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and 
Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of the study.  


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23 
 
REFERENCES 
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Society; 2014. 
2. American Cancer Society.  Global Cancer Facts & Figures 2nd Edition.  Atlanta:  
American Cancer Society; 2011. 
3. Chau I, Norman AR, Cunningham D et al.  Multivariate prognostic factor analysis in 
locally advanced and metastatic esophago-gastric cancer--pooled analysis from three 
multicenter, randomized, controlled trials using individual patient data.  J Clin Oncol. 
2004 Jun 15;22(12):2395-403. 
4. Ford HE, Marshall A, Janowitz T et al.  Docetaxel versus active symptom control for 
refractory oesophagogastric adenocarcinoma (COUGAR-02): an open-label, phase 3 
randomised controlled trial.  Lancet Oncol. 2014 Jan;15(1):78-86. 
5. Fuchs CS, Tomasek J, Yong CJ et al.  Ramucirumab monotherapy for previously treated 
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international, randomised, multicentre, placebo-controlled, phase 3 trial. The Lancet, 
Volume 383, Issue 9911, Pages 31 - 39, 4 January 2014. 
6. Wilke H, Muro K, Van Cutsem E, et al.  Ramucirumab plus paclitaxel vers placebo plus 
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junction adenocarcinoma (RAINBOW): a double-blind randomised phase 3 trial. The 
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7. Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, Weber JS, Joshua AM, 
Hwu W-J, Gangadhar TC, Patnaik A, Dronca R, Zarour H, Joseph RW, Boasberg P, 
Chmielowski B, Mateus C, Postow MA, Gergich K, Elassaiss-Schaap J, Li XN, Iannone 
R, Ebbinghaus SW, Kang SP, Daud A. Anti-programmed-death-receptor-1 treatment with 
pembrolizumab in ipilimumab-refractory advanced melanoma: A randomised dose-
comparison cohort of a phase 1 trial. The Lancet;384:1109-1117. 
8. Hodi, F.S., S.J. O'Day, D.F. McDermott, R.W. Weber, J.A. Sosman, J.B. Haanen, R. 
Gonzalez, C. Robert, D. Schadendorf, J.C. Hassel, W. Akerley, A.J.M. van den Eertwegh, 
J. Lutzky, P. Lorigan, J.M. Vaubel, G.P. Linette, D. Hogg, C.H. Ottensmeier, C. Lebbé, C. 
Peschel, I. Quirt, J.I. Clark, J.D. Wolchok, J.S. Weber, J. Tian, M.J. Yellin, G.M. Nichol, 
A. Hoos, and W.J. Urba. 2010. Improved Survival with Ipilimumab in Patients with 
Metastatic Melanoma. New England Journal of Medicine. 363:711-723. 
9. Brahmer, J.R., C.G. Drake, I. Wollner, J.D. Powderly, J. Picus, W.H. Sharfman, E. 
Stankevich, A. Pons, T.M. Salay, T.L. McMiller, M.M. Gilson, C. Wang, M. Selby, J.M. 
Taube, R. Anders, L. Chen, A.J. Korman, D.M. Pardoll, I. Lowy, and S.L. Topalian. 2010. 
Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106) in Refractory 
Solid Tumors: Safety, Clinical Activity, Pharmacodynamics, and Immunologic Correlates. 
Journal of Clinical Oncology. 28:3167-3175. 
10. Hamid, O., C. Robert, A. Daud, F.S. Hodi, W.-J. Hwu, R. Kefford, J.D. Wolchok, P. 
Hersey, R.W. Joseph, J.S. Weber, R. Dronca, T.C. Gangadhar, A. Patnaik, H. Zarour, 
A.M. Joshua, K. Gergich, J. Elassaiss-Schaap, A. Algazi, C. Mateus, P. Boasberg, P.C. 
Tumeh, B. Chmielowski, S.W. Ebbinghaus, X.N. Li, S.P. Kang, and A. Ribas. 2013. 
Safety and Tumor Responses with Lambrolizumab (Anti–PD-1) in Melanoma. New 
England Journal of Medicine. 369:134-144. 


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11. Robert, C., L. Thomas, I. Bondarenko, S. O'Day, J. Weber, C. Garbe, C. Lebbe, J.-F. 
Baurain, A. Testori, J.-J. Grob, N. Davidson, J. Richards, M. Maio, A. Hauschild, W.H. 
Miller, P. Gascon, M. Lotem, K. Harmankaya, R. Ibrahim, S. Francis, T.-T. Chen, R. 
Humphrey, A. Hoos, and J.D. Wolchok. 2011. Ipilimumab plus Dacarbazine for 
Previously Untreated Metastatic Melanoma. New England Journal of Medicine. 364:2517-
2526. 
12. Topalian, S.L., M. Sznol, D.F. McDermott, H.M. Kluger, R.D. Carvajal, W.H. Sharfman, 
J.R. Brahmer, D.P. Lawrence, M.B. Atkins, J.D. Powderly, P.D. Leming, E.J. Lipson, I. 
Puzanov, D.C. Smith, J.M. Taube, J.M. Wigginton, G.D. Kollia, A. Gupta, D.M. Pardoll, 
J.A. Sosman, and F.S. Hodi. 2014. Survival, Durable Tumor Remission, and Long-Term 
Safety in Patients With Advanced Melanoma Receiving Nivolumab. Journal of Clinical 
Oncology. 32:1020-1030. 
13. Ott PA, Hodi FS, Robert C. Ctla-4 and pd-1/pd-l1 blockade: New immunotherapeutic 
modalities with durable clinical benefit in melanoma patients. Clinical Cancer Research 
2013;19:5300-5309. 
14. Ohigashi Y, Masayuki Sho M, Yamada Y et al.  Clinical Significance of Programmed 
Death-1Ligand-1and Programmed Death-1Ligand-2 Expression in HumanEsophageal 
CancerClin Cancer Res 2005;11:2947-2953. 
15. Ralph C, Elkord E, Burt DJ, O'Dwyer JF, Austin EB, Stern PL, Hawkins RE, 
Thistlethwaite FC. Modulation of lymphocyte regulation for cancer therapy: A phase ii 
trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clinical 
Cancer Research 2010;16:1662-1672 
16. Muro K, Bang Y, Shankaran V, et al.  Relationship between PD-L1 expression and 
clinical outcomes in patients with advanced gastric cancer treated with the anti-PD-1 
monoclonal antibody Pembrolizumab (MK-3475) in KEYNOTE-012.  Presented by K. 
Muro at the GI Cancers Symposium in San Francisco, CA on January 16th, 2015. 
17. Doi T, Piha-Paul S, Jalal S et al.  Pembrolizumab (MK-3475) for patients with advanced 
esophageal carcinoma:  preliminary results from KEYNOTE-028.  Presented by T. Doi at 
the ASCO Symposium in Chicago, IL on March 31st, 2015. 
18. Turner JR, Shen LH, Crum CP, Dean PJ, Odze RD.  Low prevalence of human 
papillomavirus infection in esophageal squamous cell carcinomas from North America: 
analysis by a highly sensitive and specific polymerase chain reaction-based approach. 
Hum Pathol. 1997 Feb;28(2):174-8. 
19. Wolchok, J.D., A. Hoos, S. O'Day, J.S. Weber, O. Hamid, C. Lebbé, M. Maio, M. Binder, 
O. Bohnsack, G. Nichol, R. Humphrey, and F.S. Hodi. 2009. Guidelines for the 
Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response 
Criteria. Clinical Cancer Research. 15:7412-7420. 
20. Ribas, A, Robert, C, Hodi, S et al. 1Proc Am Soc Clin Oncol. 2015; 33 (abstract 3001.) 
21. Muro, K. et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer 
(KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 17, 717-26 
(2016). 
 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 
 
 
 
 
 


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26 
APPENDIX B 
EVENTS OF CLINICAL INTEREST 
 
1. OVERVIEW 
 
The purpose of this document is to provide study sites with guidance on the identification and management 
of Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) program.   
 
Based on the literature review [1-11], and consideration of mechanism of action of pembrolizumab, 
potential immune-related adverse events (irAEs) are the primary Event of Clinical Interest (ECI). Immune-
related AEs are adverse events associated with the treatment of patients with immunotherapy treatments 
that appear to be associated with the immune therapy’s mechanism of action. Based on these potential 
irAEs, the sponsor has defined a list of specific adverse event terms (ECIs) that are selected adverse 
experiences that must be reported to Merck within 24 hours from the time the Investigator/physician is 
aware of such an occurrence, regardless of whether or not the investigator/physician considers the event to 
be related to study drug(s). In addition, these ECIs require additional detailed information to be collected 
and entered in the study database.  ECIs may be identified through spontaneous patient report and / or 
upon review of subject data. Table 1 provides the list of terms and reporting requirements for AEs that 
must be reported as ECIs for MK-3475 protocols.  Of note, the requirement for reporting of ECIs applies 
to all arms, including comparators, of MK-3475 clinical trials  
 
Given that our current list of events of clinical interest is not comprehensive for all potential immune-
related events, it is possible that AEs other than those listed in this document may be observed in patients 
receiving pembrolizumab. Therefore, any Grade 3 or higher event that the investigator/physician considers 
to be immune-related should be reported as an ECI regardless of whether the specific event term is in 
Table 1 and reported to Merck within 24 hours from the time the Investigator/physician is aware of 
such an occurrence.  Adverse events that are both an SAE and an ECI should be reported one time as an 
SAE only, however the event must be appropriately identified as an ECI as well in the database.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2: Events of Clinical Interest 
Pneumonitis (reported as ECI if  ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat 
the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
 
 
Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the 
AE) 
Autoimmune hemolytic anemia  
Aplastic anemia  
Thrombotic Thrombocytopenic Purpura 
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura  (ITP) 
Disseminated Intravascular Coagulation 
(DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if  ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase elevations (ALT and/or AST) 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if  ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if  ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
Any rash considered clinically significant in the physician’s judgment 
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 


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Each of the events above is described within this guidance document, along with site 
requirements for reporting these events to the Sponsor.  The information collected should be 
entered into the narrative field(s) of the Adverse Event module in the database (please note, if 
narrative entry into the database is not available, please use the narrative text box on the 
1727/AER Form).  If additional Medical History or Concomitant Medications are reported, the 
Medical History and Concomitant Medication modules in the database must be updated.   
 
In addition, the guidelines include recommendations on the management of these ECIs. These 
guidelines are intended to be applied when the physician determines the events to be related to 
pembrolizumab. Note: if after the evaluation the event is determined not to be related, the 
physician is instructed to follow the ECI reporting guidance but does not need to follow the 
treatment guidance (below). Therefore, these recommendations should be seen as guidelines and 
the treating physician should exercise individual clinical judgment based on the patient.  For any 
question of dose modification or other treatment options, the specific language in the protocol 
should be followed.  Any questions pertaining to the collection of this information or management 
of ECIs should be directed to your local Sponsor contact.  
 
Dose Modification/Discontinuation 
 
The treatment guidance provides specific direction when to hold and/or discontinue 
pembrolizumab for each immune related adverse event.  Of note, when the guidance states to 
“discontinue” pembrolizumab this is the permanent discontinuation of treatment with 
pembrolizumab. “Hold” means to stop treating with pembrolizumab but resumption of treatment 
may be considered assuming the patient meets the criteria for resumption of treatment.   
 
 
2. ECI REPORTING GUIDELINES 
 
ECIs are selected non-serious and serious adverse experiences that must be reported to Merck 
within 24 hours regardless of attribution to study treatment.  The AEs listed in this document and 
any event that meets the ECI criteria (as noted) in Table 1 or in the respective protocol (event 
term and Grade) must be reported regardless of physician-determined causality with study 
medication and whether or not considered immune-related by the physician (unless otherwise 
specified).   Physicians/study coordinators/designated site personnel are required to record these 
experiences as ECIs on the Adverse Experience electronic Case Report Forms (eCRFs) (or on 
paper) and to provide supplemental information (such as medical history, concomitant 
medications, investigations, etc.) about the event.   
 
– Please refer to the Data Entry Guidelines (DEGs) for your protocol.  
– Please refer to protocol for details on reporting timelines and reporting of Overdose and 
Drug Induced Liver Injury (DILI).   
 
 
 


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3. ECI CATEGORIES AND TERMS 
 
This section describes the ECI categories and outlines subject management guidelines when an 
ECI is reported.      
3.1 Pneumonitis 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to 
the Sponsor within 24 hours of the event: 
– Pneumonitis 
– Interstitial lung disease 
– Acute interstitial pneumonitis  
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a 
cardiology consultation should be considered.  
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral 
infection.  It is important that patients with a suspected diagnosis of pneumonitis be 
managed as per the guidance below until treatment-related pneumonitis is excluded.  
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted.  Management of the treatment of suspected pneumonitis with steroid treatment 
should not be delayed for a therapeutic trial of antibiotics.  If an alternative diagnosis is 
established, the patient does not require management as below; however, the AE should be 
reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab. 
– Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– Consider ID consult 
– Conduct an in person evaluation approximately twice per week 
– Consider frequent Chest X-ray as part of monitoring 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.   
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.    
– Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the 
patient develops a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
– Report as ECI 
– Discontinue pembrolizumab. 
– Hospitalize patient 
– Bronchoscopy with biopsy and/or BAL is recommended. 


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– Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When 
symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg 
once per day or dexamethasone 4 mg every 4 hours) taper should be started and continued 
over no less than 4 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 
48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional 
anti-inflammatory measures upon symptom relief and initiate a prolonged steroid taper 
over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of 
steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and 
administer additional anti-inflammatory measures, as needed 
– Add prophylactic antibiotics for opportunistic infections. 
 
3.2 Colitis 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of 
systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event:  
– Colitis  
– Colitis microscopic 
– Enterocolitis 
– Enterocolitis hemorrhagic  
– Gastrointestinal perforation 
– Intestinal obstruction  
– Necrotizing colitis 
– Diarrhea 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 
disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy.   However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 
hours, abdominal pain, mucus or blood in stool):   
– Report as ECI 
– Hold pembrolizumab.  
– Symptomatic Treatment 
– For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood 
and/or mucus,  
o Consider GI consultation and endoscopy to confirm or rule out colitis  
o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
– When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.    
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– If symptoms worsen or persist > 3 days treat as Grade 3 


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Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
– Report as ECI 
– Hold pembrolizumab.  
– Rule out bowel perforation.  Imaging with plain films or CT can be useful. 
– Recommend consultation with Gastroenterologist and confirmation biopsy with 
endoscopy. 
– Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral 
steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours).  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  Taper over 6 to 8 weeks in patients with diffuse and severe 
ulceration and/or bleeding. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 
48 to 72 hours, consider treatment with additional anti-inflammatory measures as 
described in the literature [5]. Discontinue additional anti-inflammatory measures upon 
symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms 
worsen during steroid reduction, initiate a retapering of steroids starting at a higher dose of 
80 or 100 mg followed by a more prolonged taper and administer additional anti-
inflammatory measures as needed.  
 
Grade 4 events:  
– Report as ECI 
– Permanently discontinue pembrolizumab. 
– Manage as per Grade 3. 
 
3.3 Endocrine 
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require 
holding/discontinuation/ modification of pembrolizumab dosing, are considered ECIs and 
should be reported to the Sponsor within 24 hours of the event:   
– Adrenal insufficiency 
– Hyperthyroidism 
– Hypophysitis 
– Hypopituitarism  
– Hypothyroidism 
– Thyroid disorder  
– Thyroiditis  
 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection.  However, the AE should be reported regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism 
Grade 2-4 events: 
– Report as ECI if appropriate 
– Hold pembrolizumab 


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– Rule out infection and sepsis with appropriate cultures and imaging. 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Pituitary gland imaging should be considered (MRIs with gadolinium and selective cuts of 
the pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
– Treat with prednisone 40 mg p.o. or equivalent per day.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
Replacement of appropriate hormones may be required as the steroid dose is tapered.  
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks.  
– Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis. 
– Consultation with an endocrinologist may be considered. 
 
Hyperthyroidism and Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
– Report as ECI if appropriate (see Table 1) 
– Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
– Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is 
instituted.  
– In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy.  
– In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care.  
– Consultation with an endocrinologist may be considered. 
 
Grade 3 hyperthyroidism events: 
– Report as ECI 
– Hold pembrolizumab.  
– Rule out infection and sepsis with appropriate cultures and imaging. 
– Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by 
oral prednisone 1 to 2 mg/kg per day.  When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.  
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
 


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Grade 4 hyperthyroidism events: 
– Report as ECI 
– Discontinue pembrolizumab.  
– Manage as per Grade 3 
 
Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
The following AE terms are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
– Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA)  
– Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA). 
 
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt worsening 
of pre-existing diabetes associated with laboratorial evidence of beta cell failure. All attempts 
should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), T2DM 
decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or poorly 
controlled pre-existing diabetes (either T1DM or T2DM), but events meeting the above criteria 
should be reported as ECIs regardless of etiology. The patients may present with hyperglycemia 
(abrupt onset or abrupt decompensation) with clinical evidence of diabetic ketoacidosis or 
laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic 
acidosis, or low or undetected c-peptide. 
 
Course of Action 
T1DM should be immediately treated with insulin. 
 
T1DM or Grade 3-4 Hyperglycemia events: 
- 
Report as ECI if appropriate (see Table 1) 
- 
Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell failure, and resume pembrolizumab when patients are 
clinically and metabolically stable.  
- 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-
4 hyperglycemia associated with metabolic acidosis or ketonuria.  
- 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
- 
Consultation with an Endocrinologist is recommended. 
- 
Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and 
insulin may be obtained.  
 
3.4 Hematologic 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic 
steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 
hours of the event: 
– Autoimmune hemolytic anemia 
– Aplastic anemia 
– Disseminated Intravascular Coagulation (DIC) 


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– Haemolytic Uraemic Syndrome (HUS) 
– Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– Thrombotic Thrombocytopenic Purpura (TTP) 
– Any Grade 4 anemia regardless of underlying mechanism 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection.   
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, 
bone marrow biopsy or Coomb’s test, etc., should be considered to confirm the diagnosis. 
However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab 
– Prednisone 1-2 mg/kg daily may be indicated 
– Consider Hematology consultation. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 events: 
– Report as ECI 
– Hematology consultation.  
– Hold pembrolizumab   Discontinuation should be considered as per specific protocol 
guidance. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Report as ECI 
– Hematology consultation 
– Discontinue pembrolizumab for all solid tumor indications; refer to protocol for 
hematologic malignancies. 
– Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
 
3.5 Hepatic 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification 
or use of systemic steroids to treat the AE), are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event:   
– Autoimmune hepatitis  
– Hepatitis  
– Transaminase elevations 
 


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All attempts should be made to rule out other causes such as metastatic disease, infection or other 
hepatic diseases. However, the AE should be reported regardless of etiology. 
 
Drug Induced Liver Injury (DILI) 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient 
meets the laboratory criteria for potential DILI defined as:  
• An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is 
greater than or equal to three times (3X) the upper limit of normal (ULN) and  
• An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN 
and 
• At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN,  
• As a result of within-protocol-specific testing or unscheduled testing. 
 
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a DILI 
event.   
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 
to 3.0 times ULN. 
– Monitor liver function tests more frequently until returned to baseline values (consider 
weekly). 
o Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT 
returns to grade 1 or baseline, taper steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic infections, and resume pembrolizumab 
per protocol  
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– Permanently discontinue pembrolizumab for patients with liver metastasis who begin 
treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% 
relative to baseline and lasts ≥1 week. 
 
Grade 3 events: 
– Report as ECI 
– Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin 
>3.0 times ULN.   
– Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, 
if necessary 
– Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours.  When 
symptoms improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 
hours or prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 
weeks.  


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– If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, 
oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not 
recommended due to its potential for hepatotoxicity. 
– Several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events:  
– Report as ECI 
– Permanently discontinue pembrolizumab 
– Manage patient as per Grade 3 above 
 
3.6 Neurologic 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
– Autoimmune neuropathy 
– Demyelinating polyneuropathy 
– Guillain-Barre syndrome 
– Myasthenic syndrome 
 
All attempts should be made to rule out other causes such as metastatic disease, other medications 
or infectious causes. However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Report as ECI 
– Moderate (Grade 2) – consider withholding pembrolizumab.  
– Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
– Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
– Report as ECI 
– Discontinue pembrolizumab 
– Obtain neurology consultation.  Consider biopsy for confirmation of diagnosis 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. If condition worsens, consider IVIG or other immunosuppressive therapies 
as per local guidelines 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. 
 


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3.7 Ocular 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic 
steroids to treat the AE, is considered an ECI and should be reported to the Sponsor within 24 
hours of the event: 
– Uveitis 
– Iritis  
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other 
ocular disease (e.g. glaucoma or cataracts). However, the AE should be reported regardless of 
etiology. 
 
Course of Action 
Grade 2 events:  
– Evaluation by an ophthalmologist is strongly recommended. 
– Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. 
– Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with 
topical immunosuppressive therapy. 
 
Grade 3 events: 
– Evaluation by an ophthalmologist is strongly recommended  
– Hold pembrolizumab and consider permanent discontinuation as per specific protocol 
guidance. 
– Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events:  
– Evaluation by an ophthalmologist is strongly recommended  
– Permanently discontinue pembrolizumab. 
– Treat with corticosteroids as per Grade 3 above 
 
3.8 Renal 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor within 
24 hours of the event: 
– Nephritis 
– Nephritis autoimmune 
– Renal failure 
– Renal failure acute 
 
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids to 
treat the AE. 
 
All attempts should be made to rule out other causes such as obstructive uropathy, progression of 


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disease, or injury due to other chemotherapy agents.  A renal consultation is recommended. 
However, the AE should be reported regardless of etiology. 
 
Course of Action 
Grade 2 events: 
– Hold pembrolizumab 
– Treatment with prednisone 1-2 mg/kg p.o. daily. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3-4 events:  
– Discontinue pembrolizumab 
– Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent 
once per day.   
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks.   
 
3.9 Skin 
Rash and Pruritus 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the 
Sponsor within 24 hours of the event:  
– Pruritus 
– Rash 
– Rash generalized 
– Rash maculo-papular 
– In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in 
the physician's judgment, should be treated as an ECI. Clinical significance is left to the 
physician to determine, and could possibly include rashes such as the following:  
o rash with a duration >2 weeks; OR  
o rash that is >10% body surface area; OR  
o rash that causes significant discomfort not relieved by topical medication or temporary 
cessation of study drug. 
 
Other Skin ECIs 
The following AEs should always be reported as ECIs, regardless of grade, and should be 
reported to the Sponsor within 24 hours of the event:  
– Dermatitis exfoliative 
– Erythema multiforme 
– Steven’s Johnson syndrome 
– Toxic epidermal necrolysis 
 
Please note, the AE should be reported regardless of etiology. 
 


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Course of Action 
Grade 2 events: 
– Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in 
combination with oral anti-pruritics (e.g., diphenhydramine HCl or hydroxyzine HCl).  
– Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
Grade 3 events: 
– Hold pembrolizumab. 
– Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or 
equivalent once per day or dexamethasone 4 mg four times orally daily.  When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– Permanently discontinue pembrolizumab. 
– Dermatology consultation and consideration of biopsy and clinical dermatology 
photograph. 
– Initiate steroids at 1 to 2 mg/kg prednisone or equivalent.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
 
1.1.1 3.9.1. Immediate Evaluation for Potential Skin ECIs 
 
A. Photographs:  
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as 
possible. Obtain appropriate consent for subject photographs if a consent form addendum is 
required by your IRB/ERC.  
– Take digital photographs of:  
o the head (to assess mucosal or eye involvement),  
o the trunk and extremities, and  
o a close-up of the skin lesion/rash.  
 
– If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance.  
– The time/date stamp should be set in the 'ON' position for documentation purposes.  
– Photographs should be stored with the subject’s study records.  
– The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will 
provide guidance to the site, if needed.  
 
B. Past Medical History:  
Collect past medical history relevant to the event, using the questions in Appendix C (Past 


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40 
Medical History Related to Dermatologic Event) as a guide. Any preexisting conditions not 
previously reported (e.g., drug allergy) should be entered into the Medical History eCRF.  
 
C. Presentation of the Event:  
Collect information on clinical presentation and potential contributing factors using the questions 
in Appendix D (Presentation of the Dermatologic Event) as a guide. This information should be 
summarized and entered in narrative format in the AE eCRF. Please use the available free-text 
fields, such as Signs and Symptoms. Note pertinent negatives where applicable to reflect that the 
information was collected. Any treatments administered should be entered on the Concomitant 
Medication eCRF.  
 
D. Vitals Signs and Standard Laboratory Tests:  
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the 
Vital Signs eCRF.  Perform standard laboratory tests (CBC with manual differential and serum 
chemistry panel, including LFTs).  
 
E. Focused Skin Examination:  
Perform a focused skin examination using the questions in Appendix E (Focused Skin 
Examination) as a guide. Information should be summarized and entered on the Adverse 
Experience eCRF as part of the narrative.  
 
F. Dermatology Consult  
Refer the subject to a dermatologist as soon as possible.  
– For a “severe rash”, the subject must be seen within 1-2 days of reporting the event.  
– For clinically significant rash, the subject should be seen within 3-5 days.  
 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory or to 
a pathologist experienced in reviewing skin specimens.  
 
The site should provide the dermatologist with all relevant case history, including copies of 
clinical photographs and laboratory test results.  
 
3.10 Other 
The following AEs, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
– Myocarditis 
– Pericarditis 
– Pancreatitis 
– Any additional Grade 3 or higher event which the physician considers to be immune 
related 
 
All attempts should be made to rule out other causes.  Therapeutic specialists should be consulted 
as appropriate. However, the AE should be reported regardless of etiology. 
 
 


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41 
Course of Action 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
– Withhold pembrolizumab.   
– Systemic corticosteroids may be indicated.  
– Consider biopsy for confirmation of diagnosis. 
– If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
 
Grade 3 events: 
– Hold pembrolizumab 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day.   
– When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.   
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment 
may be restarted and the dose modified as specified in the protocol 
 
Grade 4 events: 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day.   
– Discontinue pembrolizumab  
 
3.11 Infusion Reactions 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
– Allergic reaction 
– Anaphylaxis 
– Cytokine release syndrome 
– Serum sickness 
– Infusion reactions 
– Infusion-like reactions 
 
Please note, the AE should be reported regardless of etiology. 
 
Course of Action 
Refer to infusion reaction table in the protocol and below. 


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42 
Infusion Reactions  
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should 
be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
 
Diphenhydramine 50 mg p.o. 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
p.o. (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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43 
 
3.12 Follow-up to Resolution  
 
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated with 
information regarding duration and clinical course of the event. Information obtained from the 
consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. Free-
text fields should be used to record narrative information:  
 
– Clinical course of the event  
– Course of treatment  
– Evidence supporting recovery  
– Follow-up to the clinical course  
 
Any treatments administered for the event should also be entered in the Concomitant Medication 
eCRF.  


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44 
4. APPENDIX B REFERENCES 
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.  Nature 
Reviews Cancer 2012; 12:252-264. 
 
2. Weber JS Practical Management of Immune-Related Adverse Events from Immune 
Checkpoint Protein Antibodies for the Oncologist. American Society of Clinical Oncology 
2012; 1092-9118/10/1-10. 
 
3. Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse Events 
and 
Kinetics 
of 
Response 
With 
Ipilimumab. 
J 
Clin 
Oncol 
30. 
2012. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750. 
 
4. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with 
Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010. 
 
5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 
366:2443-2454. 
 
6. Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 
Antibody in Patients with Advanced Cancer.  N Engl J Med 2012; 366:2455-2465. 
 
7. Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, 
phase II study comparing the tolerability and efficacy of ipilimumab administered with or 
without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin 
Cancer Res 15:5591-5598, 2009. 
 
8. Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the 
Management of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–66. 
 
9. Phan GQ, Weber JS, and Sondak VK.  CTLA-4 Blockade with Monoclonal Antibodies in 
Patients with Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–
3021. 
 
10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse 
reactions—YERVOY 
Risk 
Evaluation 
and 
Mitigation 
Strategy 
(REMS). 
http://www.yervoy.com/hcp/rems.aspx 
 
11. Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised March 2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf 
 


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45 
APPENDIX C – PAST MEDICAL HISTORY RELATED TO DERMATOLOGIC EVENT 
 
Past Medical History:  
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the Medical 
History eCRF.  
 
1. Does the subject have any allergies? 
 
 
 
□ Yes □ No  
If yes, please obtain the following information:  
 
a. Any allergy to drugs (including topical or ophthalmic drugs)?   
□ Yes □ No  
 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc): 
____________________________________________________________  
____________________________________________________________  
 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.? 
□ Yes □ No  
Describe the agent and type of allergic response 
____________________________________________________________ 
____________________________________________________________ 
 
c. Any allergy to food? 
 
 
 
 
□ Yes □ No  
 
Describe the food and type of allergic response: 
____________________________________________________________ 
____________________________________________________________  
 
d. Any allergy to animals, insects? 
 
 
 
□ Yes □ No  
 
Describe the allergen and type of allergic response: 
____________________________________________________________ 
____________________________________________________________  
 
e. Any other allergy? 
 
 
 
 
□ Yes □ No  
 
Describe the allergen and type of allergic response: 
___________________________________________________________ 
___________________________________________________________  
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? 
□ Yes □ No  
If so what kind? ______________________________________________  
 
3. Has the subject ever been treated for a skin condition? 
 
 
□ Yes □ No  
If so what kind? ______________________________________________  
 
4. Is the current finding similar to a past experience? 
 
 
□ Yes □ No  
 


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46 
 
APPENDIX D – PRESENTATION OF THE DERMATOLOGIC EVENT 
 
Presentation of the event:  
Collect information on clinical presentation and potential contributing factors. Key information should be 
summarized and entered on the Adverse Experience eCRF. Any treatments administered should be entered 
on the Concomitant Medication eCRF.  
 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
_____________________________________________________________________ 
2. Has the subject contacted any known allergens?  
 
 
□ Yes □ No  
 
If so what kind? _________________________________________________  
 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, 
personal care product, poison ivy, etc.)?  
 
 
 
□ Yes □ No  
 
If so what kind? _________________________________________________  
 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and supplement)?            
□ Yes □ No  
 
If so what kind? _________________________________________________  
 
5. Has the subject consumed unaccustomed, special or unusual foods?  
 
□ Yes □ No  
 
If so what kind? _________________________________________________  
 
6. Does the subject have or had in the last few days any illness?  
 
□ Yes □ No  
 
If so what kind? _________________________________________________  
 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No  
 
If so who and what? ______________________________________________ 
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g. 
Molluscum Contagiosum)?   
 
 
 
 
□ Yes □ No  
 
9. Has the subject had recent sun exposure?  
 
 
 
□ Yes □ No  
10. For the current rash, have there been any systemic clinical signs? 
 
□ Yes □ No  
If so what kind? ________________________________________________  
i. Anaphylaxis?  
 
□ Yes □ No  
ii. Signs of hypotension? 
 
□ Yes □ No  
iii. Signs of dyspnea? 
 
□ Yes □ No  
iv. Fever, night sweats, chills? 
□ Yes □ No  


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47 
 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine 
therapy? 
 
 
 
  
 
 
□ Yes □ No  
If so what kind? _____________________________________________________  
 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid?  
□ Yes □ No  
 
List medication(s) and dose(s): _________________________________________  
__________________________________________________________________ 
 
13. Is the rash pruritic (itchy)? 
 
 
 
 
□ Yes □ No  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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48 
APPENDIX E – FOCUSED SKIN EXAMINATION 
 
Focused Skin Examination:  
Key information should be summarized and entered on the Adverse Experience eCRF.  
 
Primary Skin Lesions Description  
Color: ________________________________________________________  
 
General description:  
______________________________________________________________  
______________________________________________________________  
 
Describe the distribution of skin reaction, skin eruption, or rash on the body:  
______________________________________________________________  
______________________________________________________________  
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
______________________________________________________________  
______________________________________________________________  
 
Any associated signs on physical examination? 
______________________________________________________________ 
 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
 
 
 
 
 
 
 
 
PHARMACY MANUAL 
 
PEMBROLIZUMAB (MK-3475) 
KEYNOTE 291 
 
 
 
 Merck Sharp & Dohme Corp., NJ, USA 
 
 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
1 
 
 
SUMMARY OF REVISIONS 
 
The following are a list of revisions to the Pharmacy Manual for pembrolizumab 
(MK-3475): 
 
 
Revision Date 
Revisions to Document 
New Version #: 
10-Dec-14 
 
Global change: updated  MK-3475 to 
pembrolizumab 
2.0 
 
10-Dec-14 
 
Global change: Inserted header Pembrolizumab 
(MK-3475) Pharmacy Manual for Investigational 
Studies 
2.0 
10-Dec-14 
Expanded table of contents 
2.0 
10-Dec-14 
Removed  trailing zeros after decimal points  
2.0 
10-Dec-14 
Section 2:  
Revised footnote 1 in trial treatment table 
2.0 
10-Dec-14 
 
Section 3.1: Removed text, “The pH is maintained 
using a 10 mM histidine buffer” 
2.0 
 
10-Dec-14 
 
Section 3.2:  
Added text to emphasize normal saline as 
preferred diluent  
 
Insert cautionary statement regarding drug 
transport and delivery  
 
Inserted text that any deviation from the guidance 
listed in this manual, must be discussed with 
sponsor 
2.0 
10-Dec-14 
 
Section 3.3: 
Clarified weight based dosing calculation for 
changes in weight (10% rule)  
 
Removed calculation for 200 mg fixed dosing 
2.0 
10-Dec-14 
 
Section 3.4:  
Clarified preferred method of dose preparation  as 
volumetric reconstitution 
 
Clarified reconstitution technique. 
2.0 
10-Dec-14 
 
Section 3.6: 
2.0 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
2 
 
 
Inserted text stating infusion rates may differ for 
infusion reactions 
 
Inserted text that entire bag  needs to be dosed 
during infusion 
 
Removed  text regarding excess volume 
preparation  
 
Added text to document volume administered per 
DEG instructions 
10-Dec-14 
 
Section 4.2  
Added text to emphasize normal saline as 
preferred diluent 
 
Insert cautionary statement regarding drug 
transport and delivery  
 
Inserted text that any deviation from the guidance 
listed in this manual, must be discussed with 
sponsor 
2.0 
10-Dec-14 
 
Section 4.3: 
Clarified weight based dosing calculation for 
changes in weight (10% rule)  
 
Removed calculation for 200 mg fixed dosing 
2.0 
10-Dec-14 
 
Section 4.4: 
Clarified preferred method of dose preparation  as 
volumetric method 
2.0 
10-Dec-14 
 
Section 4.5: 
Inserted text stating infusion rates may differ for 
infusion reactions 
 
Inserted text that entire bag  needs to be dosed 
during infusion 
 
Removed  text regarding excess volume 
preparation 
 
Added text to document volume administered per 
DEG instructions 
2.0 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
3 
 
 
21-Oct-15 
Section 2: 
 
Text added to footnote 2 for sourcing and 
recording of lot number, manufacturer, and expiry 
date.  
 
3.0 
21-Oct-15 
Section 3.2: 
 
Added guidance for collection of the following 
diluent information (manufacturer, lot, and 
expiry). 
 
Removed the following text, “ unless instructed by 
the sponsor in writing” in the following sentence : 
 
Pembrolizumab (MK-3475) SHOULD NOT BE 
MIXED WITH OTHER DILUENTS unless 
instructed by the SPONSOR in writing. 
 
Added diluted drug product in the following 
sentence:  
 
Sites should follow their SOPs for drug transport 
and delivery, with all possible effort to minimize 
agitation of the reconstituted and diluted drug 
product between the pharmacy and the clinic 
 
3.0 
21-Oct-15 
Section 3.3: 
 
Clarified re-calculation of weight based dosing 
guidance.  
 
3.0 
21-Oct-15 
Section 3.5  
 
Additional text added for concentration range 
requirements.  
 
3.0 
21-Oct-15 
Section 3.7: 
 
Removed chemotherapeutic waste designation for 
solution remaining in vials that must be discarded.  
3.0 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
4 
 
 
 
21-Oct-15 
Section 4.1:  
 
Text added about cap color.  
 
3.0 
 
 
21-Oct-15 
 
 
 
Section 4.2:  
 
Added guidance for collection of the following 
diluent information (manufacturer, lot, and 
expiry). 
 
 
 
3.0 
21-Oct-15 
Section 4.3: 
 
Clarified re-calculation of weight based dosing 
guidance. 
 
 
3.0 
21-Oct-15 
Section 4.4: 
 
Additional text added for concentration range 
requirements.  
 
3.0 
21-Oct-15 
Section 4.5: 
 
Added the following text regarding infusion set 
materials: 
 
*Contact Sponsor for materials not listed above 
 
 
3.0 
21-Oct-15 
Section 4.6: 
 
Added text for discarding used vials.  
3.0 
28-Feb-17 
Section 2.0: 
 
Updated footnote in trial treatment table to include 
SmPC and guidance regarding locally sourced 
drug. 
4.0 
28-Feb-17 
Section 3.1  
4.0 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
5 
 
 
 
Added text stating formulation is latex free 
28-Feb-17 
Section 3.2 
 
Added rounding guidance.  
 
Added guidance on temperature excursions. 
 
Clarified 4 hour room temperature time limitation. 
 
Updated language around particulates. 
4.0 
28-Feb-17 
Section 3.3 
 
Updated units from lb to kg to align with weight 
based dosing examples.  
4.0 
28-Feb-17 
Section 3.4  
 
Clarified use of biosafety cabinets. 
 
Updated gravimetric dosing guidance.  
 
Added statement for use of spikes.  
 
Updated text for potential for foaming.  
 
4.0 
28-Feb-17 
Section 3.5  
 
Deleted duplicate text regarding use of biosafety 
cabinets.  
 
Updated text regarding formation of particulates. 
 
4.0 
28-Feb-17 
Section 3.6 
 
Added guidance for preparation of placebo.  
 
4.0 
28-Feb-17 
Section 3.7 
 
Added instructional text that states 250mL volume 
is only applicable to weight based studies. 
4.0  
28-Feb-17 
Section 3.8 
4.0 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
6 
 
 
 
Clarified instructions for return of un-used vials.  
28-Feb-17 
Section 4.1  
 
Added text stating formulation is latex free. 
 
Updated cap color for liquid formulation. 
 
Added text regarding overfill volume.  
4.0 
28-Feb-17 
Section 4.2 
 
Added rounding guidance.  
 
Added guidance on temperature excursions. 
 
Clarified 4 hour room temperature time limitation. 
 
Updated language around particulates. 
4.0 
28-Feb-17 
Section 4.3 
 
Updated units from lb to kg to align with weight 
based dosing examples. 
4.0 
28-Feb-17 
Section 4.4  
 
Clarified use of biosafety cabinets. 
 
Updated gravimetric dosing guidance.  
 
Added statement for use of spikes.  
 
Updated text for potential for foaming.  
 
4.0 
28-Feb-17 
Section 4.5  
 
Added guidance for preparation of placebo. 
 
4.0 
28-Feb-17 
Section 4.6 
 
Added instructional text that states 250mL volume 
is only applicable to weight based studies. 
 
4.0 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
7 
 
 
Additional text added regarding formation of 
foam. 
 
28-Feb-17 
Section 4.7 
 
Clarified instructions for return of un-used vials. 
4.0  
21-Mar-2018 
Section 1.0: 
 
Added unblinded clinical scientist to contact list 
Updated CDS title to CS 
Updated IVRS to IRT throughout document 
 
5.0 
 
 
21-Mar-2018 
Section 3.2 
 
Added text for temperature excursions that 
temperature data needs to be included in clinical 
complaint.  
 
Clarified for blinded studies that uCRA should be 
contacted for temperature excursions.  
 
Updated the room temperature allowance from 4 
hours to 6 hours and clarified fridge time 
allowance.  
 
Clarified the start of room temperature time. 
 
5.0 
21-Mar-2018 
 
Section 3.6 
 
Revised flushing statement. 
 
Section 3.7 
 
Updated drug destruction instructions. 
 
5.0 
 
 
21-Mar-2018 
Section 4.2 
 
Added text for temperature excursions that 
temperature data needs to be included in clinical 
complaint.  
 
5.0 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
8 
 
 
Clarified for blinded studies that uCRA should be 
contacted for temperature excursions.  
 
Updated the room temperature allowance from 4 
hours to 6 hours and clarified fridge time 
allowance. 
 
Clarified the start of room temperature time. 
 
21-Mar-2018 
Section 4.4 
 
Updated room temperature time allowance to 6 
hours and clarified cumulative storage time.  
 
5.0 
21-Mar 2018 
Section 4.5: 
 
Revised flushing statement. 
 
Section 4.6: 
 
Updated drug destruction instructions. 
 
5.0 
 
 
 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
9 
 
 
TABLE OF CONTENTS 
Contents 
1. Contact List ................................................................................................................... 10 
2. Trial Treatment ............................................................................................................. 11 
3.  
Drug Preparation – Pembrolizumab (MK-3475) Solution for Infusion ................. 12 
3.1 
DRUG PRODUCT ............................................................................................. 12 
3.2 
STABILITY AND HANDLING OF DRUG PRODUCT ................................. 12 
3.3 
DOSE CALCULATION .................................................................................... 14 
4.4 
PREPARATION OF INFUSION SOLUTION.................................................. 14 
3.5 
ADMINISTRATION ......................................................................................... 17 
3.6 
RETURN AND DISCARDING OF PEMBROLIZUMAB (MK-3475) VIALS
 
19 
 
 
 
 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
10 
 
 
 
1. Contact List 
 
Merck Sharp & Dohme Corp., NJ, USA (Pharmacy Manual questions only) 
For questions regarding the details outlined within this Pharmacy Manual, please contact 
your clinical scientist (CS)   
Waheeda Sirah, Associate Prin. Scientist 
Phone:  1-732-594-2230 
E-mail:  waheeda_sirah@merck.com 
 
 
 


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
11 
 
 
2. Trial Treatment  
 
Trial Treatment Table 
 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
pembrolizumab 
(MK-3475) 1 
2 or 10 mg/kg 
Q3W 
IV infusion 
Day 1 of each 
cycle1 
Experimental 
1 Refer to protocol for specific study drug administration sequence for combination studies of pembrolizumab (MK-3475) 
and chemo/immunotherapy  


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
12 
 
 
 
3.  Drug Preparation – Pembrolizumab (MK-3475) Solution for 
Infusion 
3.1 DRUG PRODUCT  
 
Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial 
 
• Pembrolizumab (MK-3475) Solution for Infusion is a sterile, non-pyrogenic aqueous 
solution supplied in single-use Type I glass vial containing 100 mg/4 mL of 
pembrolizumab (MK-3475). The product is preservative-free, latex free solution which 
is essentially free of extraneous particulates. 
 
• Cap color of MK-3475 (Pembrolizumab) 100 mg vials: 
 
• Both red, salmon, and blue color caps may be used. Though the cap color 
may be different, the product inside the vial is the same MK-3475 drug 
product. 
 
• Pembrolizumab (MK-3475) Solution for Infusion vials are filled to a target of 4.25mL 
(106.25mg) to ensure recovery of 4.0mL (100mg). 
 
 
3.2 STABILITY AND HANDLING OF DRUG PRODUCT 
 
• 
Pembrolizumab (MK-3475) Solution for Infusion, 100 mg/ 4 mL vial:  
pembrolizumab (MK-3475) Solution for Infusion vials should be stored at refrigerated 
conditions 2 – 8 °C (36 - 46 °F) and protected from light. 
 
• To determine whether to report a temperature excursion, the temperature values should 
be rounded to whole numbers. 
 
 
 
 
 
 
• Rounding: 
 
o Decimal values from 0.1 to 0.4 round down to the nearest whole number  


Pembrolizumab (MK-3475) Pharmacy Manual for Investigational Studies 
Template Version 5.0  
21-Mar- 2018 
Study Version 3.0 
10-MAY-2018 
 
 
 
 
 
13 
 
 
(e.g., 8.3 = 8) 
o Decimal values from 0.5 to 0.9 round up to the nearest whole number  
(e.g., 8.7 = 9) 
• Then compare the rounded values to the required temperature range to determine if 
there's an excursion. 
• All temperature excursions, however small, must be reported by the site to the Clinical 
Complaint Intake mailbox (clinical.complaints.intake@merck.com) for investigation 
within 1 business day using the Clinical Supply Complaint & GCP Inquiry Form (excel 
version) and attached temperature data.  All Clinical Supply stock that is subject to an 
investigation must be placed in quarantine and remain unavailable to dispense to 
patients until disposition has been determined. 
• Please note temperature excursions after drug product is prepared are out of scope of 
the clinical complaint process. Please contact HQ clinical study team for further 
guidance.  
Note: vials should be stored in the original box to ensure the drug product is protected    
from light. 
 
• Pembrolizumab (MK-3475) infusion solutions should be prepared in 0.9% Sodium 
Chloride Injection, USP (normal saline) or regional equivalent or 5% Dextrose 
Injection, USP (5% dextrose) or regional equivalent and the final concentration of 
pembrolizumab (MK-3475) in the infusion solutions should be between 1 mg/mL and 10 
mg/mL.  
 
• Please note, the preferred diluent is 0.9% Sodium Chloride and 5% dextrose is only 
permissible if normal saline is not available. 
 
• Local guidelines should be followed for collection of diluent information such as 
manufacturer, lot and expiry. When the diluent is provided by Merck, the drug 
accountability log should be used for collection of diluent information. 
 
• Pembrolizumab (MK-3475) SHOULD NOT BE MIXED WITH OTHER DILUENTS.  
 
• Pembrolizumab (MK-3475) solutions may be stored at room temperature for a 
cumulative time of up to 6 hours. The 6 hour countdown begins when the vial is pierced, 
and includes room temperature storage of admixture solutions in the IV bags and the 
duration of infusion. (Please note this 6 hour timeframe is to provide a microbial control 
strategy. The microbial clock only starts when the product stopper is pierced and not 
when the vial is removed from the refrigerator.) 
 


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• In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F), 
total cumulative storage time at room temperature and refrigeration should not exceed 24 
hours.  
 
• If refrigerated, allow the IV bags to come to room temperature prior to use.   
 
• Parenteral drug products should be inspected visually for particulate matter and 
discoloration prior to administration. Discard the drug product vial if visible particles are 
observed. 
 
•    Sites should follow their SOPs for drug transport and delivery, with all possible effort 
to minimize agitation of the drug product between the pharmacy and the clinic 
 
• DO NOT USE PEMBROLIZUMAB (MK-3475) IF DISCOLORATION IS 
OBSERVED. 
 
• DO NOT SHAKE OR FREEZE THE VIAL(S). 
 
• DO NOT ADMINISTER THE PRODUCT AS AN INTRAVENOUS (IV) PUSH OR 
BOLUS. 
 
• DO NOT COMBINE, DILUTE OR ADMINISTER IT AS AN INFUSION WITH 
OTHER MEDICINAL PRODUCTS. 
 
• Any departure from the guidance listed in this manual, must be discussed with 
sponsor 
 
 
3.3 DOSE CALCULATION 
 
Follow directions applicable to the dose level (mg/kg) of the study. 
 
200 mg Fixed Dose 
 
•  2 vials (100 mg/4 mL) 
•  8 mL total  
 
 
 
4.4 PREPARATION OF INFUSION SOLUTION 
 


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• Aseptic technique must be strictly observed throughout the preparation procedure  
 
•    Use of a biosafety cabinet is preferred since no anti-microbial preservative is present 
in the product; however, it is not mandatory unless specified by site standard operating 
procedure. 
 
• Equilibrate required number of pembrolizumab MK-3475 vials to room temperature 
 
• The preferred method of dose preparation is the volumetric method 
 
• Sponsor recommends reconstitution and administration of pembrolizumab (MK-3475) 
that follows the parameters in this manual, however if use of gravimetric preparation is 
mandatory due to local site procedures, the following requirements must be satisfied and 
documented: 
• Draw the required volume up to 4.0 mL (100 mg) of pembrolizumab from each 
vial 
• Limit the number of punctures of each vial to one 
 
• For gravimetric preparation method using density of pembrolizumab solution, a value of 
1.03 g/mL should be used 
 
• Merck does not support methods of preparation of non-Merck agents beyond what is 
stated in the product literature.  Sites should reference the SmPCs or packaging inserts 
for preparation instructions 
 
• If the site procedures require use of spikes or other closed system transfer devices 
(CSTDs), please contact sponsor for approval 
 
• Choose a suitable infusion bag size so that the following conditions are met: 
• Concentration of pembrolizumab MK-3475 is between 1 mg/mL and 10 
mg/mL 
• The infusion volume to bag capacity ratio should not be less than 0.3.  In other 
words, the bag must be filled to at least 30% of its capacity.   
 
• Choose a suitable infusion bag material. The bag may be empty or it may contain normal 
saline The following infusion bag materials are compatible with pembrolizumab (MK-
3475):  
 
▪ PVC plasticized with DEHP 


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▪ Non-PVC (polyolefin) 
▪ EVA 
▪ PE lined polyolefin 
      *Contact Sponsor for materials not listed above 
 
• Calculate the volume of pembrolizumab (MK-3475) and normal saline required to 
prepare the infusion (admixture) bag 
 
Volume of pembrolizumab (MK-3475) (mL) = required dose amount (mg) / 25 (mg/mL) 
 
Volume of normal saline = total infusion volume – volume of pembrolizumab (MK-3475) 
from above 
 
• If a bag pre-filled with normal saline is being used, remove the excess volume of normal 
saline using a sterile syringe (Polypropylene, latex-free) attached to a suitable needle. 
Keep in consideration the excess bag fill volume as well as the volume of pembrolizumab 
(MK-3475) to be added to the bag to prepare the infusion solution. This helps ensure that 
the concentration in the bag can be accurately calculated and falls within the acceptable 
range of 1 mg/mL to 10 mg/mL. If the site would like to proceed without removing excess 
saline they must ensure that the concentration of MK-3475 would still fall within 
acceptable range. 
 
• If an empty bag is being used, withdraw the necessary volume of normal saline from 
another appropriate bag and inject into the empty bag. Keep in consideration the volume 
of pembrolizumab (MK-3475) to be added to the bag to prepare the infusion solution. 
 
• Withdraw the required volume of pembrolizumab (MK-3475) from the vial(s) (up to 4 
mL from each vial) using a sterile syringe attached to a suitable needle. The vial(s) may 
need to be inverted to remove solution. 
 
Volume of pembrolizumab (MK-3475) (mL) = required dose amount (mg) / 25 (mg/mL) 
 
Note: If it is necessary to use several vials, it is advisable to withdraw from several vials 
into a suitable size single use syringe using a new needle for each vial.  
 
• Add the required pembrolizumab (MK-3475) into the infusion IV bag containing normal 
saline and gently invert the bag 10-15 times to mix the solution. 
 
• Pembrolizumab (MK-3475) solutions may be stored at room temperature for a 
cumulative time of up to 6 hours. This includes room temperature storage of admixture 
solutions in the IV bags and the duration of infusion.  


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• In addition, IV bags may be stored under refrigeration at 2 °C to 8 °C (36 °F to 46 °F), 
total cumulative storage time at room temperature and refrigeration should not exceed 24 
hours.  
 
• If refrigerated, allow the IV bags to come to room temperature prior to use.   
 
• If the infusion bag is excessively handled or shaken, particulates may form. If this occurs 
discard the bag and create a new bag taking care not to shake. Please contact your HQ 
clinical study team if particulates are noticed for further instructions.  Be prepared to 
provide the following information: 
• IV bag manufacture, lot and expiry 
• Target volume of admixture solution in the IV bag (e.g. 100 mL, 200 mL etc.) 
• Amount of drug product (mL or mg) added to the bag 
• Drug product lot 
• Brief description of the nature of visible particles (color, shape, size, numbers 
etc.). 
  
• DO 
NOT 
FREEZE 
THE 
PEMBROLIZUMAB 
(MK-3475) 
INFUSION 
SOLUTION. 
 
• Discard any unused portion left in the vial as the product contains no preservative 
 
3.5 ADMINISTRATION 
 
• Pembrolizumab (MK-3475) infusions should be administered in 30 minutes, with a 
window of -5 and +10 minutes, using an infusion pump. A central catheter is not required 
for infusion; however, if a subject has a central venous catheter in place, it is 
recommended that it be used for the infusion.  
 
• The following infusion set materials are compatible with (pembrolizumab) MK-3475: 
 
o PVC Infusion set that is plasticized using DEHP 
o PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
o Polyethylene lined PVC infusion set 
o PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate 
(DEHT) 
o Polyurethane set 
 
*Contact Sponsor for materials not listed above 


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• A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-linefilter made of 
polyethersulfone (PES) must be used during administration to remove any adventitious 
particles.  If the infusion set does not contain 0.2 to 5 µm in-line filter, it is recommended 
to use 0.2 to 5 µm add-on filter which may contain an extension line (Note: the materials 
of the extension line and filter should be as mentioned above). 
 
• Attach the infusion line to the pump and prime the line, either with normal saline (at least 
25 mL) or with infusion solution as per local SOP, before starting the infusion. 
 
• Infuse pembrolizumab (MK-3475) over approximately 30 minutes, with a window of  
        -5 and +10 minutes, through a peripheral line or indwelling catheter.  
 
• Ensure the entire contents of the bag are dosed and all remaining drug solution in the line 
is administered through saline flushing.  
 
• Document volume administered according to data entry guidelines. 
 
• In case of infusion reactions, infusion rate may differ; refer to protocol for specific 
instructions.  
 
• Whenever possible, the lowest infusion rate should be used that will allow completion of 
the infusion within the 30 minutes.  
 
• Maximum rate of infusion should not exceed 6.7 mL/min. through a peripheral line or 
indwelling catheter.  
• However, when it is necessary to infuse a larger volume (i.e. 250 mL), the flow rate may 
go as high as 10 mL/min (maximum) in order to keep the infusion within the window as 
defined above.  
 
 
• DO NOT CO-ADMINISTER OTHER DRUGS THROUGH THE SAME 
INFUSION LINE. 
 
• UNUSED INFUSION SOLUTION FOR INJECTION SHOULD NOT BE USED 
FOR ANOTHER INFUSION OF THE SAME SUBJECT OR DIFFERENT 
SUBJECT. 
 


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• Caution: Do not shake the vials/bags otherwise this may result in formation of foam. 
If foam is noticed in either vial or bag, the drug product will need to be discarded. 
A new preparation should be made, taking care not to shake or agitate the product. 
 
3.6 RETURN AND DISCARDING OF PEMBROLIZUMAB (MK-3475) VIALS 
 
Unused pembrolizumab (MK-3475) Solution for Infusion vial(s) shall be returned to the 
designated facility for destruction. 
o For US clinical sites, return to the central depot that shipped supplies to the 
site:  
▪ Fisher Clinical Services, Return and Destruction Center, 700B Nestle 
Way, Breinigsville, PA 18031 
▪ Merck & Co., Inc. 770 Sumneytown Pike B-78A West Point, PA 19486 
 
o For ex-US clinical sites, consult with local Merck subsidiary for facility 
address. 
 
•     Solution remaining in a used vial should be discarded according to your local 
procedures. 
 
•     Any information on the label identifying the subject should be redacted prior to 
returning the study medication. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol #16-293: Drafted (01/10/17) (LC)/Approved (1/10/17) (CG) 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
16-293 
Protocol Name: 
A Phase II Study of Pembrolizumab in Refractory Advanced Esophageal Cancer 
DFCI Site PI: 
Peter Enzinger, MD 
DFCI Research Nurse: 
Christopher Graham, RN, BSN ; Laura Casadonte, RN, BSN, OCN 
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
              SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study 
Design 
 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 (Section 3.2) 
 
A cycle is defined as 3 weeks (Section 1.1) 
Dose 
Calc. 
 
Pembrolizumab is dosed in mg and is a fixed dose (Section 6.1, Table 2) 
Study Drug  
Administration 
Agent Administration Guidelines are found in Section 6 
 
Pembrolizumab: 
o 
Administered via IV infusion over 30 minutes (-5/+10 minutes) on Day 1 of each 3 week cycle (Section 
6.1.1) 
o 
Required to thaw to room temperature prior to administration (Pharmacy Manual) 
Dose  
Mods & 
Toxicity 
Criteria to Treat, Dose Modifications/Dosing Delay for Toxicity are outlined in Section 7 
 
This protocol uses NCI CTCAE criteria, version 4.0 (Section 8.1) 
Con 
Meds 
Concomitant Therapy Guidelines are in Section 6.2 
 
Acceptable concomitant medications can be found in Section 6.2.1 
 
Prohibited concomitant medications can be found in Section 6.2.2 
 
Please review the cited sections for permitted, prohibited, and “use with caution” medications/therapies/foods 
Required  
Data  
Study Calendar and Assessment Required data are outlined in Section 11 
 
Vital signs: The time points are in Section 11 
 
Biopsies: The time points are in Section 11 
Tips 
All study drugs require documentation of exact administration time.