Phase I Trial of MK-3475 and Concurrent Chemo/Radiation for the Elimination of Small Cell Lung Cancer
Phase: PHASE1
Conditions: Extensive Stage Small Cell Lung Carcinoma, Limited Stage Small Cell Lung Carcinoma, Neuroendocrine Neoplasm
Sponsor: M.D. Anderson Cancer Center

DATE: 07/10/2020 
TITLE: 
Phase I Trial of MK-3475 and Concurrent Chemo/Radiation 
for the Elimination of Small Cell Lung Cancer 
NCT NUMBER: 02402920 

Product:  MK-3475  
1 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
 
 
 
SPONSOR: MDACC 
 
TITLE: 
 
Phase I Trial of MK-3475 and Concurrent 
Chemo/Radiation for the Elimination of Small Cell Lung 
Cancer  
 
IND NUMBER: 
 
EudraCT NUMBER: 
 
 

Product:  MK-3475  
2 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
Table of Contents 
 
1.0 
Trial Summary 
2.0 
Trial Design 
3.0 
Objective(s) & Hypothesis(es) 
4.0 
Background & Rationale 
5.0 
Methodology 
6.0 
Trial Flow Chart 
7.0 
Trial Procedures 
8.0 
Chemotherapy 
9.0 
Statistical Analysis Plan 
10.0 
Labeling, Packaging, Storage and Return of Clinical Supplies 
11.0 
Administrative and Regulatory Details 
12.0 
List of References 
13.0 
Appendices 

Product:  MK-3475  
3 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase I Trial of MK-3475 and 
Concurrent Chemo/Radiation for the 
Elimination of Small cell lung cancer  
 
Trial Phase 
I 
Clinical Indication 
SCLC 
Trial Type 
Investigator initiated 
Type of control 
None 
Route of administration 
IV 
Trial Blinding 
NO 
Treatment Groups  
 
Number of trial subjects 
 
Estimated duration of trial 
 
Duration of Participation 
 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design: 3x3 dose escalation  
2.2 
Trial Diagram 
 
 

Product:  MK-3475  
4 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
 

Product:  MK-3475  
5 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
Part A: Is only for patients with Limited Stage SCLC, we will allow induction 
chemotherapy. The total cycles of chemotherapy recommended will be 4, as such if a 
patient had two cycles of induction chemotherapy they would only get an additional two 
with MK-3475.  PCI will be allowed based on the treating physician discretion and will be 
done after chemotherapy has been completed.  PCI will delay the next dose of MK-3475 
by one cycle and PCI should start approximately three weeks after MK-3475. MK-3475 
can be resumed following the completion of PCI. LS-SCLC patients, who achieve systemic 
disease control during/after completion of 16 cycles of MK-3475, will be eligible to get 
additional 16 cycles of MK-3475, provided they did not exhibit severe (grade >3) MK-
3475 related toxicity during therapy. Systemic disease control is defined as stable disease 
or 
partial 
response 
or 
complete 
response, 
based 
on 
irRC 
criteria.
 
* Eligible patients may receive additional 16 cycles. 
 
 
Part B: Is only for patients with Extensive Stage SCLC who are receiving consolidation XRT 
after 1-6 cycles of chemotherapy. Patients needing PCI are encouraged to have it completed 
prior to enrollment in this trial. If PCI needs to be given on study, after thoracic XRT, then it 
should be done in a manner consistent with part A.  PCI will delay the next dose of MK-3475 
by one cycle and PCI should start approximately three weeks after MK-3475. MK-3475 can 
be resumed following the completion of PCI.) Patients needing XRT treatment to other sites 
outside the thorax will be allowed, but is encouraged to be done prior to starting the trial.   
 

Product:  MK-3475  
6 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: Safety of MK 3475 plus chemo/radiation for LS-SCLC and safety of MK 3475 
plus radiation for ES-SCLC  
Hypothesis: MK-3475 with chemoradiation for LS-SCLC and with radiation for ES-SCLC 
will demonstrate an acceptable toxicity profile comparable to previous trials  
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  MK-3475 will improve PFS compared to historical controls for LS-SCLC and 
ES-SCLC.  
Hypothesis:  The addition of MK3475 will provide T cell activation that will help improve 
both local and distant disease progression in SCLC. 
3.3 
Exploratory Objective 
(1) 
Objective:  
MK-3475 will increase T cells and CD8 positive cells in non-irradiated tumors, compare 
before and after MK-3475. 
Radiation will turn the tumor into a vaccine produce new antigens and stimulate T cells 
which can then circulate and increase T cell responses in the non-irradiated tumors 

Product:  MK-3475  
7 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 8].  The structure 
of murine PD-1 has been resolved [9].  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade [7; 10; 11; 12].  The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins [13; 14].  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells [15; 16].  Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells [17].  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety 
of cell types, including non-hematopoietic tissues as well as in various tumors [18; 19; 20; 13].  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains 
in the extracellular region and contain short cytoplasmic regions with no known signaling 
motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-
L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves 
to dampen unwarranted T-cell function in peripheral tissues [13].  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels 
of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion 
in subjects with melanoma (MEL) [21].  This suggests that the PD-1/PD-L1 pathway plays a 

Product:  MK-3475  
8 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
critical role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention. 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.   
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
 
Radiation has been demonstrated to provide clear survival advantages to patients with both 
limited stage and extensive stage SCLC1,2. Radiations historical use has been to provide local 
control, by sterilizing tumor that is non-surgically resectable.  Radiations ability to sterilize not 
only the primary tumor but lymph nodes and draining lymphatic channels have made it an 
integral part of the treatment of many solid tumors include SCLC which have a proclivity for 
metastatic spread.   
 
Moreover, despite the known benefit of ionizing radiation in terms of local tumor 
control, it also enhances the release of cytokines such as TGF-β, a known inducer of tumor 
invasion and the epithelial-mesenchymal transition.3-5 On the other hand, radiation can also 
promote the immune response through the induction of neoantigens and the stimulation of 
factors such as interferon-gamma that can actually enhance T cell infiltration.6 This dual ability 
to control local tumor progression yet also influence metastatic spread and immune response 
constitute a compelling argument for including radiation in tests of the current arsenal of 
immune checkpoint inhibitors now entering the clinic.  
 
The rational for this trial is based on combing MK-3475 with concurrent radiation in order to 
use radiation ability to turn a tumor into an in situ-vaccine in order to prime an immune 
response.  MK-3475 will provide T cell activation to allowing for priming and expansion of 
these activated T cells, which can then enter the systemic circulation and enhance systemic 
tumor control, and concept often referred to as the abscopal affect. Small Cell lung cancer is a 
disease with a high failure rate both locally and distantly. As such improvement in both 
systemic and local therapy are urgently needed.  Furthermore Small Cell Lung Cancer has one 
of the highest endogenous mutation rates of any cancer with up to 7 mutations per 1 million 
bases7, all these unique mutations can potentially be used as new antigen for immune 
stimulation.  All this contributes to SCLC being ideal tumor type to evaluate checkpoint 
inhibitors such as MK-3475.  

Product:  MK-3475  
9 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
Radiation for limited stage disease will be administered at the standard doses of 45Gy in twice 
daily fractions, with concurrent chemotherapy, either cisplatin and etoposide or carboplatin 
and etoposide.  Patients with extensive stage disease will receive thoracic radiation to 45 Gy 
in daily fractions, without concurrent chemotherapy. While on study, patients are allowed to 
have further radiation to other clinically appropriate sites as per the discretion of their treating 
radiation oncologist. 
MK-3475: Will be started at 100 mg, 1/2 the MTD of MK-3475 alone (based on MTD dose of 
200mg Q 3 weeks).  The dose will be changed as per our 3x3 dose escalation rules and either 
decreased to 70mg, continued at 100m or increased to 150mg and eventually 200mg. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
Part A LS-SCLC: The primary endpoint is safety in order to establish the MTD of MK-3475 
with concurrent chemo and radiation. The primary acute toxicity for chemo and radiation is 
esophagitis with a rate of ≥ 32%8.  While the long term toxicity rate of grade 3 pneumonitis is 
around 13%9.  
Part B ES-SCLC: The primary endpoint is safety in order to establish the MTD of MK-3475 
with concurrent radiation. The primary acute toxicity for chemo and radiation is esophagitis 
with a rate of ≥ 32%8.  While the long term toxicity rate of grade 3 pneumonitis is around 
13%9.  
 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Modified for clarification as some patient with induction therapy could have no 
measurable disease. Have a performance status of 0 or 1 or 2 on the ECOG Performance 
Scale. 
4. Demonstrate adequate organ function as defined below; all screening labs should be 
performed within 10 days of treatment initiation.   

Product:  MK-3475  
10 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
5. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 2 weeks of study entry.  If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.   
6. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
7. Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
8. Histologic diagnosis of either limited state SCLC (LS-SCLC), or Extensive stage 
SCLC (ES-SCLC) or neuroendocrine tumor.  
 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 

Product:  MK-3475  
11 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
1. Is currently participating in or has participated in a study of an investigational agent 
(except glutamine) or using an investigational device within 2 weeks of the first dose 
of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. With the exception of physiologic steroid replacement.   
3. Has had a prior monoclonal antibody 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 agents 
administered more than 4 weeks earlier.  
4. Has had prior chemotherapy, targeted small molecule therapy, within 2 weeks prior to 
study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse 
events due to a previously administered agent. Prior radiation does not require a 
washout period.   
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
5. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.   
6. 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.   
7. Has an active automimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects with 
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Subjects with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 
8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
9. Has an active infection requiring systemic therapy. 

Product:  MK-3475  
12 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
10. 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.   
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
12. 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. 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137. 
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below.  
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
MK-3475 70-200 mg  
Q 3 weeks IV infusion 
16 cycles 
Experimental 
The MK-3475 dosing interval may be increased due to toxicity as described in Section 
5.2.1.2. 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
The dose amount required to prepare the MK-3475 infusion solution will be based on the dose 
level which a patient is being treated on as per table 1.  
 

Product:  MK-3475  
13 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
Radiation will be given as per our institutional standard. For the patient in the LS-SCLC arm 
we will use 45Gy delivered BID over 15 days (we will allow a GTV boost to 54Gy, as long as 
the PTV dose remains at 45Gy).  For patients with ES-SCLC we will use a dose of 45Gy daily 
(we will allow at GTV boost dose to 52.5Gy, as long as the PTV dose remains at 45Gy).   
5.2.1.2 Dose Modification  
MK-3475 will be withheld for drug-related Grade 4 hematologic toxicities, non-hematological 
toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-threatening AEs as 
per Table 3 below. 
Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with Sponsor) 
Hematological Toxicity 
 
1, 2, 3 
No 
N/A 
N/A 
N/A 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
Non-hematological toxicity 
 
Note:  Exception to be treated 
similar to grade 1 toxicity  
• Grade 2 alopecia 
• Grade 2 fatigue 
 
For additional information 
regarding Adverse Events 
with a potential Immune-
Etiology reference Section 
5.6.1.1. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks:  Same 
dose and 
schedule 
(reference 
Section 5.6.1.2 
for 
recommendations 
regarding 
pneumonitis) 
Clinical AE does 
not resolve 
within 4 weeks:  
May increase the 
dosing interval 
by  1 week for 
each occurrence 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 

Product:  MK-3475  
14 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with Sponsor) 
3, 4 
 
Yes 
 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
 
May increase the 
dosing interval 
by 1 week for 
each occurrence 
 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with the Sponsor.  With investigator and Sponsor 
agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks may 
continue treatment in the trial only if asymptomatic and controlled.  For information on the 
management of adverse events, see Section 5.6.1.   
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of MK-3475 should be discontinued from trial treatment. 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
MK-3475 will be administered as a 30 minute IV infusion (treatment cycle intervals may be 
increased due to toxicity as described in Section 5.2.1.2).  Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible.  However, given the variability 
of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
The Procedures Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 

Product:  MK-3475  
15 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
5.3 
Stratification 
There is no stratification for this trial.  
5.4 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Sponsor.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
Investigator, the Sponsor, and the subject.  
5.4.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than MK-3475 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) 
are live attenuated vaccines, and are not allowed. 

Product:  MK-3475  
16 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
• 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. 
5.5 
Correlative Studies relating to immunologic response:  
The immunotherapy platform will perform immune monitoring, including but not limited to 
evaluation of  CD4 and CD8 T cells in peripheral blood and available tumor samples as 
previously published, 19,22. All samples will be collected and analyzed as per a separate IRB-
approved lab protocol.  
  
5.5.1. Tumor tissues  
Tumor tissue collected for diagnostic purposes within 3 months of study entry will be banked 
under an IRB-approved laboratory protocol and ten to thirty unstained slides or fresh frozen 
tumor from available tissues will be collected for baseline immune system testing before radiation 
treatment  
Optional biopsy after the completion of radiation therapy:  
A biopsy will be done (optional) within 7 days after completion of radiation therapy for 
immune response monitoring. 
5.5.2. Peripheral blood  
Up to 150 mL of peripheral blood will be collected under an IRB-approved laboratory 
protocol (optional) for immune system monitoring described in this clinical protocol at 
the following time points:  
• First collection: At baseline before the start of radiation therapy 
• Second collection: within 7 days after completion of radiation therapy. 
 The treating physician or designee will have the option to cancel the laboratory 
protocol collection for patient safety without protocol deviation. 

Product:  MK-3475  
17 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
• Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).  In symptomatic 
subjects, infectious etiologies should be ruled out, and if symptoms are persistent 
and/or severe, endoscopic evaluation should be considered. 
o In subjects with severe enterocolitis (Grade 3), MK-3475 will be permanently 
discontinued and treatment with systemic corticosteroids should be initiated at 
a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and continued 
over at least 1 month. 
o In subjects with moderate enterocolitis (Grade 2), MK-3475 should be withheld 
and anti-diarrheal treatment should be started.  If symptoms are persistent for 
more than one week, systemic corticosteroids should be initiated (e.g., 0.5 
mg/kg/day of prednisone or equivalent).  When symptoms improve to Grade 1 
or less, corticosteroid taper should be started and continued over at least 1 
month.  Regarding guidelines for continuing treatment with MK-3475, see 
Section 5.2. 
o All subjects who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. 
• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
• Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard institutional 
practice. 
• Immune-related adverse events: Please see Section 5.6.1.1 below and the separate 
guidance document in the administrative binder regarding diagnosis and management 
of adverse experiences of a potential immunologic etiology.   
• Management of Infusion Reactions:  Acute infusion reactions (which can include 
cytokine release syndrome, angioedema, or anaphylaxis) are different from 

Product:  MK-3475  
18 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs.  Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness 
of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; 
Hypotension; Myalgia (muscle pain); Nausea; Pruritis/itching; Rash/desquamation; 
Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation 
of tumor pain due to treatment); Urticaria (hives, welts, wheals); Vomiting. 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-3475. 
 
Table 5  Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
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 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: 
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 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
 
No subsequent dosing 

Product:  MK-3475  
19 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
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. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) (Appendix 13.4) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.  irAEs may be predicted based on the nature of the MK-3475 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action.  Special attention should be paid to AEs that may be suggestive 
of potential irAEs.  An irAE can occur shortly after the first dose or several months after the 
last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of Clinical 
Interest and Immune-Related Adverse Event Guidance Document located in the 
Administrative Binder.  Subjects who develop a Grade 2 or higher irAE should be discussed 
immediately with the Sponsor.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 6. 
Table 6 General Approach to Handling irAEs 
irAE 
Withhold/Discontinue MK-
3475? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold MK-3475 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold MK-3475 
Discontinue if unable to reduce 
corticosteroid dose to < 10 mg 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 

Product:  MK-3475  
20 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
per day prednisone equivalent 
within 12 weeks of toxicity 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 4 
weeks. 
 
5.6.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving MK-3475 and have 
an evaluation.  The evaluation may include bronchoscopy and pulmonary function tests to rule 
out other causes such as infection.  If the subject is determined to have study drug associated 
pneumonitis, the suggested treatment plan is detailed in Table 7. 
Table 7 Recommended Approach to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue MK-
3475? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold MK-3475, may 
return to treatment if improves 
to Grade 1 or resolves within 
12 weeks 
Systemic corticosteroids are indicated.  Taper if 
necessary. 
Grade 3 and Grade 4 
Discontinue MK-3475 
Systemic corticosteroids are indicated. The use of 
infliximab may be indicated as appropriate.  Refer to 
the Event of Clinical Interest and Immune-related 
Adverse Event Guidance Document for additional 
recommendations. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
• First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
• Second episode of pneumonitis – permanently discontinue MK-3475 if upon 
rechallenge subject develops pneumonitis ≥ Grade 2 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 

Product:  MK-3475  
21 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
5.7.2 Contraception 
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to 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. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with MK-3475, 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 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 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether MK-3475 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. 

Product:  MK-3475  
22 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
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.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.3 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7.1 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of treatment with MK-3475 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop MK-3475 after 24 months may be eligible for up to one year of additional 
study treatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 7.1.5.2.1. 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 

Product:  MK-3475  
23 
Protocol/Amendment No.:   
2014-1003  
version 20 
 
 
 
 
 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up.  After documented disease progression each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
5.9 
Subject Replacement Strategy 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
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. 

Product:  MK-3475  
24 
Protocol/Amendment No.:   
2014-1003 
version 6 
fsdd 
 
 
 
 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart (All scheduled tests will be given a window of +/- 3 days) 
Treatment Cycle/Title:   
Main 
Study 
Screening 
1 
2 
3 
4 
5 
6-16 
(additional 16 
cycles, for 
eligible 
patients 
Post MK-
3475 
Follow up 
Survival Follow-
Up 
(>2yrs)a 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
Every 12 
weeks post 
discon 
Every 12 weeks  
Administrative Procedures 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
 
X 
X 
X 
X 
X 
X 
X 
Xa 
 
Trial Treatment Administration 
 
 
X 
X 
X 
X 
X 
X 
 
 
Survival Status 
 
 
 
 
 
 
 
 
Xa, f 
Xa, f 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
 
X 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: Analysis Performed by LOCAL Laboratory 
Pregnancy Test – Urine or Serum β-HCG 
 
Xd 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
 
X 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
Xf 
Xf 
Xf 
Xf 
Xf 
Xf 
 
 
Comprehensive Serum Chemistry Panel 
(BMP) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
T3, FT4 and TSHb 
 
Xb 
 
Xb 
 
Xb 
 
Xb 
 
 
PFT’s 
 
X 
 
 
 
 
 
 
Xc, f 
 
Biopsyc 
 
 
Xg 
 
 
 
 
 
 
 

Product:  MK-3475  
25 
Protocol/Amendment No.:   
2014-1003 
version 6 
fsdd 
 
 
 
 
Treatment Cycle/Title:   
Main 
Study 
Screening 
1 
2 
3 
4 
5 
6-16 
(additional 16 
cycles, for 
eligible 
patients 
Post MK-
3475 
Follow up 
Survival Follow-
Up 
(>2yrs)a 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
Every 12 
weeks post 
discon 
Every 12 weeks  
Blood Biomarker Testingc 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy Measurements 
Tumor Imaging (CT or PET scan)e 
 
X 
 
 
 
X 
 
Xf 
Xc, f 
Xc, f 
 
a. Can be done over the phone. 
b. Thyroid functions will be performed with every other MK-3475 cycle, if the first three test are WNL then it can be stopped. 
c. Optional biopsy after radiation treatment 
d. Within 2 weeks of study entry for women with child bearing potential.   
e. Imaging should be performed approximately every 12 weeks (± 4 weeks). 
f. standard of care 
g. Within 3 months of study entry 
 
 
 

Product:  MK-3475 
26 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.f 
7.1.1.2 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.3 Concomitant Medications Review 
7.1.1.3.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.3.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 

Product:  MK-3475 
27 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
7.1.1.4 Disease Details and Treatments 
7.1.1.4.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.4.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.4.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
7.1.1.5 Trial Compliance (Medication/Diet/Activity/Other) 
Patients will be monitored for treatment compliance in addition to general compliance with 
clinic visits, prohibited activities, and concomitant medication. In the event that a patient is 
unwilling or unable to maintain compliance, then the patient can be removed from the study 
pending investigator and treating physician discretion. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 13.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
All AEs of unknown etiology associated with MK-3475 exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.6.1.1 and the separate guidance document in the administrative 
binder regarding the identification, evaluation and management of AEs of a potential 
immunological etiology.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   

Product:  MK-3475 
28 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
7.1.2.2 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 13.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.  After Cycle 8 assessment of ECOG status will be 
performed every other cycle in conjunction with the directed or full physical exam. 
7.1.2.5 Tumor Imaging and Assessment of Disease 
Response and progression will be evaluated in this study using guidelines proposed by the 
Immune Related Response Criteria (irRC).  Patients with measurable disease will also be 
assessed using standard RECIST v 1.1 and World Health Organization (WHO) treatment 
response criteria. 
 
7.1.2.5.1 irRC: Measurable Disease Prior to Therapy 
Index lesions: Up to 15 index lesions per patient (5 per organ, up to 10 visceral and 5 
cutaneous) with minimum size 5 x 5 mm will be accurately measured in two dimensions (two 
largest perpendicular diameters) on CT or MRI scan (slice thickness no greater than 5 mm) 
prior to therapy initiation.  Lesions measured with calipers by clinical exam may be 
conducted on lesions no smaller than 10 mm in the smallest dimension. Lesions that cannot 
be accurately measured with calipers should be recorded as non-measurable. 
XRT-treated index lesions: Defined as all index lesions treated by XRT as part of this 
protocol. 
Non-XRT-treated index lesions: Defined as all index lesions not treated by XRT as part of 
this protocol. 
irRC: Index and non-Index Lesions: 
For the irRC, index and measurable new lesions are taken into account (in contrast to 
conventional WHO treatment response criteria, which do not require the measurement of 
new lesions, nor are new lesion measurements included in the assessment of evolving tumor 

Product:  MK-3475 
29 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
burden). At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral 
lesions and five cutaneous index lesions) is calculated. At each subsequent tumor assessment, 
the SPD of the index lesions and of new, measurable lesions (≥5 x 5 mm; up to 5 new lesions 
per organ: 5 new cutaneous lesions and 10 new visceral lesions) are added together to 
provide the total tumor burden. In addition to a global irRC which will encompass all lesions 
under the previous definition, the irRC of lesions included within the XRT PTV and outside 
the XRT PTV will also be assessed as follows:  
1. Global irRC: irRC that factors all lesions including both index and non-index as 
outlined in 9.2.4. 
 
2. In-Field irRC: irRC in which only index within the XRT PTV will be considered 
and any non-index lesions arising inside the XRT PTV 
 
3. Out-Field irRC: irRC in which only index lesions outside the XRT PTV will be 
considered and any non-index lesions arising outside the XRT PTV 
 
7.1.2.5.2 Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or physical 
calipers. All baseline evaluation studies should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of treatment. The 
same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
Chest x-ray. Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, cross sectional imaging is 
preferable. 
Multidetector CT, PET/CT. These techniques should be performed with contiguous slices 
of 5 mm or less in thickness. This applies to tumors of the neck, chest, abdomen and pelvis. 
Head and neck tumors and those of extremities may require specific imaging protocols or 
evaluation with ultrasound. When the primary endpoint of the study is objective response 
evaluation, US should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions, and thyroid nodules. US might also be useful to confirm the complete disappearance 
of superficial lesions usually assessed by clinical examination. 
Endoscopy, Laparoscopy. These will not be used to assess response on this study. 

Product:  MK-3475 
30 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response. 
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) if clinically indicated. 
7.1.2.5.3 Immune Related Response Criteria (irRC). 
Evaluation of Target Lesions 
Response in new patients will be conducted using the Immune Related Response Criteria 
(irRC) as described in10. “For irRC, only index and measurable new lesions are taken into 
account. At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral 
lesions and five cutaneous index lesions) is calculated. At each subsequent tumor assessment, 
the SPD of the index lesions and of new, measurable lesions (≥5 x 5mm; up to 5 new lesions 
per organ: 5 new cutaneous lesions and 10 visceral lesions) are added together to provide the 
total tumor burden:” 
For the purposes of this study, 3 separate tumor burdens will be calculated for each patient 
and used to define 3 separate irRCs as discussed in 9.3. All criteria will be considered 
separately for all 3 irRCs: global, in-field, and out-field. 
Global Tumor Burden = SPD(all index lesions) + SPD(new, measurable lesions) 
In-Field Tumor Burden = SPD(all index lesions targeted by XRT in this protocol) + 
SPD(new, measurable lesions inside the XRT PTV) 
Out-Field Tumor Burden = SPD(all index lesions NOT targeted by XRT in this protocol) + 
SPD(new, measurable lesions outside the XRT PTV) 
Complete Response (irCR): irCR, complete disappearance of all lesions (whether 
measurable or not, and no new lesions) confirmation by a repeat, consecutive assessment no 
less than 4 wk from the date first documented.  
Partial Response (irPR): irPR, decrease in tumor burden ≥50% relative to baseline 
confirmed by a consecutive assessment at least 4 wk after first documentation. 
Progressive Disease (irPD): irPD, increase in tumor burden ≥25% relative to nadir 
(minimum recorded tumor burden) confirmation by a repeat, consecutive assessment no less 
than 4 wk from the date first documented.  
1. If a patient is classified as having irPD at a post-baseline tumor assessment, then 
confirmation of irPD by a second scan in the absence of rapid clinical deterioration is 
required. The definition of confirmation of progression represents an increase in 
tumor burden ≥25% compared with the nadir at two consecutive time points at least 4 
wk apart. It is recommended that this be done at the discretion of the investigator 

Product:  MK-3475 
31 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
because follow-up with observation alone may not be appropriate for patients with a 
rapid decline in performance status. 
 
Stable Disease (irSD): irSD, not meeting criteria for irCR or irPR, in absence of irPD. In 
contrast to other response criteria, this criteria does not require repeat confirmation. 
7.1.2.6 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
The total amount of blood/tissue to be drawn/collected over the course of the trial (from pre-
trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by visit 
and by sample type per subject can be found in the Procedures Manual.  
 
Laboratory tests for screening should be performed within 28 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment.  
 
7.1.3 Other Procedures 
7.1.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with MK-
3475 may discontinue treatment with the option of restarting treatment if they meet the criteria 
specified.  After discontinuing treatment following assessment of CR, these subjects should 
return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed 
to the Follow-Up Period of the study (described in Section 7.1.4.4). 
7.1.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.4.1 Screening 
The screening assessment will consist of a full history and physical exam, along with listed 
laboratory screening tests including a pregnancy test in PT/INR.  
7.1.4.2 Treatment Period 
During treatment patients will have a review of all concurrent medication, vitals and review of 
adverse events. During radiation delivery patients will see a doctor weekly to review treatments 
address issues, any potential side effects.  

Product:  MK-3475 
32 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
7.1.4.3 Post-Treatment Visits 
Following the completion of this study, patients will follow up one month later with new 
imaging studies to assess response to treatment.  At this time we will also perform a physical 
exam, vitals, medication review, and assess for any prior and or new toxicities and or side 
effects. Following this the same assessment will be performed every three months for the next 
2 years and then every 6 months after that.   
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.   
7.1.4.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 12 weeks (90 ± 14 days) by radiologic 
imaging to monitor disease status.  Every effort should be made to collect information 
regarding disease status until the start of new anti-neoplastic therapy, disease progression, 
death, end of the study.  Information regarding post-study anti-neoplastic treatment will be 
collected if new treatment is initiated. 
7.1.4.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and 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.  
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 

Product:  MK-3475 
33 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
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. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 by 20% over the prescribed dose. No specific information is available on 
the treatment of overdose of MK-3475. In the event of overdose, MK-3475 should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 

Product:  MK-3475 
34 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.2 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.  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) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
Refer to Table 10 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.  

Product:  MK-3475 
35 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be 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 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 

Product:  MK-3475 
36 
Protocol/Amendment No.:   
2014-1003 
 
 
 
 
 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to the Sponsor within 24 hours and to Merck Global Safety within 
2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.”  This document provides guidance 
regarding identification, evaluation and management of ECIs and irAEs.  Additional ECIs are 
identified in this guidance document and also need to be reported to the Sponsor within 24 
hours and to Merck Global Safety within 2 working days of the event.   
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not 
related to the Merck’s product, must be reported within 24 hours to the Sponsor and to Merck 
Global Safety within 2 working days. 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

Product:  MK-3475 
37 
Protocol/Amendment No.:   
 
 
 
 
 
 
Table 10 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 

Product:  MK-3475 
38 
Protocol/Amendment No.:   
 
 
 
 
 
 
 
 
 
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.) 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
39
7.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 CHEMOTHERAPY 
Part A LS-SCLC: 
All patients will receive chemotherapy with either cisplatin and etoposide or carboplatin and 
etoposide. All patients should receive four cycles of chemotherapy, given over 3 weeks each, 
unless there is evidence of disease progression or patient intolerance.  Cisplatin and etoposide is 
the preferred regimen; for patients unable to tolerate cisplatin in the opinion of the treating 
clinician, carboplatin/etoposide is an acceptable alternative. 
 
8.1 Drug Supply and Storage 
 
Cisplatin, carboplatin, and etoposide are standard, commercially available drugs.  Investigators 
will use commercially available supplies and will store drug as per the instructions provided in the 
package insert. This section does no apply to induction chemotherapy given prior to trial 
enrolment.  
 
8.2 Drug Administration 
 
8.2.1 Etoposide 
 
During cycles 1-4, etoposide 100 mg/m2 IV will be administered over approximately 4 hours on 
days 1, 2, and 3 of each 3 week cycle.  BSA will be obtained by the Mosteller equation:   
BSA= (( ht(cm) * wt(kg) ) / 3600)1/2 
Etoposide will be given for up to 4 cycles. 
 
8.2.2 Cisplatin 
 
During cycles 1-4 of the induction phase, subjects for whom cisplatin/etoposide has been selected 
as chemotherapy will receive cisplatin IV at a dose of 80 mg/m2 on day 1 of each 3 week cycle.  
The dosage will be administered over approximately 2 hours.  BSA will be obtained by the 
Mosteller equation.  Cisplatin will be given for up to four cycles. 
 
Pre-hydration and post-hydration can be administered per institutional standards. 
 
8.2.3 Carboplatin 
 
During cycles 1-4 of the induction phase, subjects for whom carboplatin/etoposide has been 
selected as chemotherapy will receive carboplatin IV at AUC 5 on day 1 of each 3 week cycle.  

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
40
The dosage will be administered over approximately 30 minutes.  AUC should be calculated using 
the Calvert formula.  Carboplatin will be given for up to four cycles. 
 
Creatinine clearance must be calculated prior to every dose of carboplatin using the Cockroft-Gault 
formula for estimating creatinine clearance in mL/min based on serum creatinine: 
 
 
Men:  
[(140-Age (yrs)) * weight (kg)] 
 
 
 
[72 * serum creatinine (mg/dL)] 
 
 
Women: 
[(140-Age (yrs)) * weight (kg)]      *0.85 
 
 
 
[72 * serum creatinine (mg/dL)] 
 
If calculated GFR is greater than 125 mL/min, the maximum GFR used to calculate carboplatin 
dose should be 125 mL/min to avoid potential toxicity due to overdosing. 
 
8.2.4 Cisplatin Versus Carboplatin 
 
Cisplatin is the preferred platinum agent.  For patients unable to tolerate cisplatin in the opinion of 
the treating clinician, carboplatin is an acceptable alternative.  Subjects are allowed to switch from 
cisplatin to carboplatin during therapy, if the subject becomes ineligible for further cisplatin 
therapy in the opinion of the treating clinician, and the clinician feels that switching to carboplatin 
is in the best interest of the subject 
 
8.3 Dose Delays and Dose Modifications for Cytotoxic Chemotherapy 
 
8.3.1 Dose Delays 
 
Drug related toxicities must be resolved to baseline or ≤ grade 1 (with the exception of alopecia 
and grade 2 fatigue) prior to administering the next dose.  Subjects should not receive the next 
cycle of chemotherapy if any of the following apply: 
 
• Absolute neutrophil count (ANC) <1500/mm3 
• Platelet count <100,000/mm3 
• Hemoglobin <9 g/dL 
• Total bilirubin >2.5 times the upper limit of normal (ULN) 
• AST and ALT >2.5 times ULN, or >5 times ULN if liver metastases are present 
• Inadequate renal function defined as creatinine clearance < 45 mL/min by the standard 
Cockroft and Gault formula 
• Additionally, treatment may be delayed due to any other reasons as per the treating 
physician’s discretion. 
 
Chemotherapy treatment may be delayed up to 21 days. 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
41
 
8.3.2 Dose Modifications 
 
Dose modifications for carboplatin, cisplatin, and etoposide will follow local guidelines.  
Suggestions for dose reductions are provided below. 
 
 
Etoposide Dose 
Cisplatin Dose 
Carboplatin Dose 
Starting Dose 
100 mg/m2 
80 mg/m2 
AUC 5 
Dose Level -1 
75 mg/m2 
60 mg/m2 
AUC 4 
Dose Level -2 
50 mg/m2 
40 mg/m2 
AUC 3 
 
 
8.3.2.1 Suggested Dose Modifications for Hematologic Toxicity 
 
Drug Related Toxicity 
Etoposide 
Cisplatin 
Carboplatin 
Febrile Neutropenia (temperature 
≥38.5˚C and ANC <1000/m3) 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Platelets <25,000/m3 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Grade 4 anemia (Hgb<6.5 g/dL) 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
 
 
8.3.2.3 Suggested Dose Modifications for Non-Hematologic Toxicity 
 
For all toxicity ≤ grade 2 (except neuropathy), the dose level for all drugs should be maintained.   
All dose modifications should be made based on the worst grade toxicity seen. 
 
Drug Related Toxicity 
Etoposide 
Cisplatin 
Carboplatin 
Nausea/Vomiting ≥ Grade 3 
despite 
optimal 
medical 
treatment 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Decrease 1 dose 
level 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
42
Diarrhea ≥ Grade 3 despite 
optimal medical treatment 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Neuropathy, grade 2 lasting > 7 
days or grade 3 
No modification 
Decrease 2 dose 
levels 
No modification 
Neuropathy grade 4 
No modification 
Discontinue 
No modification 
Total bilirubin >2 x ULN 
50% of previous 
dose 
No modification 
No modification 
Total bilirubin >5 x ULN 
Discontinue 
No modification 
No modification 
Other grade ≥ 3 toxicities (except 
fatigue and arthralgia/myalgia) 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
Decrease 1 dose 
level 
 
 
9.0 STATISTICAL ANALYSIS PLAN 
Data Protection and Confidentiality 
We will have two independent phase I 3x3 escalations going on simultaneously, one for LS-SCLC 
patient in part A (with chemotherapy) and those for ES-SCLC (without chemotherapy) for part B.  
All patients who meet eligibility criteria and are enrolled in this trial will be registered in Clinical 
Oncology Research Database (CORe) at the University of Texas M D Anderson Cancer Center at 
Houston. All protocol participants must be registered in the CORE. The date in the current 
informed consent document is displayed to ensure only the most current IRB approved version is 
used.  Consent date, registration date, off study date, and evaluability data are required for all 
registrants. 
The principal investigator agrees to keep all information and results concerning the study 
confidential. The confidentiality obligation applies to all personnel involved with this clinical 
trial.  The Investigator must ensure that each participant’s anonymity will be maintained in 
accordance with applicable laws.  The principal investigator should keep a separate log of ID 
numbers, names and addresses.  Documents that contain the names associated with these ID 
numbers (e.g., written consent/assent forms), should be maintained by the Investigator in strict 
confidence except to the extent necessary to allow auditing by regulatory authorities, auditing or 
monitoring by the IRB. 
The Principal Investigator shall obtain all such permissions and authorizations as may be necessary 
or desirable to allow the collection and use of information protected under federal privacy laws 
and state privacy laws, including permission/authorization for monitoring and analysis (including 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
43
re-analysis in combination with results of other studies), for regulatory submission purposes and 
for applicable reporting (if any). 
Under this protocol, we will collaborator with Dr. Vivek Verma at the University of Nebraska. All 
data sent to Dr. Verma will be de-identified with no names, dates, or medical record numbers. The 
de-identified data will be sent in an Excel spreadsheet via MDACC encrypted email and will be 
used to perform analysis. Patient identification information will be removed from all documents. 
The data will be coded by anonymous study numbers using a key kept separate from the database 
that only the principal investigator will have access to. Data will be stored on a password and 
firewall protected computer.  
9.1 Data Set Descriptions 
 
This study will utilize a standard 3+3 design and dose de-escalation will proceed according to the 
following scheme. Three doses of MK-3475 (100 mg, 150 mg, 200 mg) will be given to 3 
different groups of 3 patients. If the toxicity is greater than 1/3 in one group then the next lower 
dose will be used. This will establish the MTD, if present.  If more than 1/3 of patients 
experience DLTs at the lowest dose (70 mg), it will be concluded that MK-3475 cannot be given 
safely with chemo/radiation. If one of three patients at any dose level experiences grade 3 or 
greater toxicity then another 3 patient will be accrued at the same dose level.  If 1/6 patients has 
grade 3 or higher toxicity then escalation will proceed, if 2/6 has grade 3 or greater toxicity then 
this is declared the MTD. If 3/6 has grade 3 or greater then we will reduce the dose level.  
 
Part A: Is only for patients with Limited stage SCLC, we will allow induction chemotherapy.  
 
 
 
 
 
 
 
 
 
 
 
DLT Assessment  
Day 22 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
44
Part B: Is only for patients with Extensive stage SCLC who are receiving consolidation XRT after 
1-6 cycles of chemotherapy.  
 
 
Table 1: Dose De-escalation, For Part A and B 
 
Dose 
Level 
MK-3475 (dose during 
XRT) 
Toxicity Assessment 
New MK 3475 dose 
+2 
200mg Q 3 weeks 
If over 1/3 grade 3 toxicity 
is seen 
150mg Q 3 weeks 
+1 
150mg Q 3 weeks 
If over 1/3 grade 3 toxicity 
is seen 
If 0/3 grade 3 toxicity is 
seen  
100mg Q 3 weeks 
 
200mg Q 3 weeks 
 
0 
(starting 
dose) 
100mg Q 3 weeks 
If over 1/3 grade 3 toxicity 
is seen 
If 0/3 grade 3 toxicity is 
seen 
70mg Q 3 weeks 
 
150mg Q3 weeks 
-1 
70mg Q 3 weeks 
If over 1/3 grade 3 toxicity 
is seen 
We will conclude MK-
3475 cannot be safely 
given after 
Chemo/radiation 
 
 
 
Once the MTD is determined for each study part we will accrue at this MTD until we reach a total 
of 40 patients for each study part.  Should DLTs occur in more than 1/3 of patients enrolled into 
this expanded cohort, dosing at that level will be stopped. A review of all DLTs observed will be 
conducted, and the need to lower the dose will be based on the discussion and agreement between 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
45
the IRB and the Investigator. Once at dose level +2, if 0/3 toxicity is seen we will not close the 
study for new patient enrollment until the third patient has passed the DLT assessment period, 
because even if this third patient has a DLT was seen it would no change the dose for future patients 
as another 3 patients at the same dose level would be needed.  
 
All patients who receive any MK-3475 will be considered evaluable for response and will be 
included in the efficacy data set. 
 
DLT is defined as any: 
• DLTs are defined as any adverse event(s) considered related to the combination of MK-3475 
plus radiation as described below: 
• Any ≥ Grade 3 bronchospasm or other hypersensitivity reaction; 
• Any other ≥ Grade 3 non-skin related adverse event with the exception of laboratory 
abnormalities; 
• Any Grade 4 laboratory abnormalities, except AST, ALT, or total bilirubin; 
 AST or ALT > 8 x ULN, 
 Total bilirubin > 5 x ULN; 
o Any other Grade 4 adverse event; 
1. Any adverse event, laboratory abnormality or intercurrent illness which, in the judgment 
of the investigator, presents a substantial clinical risk to the subject with continued study 
drug dosing; 
2. Subject experiences an allergic/infusion reaction while receiving study drug at a slower 
infusion rate due to a prior allergic/infusion reaction; 
3. Any motor neurologic toxicity ≥ Grade 3 regardless of causality; 
4. Any ≥ Grade 3 treatment-related sensory neurologic toxicity. 
5. Drug related toxicity that prevents administration of MK-3475 for > 21 days from the 
scheduled dose 
 
• The time frame for DLT assessment will be within 22 days of therapy initiation. 
• Any grade 4 neutropenia (with or without fever and/or sepsis) or thrombocytopenia 
(with or without bleeding) lasting at least 1 week or longer (as defined by the NCI-
CTC v4.0). 
• Any other grade 3 non-hematologic toxicity including symptoms/signs of vascular 
leak or cytokine release syndrome; or any severe or life-threatening complication 
or abnormality not defined in the NCI-CTCAE v4.0 that is attributable to the 
therapy. 
 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
46
 
9.2.1. Statistical Analysis 
Descriptive statistics will be computed for all relevant outcomes, including toxicity, tumor 
response, PFS, OS, and biomarker response. Descriptive analysis will include a global assessment 
of patient outcomes for parts A and B separately. All patients receiving at least 1 treatment with 
MK-3475 will be included in the analysis. 
9.2.2. Demographics and Baseline Characteristics 
Frequency distributions of gender and race will be tabulated by dose/cohort. Summary statistics 
for age, body weight, height, and Body Mass Index (BMI) will be tabulated by dose/cohort.  
9.2.3. Safety Analyses 
All recorded adverse events will be recorded per MDACC guidelines using CTCAE Version 4.0. 
Frequency of adverse events will be tabulated by grade, type, and dose/cohort. Relative 
frequencies and confidence intervals will also be constructed. 
9.2.4. Efficacy Analyses 
Efficacy data from part A and part B will be performed using the criteria below.  
1. Global irRC: irRC that factors all lesions both index and non-index. 
 
2. In-Field irRC: irRC in which only XRT-treated lesions will be considered and non-
index lesions arising inside the XRT PTV 
 
3. Out-Field irRC: irRC in which only non XRT-treated lesions will be considered and 
non-index lesions arising outside the XRT PTV 
 
Time-to-event distributions for PFS and OS will be estimated via Kaplan-Meier analysis. 
Summary statistics will be computed along with confidence intervals. The limited sample size 
precludes formal statistical comparison with historical controls. 
 
9.2.5. Sample Size/Accrual Rate  
The maximum planned number of patients will be 80, with 40 patients being treated with LS-
SCLC and 40 patients with ES-SCLC. It is estimated that approximately 1.5 patients per month 
(for both LS-SCLC and ES-SCLC) will be accrued over 26 months. With 40 patients, the 
probability of seeing at least one patient with toxicity if the true toxicity rate is 0.1 is 88%. The 
95% binomial confidence interval for 6/20 (30%) extends from 15% to 52%. 
 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
47
10.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
10.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 11. 
Table 11 Product Descriptions 
Product Name & Potency 
Dosage Form 
MK-3475 100 mg/ 4mL 
Solution for Injection 
 
10.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
10.3 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. 
10.4 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. 
10.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
48
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
11.0 ADMINISTRATIVE AND REGULATORY DETAILS 
11.1 Confidentiality 
Confidentiality will be maintained throughout this study in accordance with the Health Insurance 
Portability and Accountability Act. This study will be presented and approved by the Internal 
Review Board at MD Anderson Cancer Center.  
11.2 Compliance with Financial Disclosure Requirements 
N/A 
11.3 Compliance with Law, Audit and Debarment 
N/A 
11.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible 
for determining whether the trial and its results are subject to the requirements for submission to 
the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.     
12.0 LIST OF REFERENCES 
1. 
Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8. 
2. 
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated 
B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 
2002;8(8):793-800.   
3. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
4. 
Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.   
5. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
49
6. 
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients 
with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.   
7. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. 
Cancer Metastasis Rev 2007;26:373-400. 
8. 
Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.   
9. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic effect 
of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. Clin Cancer 
Res 2008;14(16):5220-7. 
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. Tumor 
infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. 
BMC Immunol 2010;11:19. 
11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. Histopathologic 
prognostic score in colorectal adenocarcinomas. Anticancer Res 1998;18:689-94.   
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, 
density, and location of immune cells within human colorectal tumors predict clinical 
outcome. Science 2006;313:1960-4.   
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. 
Int J Clin Oncol 2010;15:544-51.   
14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival 
of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic 
cell infiltration after interleukin-2 immunotherapy. Report of a case. Tumori 2008;94:426-30.   
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.   
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10(840):841.   
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, Winnepenninckx 
V, et al. Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in 
primary cutaneous melanoma. Cancer Immunol Immunother 2008;57:97-106.   
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of type 
and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.   

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
50
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions 
of advanced stage ovarian cancer. Cancer Immunol Immunother 2009;58:449-59.   
20. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.   
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory T 
cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor 
prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6.   
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value of 
tumour-infiltrating lynmphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-24.   
23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the 
treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346-
57.   
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.   
25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ cell 
infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in neoadjuvant 
chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 2010;59:909-19.   
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71. 
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48.   
28. Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma:  prognostic factors. 
Cancer Control 2005;12(4):223-9.   
29. Iannone R, Gergich K, Cong C, Kang P, Daud A, Dronca R, et al.  Efficacy and safety of MK-
3475 in patients with advanced melanoma.  Pigment Cell Melanoma Res 2012;25:836-903. 
30. 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:doi: 
10.1056/NEJMoa1200690.   

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
51
31. Lyford-Pike S, Peng S, Young GD, et al.  Evidence for a role of the PD-1:PD-L1 pathway in 
immune resistance of HPV-associated head and neck squamous cell carcinoma.  Cancer Res 
2013;73(2): Published online January 3. 
32. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent R, Ford R, et al.  New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 
33. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al.  Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria.  Clin 
Cancer Res 2009;15(23):7412-20. 
34. Blum JL, Jones SE, Buzdar AU, LoRusso PM, et al. Multicenter Phase II Study of 
Capecitabine in Paclitaxel-Refractory Metastatic Breast Cancer. J Clin Oncol 17: 485-493, 
1999 
35. Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, et al. Gemcitabine plus 
vinorelbine monotherapy in patients with metastatic breast cancer previously treated with 
anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research 
Group (GEICAM) trial. Lancet Oncol. 2007;8(3):219. 
36. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, et al.  Phase III Trial of 
Doxorubicin, Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line 
Chemotherapy for Metastatic Breast Cancer: An Intergroup Trial (E1193).   J Clin Oncol. 
2003;21(4):588. 
37. Stewart JSW, Ezra E.W. Cohen EEW, Licitra L, Van Herpen CML, et al.  Phase III Study of 
Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous Cell Carcinoma 
of the Head and Neck.  J Clin Oncol. 2009;27(11):1864. 
38. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, et al.  Open-Label, Uncontrolled, 
Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of Cetuximab As a Single 
Agent in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head 
and Neck Who Failed to Respond to Platinum-Based Therapy.   J Clin Oncol. 
2007;25(16):2171. 
39. Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, et al.  Phase III Trial of 
Vinflunine Plus Best Supportive Care Compared With Best Supportive Care Alone After a 
Platinum-Containing Regimen in Patients With Advanced Transitional Cell Carcinoma of the 
Urothelial Tract.  J Clin Oncol. 2009;27(27):4454 
40. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, et al.  Phase II Study of 
Pemetrexed for Second-Line Treatment of Transitional Cell Cancer of the Urothelium.  J Clin 
Oncol. 2006;24(21):3451 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
52
41. Clopper C and Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 1934;26:404-413. 
Additional references  
1 
Slotman, B. et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. The 
New England journal of medicine 357, 664-672, doi:10.1056/NEJMoa071780 (2007). 
2 
Murray, N. & Turrisi, A. T., 3rd. A review of first-line treatment for small-cell lung cancer. 
Journal of thoracic oncology : official publication of the International Association for the 
Study of Lung Cancer 1, 270-278 (2006). 
3 
Morrison, C. D., Parvani, J. G. & Schiemann, W. P. The relevance of the TGF-beta Paradox 
to EMT-MET programs. Cancer Lett, doi:S0304-3835(13)00211-5  
4 
Andarawewa, K. L. et al. Ionizing radiation predisposes nonmalignant human mammary 
epithelial cells to undergo transforming growth factor beta induced epithelial to 
mesenchymal transition. Cancer Res 67, 8662-8670, doi:67/18/8662 
5 
Jung, J. W. et al. Ionising radiation induces changes associated with epithelial-
mesenchymal transdifferentiation and increased cell motility of A549 lung epithelial cells. 
Eur J Cancer 43, 1214-1224, doi:S0959-8049(07)00121-9 
6 
Baschnagel, A. M. et al. c-Met Expression Is a Marker of Poor Prognosis in Patients With 
Locally Advanced Head and Neck Squamous Cell Carcinoma Treated With 
Chemoradiation. International journal of radiation oncology, biology, physics 88, 701-
707, doi:10.1016/j.ijrobp.2013.11.013 (2014). 
7 
Peifer, M. et al. Integrative genome analyses identify key somatic driver mutations of 
small-cell lung cancer. Nat Genet 44, 1104-1110, doi:10.1038/ng.2396 (2012). 
8 
Turrisi, A. T., 3rd et al. Twice-daily compared with once-daily thoracic radiotherapy in 
limited small-cell lung cancer treated concurrently with cisplatin and etoposide. The New 
England journal of medicine 340, 265-271, doi:10.1056/NEJM199901283400403 (1999). 
9 
Roach, M., 3rd et al. Radiation pneumonitis following combined modality therapy for lung 
cancer: analysis of prognostic factors. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 13, 2606-2612 (1995). 
10 
Wolchok, J. D. et al. Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clinical cancer research : an official journal of 
the American Association for Cancer Research 15, 7412-7420, doi:10.1158/1078-
0432.CCR-09-1624 (2009). 
 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
53
13.0 APPENDICES 
13.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
13.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
13.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT 
or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, 
S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
54
J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
13.4 
 
 
 
 
 
 
 
 
MK-3475 
 
 
 
 
 
 
 
 
 
 
 
 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
55
PEMBROLIZUMAB PROGRAM 
(MK-3475) 
 
 
 
EVENT OF CLINICAL INTEREST  
 
GUIDANCE DOCUMENT 
 
 
Version 3.0 
 
 
 
 
 
 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
56
 
 
 
 
 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
57
REVISION HISTORY LOG 
 
Version 
Effective 
Date* 
Revision 
Author 
Action 
1 
08-Aug-2012 
Kevin Gergich 
Initial Release of guidance document for MK-3475 
 
2 
07-June-2013 
Marty Huber, 
Kevin Gergich, 
Holly Brown 
Revised title, formerly was “MK-3475 Immune-Related 
Adverse Event Identification, Evaluation and Management 
Guidance Document for Investigators” 
 
Revised the format of irAE Guidance document, including 
layout, font, sectioning, etc. for consistency with Sponsor 
Events of Clinical Interest guidance documents. 
 
Modified Categories for irAEs: 
– 
Replaced GI with Colitis category. 
– 
Removed Neurologic category. 
– 
Added Renal category. 
 
Removed detail in the irAE Guidance document that can be 
located in the Investigator’s Brochure for MK-3475. 
 
Removed details regarding non-MK-3475 compounds. 
 
Added ECI reporting guidelines. 
 
Included a Table Events of Clinical Interest: Immune-
Related Adverse Events that includes the key terms. 
– 
Also placed a pull-out quick-review sheet in the 
Appendix. 
 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
58
Updated background, diagnosis and course of treatment 
details for irAEs. 
 
3 
 
Marty Huber, 
Kevin Gergich, 
Holly Brown 
Renamed the document: “Pembrolizumab Program (MK-
3475) - Events of Clinical Interest Guidance Document”. 
 
Introduced generic name: pembrolizumab (MK-3475) and 
inserted throughout the document. 
 
Updated Overview – Section 1  
- Clarified the scope of the document and the reporting 
window for ECIs 
 
- Updated Table 1 with medDRA Preferred Terms for 
adverse events to correspond with reporting of terms to 
clinical database, rearranged the order, and updated the 
reporting criteria. 
 
- Updated the dose modification/discontinuation section to 
clarify discontinuation and hold terminology. 
 
Updated Section 2 – ECI Reporting Guidelines  
– Clarified that ECIs must be reported to Merck within 24 
hours regardless of attribution to study treatment or 
etiology. 
 
Updated Section 3  
– For All Sections, removed the Course of Action for 
Grade 1 events. 
 
- Section 3.1 Pneumonitis 
– 
Moved Pneumonitis to beginning of ECI Section 
– 
Updated management guidelines for Grade 2 and 
Grade 3-4 events 
 
- 
Section 3.2 Colitis:   

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
59
- 
Updated AE terms and ECI criteria, updated 
course of action language for clarity  
 
- Section 3.3 Endocrine:   
- 
Updated ECI criteria and updated course of action 
language for clarity.   
- 
Added subsections for hypophysitis, 
hyperthyroidism and hypothyroidism to clarify 
management guidelines. 
 
- Section 3.4 Hematologic:   
- 
New section added. 
 
- Section 3.5:  Hepatic:   
- 
Updated terms and added additional guidance for 
reporting of DILI ECI; updated course of action 
for clarity 
 
- Section 3.6 Neurologic:  
- 
New section added. 
 
- Section 3.7 Ocular:   
- 
Changed the name of this section from Eye to 
Ocular 
- 
Added the term “iritis”, updated ECI guidance, 
and updated course of action language for clarity 
 
- Section 3.8 Renal:  
- 
Updated section for clarity. 
 
- Section 3.9 Skin:   
- 
Updated list of terms and added terms for 
reporting of other skin ECIs; added section 3.9.1: 
Immediate Evaluation for Potential Skin ECIs 
 
- Section 3.10 Other:  

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
60
- 
Updated list of terms for clarity; revised course of 
action for clarity.   
 
 
- Section 3.11 Infusion Reactions:   
- 
New section added. 
 
- Section 3.12:  Follow-up to Resolution:  
- 
New section added. 
 
- Section 4:  
- 
References updated. 
 
- Section 5:  
- 
ECI table updated for consistency with Table 1.  
 
- Section 6: Appendix 2 – Past Medical History Related to 
Dermatologic Event:  New section added. 
 
- Section 7: Appendix 3 – Presentation of the Dermatologic 
Event:  New section added. 
 
- Section 8: Appendix 4 – Focused Skin Examination:  New 
section added. 
*Ensure that you are using the most current version of this document.  

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
61
TABLE OF CONTENTS 
 
 
 
1. OVERVIEW ........................................................................................................................ 1 
2. ECI REPORTING GUIDELINES .................................................................................... 4 
3. ECI CATEGORIES AND TERMS ................................................................................... 4 
3.1 Pneumonitis ................................................................................................................... 4 
3.2 Colitis ............................................................................................................................. 6 
3.3 Endocrine ....................................................................................................................... 7 
3.4 Hematologic ................................................................................................................... 9 
3.5 Hepatic ......................................................................................................................... 10 
3.6 Neurologic .................................................................................................................... 12 
3.7 Ocular .......................................................................................................................... 13 
3.8 Renal ............................................................................................................................ 14 
3.9 Skin ............................................................................................................................... 15 
3.9.1. Immediate Evaluation for Potential Skin ECIs ..................................................... 16 
3.10 Other .......................................................................................................................... 19 
3.11 Infusion Reactions ..................................................................................................... 20 
3.12 Follow-up to Resolution ............................................................................................ 23 
4. REFERENCES .................................................................................................................. 23 
5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table ........................... 25 
6. APPENDIX 2 – Past Medical History Related to Dermatologic Event ....................... 27 

Pembrolizumab Event of Clinical Interest Guidance Document 
Final 10-Sept-2014 
Version 3.0 
 
 
 
62
7. APPENDIX 3 – Presentation of the Dermatologic Event.............................................. 28 
8. APPENDIX 4 – Focused Skin Examination ................................................................... 32 
 
 
 

Product:  MK-3475 
1 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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 in the database.   
Table 3: 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 

Product:  MK-3475 
2 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
 
 
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 
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 
 
 

Product:  MK-3475 
3 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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 
 
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.   
 

Product:  MK-3475 
4 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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).   
 
 
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 
 

Product:  MK-3475 
5 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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. 
– 
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. 
 

Product:  MK-3475 
6 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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 >1 week, 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 
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persist for greater than 3 days): 
– 
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. 

Product:  MK-3475 
7 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
– 
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 events: 
– 
Report as ECI if appropriate 
– 
Hold pembrolizumab  
– 
Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until 
returned to baseline values. 

Product:  MK-3475 
8 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
– 
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.  
– 
Consultation with an endocrinologist may be considered. 
 
Grade 3 events: 
– 
Report as ECI 
– 
Hold pembrolizumab.  
– 
Endocrine consultation is recommended. 
– 
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.   
– 
Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, and 
electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal crisis. 
– 
Hospitalization and endocrine consultation should be considered.   
 
Grade 4 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab.  
– 
Manage as per Grade 3 
 
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 events (and Grade 3-4 hypothyroidism): 
– 
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.  

Product:  MK-3475 
9 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
– 
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. 
 
Grade 4 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab.  
– 
Manage as per Grade 3 
 
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) 
– 
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. 
 

Product:  MK-3475 
10 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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 
 
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. 
 

Product:  MK-3475 
11 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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.  

Product:  MK-3475 
12 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
– 
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 

Product:  MK-3475 
13 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
– 
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. 
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. 
 
 

Product:  MK-3475 
14 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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 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.   
 
 

Product:  MK-3475 
15 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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. 
 
Course of Action 
Grade 2 events: 

Product:  MK-3475 
16 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
– 
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. 
 
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.  

Product:  MK-3475 
17 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
– 
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 2 (Past 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 
3 (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 4 (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.  

Product:  MK-3475 
18 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
 
The site should provide the dermatologist with all relevant case history, including copies of clinical 
photographs and laboratory test results.  

Product:  MK-3475 
19 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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. 
 
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  
 

Product:  MK-3475 
20 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
 
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. 
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 

Product:  MK-3475 
21 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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). 

Product:  MK-3475 
22 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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 

Product:  MK-3475 
23 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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.  
4. 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. 
 

Product:  MK-3475 
24 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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 
 

Product:  MK-3475 
25 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
5. APPENDIX 1 –EVENTS OF CLINICAL INTEREST (ECI) – REFERENCE 
TABLE 
 
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 
 
 
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 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 

Product:  MK-3475 
26 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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 
 
 

Product:  MK-3475 
27 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
6. APPENDIX 2 – 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: _____________________  
____________________________________________________________  

Product:  MK-3475 
28 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
 
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  
 
7. APPENDIX 3 – PRESENTATION OF THE DERMATOLOGIC EVENT 
 
Presentation of the event:  

Product:  MK-3475 
29 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
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? __________________________________________________  

Product:  MK-3475 
30 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
 
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  
 
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): _________________________________________  

Product:  MK-3475 
31 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
___________________________________________________________________ 
 
13. Is the rash pruritic (itchy)? □ Yes □ No  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Product:  MK-3475 
32 
Protocol/Amendment No.:   
2014-1003 
 
  
 
 
 
 
8. APPENDIX 4 – 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? 
______________________________________________________________