Phase II Study of MK-3475 as Maintenance Therapy in Extensive Stage Small Cell Lung Cancer (SCLC) Patients
Phase: PHASE2
Conditions: Extensive Stage Small Cell Lung Carcinoma
Sponsor: Barbara Ann Karmanos Cancer Institute

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2014-111: Phase II study of MK-3475 as Maintenance Therapy in Extensive Stage Small 
Cell Lung Cancer (SCLC) Patients  
 
Principal Investigator 
Ammar Sukari, MD 
Professor, Department of Oncology 
4100 John R, 4 HWCRC 
Detroit, MI 48201 
sukaria@karmanos.org   
Tel: 313-576-8778 
Fax: 313-576-8702 
 
Co-Investigators 
Antoinette Wozniak, MD 
Misako Nagasaka, MD 
Manish Thakur, MD 
 
Bio-Statistician 
Wei Chen, PhD 
 
Correlative Studies 
Julie Boerner, PhD 
QualTek Clinical Laboratories 
 
Study Coordinator 
Jaclyn Ventimiglia 
 
Research Nurse 
Cathy Galasso, RN 
 
 
 
Version Date- 09/19/2014 
Version Date- 10/20/2014 
Version Date- 12/12/2014 
Version Date- 02/21/2015 
Version Date- 06/08/2015 
 
Version Date- 08/31/2015 
Version Date- 10/31/2015 
Version Date- 03/08/2016 
Version Date- 09/06/2016 
Version Date- 11/28/2016 
Version Date- 03/15/2017 
Version Date- 07/24/2017 

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Participating Centers: 
Cleveland Clinic 
Nathan A. Pennell, MD, PhD 
9500 Euclid Ave. 
Cleveland, OH 44195 
penneln@ccf.org  
Tel: 216-445-9282 
 
Penn State Milton S. Hershey Medical Center 
Chandra Prakash Belani, MD 
Penn State Hershey Cancer Institute 
500 University Dr. 
Hershey, PA 17033 
cbelani@psu.edu 
Tel: 717-531-1078 
 
Montefiore-Einstein Center for Cancer Care 
Balaz Halmos, MD 
1695 Eastchester Road 
Bronx, NY 10461 
& 
Montefiore Medical Center 
111 East 210th Street 
Bronx, NY 10467 
bahalmos@montefiore.org 
Tel: 718-405-8404 
 
Rush University Medical Center 
Mary J. Fidler, MD 
Division of Hematology & Oncology 
1725 W. Harrison St., Suite 1010 and 1059 
Chicago, IL 60612 
mary_fidler@rush.edu 
Tel: 312-942-3375 
 
University of Michigan 
Gregory Peter Kalemkerian, MD 
University of Michigan Comprehensive Cancer Center 
1500 E. Medical Center Dr. 
Ann Arbor, MI 48109 
kalemker@umich.edu 
Tel: 734-647-8902 

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Index 
1. Trial Summary 
 
 
 
 
 
 
 
5 
 
2. Trial Design  
 
 
 
 
 
 
 
5 
 
3. Objectives & Hypothesis 
 
 
 
 
 
 
5 
 
4. Background & Rationale 
 
 
 
 
 
 
6 
Small Cell Lung Cancer 
 
 
 
 
 
 
6 
Immune Surveillance and PD-1 
 
 
 
 
 
6 
MK-3475 
 
 
 
 
 
 
 
 
7 
Targeting PD-1 in SCLC 
 
 
 
 
 
 
9 
Rationale 
 
 
 
 
 
 
 
 
11 
 
5. Eligibility 
 
 
 
 
 
 
 
 
13 
Inclusion Criteria  
 
 
 
 
 
 
 
13 
Exclusion Criteria 
 
 
 
 
 
 
 
14 
 
6. Trial Treatments 
 
 
 
 
 
 
 
16 
Dose Modification 
 
 
 
 
 
 
 
17 
Timing of Dose Administration 
 
 
 
 
 
18 
Concomitant Medication/Vaccinations 
 
 
 
 
19 
Rescue Medications and AE management 
 
 
 
 
20 
Contraception/Pregnancy/Nursing 
 
 
 
 
 
30 
Subject Discontinuation Criteria 
 
 
 
 
 
31 
Subject Replacement Strategy 
 
 
 
 
 
32 
 
7. Trial Flow Chart 
 
 
 
 
 
 
 
33 
 
8. Trial Procedures 
 
 
 
 
 
 
 
35 
Registration Procedure 
 
 
 
 
 
 
35 
Informed Consent 
 
 
 
 
 
 
 
35 
Disease Details  
 
 
 
 
 
 
 
35 
 
Clinical Procedures and Assessment   
 
 
 
 
36 
 
Withdrawal/Discontinuation  
 
 
 
 
 
38 
 
Visit Requirements/Safety Follow Up/Retreatment  
 
 
38 
 
Assessing and Recording Adverse events 
 
 
 
 
39 

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9. Correlative Studies  
 
 
 
 
 
 
42 
 
10. Definitions of End Points 
 
 
 
 
 
 
43 
 
11. Statistical Analysis Plan 
 
 
 
 
 
 
44 
Study Design and Primary Endpoint  
 
 
 
 
44 
Sample Size and Accrual Rate 
 
 
 
 
 
44 
Analysis Plan for Secondary Endpoints 
 
 
 
 
45 
 
12. Labeling, Packaging, Storage, Returning of Clinical Supplies 
 
45 
Investigational Product 
 
 
 
 
 
 
45 
Packaging and Labeling Information  
 
 
 
 
45 
Storage and Handling Requirements  
 
 
 
 
46 
Returns and Reconciliation 
 
 
 
 
 
 
46 
 
13. Administrative and Regulatory Details 
 
 
 
 
46 
Confidentiality 
 
 
 
 
 
 
 
46 
Compliance with Financial Disclosure Requirements 
 
 
46 
Compliance with Trial Registration and Results Posting Requirement 
46 
Data and Safety Monitoring  
 
 
 
 
 
47 
Oversight of Participating Sites 
 
 
 
 
 
47 
 
14. References 
 
 
 
 
 
 
 
 
48 
 
15. Appendixes  
 
 
 
 
 
 
 
51 
ECOG Performance Status 
 
 
 
 
 
 
51 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)  
51 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria  
51 
Events of Clinical Interest and Immune Related Events 
 
 
52 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Maintenance Therapy of MK-3475 in SCLC patients. 
Trial Phase 
II 
Clinical Indication 
Small Cell Lung Cancer 
Trial Type 
Single Arm Open Label Phase II 
Route of administration 
Intravenous 
Trial Blinding 
N/A 
Treatment Groups  
N/A 
Number of trial subjects 
45 
Estimated duration of trial 
18 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 Trial Diagram 
 
 
 
 
The primary end point of the study is to assess Progression Free Survival (PFS) by RECIST 
1.1. However it is well recognized that patients on immune check point inhibitors may 
experience pseudo-progression or can have delayed response. Therefore patients who do not 
have development of significant signs or symptoms of progression or significant decline in 
performance status or the patient/the treating physician feel the need to start next treatment, 
will require evidence of progression on 2 scans more than 4 weeks apart. Both RECIST 
defined PFS and this modified PFS will be reported for all patients enrolled on the trial.   
 
3.0 OBJECTIVE(S) & HYPOTHESIS 
3.1 Primary Objective(s) & Hypothesis 
Objective: To assess RECIST 1.1 defined PFS in extensive stage SCLC patients, who have 
CR, PR or stable disease following minimum of 4 cycles of platinum (cisplatin or 
carboplatin) and etoposide. 
Hypothesis:  Maintenance therapy with MK-3475 will increase progression free survival 
(PFS) in extensive stage SCLC patients, who have non-progressing disease following 
completion of combination chemotherapy with a platinum analogue and etoposide.   
 
CR, PR, SD 
Following 4 
cycles of 
EC or EP. 
PCI allowed 
MK-3475, 200 
mg IV every 3 
weeks  
Disease 
assessment 
every 6 
weeks.  

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3.2 Secondary Objective(s) & Hypothesis(es) 
1. To assess modified PFS in all patients enrolled (see section 10.2 for definition).  
2. To assess overall survival of patients enrolled on the trial. 
3. To assess PD-L1 expression in archival tumor tissues and in circulating tumor cells 
(CTCs) and correlate the expression to RECIST defined PFS.  
 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
Small Cell Lung Cancer (SCLC) 
Of the over 225,000 patients diagnosed with lung cancer each year, 13% or about 
30,000 patients have SCLC (1). Approximately 66% of the patients have advanced 
stage disease at the time of diagnosis. The current standard of care treatment for these 
patients is the chemotherapy combination of a platinum agent and etoposide (2). The 
median survival with this therapy is only about 10 months, with a progression free 
survival (PFS) of about 5 months. Despite multiple clinical trials, no therapy has 
improved outcomes of these patients compared to the current standard of care treatment 
for the last 20 years. Also very few agents are effective in patients with recurrent SCLC 
and of the agents that are considered effective the efficacy is very modest. Another 
challenging aspect of managing SCLC patients is that most of these patients are very 
symptomatic at the time of diagnosis and require prompt initiation of systemic therapy. 
The short PFS with initial chemotherapy and the limited number of agents that have 
benefit in recurrent SCLC, makes this an ideal clinical situation to explore maintenance 
therapy. Previous trials exploring maintenance therapy have shown only modest benefit 
in improving PFS with no improvement in overall survival and therefore maintenance 
therapy is not part of the standard therapy for SCLC patients (3,4,5). It is important to 
note that in these maintenance trials the median PFS following disease 
stabilization with initial chemotherapy is consistently about 2 months in patients 
who received chemotherapy without maintenance therapy.  
 
4.2 Immune Surveillance and PD-1 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (6).  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and 
favorable prognosis in various malignancies (7,8,9).  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 (10,11,12,13).  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 

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(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) (10,11).  PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-
cells, T regs and Natural Killer cells.  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells (14).  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 (12, 13).  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-
L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor.  This suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor immune evasion and should be considered as an attractive 
target for therapeutic intervention. 
4.2.1  
MK-3475 (Pembrolizumab) 
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 (15). This 
blockade enhances functional activity of the target lymphocytes to facilitate tumor 
regression and ultimately immune rejection.  
 
Merck is studying MK-3475 for various oncology indications. Protocol 001 (PN001), 
an open-label Phase I study is being conducted to evaluate the safety and clinical 
activity of MK-3475 when administered as monotherapy (Investigator’s Brochure). The 
dose escalation portion of this study evaluated three dose levels of single agent MK-
3475 (1 mg/kg, 3 mg/kg, and 10 mg/kg), in patients with advanced solid tumors. All 
three dose levels were well tolerated and no dose-limiting toxicities (DLTs) were 
observed, therefore the maximum tolerated dose (MTD) has not been determined. 
Many other trials are ongoing in various tumors types. In addition trials are evaluating 
the addition of MK-3475 to chemotherapy, ipilimumab and tyrosine kinase inhibitors.  
 
MK-3475 strongly enhances T-lymphocyte immune responses in cultured blood cells 
from healthy human donors, cancer patients, and primates (Investigator’s Brochure). In 
T-cell activation assays using human donor blood cells, the EC50 (concentration where 
50% of the maximum effect is achieved) has been ~0.1 to 0.3 nM. In addition to 
interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFN), and 
levels of other cytokines were found to be modulated by MK-3475. The antibody 
potentiates existing immune responses only in the presence of antigen and does not 
nonspecifically activate T-cells. Using an anti-murine PD-1 analog antibody, PD-1 
blockade has been shown to significantly inhibit tumor growth in a variety of syngeneic 
murine tumor models. In these experiments in mice, anti-PD-1 therapy is synergistic 

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with chemotherapeutic agents such as gemcitabine and 5-fluorouracil (5-FU) and 
combination therapy results in increased complete tumor regression rates in vivo. 
 
As of 26-Jul-2013, there have been 789 patients treated in a phase I trial (PN001) with 
MK-3475 as a 30-minute IV infusion. Of these 789 patients, preliminary data are 
available from 479 patients. Based upon this safety database consisting of patients 
treated up to 10 mg/kg once every two to three weeks, MK-3475 has been generally 
well-tolerated at doses up to 10 mg/kg every other week without DLTs. One (0.002%) 
patient assayed to date had samples confirmed positive for ADA, but no impact on 
safety has been observed. Five other clinical studies (PN002, PN006, PN010, PN011, 
and PN012) are ongoing however preliminary data analyses are not yet available.  
 
MK-3475 PK results have been obtained from phase I trial following the first dose at 1, 
3 and 10 mg/kg IV of MK-3475 administered to 17 patients with solid tumors. 
Exposure to MK-3475 is approximately linear in the dose range of clinical relevance 
(1-10 mg/kg).The observed pharmacokinetic profile of MK-3475 was typical of other 
IgG mAbs with a half-life (t½) of approximately 2 to 3 weeks. There was no indication 
of dose dependency of half-life in the 3 dose groups and a dose related increase in 
exposure was observed from 1 to 10 mg/kg. The long half-life supports a dosing 
interval of every 2 or 3 weeks. Exposure obtained with sparse sampling after dosing 
melanoma and non-small cell lung cancer (NSCLC) patients at 2 and 10 mg/kg, every 2 
or 3 weeks, is consistent with this profile.  
 
Durable objective responses have been reported in patients with melanoma and NSCLC 
(15, 16). Adverse events have generally been manageable and infrequently require 
discontinuation of MK-3475 treatment. MK-3475 phase I trial enrolled 207 patients 
with NSCLC who experienced progression of cancer after previous systemic therapy. 
The preliminary objective response rate (ORR) by RECIST v1.1 is 23% (95% CI 16%, 
30%) in patients with tumors deemed to be PD-L1 positive and 9% (95% CI 2%, 23%) 
in patients with tumors that were PD-L1 negative, for an overall response rate of about 
17%. The median response duration is 31 weeks.  
 
Patients were required to submit a newly obtained tumor biopsy prior to initiating 
therapy with MK-3475 to evaluate the tumors for expression of PD-L1, the presumptive 
predictive biomarker of MK-3475, using an immunohistochemistry assay. A modified 
H-score scoring system of PD-L1 expression was established for NSCLC by analyzing 
tumor specimens from resected NSCLC specimens. This scoring system was then 
applied to the samples from these NSCLC patients. A receiver-operating characteristics 
curve was constructed from the data and the Youden Index identified from that analysis 
to help determine a preliminary cut point. A stated above, preliminary data suggest 
higher levels of PD-L1 expression are associated with increased activity. Additional 
data are required to define the optimal PD-L1 cut point. 
 
The safety of MK-3475 was characterized in the 1-month repeat-dose toxicity study in 
cynomolgus monkeys when administered as IV doses of 6, 40 or 200 mg/kg once a 
week (a total of five doses) and in the 6-month repeat-dose toxicity study in 
cynomolgus monkeys when administered as IV doses of 6, 40 or 200 mg/kg every other 
week (a total of 12 doses). MK-3475 was well-tolerated in cynomolgus monkeys with a 

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systemic exposure (AUC) of up to approximately 170,000 μg.day/mL over the course 
of the 1-month study, and with a systemic exposure (AUC) of up to approximately 
67,500 μg.day/mL over the course of the 6-month study. No findings of toxicological 
significance were observed in either 1-month or 6-month toxicity study with MK-3475 
and the NOAEL was ≥200 mg/kg. In addition, no findings of toxicological relevance 
were observed in the in vitro tissue cross-reactivity study using human and cynomolgus 
monkey tissues. There were no nonclinical findings that would preclude testing of MK-
3475 in clinical trials.  
 
Out of a total of 479 patients treated on the phase I trial, 466 (97.3%) experienced 
treatment emergent AEs of which 368 (76.8%) were considered drug-related. SAEs 
were reported in 30.1% of patients, but SAEs that were attributed as potentially 
(possibly, probably, or definitely) drug-related by Investigators were reported in 6.7% 
of patients overall. Five patients died within 30 days of the last dose of MK-3475; none 
of the deaths were considered drug-related. Some of the common adverse events were 
fatigue, pruritus, nausea, diarrhea, cough, dyspnea, skin rash, muscle cramps, fever, 
hypo or hyperthyroidism, flu like symptoms, neutropenia.  
 
An important concern with a drug like MK-3475 is that patients may experience 
immune mediated adverse events. Though it is not completely clear that all the listed 
events were definitely immune related, the following AEs were considered to have an 
immune etiology. These include rash, vitiligo, hypothyroidism, colitis, hepatitis, 
adrenal insufficiency and pneumonitis. All these AEs were observed in less than 5% of 
the patients.  
The most common drug related ≥ grade 3 AEs were fatigue, diarrhea, liver enzyme 
elevation. All these AEs were observed in less than 2 % of the patients. Some of the 
other ≥ grade 3 AEs included renal failure, pancreatitis, pneumonitis, anemia, 
pancytopenia.   
4.2.2 Targeting PD-1 in SCLC 
The role of anti-tumor immunity is not well defined in SCLC. However several studies 
suggest that anti-tumor immunity may play a role in controlling SCLC. SCLC patients 
can have a variety of paraneoplastic syndromes, some of which are immune mediated. 
Certain datasets suggest that patients with immune mediated paraneoplastic disorders 
may have a longer survival (17,18,19). In addition, it has been observed that patients, 
with tumors that have a higher ratio of effector T cells to regulatory T cells, have better 
outcomes and are more likely to have limited stage disease (20). Recent data also shows 
that lung cancer, both small cell and non-small cell lung cancers have a high rate of 
mutations (21). This high rate of mutations raises the possibility that there are many 
neo-antigens expressed on tumor cells, that are not expressed on normal cells and these 
antigens could serve as targets for the immune cells. All these observations raise the 
strong possibility that activation of an anti-tumor immune response may control and 
even shrink small cell lung cancer.   
 
Multiple different immune based strategies have been evaluated in SCLC patients. 
These include vaccines, immune response modifiers and immune check point 

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inhibitors. An anti-idiotypic antibody BEC2 administered with BCG as an adjuvant has 
been tested in SCLC patients (22). This antibody mimics the ganglisoide GD3 
expressed in a large proportion of SCLCs and therefore can induce anti-tumor 
immunity targeting GD-3. In a 15 patient exploratory study administration of BEC2 
induced anti-GD-3 antibodies in 5 patients, who had the longest relapse free survival. A 
subsequent phase III study in limited stage SCLC patients following completion of 
therapy failed to show clinical benefit (23). However the study showed that there was a 
trend towards improved survival in one-third of the patients who developed a humoral 
response. These data suggest that effective immune therapy could provide clinical 
benefit in SCLC patients when administered as maintenance therapy.   
 
Recently, Reck, et al, published the results of a randomized three arm phase II trial 
evaluating the addition of ipilimumab to chemotherapy in patients with extensive stage 
SCLC (24). Iplimumab is a monoclonal antibody targeting CTLA-4, a negative 
regulator of T-cell activation. Patients in this study received ipilimumab either starting 
with the first cycle of chemotherapy or was started after the first 2 cycles. Patients on 
the control arm received placebo with chemotherapy. In this study the patients who 
received Ipilimumab in a phased in fashion (after the first 2 cycles) had a significantly 
higher ir (immune related) PFS compared to patients on the control arm. It is well 
recognized that patients on immune check point inhibitors may experience ‘pseudo’ 
progression probably due to inflammation in the region of the cancer and can have a 
delayed response to therapy. Therefore in many immune therapy trials modified 
response criteria are utilized to assess progression free survival (ir response criteria).  
Significant improvement in irPFS was not observed in the patients who received 
ipilimumab starting with the first cycle of chemotherapy. Also improvement in 
RECIST defined PFS was not observed. Interestingly, patients who received 
ipilimumab in a phased in fashion had improved survival, with a median of 12.9 
months compared to patients who received chemotherapy alone, with a median of 9.9 
month. Similar results were observed with this agent in NSCLC patients (25). It is 
unclear why clinical benefit was only observed in patients who received ipilimumab in 
a phased in fashion. The possible reasons are that the cytotoxic effect of chemotherapy 
may release tumor antigens into the general system priming the effect of ipilimumab 
and that the concomitant administration of steroids during chemotherapy may limit the 
efficacy of the ipilimumab. A randomized phase III study evaluating phased in 
iplimumab in combination with chemotherapy has completed enrollment.   
 
In preliminary clinical studies utilizing anti-PD-1 antibodies promising anti-tumor 
activity has been observed in patients with different tumor types including non-small 
cell lung cancer (16, 26). In addition, initial trials suggest that these drugs maybe better 
tolerated than anti-CTLA4 antibodies since anti-CTL4 antibodies generate more 
systemic activation of T cells and anti-PD-1 generate more tissue based activation of 
immune T cells (27).  
Currently there is no data available regarding the use of anti-PD-1 or anti-PD-L1 
antibodies in SCLC patients. There is indirect evidence to suggest that targeting PD-1 
will be beneficial in SCLC patients. Promising activity with both anti-PD-1 and anti-
PD-L1 therapies has been observed in NSCLC. In addition, recent data suggests that 
benefits from anti-PD-L1 antibody MPDL3280A are more likely in NSCLC patients 

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who are smokers (28). This is possibly related to higher rate of genetic alterations in 
smoking related NSCLCs and therefore higher expression of antigens on these tumors 
(21). Almost all patients with SCLC are smokers and generally have a prolonged 
history of smoking, making it likely that patients with these tumors will benefit from 
targeting PD-1 pathway.  
4.3 Rationale  
4.2.1 Rationale for the Trial and Selected Subject Population 
The outcomes of SCLC patients have not changed from over 20 years. The 
characteristic features of this cancer are high initial response rate followed by rapid 
progression/relapse of the tumor. Therefore this is an ideal tumor to consider 
maintenance therapy. It is challenging to continue therapy with currently available 
chemotherapy drugs. Therefore it is imperative to evaluate other agents as maintenance 
therapy with the goal of prolonging disease control and possibly survival. There is 
indirect evidence that immune therapy may be beneficial in SCLC patients.    
Based on all the discussed data, we hypothesize that maintenance MK-3475 
following completion of initial chemotherapy in patients with extensive stage 
SCLC will result in improved progression free survival. To test our hypothesis we 
propose to conduct a single arm phase II study evaluating the efficacy of MK-3475 as 
maintenance therapy in extensive stage SCLC patients following completion of first 
line chemotherapy. We believe that immune based therapy is most likely to be 
beneficial in SCLC patients following ‘debulking’ of the tumor with chemotherapy and 
improvement of patient’s performance status with disease shrinkage and control. 
Patients who have complete or partial response or stable disease will be eligible for the 
trial and will receive MK-3475. We believe that in this setting a single arm phase II 
study is appropriate since the duration of progression free survival following initial 
chemotherapy is very well established in this clinical setting over a long period of time 
and over several trials.  
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
MK-3475 showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  Recent data from 
other clinical studies within the MK-3475 program has shown that a lower dose of MK-
3475 and a less frequent schedule may be sufficient for target engagement and clinical 
activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 

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engagement is durable (>21 days).  This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q2W and Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights.  MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication.  The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight 
based regimen are anticipated to remain well within the established exposure margins 
of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins are based 
on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The 
population PK evaluation revealed that there was no significant impact of tumor burden 
on exposure. In addition, exposure was similar between the NSCLC and melanoma 
indications. Therefore, there are no anticipated changes in exposure between different 
indication settings. Based on all these data MK-3475 will be administered at a 
standard flat dose of 200 mg every 3 weeks.  
4.2.3 Rationale for Efficacy Endpoints 
We have selected progression free survival as defined by RECIST criteria as the 
primary endpoint. This was the primary endpoint in most maintenance trials conducted 
in SCLC patients to date. Consistently the median PFS in these maintenance trials 
following induction therapy in responding or stable disease patients is about 2 months 
in the control arm. Therefore it will be possible to assess if the results with maintenance 
MK-3475 are better than this historical data and thus encouraging enough to continue 
further evaluation of this drug in this setting.  
It is well recognized that patients treated with immune therapy may have pseudo 
progression or can have delayed response. Therefore many trials of immune therapy 
assess not only PFS as defined by RECIST criteria but also a modified PFS. The 
modified criteria require progression on 2 sequential scans, at least 4 weeks apart for 
definition of progression. The patients will continue on study therapy until these criteria 
are met, unless there is a decline in patient’s performance status or symptoms that is 
considered not acceptable by the patient or the treating physician, or the patient wants 
to discontinue therapy for any reason.      
In this trial we will not only assess PFS by RECIST criteria but will also assess PFS by 
this modified criteria as well. In addition we will assess response to MK-3475 by 
RECIST and overall survival.  
 

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4.2.3.1 Biomarker Research 
Emerging data suggests that expression of PD-L1 on the tumor may predict for benefit 
from the MK-3475 and other anti-PD-1. Benefit has also been observed in patients 
whose tumors don’t express PD-L1 but the percentage of such patients who benefit is 
far less. This difference in efficacy with anti- PD-1 drugs has been observed across 
tumor types. The rate of PD-L1 expression in SCLC is not well defined. We therefore 
plan to assess the expression of PD-L1 in tumors of patients enrolled on the trial and 
correlate the presence of PD-L1 with efficacy end points.   
Tumor content in diagnostic biopsies is likely to be limited in SCLC patients. In 
addition, biopsy of residual tumor following initial chemotherapy may be challenging. 
Circulating tumor cells (CTCs) hold great promise as a readily available source 
material that can offer real-time insight into a tumor’s genomic architecture. CTCs can 
be detected in small cell lung cancer patients and appear to have prognostic importance 
(20, 21). We propose to collect CTCs and assess PD-L1 expression in CTCs an attempt 
to correlate PD-L1 expression in CTCs with patient’s primary tumor and with efficacy 
parameters.   
 
5.0 ELIGIBILITY 
5.1 Inclusion Criteria 
1. Patients with extensive stage SCLC who have completed at least 4 cycles of 
platinum (carboplatin/cisplatin) and etoposide chemotherapy as their first line 
therapy and have responding or stable disease to this therapy are eligible for 
this study. Patients who received platinum/etoposide previously for SCLC and 
it was repeated for recurrence will not be eligible. 
2. Patients should be willing and able to provide written informed consent for the 
trial. 
3. Be  18 years of age on day of signing informed consent. 
4. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
5. Demonstrate adequate organ function as defined in Table 1, all screening labs 
should be performed within 14 days of treatment initiation.   
 
 
 
 
 

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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 
 
≥45 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 
aCreatinine clearance should be calculated per institutional standard. 
 
6. Female subject of childbearing potential should have a negative urine or 
serum pregnancy within 1 week prior to receiving the first dose of study 
medication.  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.   
7. 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.  
8. 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. 
5.2 Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating in or has participated in a study of an investigational 
agent within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
greater than 10 mg/day prednisone equivalent or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or 
who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier.  

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4. Has had prior chemotherapy, targeted small molecule therapy, or definitive 
radiation therapy within 2 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a 
previously administered agent. Patients who received palliative radiation to 
any site or prophylactic cranial radiation (≤ 30 Gy) or thoracic RT can 
start therapy with the study drug 7 days after the last day of radiation 
therapy as long as they have recovered from any adverse effects (i.e., ≤ 
Grade 1 or at baseline) of such radiation therapy.  
- 
Note:  Subjects with ≤ Grade 2 neuropathy or adverse events that are 
not considered clinically meaningful such as alopecia 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. Patient will be eligible if other malignancy is controlled and the 
treating physician determines that the patient’s outcome is unlikely to be 
affected by the other tumor.    
6. Has symptomatic central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  Subjects with previously treated brain metastases 
may participate provided they are clinically stable and any neurologic 
symptoms have returned to baseline, have no clinical evidence of new or 
enlarging brain metastases, and are not using steroids greater than prednisone 
10mg/day or equivalent dose of another steroid, prior to start of trial 
treatment.   
7. Has an active automimmune disease, including a paraneoplastic syndrome of 
autoimmune nature, requiring systemic treatment other than chemotherapy for 
SCLC, within the past 3 months or a documented history of clinically severe 
autoimmune disease, or a syndrome that requires or required 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 active, non-infectious pneumonitis. 
9. Has an active infection requiring therapy. 
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.   

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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, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab or any other antibody or drug specifically 
targeting T-cell co-stimulation or checkpoint pathways). 
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.   
 
6.0 TRIAL TREATMENTS/PROCEDURE 
All patients deemed eligible and registered with Study Coordinator, the Clinical Trials Office 
at Karmanos Cancer Institute, will initiate study therapy within 5 days of registration. Please 
see section 7.0 for all required tests and assessments prior to registration. This is a single arm 
study so all eligible patients will receive the study treatment MK-3475.  
Patients will start therapy no earlier than 3 weeks from the first day of the last cycle of 
platinum/etoposide chemotherapy and no later than 8 weeks from the first day of the last 
cycle of chemotherapy. Due to logistical and administrative issues therapy maybe started 
within 48 hours before the 3 weeks from the first day of the last cycle of chemotherapy or 
within 48 hours after 8 weeks of the first day of the last cycle of chemotherapy, after 
consultation with the Principal Investigator.  
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
MK-3475 200 mg 
Every 3 
weeks 
IV infusion 
 
Treatment will continue for 24 months unless patient experiences intolerable adverse events 
or disease progression or patient desires to discontinue therapy.  
 

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6.1.1 Dose Modification 
6.1.1.1 
Dose Modification  
There is no dose reduction allowed on the protocol. However the dosing 
frequency can be increased from 3 weeks to every 4 weeks. 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. In addition, the drug can be held for any 
grade of toxicity by the treating physician if it is felt that it is in the best 
interest of the patient  
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* 
* Patient should 
not have febrile 
neutropenia or 
thrombocytopenia 
associated with 
hemorrhage. For 
grade 2 and 3 
neutropenia and 
thrombocytopenia 
patients should 
undergo at least 
weekly blood 
counts 
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 
6.3.1.1 
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 
Toxicity does not 
resolve within 12 
weeks of last infusion 

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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 
 
Toxicity does not 
resolve within 12 
weeks of last infusion 
Permanent 
discontinuation should 
be considered for any 
severe or life-
threatening event 
 
 
With investigator and Principal Investigator 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. A patient who requires longer than 12 
weeks but less than 24 weeks to recover from an adverse event that led to the 
withholding of the drug could be restarted on the drug IF the treating 
physician believes that it is in the best interest of the patient to restart the 
drug and the patient is agreeable. This has to be discussed with the Principal 
Investigator before restarting the drug.  
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. 
6.1.2 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 7.0).  Trial treatment may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons, including patient’s desire. 
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). 
Merck will provide Pharmacy Manual which contains specific instructions for MK-
3475 dose calculation, reconstitution, preparation of the infusion fluid, and 
administration. 
 

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6.2 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 Principal Investigator.  The final 
decision on any supportive therapy or vaccination rests with the investigator.  However, 
the decision to continue the subject on trial therapy or vaccination schedule requires the 
mutual agreement of the Investigator, and the subject.  
6.2.1 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare 
may be administered at the discretion of the investigator in keeping with the 
community standards of medical care.  All concomitant medication will be 
recorded on the case report form (CRF). All concomitant medications at the time 
of study enrollment and study therapy discontinuation should be recorded.   
6.2.2 
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 
 Investigational agents other than MK-3475 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed after consultation with the Principal Investigator   
 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.  
 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 Principal Investigator.  
 Patients CAN continue on bone modifying agents such as zolendronic 
acid or densumomab if deemed necessary by the treating physician.  

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6.3 Rescue Medications & AE Mangement 
6.3.1 
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 or greater), 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. If the treating 
physician believes that the patient is deriving clinical benefit from the 
study drug, then the treating physician after consultation with the 
Principal Investigator may discuss with the patient regarding 
continuing therapy with MK-3475  
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. 

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 Immune-related adverse events: Please see Section 6.3.1.1 below 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 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 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-3475. 
 
 
Table 4  Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  Otherwise 
dosing will be held until symptoms resolve and 
the subject should be premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
trial treatment administration. 
 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 

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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 
6.3.1.1 Supportive Care Guidelines for Events of Clinical Interest and 
Immune-related Adverse Events (irAEs) 
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. Examples of such events 
include pneumonitis, pancreatitis, thyroid disorders.   
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 possible irAEs is included in the 
Appendix in Section 15.4. Subjects who develop a Grade 2 or higher irAE 
should be discussed immediately with the Principal Investigator.   
 
 
 
 

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Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed 
in Table 5. 
Table 5.  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 per day prednisone 
equivalent within 12 weeks of 
toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 
4 weeks. 
 
6.3.1.1.1 
Management of Possible immune related Adverse Events 
(irAEs) (see also Appendix, Section 15.4) 
Each of the clinical conditions listed below can have causes other than 
immune related. Appropriate evaluation to determine the cause of the events 
is necessary and only after other possible causes have been determined to be 
less likely should the Principal Investigator be contacted within 72 hours. 
Please note if the ECI meets the SAE reporting guidelines then the SAE 
reporting guidelines should be followed.   
6.3.1.1.1a 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, and a Clostridium difficile titer.  
Course of Action 
Grade 1 diarrhea:  
– Treat symptomatically (loperamide, oral hydration, electrolyte substitution and 
ADA colitis diet). 
– Endoscopy is recommended if symptoms persist. 
Grade 2 diarrhea (or persistent Grade 1):   
– Hold MK-3475. 
– GI consultation and endoscopy is recommended to confirm or rule out colitis for 
Grade 2 diarrhea that persists >1 week or Grade 1-2 diarrhea with rectal bleeding 
(additional guidelines for the treatment of persistent colitis are provided below).   

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– Grade 1 events that persist for >1 week or Grade 2 events should be treated with 
the addition of oral diphenoxylate hydrochloride and atropine sulfate four times 
daily and budesonide 9 mg daily.  
– Grade 2 diarrhea with diffuse ulceration and bleeding seen on endoscopy may 
require oral steroids with prolonged taper and represent an increased risk for the 
development of bowel perforation. 
– When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
Grade 3-4 diarrhea (or Grade 2 diarrhea that persist after initial steroid treatment): 
– Hold/Discontinue MK-3475. 
– Rule out bowel perforation.  Imaging with plain films or CT can be useful. 
– Consider consultation with Gastroenterologist and confirmation biopsy with 
endoscopy 
– Treat with intravenous steroids (methylprednisolone 125 mg) followed by high 
dose oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg 
every 4 hours)  When symptoms improve to Grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks.  Taper over 6 to 8 weeks in 
patients with diffuse and severe ulceration and/or bleeding. 
– If IV steroids followed by high dose oral steroids does not reduce initial 
symptoms within 48 to 72 hours, consider treatment with infliximab at 5 mg/kg 
once every 2 weeks. Discontinue infliximab upon symptom relief and initiate a 
prolonged steroid taper over 45 to 60 days. If symptoms worsening 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 infliximab.  CAUTION: 
infliximab is contraindicated in patients with bowel perforation or sepsis [12]. 
– If symptoms persist despite the above treatment a surgical consult should be 
obtained. 
After patient has recovered the treating physician may consider restarting therapy 
with the study drug after consultation with the Principal Investigator.  
 
 
 
 
 

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6.3.1.1.1b Endocrine Abnormalities 
Possible endocrine disorders that could arise include- Adrenal Insufficiency, 
Hypothyroidism, Hyperthyroidism, Thyroditis, Hypophysitis, Hypopituitarism.  
Course of Action 
Grade 1-2 events: 
– Monitor thyroid function or other hormonal level tests and serum chemistries 
more frequently until returned to baseline values. 
– If hypophysitis is considered, pituitary gland imaging should be considered 
(MRIs with gadolinium and selective cuts of the pituitary can show enlargement 
or heterogeneity and confirm the diagnosis). 
– Thyroid hormone and/or steroid replacement therapy should be considered in 
appropriate patients.  
 
Symptomatic pan-hypopituitarism and any Grade 3-4 events 
– Hold/discontinue MK-3475. 
– Consider Endocrine consultation. 
– 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.  
– Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and 
hyperkalemia) constitutes adrenal crisis. Hospitalization and intravenous 
methylprednisolone should be initiated. 
After patient has recovered the treating physician may consider restarting therapy 
with the study drug after consultation with the Principal Investigator.  
 
6.3.1.1.1c Ocular Events 
The following AE term, if considered Grade ≥2, is considered an ECI and should be 
reported to the Principal Investigator within 72 hours of the event: 
– Uveitis 

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Course of Action for Ocular Events 
Grade 1-2 events:  
– Evaluation by an ophthalmologist is strongly recommended. 
– Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
– Discontinue MK-3475 if symptoms persist despite treatment with topical 
immunosuppressive therapy. 
Grade 3-4 events: 
– Discontinue MK-3475. 
– 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. 
After patient has recovered the treating physician may consider restarting therapy 
with the study drug after consultation with the Principal Investigator.  
6.3.1.1.1d Hepatic 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be 
reported to the Principal Investigator within 72 hours of the event. 
Symptoms may include (but not limited to): 
– Elevations in:  
AST >2.5 times upper limit of normal (ULN), ALT >2.5 times 
ULN, Total bilirubin >1.5 times ULN, Fever, Malaise, Upper quadrant abdominal 
pain. 
Course of Action 
Grade 1 events: Monitor liver function tests more frequently until returned to baseline 
values. 
Grade 2 events: Monitor liver function tests more frequently until returned to baseline 
values. 
Grade 3-4 events: Discontinue MK-3475 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 

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every 4 hours or prednisone at 1 to 2 mg/kg should be started and continued over 
no less than 4 weeks.  
– 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 [12]. 
– Several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. 
After patient has recovered the treating physician may consider restarting therapy 
with the study drug after consultation with the Principal Investigator.  
6.3.1.1.1e 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 
Course of Action 
Grade 1 events: 
– Mild (Grade 1) irAEs – provide symptomatic treatment. 
Grade 2 events: 
– Moderate (Grade 2) or Grade 1 irAEs that do not improve with symptomatic 
treatment – consider withholding MK-3475.  Systemic corticosteroids may be 
indicated. 
Grade 3-4 events: 
– Clinically significant or severe (≥ Grade 3) irAEs 
– Discontinue MK-3475 
– 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 or 
equivalent once per day.   

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When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.   
Discontinue MK-3475 if unable to reduce corticosteroid dose for irAEs to ≤10 mg.    
After patient has recovered the treating physician may consider restarting therapy 
with the study drug after consultation with the Principal Investigator.  
6.3.1.1.1f Dermatologic 
The following AEs should always be reported as ECIs, regardless of CTCAE grade, and 
should be reported to the Principal Investigator within 72 hours of the event:  
– Dermatitis Exfoliative 
– Erythema Multiforme 
– Stevens-Johnson Syndrome 
– Toxic Epidermal Necrolysis 
The following AE terms should only be reported as an ECI if they are considered to be 
immune related, ≥ Grade 3 or result in dose modification or discontinuation:   
– Pruritus 
– Rash 
– Rash generalized 
– Rash maculo-papular 
– Vitiligo 
 
Course of Action with MK-3475  
Grade 1-2 events: 
– Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in 
combination with oral antipruritics (e.g., diphenhydramine HCl or hydroxyzine 
HCl).  
– Treatment with oral steroids is at investigator discretion for Grade 2 events. 
Grade 3 events: 
– Hold MK-3475. 
– Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 

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– 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. 
Grade 4 events: 
– Permanently discontinue MK-3475. 
– 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. 
 
6.3.1.1.1g  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 
6. 
Table 6  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 
 

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6.3.1.1.1h Other  
The following AEs are considered ECIs and should be reported to the Principal 
Investigator within 72 hours of the event: 
– Autoimmune Neuropathy 
– Demyelinating Polyneuropathy 
– Guillain-Barre 
– Myasthenia Gravis-like Syndrome 
– Non-infectious myocarditis 
– Non-infectious pericarditis 
– Pancreatitis 
– Rapid onset of Grade 3 fatigue in the absence of disease progression 
 
 
Course of Action 
 
– Mild (Grade 1) irAEs – provide symptomatic treatment. 
– Moderate (Grade 2) or Grade 1 irAEs that do not improve with symptomatic 
treatment – consider withholding MK-3475.  Systemic corticosteroids may be 
indicated. Consider biopsy for confirmation of diagnosis. 
– Clinically significant or severe (≥Grade 3) irAEs –discontinue MK-3475 and treat 
with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day.  Report as ECI.  
 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.   
 
Discontinue MK-3475 if unable to reduce corticosteroid dose for irAEs to ≤10 mg.    
MK-3475 treatment may be restarted and the dose modified as specified in the protocol 
 
 
6.4 Contraception/Pregnancy/Nursing 
6.4.1 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.  

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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. 
6.4.2 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 
Principal Investigator 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. 
6.4.3 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. 
6.5 Subject 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 Principal Investigator 
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 8.1.5. 
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 or decides to discontinue study therapy for any reason. 

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 Confirmed radiographic disease progression according to modified response 
criteria (see section 10.2).  
 Unacceptable adverse experiences  
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 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 8.1.6.1.2 
 Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in Section 7 
(Protocol Flow Chart) and Section 8.1.6 (Visit Requirements).  After the end of 
treatment, each subject will be followed for 30 days for adverse event monitoring.  
Subjects who discontinue for reasons other than progressive disease will have post-
treatment follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent or becoming lost to follow-up.  After 
documented disease progression each subject will be followed by telephone for 
overall survival until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
6.6 Subject Replacement Strategy 
Patients will only be replaced if the patient withdraws consent before the first dose 
of therapy.  
 
 
 
 

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7.0 TRIAL FLOW CHART  
7.1 Study Flow Chart 
 
Trial Period: 
Treatment Cycles 
  
  
  
  
  
  
Treatment Cycle/Title: 
Main Study 
Screening 
(Visit 2) 
1 
2 
3 
4 
To be repeated 
beyond 8 cycles 
Safety Follow-Up/ 
EOT 
Progression Free     
Follow-Up Phase 11 
Survival 
Follow-Up 
5 
6 
7 
8 
Scheduling Window 
(Days): 
-28 to -1 
  
±3 
±3 
±3 
±3 
±3 
±3 
±3 
~30 days after last 
dose/ before 
initiation of new tx  
Every 12 weeks  
+/- 2weeks 
Every 12 
weeks  
+/- 2 
weeks 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/Exclusion 
Criteria 
X 
  
  
  
  
  
  
  
  
 
  
 
  
  
Medical 
History/Physical1 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
Medication Review2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Trial 
Treatment 
Administration3 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
Survival Status 
  
  
  
  
  
  
  
  
  
  
X 
Review Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Full 
Physical 
Examination1 
X 
  
  
  
 
  
  
  
  
 
  
 
  
  
Directed 
Physical 
Examination1 
  
X 
X 
X 
X 
X 
X 
  
X 
X 
 
 
  
Vital Signs and Weight3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
ECOG 
Performance 
Status3 
X 
X 
X 
X 
X 
X 
X 
  
X 
X 
 
 
  
Pregnancy Test – Urine 
or Serum -HCG4 
X 
  
  
  
 
  
  
  
  
 
  
 
  
  
CBC with Differential5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Comprehensive 
Serum 
Chemistry Panel5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
  
Urinalysis 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
T3, FT4 and TSH6 
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
Tumor Imaging7 
X 
  
X 
  
X 
  
X 
  
  
  
  
X 
  
Archival 
Tissue 
Collection8 
X 
  
  
  
 
  
  
  
  
 
  
 
  
  
Correlative Studies Blood 
Collection9 
 
X  
X 
X 
  
  
  
  
  
  
  
  
  
  
Retreatment10 
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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1. Patients should undergo a detailed history and physical examination during screening. 
A full examination, to be performed to determine eligibility, means that based on the 
patient’s medical history and all relevant systems have been examined. All patients 
should undergo a focused history and physical examination during each treatment day 
for the first 6 cycles. After the first 6 cycles history and physical examination can be 
performed every other cycle.  
2. All medications need to be reviewed at screening visit. During follow up visits any 
changes in medications should be documented. 
3. MK-3475 will be administered at a dose of 200 mg IV every 3 weeks for a maximum 
of 2 years. Prior to each administration vital signs- heart rate, blood pressure, 
temperature, weight, respiratory rate should be documented. Performance status needs 
to be documented on the day of study drug administration for the first 6 doses. After 
the first 6 doses it should be documented as deemed appropriate by the treating 
physician.  
4. Pregnancy test should be performed within 1 week of the first dose of MK-3475 in 
appropriate women.  
5. Patients should undergo CBC with differential count, a multiphasic profile consisting 
of serum electrolytes, BUN, serum creatinine, AST, ALT, serum bilirubin, alkaline 
phosphatase, and calcium with each treatment. . Baseline labs should be done within 
2 weeks of the first dose of MK-3475. During the trial, laboratory tests can be done 
within 48 hours of the administration of MK-3475.   
6. Patients should undergo Thyroid tests within 2 weeks of the first dose. These should 
be repeated at least every 4 cycles.  
7. Patients should undergo appropriate scans, including brain scan, during screening, to 
document the status of the patient' cancer. The screening scans should be done within 
3 weeks before the first dose of MK-3475. Patients should undergo appropriate scans 
to restage the patient after every 2 cycles for the first 6 cycles. For the first 6 cycles 
the re-staging scans should be performed within 1 week of the next cycle. After the 
first 6 cycles, the scans can be done as often as necessary by the treating physician 
but should be done at least every 4 cycles.  
8. Archival tumor tissue will be retrieved to assess tumor PD-L1 status. Any tissue 
available should be submitted. Patient will be eligible even if tumor tissue cannot be 
submitted.  
9. Patients will undergo blood collection for Circulating Tumor Cells (CTCs). This can 
be done on the first day of the first cycle prior to dosing MK-3475. This should also 

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be done on the first day of the second cycle and first day of the third cycle even if the 
drug is being held.   
10. Patients who have completed 24 months on MK-3475 and stop therapy without 
progression can be retreated if patient has further progression. Patient will have to 
meet all original eligibility criteria and will be assessed and managed as a new patient 
starting on therapy. See section 8.1.6. 
11. Every 12 weeks until the start of the next treatment for patient’s cancer, disease 
progression, death, end of study.   
8.0      TRIAL PROCEDURES 
8.1.1 Registration Procedures 
Eligible patients will be entered on the study centrally at the clinical trials office 
of the Karmanos Cancer Center/Wayne State University, by, the Study 
Coordinator (or a designated study coordinator). All sites should call the Study 
Coordinator) after initiating screening.  
An eligibility check list will be generated by the Study team at Karmanos Cancer 
Institute. This eligibility check list has to be completed by each site and signed by 
the responsible investigator. Once this is received by Study Coordinator and 
confirmed by him/her, the patient will be registered. A registration confirmation 
will be sent to the site (sites other than Karmanos Cancer Instittue).  
Once registration has occurred patient has to be treated within 5 days. If patient 
does not start therapy within 5 days of registration, the reasons for delay should 
be communicated to the Principal Investigator. He will then decide if the patient 
can continue on study therapy.  
8.1.2 Informed Consent 
The Investigator must obtain documented consent from each potential subject 
prior to participating in a clinical trial and conducting trial specific procedures.  
The informed consent will adhere to individual Institutional Review Board 
requirements, applicable laws and regulations. 
8.1.3 Disease Details  
The known sites of metastases at the time of diagnosis and study entry will be 
recorded. The number of cycles of platinum based chemotherapy received and the 
date of the last cycle of chemotherapy should be recorded.  
Details of any radiation administered for the management of SCLC will be 
recorded. This will include site radiated, dose and dates.  

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8.1.4 Clinical Procedures/Assessments 
8.1.4.1 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 15.2).  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 5.4.1.1)  
Please refer to section 7.2 for detailed information regarding the assessment and 
recording of AEs.   
8.1.4.2 Tumor Imaging and Assessment of Disease 
Patients will undergo scans to assess the status of the cancer within 3 weeks 
before the first dose of MK-3475. All known areas of metastases should be 
imaged. Patients will undergo restaging scans every 2 cycles for the first 6 cycles. 
Subsequently they can be done as often as necessary, but should be done at least 
every 4 cycles.  
The treating physician will decide which scans need to be done to appropriately 
assess the status of the cancer.  
8.1.4.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in 
this trial are provided below.   
 
 

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Table 8  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis (only at baseline) 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Total thriiodothyronine (T3)α 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
Free tyroxine (T4)α 
Red Blood Cell Count 
Creatinine 
Microscopic exam (If abnormal)  
Thyroid stimulating hormone (TSH)α 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
 
 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. This 
is needed only at baseline  
‡ If considered standard of care in your region. 
α These tests are to be conducted at baseline. Once the patient is on trial therapy tests to be conducted at least every 4 cycles. 
 
 
 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 14 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 48 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.  
8.1.5 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.  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 (see section 8.1.6).  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety 
Follow-up Visit (described in Section 8.1.6.1). 
8.1.6 Visit Requirements/Safety Follow Up Visit/Retreatment 
Visit requirements are outlined in Section 7.0 - Trial Flow Chart.   Specific procedure-
related details are provided above in Section 8.1 - Trial Procedures. 
It is recognized that the safety follow up visit maybe difficult to accomplish in 
patients with extensive stage small cell lung cancer.   However, every effort should 
be made to conduct a Safety Follow-Up Visit 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.  
8.1.6.1 
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 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 or if the subject 
begins retreatment with MK-3475 as detailed in Section 8.1.6.1.2  
Subjects who are eligible to receive retreatment with MK-3475 according to the 
criteria in Section 8.1.6.1.2 will move from the follow-up phase to the Second 
Course Phase when they experience disease progression.   

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8.1.6.1.1 Survival Follow-up 
Once a subject experiences confirmed disease progression according to modified 
response criteria 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.  
8.1.6.1.2 Retreatment 
Patients who have disease progression following completion of 2 years of therapy 
with MK-3475 can be re-treated with this drug if the patient meets all eligibility 
criteria as in Section 5.0 except for the criteria of stable or responding disease 
following chemotherapy.  
The schedule of study activities will be according to the study flow chart Section 
6.0.   
8.2 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 MK-3475, is also an adverse 
event. 
Adverse events may occur during the course of the use of MK-3475 from overdose 
(whether accidental or intentional), from abuse and from withdrawal. 
All adverse events will be recorded from the time the patient starts therapy with the 
study drug through 30 days following cessation of treatment and at each examination 
on the Adverse Event case report forms/worksheets.  
Merck or Principal Investigator will also forward to individual sites relevant SAE 
reports occurring on MK-3475. These should be forwarded to appropriate 
regulatory authorities according to local rules and regulations.  

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8.2.1 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 MK-
3475, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
If a dose of MK-3475 meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology 
“accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 
24 hours to the Principal Investigator and within 2 working days hours to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
8.2.2 
Reporting of Pregnancy and Lactation to the Principal 
Investigator 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 completing the trial, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be 
followed to the completion/termination of the pregnancy.  Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).  If the pregnancy continues to term, 
the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Study Coordinator and within 
2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 993-1220) 
 

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8.2.3 
Immediate Reporting of Adverse Events  
8.2.3.1 
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  
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 MK-3475, must be reported within 
2 working days of learning to the Principal Investigator and to Merck Global 
Safety.  
Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician to be related to MK-3475 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 Principal Investigator and to 
Merck. 
SAE reports and any other relevant safety information are to be forwarded to 
the study coordinator and the Merck Global Safety facsimile number:  +1-215-
993-1220 
All subjects with serious adverse events must be followed up for outcome. 
8.2.4 
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 

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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. 
 
 
9.0 CORRELATIVE STUDIES 
 
Response rates to PD-1 and PD-L1 targeted agents indicate that a subset of patients derive 
greater benefit from this treatment strategy, whereas some patients have no benefit. To 
complement this study and increase its scientific yield, we are proposing several scientific 
correlates in an attempt to identify potentially predictive biomarkers for MK-3475. While 
these are unlikely to be definitive, based on the relatively small numbers of patients involved, 
the data collected will help guide the development of potential biomarkers in future studies as 
well as identify patients most likely to benefit or not benefit from MK-3475. Some of these 
studies will be limited to patients randomized to the treatment arm.  
 
Preliminary data suggest that tumor PD-L1 expression may be a predictive marker for MK-
3475 (18). In an effort to characterize PD-L1 expression in SCLC, we will collect archived 
tumor specimens from all participants for PD-L1 expression analyses. PD-L1 expression will 
be assessed by QualTek Clinical Laboratories, Pennsylvania. Tissue for PD-L1 testing should 
be sent to QualTek Clinical Laboratories, 300 Pheasant Run, Newton, PA 18940. Tumor 
tissues by participating sites will be sent to Dr. Julie Boerner, Director of the Biobanking and 
Correlative Sciences Core at Karmanos Cancer Institute. Address for shipping is the same as 
shipping blood for CTC assessment as mentioned in section 9.1. 
 
Tumor content in diagnostic biopsies is likely to be limited in SCLC patients. In addition, 
serial biopsies are challenging in patients with SCLC. Also after completion of 
chemotherapy, biopsy of residual tumor may be challenging. Circulating tumor cells (CTCs) 
hold great promise as a readily available source material that can offer real-time insight into a 
tumor’s genomic architecture as well as tumor burden. CTCs can be detected in small cell 
lung cancer patients and appear to have prognostic importance (20, 21). Dr. Julie Boerner, 
Director of the Biobanking and Correlative Sciences Core will supervise quantitation of 
CTCs in patients enrolled on this study. Peripheral blood (8 mL) will be collected into a Cell 
Search CTC collection tube. Tumor cells are then subject to negative immunomagnetic 
selection with anti-CD45 antibodies and positive immunomagnetic selection with EpCAM 
antibodies and fluorescently labeled for quantitation. These fluorescently labeled cells can be 
stained for PD-L1 for correlation with tumor progression assessment.  Alternatively, the 
immunomagnetic platform allows isolation of EpCAM selected cells from the peripheral 
blood from which mRNA can be reverse-transcribed for RT-PCR. Using beta-actin as an 
internal control, mRNA expression levels of target genes can be ascertained. As a correlate to 
this trial, we will collect blood prior to therapy on the first day of the first cycle, on the first 
day of second cycle, and first day of the third cycle. After processing, samples will be 
shipped to the Dr. Boerner’s laboratory (see shipping address and conditions below). Both 

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CTC counts and assessment of PD-L1 protein and mRNA expression in isolated CTCs will 
be done.  
 
9.1 Shipping of CTC samples to Karmanos Cancer Institute 
Blood (min. 7.5 ml) for CTC counting will be collected in a Cell Save purple and 
yellow marbled topped tube.  Blood for CTC isolation needs to be collected in an 
EDTA tube.  Both specimens should remain at room temperature. 
 
Blood for CTC samples should be shipped within 24 hr. to the address below at 
ambient temperatures.  The tubes are glass and special care needs to be taken to ensure 
the tubes do not break.  Bubble wrap pouches with extra cushioning works best. 
 
Ship to: 
Biobanking and Correlative Sciences Core 
Attn: Julie Boerner 
Wayne State University/Karmanos Cancer Institute 
816 HWCRC 
4100 John R. St. 
Detroit, MI  48201 
PH:  313-576-8350 
 
10.0 DEFINITIONS OF END POINTS 
All patients who are registered and have received at least one dose of the study drug will be 
eligible to be considered for all the following end points- 
10.1 Primary Endpoint- RECIST 1.1 defined Progression Free Survival (PFS)- PFS is 
defined as the duration of time from registration to time of progression. Patients 
who die without reported prior progression will be considered to have progressed 
on the day of their death. Patients who did not progress will be censored at the 
day of last tumor assessment. 
10.2 Secondary Endpoints- 
Modified Progression Free Survival- Modified PFS requires that RECIST defined 
PFS is confirmed by a second scan at least 4 weeks apart. Following issues need to be 
considered 
a. New lesion/lesions are considered as progression in RECIST defined PFS. 
However for modified PFS the largest unidirectional measurement of new 
lesion/lesions will be added to the total tumor measurement. If this exceeds 
20% on 2 consecutive scans then the patient will be considered to have tumor 

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progression according to modified PFS criteria. A new lesion or lesions alone 
will not qualify for this modified PFS definition.    
b. If patients who have RECIST defined progression are symptomatic or have 
decline in performance status or develop unacceptable laboratory 
abnormalities and the treating physician and/or the patient decide to 
discontinue therapy or change therapy then the second scan confirming 
progression is not required.  
Overall Survival- Overall survival is defined as the time from registration to time of 
death. If the patient is lost to follow-up, survival will be censored on the last date the 
patient was known to be alive. 
 
11.0  STATISTICAL ANALYSIS PLAN 
11.1 Study Design and Primary Endpoint 
This is a single arm Phase II study to evaluate the efficacy of consolidation MK-3475 in 
extensive stage SCLC patients following completion of 4 cycles of chemotherapy with 
cisplatin or carboplatin and etoposide and whose disease has either responded or 
stabilized following chemotherapy.  We propose a single arm study since the standard 
initial therapy for SCLC is well established for the last 20 years and the median PFS 
following such induction therapy is well defined, making a randomized study with 
control arm less necessary.  
The primary endpoint is PFS with RECIST criteria defined as duration of time from 
registration to time of progression.    Patients register after the induction chemotherapy 
is completed and have achieved stable or responding disease.  Patients who die without 
reported prior progression will be considered to have progressed on the day of their 
death.  Patients who did not progress will be censored at the day of last tumor 
assessment.  PFS has been the primary endpoint in most maintenance trials conducted 
in SCLC patients to date.  
11.2 Sample Size and Accrual Rate:  
 
The median PFS in SCLC patients who have stable or responding disease following 
initial chemotherapy is approximately 2 months. We expect that the experimental 
treatment will improve the median PFS 50% to 3 months. Assume an exponential and 
one-sided alpha 0.05,  40 patients accrued in 18 months with minimum follow-up time 
6 months will achieve 80% power to test the null hypothesis that median PFS is 2 
months versus the alternative of 3 months.[PASS14.0.7] (29). In this protocol, we 
assume about 10% of patients will be ineligible.  Thus, a total of 45 will be enrolled to 
study.  To assess the efficacy, we will follow each patient to at least 6 months or 
progression.  

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It is estimated that approximately 28 patients per year should be accrued once the study 
is open at all sites (4-5 sites). Thus, the accrual duration will be about 18 months and 
the study duration is 24 months including the 6 months follow-up.  All patients will be 
followed for PFS and OS to evaluate the clinical benefit of MK-3475. 
 
11.3 Analysis plan for primary and secondary endpoints 
The primary endpoint, PFS, will be estimated with the standard Kaplan-Meier method, 
from which summary statistics of interest (median, 1-year rate, etc.) will be derived. 
Both point and 95% confidence interval estimates of PFS will be calculated. In this trial 
we will also assess PFS using modified criteria as well. It is well recognized that 
patients treated with immune therapy may have pseudo progression or can have delayed 
response.  The modified PFS requires RECIST defined progression on 2 sequential 
scans at least 4 weeks apart for definition of progression.  Overall survival is defined as 
the time from start of treatment to time of death. If the patient is lost to follow-up, 
survival will be censored on the last date the patient was known to be alive.  All time-
to-event endpoints will be estimated using standard Kaplan-Meier methods, from which 
the median and confidence interval will be calculated. Point and exact confidence 
interval estimates will be calculated for the toxicities and response rates. Cox model 
will be used to evaluate the association between time to event outcomes and covariates 
such as PD-L1 status and CTCs. 
PD-L1 (yes/no) in tumor tissue and circulating tumor cells (CTCs) will be measured 
and their association will be studied with logistic regression. We will explore 
associations between PD-L1 and PFS, modified PFS, and OS using the Cox model. If 
biopsy samples are 15 patients or less, statistical analysis will be descriptive.  
 
12.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
12.1 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. 
The investigational product will be provided by Merck  
12.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 

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12.3 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. 
12.4 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the subjects 
and the amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and provided 
that appropriate records of disposal are kept. 
 
13.0 ADMINISTRATIVE AND REGULATORY DETAILS 
13.1 Confidentiality  
All efforts will be made at each participating site to maintain the confidentiality of 
patients enrolled on the trial according to institutional, local and federal guidelines.   
13.2 Compliance with Financial Disclosure Requirements  
All participating staff will disclose any financial conflicts of interest to respective 
institutional review boards or applicable compliance authorities.  
13.3 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 Principal 
Investigator 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.     

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13.4 Data and Safety Monitoring 
Scheduled meetings will occur monthly or more frequently depending on the activity of 
the protocol. These meetings will include the Principal Investigator (PI) and research 
staff involved with the conduct of the protocol, specifically the Study Coordinator and 
the Statistician. In addition the PI will contact the co-investigators on a regular basis 
(frequency to be based on the rate of enrollment) and review the clinical outcomes of 
the patients enrolled on the study.   
During these meetings the following points will be reviewed and discussed: 
 Safety of protocol participants 
 Validity and Integrity of the data  
 Enrollment rate and Eligibility of patients enrolled 
 Adherence to Protocol Requirements 
 Completeness of the Collected Data 
 Protocol Amendments if any. 
Data and Safety Monitoring Reports (DSMR) will be completed by the study 
coordinator and will be sent to the Data and Safety Monitoring Committee of the 
Karmanos Cancer Institute.  
The Karmanos Cancer Institute’s Data and Safety Monitoring Committee will provide 
the primary oversight for data and safety monitoring for this investigator initiated trial.   
13.5 Oversight of Participating sites 
This is a multi-center study with Karmanos Cancer Institute/Wayne State University as 
the coordinating site.  
Each participating site will undergo study training prior to enrollment by the site. This 
training will only occur once the study is approved by appropriate regulatory authorities 
at the site. The study training will be conducted either by the Principal Investigator or 
his designee from the Karmanos Cancer Institute (KCI) Clinical Trials Office (CTO).   
This study will utilize Karmanos Oncore (Karmanos Cancer Institute Clinical Trial 
Management System) eCRFs (electronic Case Report Forms) to capture clinical trial 
data. Appropriate personnel at all participating sites will be trained in this Oncore 
system by the Karmanos Informatics department.  

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Trial data entered in Oncore will be verified by source documentation. CRFs should be 
completed by participating sites within 10 business days of the availability of clinical 
documentation of a study visit. Data clarification and queries should be completed 
within 7 working days of notification.  
A monitor specialist from KCI CTO will remotely monitor essential clinical trial data. 
Frequency of monitoring will be based on accrual at a site but will occur at least once 
every 2 months if a patient has been enrolled.   
 
14.0 LIST OF REFERENCES 
1. 
American Cancer Society.: Cancer Facts and Figures 2013. Atlanta, Ga: American 
Cancer Society, 2013. Available online  . Last accessed January 10, 2014.  
2. 
Van Meerbeck JP, Fennell DA, De Ruysscher D. Small-cell lung cancer. Lancet 
2011;378:1741-55.  
3. 
Arnold AM, Seymour L, Smylie M et al. Phase II study of vandetanib or placebo in 
small-cell lung cancer patients after complete or partial response to induction 
chemotherapy with or without radiation therapy: National Cancer Institute of Canada 
Clinical Trials Group Study BR.20. J Clin Oncol 2007; 25: 4278-42.  
4. 
Schiller J, Adak S, Cella D, et al. Topotecan versus observation after cisplatin and 
etoposide in extensive stage small cell lung cancer: E7593- a phase III trial of the 
Eastern Cooperative Oncology Group. J Clin Oncol 2001;19:2114-22.  
5. 
Ready N, Pang H, Gu L, et al. Chemotherapy with or without maintenance sunitinib for 
untreated extensive-stage small cell lung cancer: A randomized, placebo controlled 
phase II study CALGB 30504 (ALLIANCE). J Clin Oncol 2013;31:abstract 7506.  
6. 
Disis ML.  Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8.  
7. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.  
8. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7.  
9. 
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.  
10. 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.   

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11. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
12. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
13. 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.   
14. 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.  
15. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab 
(anti-PD-1) in melanoma. N Engl J Med 2013;369:134-44.   
16. Garon E, Leighl NB, Rizvi NA, et al. Safety and clinical activity of MK-3475 in 
previously treated patients with non-small cell lung cancer. J Clin Oncol 2014;32:5s 
(abstract 8020).  
17. Graus F, Dalmou J, Rene R, et al. Anti-Hu antibodies in patients with small-cell lung 
cancer: association with complete response to therapy and improved survival. J Clin 
Oncol 1997;15;2866-72.  
18. Mawhinney E, Gray OM, McVerry F, McDonnell GV. Paraneoplastic sensorimotor 
neuropathy associated with regression of small cell lung carcinoma. BMJ Case Rep 
2010.  
19. Maddison P, Lang B. Paraneoplastic neurological autoimmunity and survival in small-
cell lung cancer. J Neuroimmunol 2008;201-02.  
20. Koyama K, Kagamu H, Miura S et al. Reciprocal CD4+ T-cell balance of effector 
CD62Llow CD4+ and CD62LhighCD25+ CD4+ regulatory T cells in small cell lung 
cancer reflects disease stage. Clin Cancer Res 2008;14: 6770-79.  
21. Alexandrov LB, Nik-Zainal S, Wedge DC et al. Signatures of mutational processes in 
human cancer. Nature 2013;500: 415-21.  
22. Grant SC, Kris MG, Houghton AN, et al. Long survival of patients with small cell lung 
cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus 
Calmette-Guérin. Clin Cancer Res 1999;5:1319-23.  
23. Giaccone G, Debruyne C, Felip E, et al. Phase III study of adjuvant vaccination with 
Bec2/bacille Calmette-Guerin in responding patients with limited-disease small-cell lung 
cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; 
Silva Study). J Clin Oncol 2005;23:6854-64.  

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24. Reck M, Bondarenko I, Luft A et al. Ipilimumab in combination with paclitaxel and 
carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from 
a randomized, double-blind, multicenter phase 2 trial. Ann Oncol 2013;24: 75-83.  
25. Lynch TJ, Bondarneko I, Luft A, et al. Ipilimumab in combination with paclitaxel and 
carboplatin as first line treatment in stage IIIB/IV non-small cell lung cancer: results 
from a randomized double-blind, ,multicenter phase II study. J Clin Oncol 
2012;30:2046-54.  
26. Brahmer JR, Tykodi SS, Chow LQ et al. Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. N Engl J Med 2012; 366: 2455-2465.  
27. McDermott DF, Atkins MB. PD-1 as a potential target in cancer therapy. Cancer Med 
2013;2:662-73.  
28. Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 
blockade in non-small cell lung cancer (NSCLC): Additional analyses from a clinical 
study of the engineered antibody MPDL3280A (anti-PDL1). Eur J Cancer 
2013;49:Suppl 2, abstract 3408.  
29. Wu, J. Single-arm phase II trial design under parametric cure models. Pharmaceutical    
Statistics, DOI: 10.1002/pst.1678. 

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15.0 APPENDICES 
15.1 ECOG Performance Status 
Table 9 
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. 
 
15.2 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)Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 Criteria for Evaluating Response in Solid Tumors 
 
 
 15.3 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, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 

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15.4 
Events of Clinical Interest and Immune Related Adverse Event 
 
The purpose of this section is to provide study sites with guidance for the identification 
of immune-related adverse experiences that are defined as Events of Clinical Interest 
(ECI) in the protocol, and to provide the documentation and reporting requirements for 
these events. ECIs are selected adverse experiences that must be reported to the 
Principal Investigator and Merck within 72 hours from the time the Investigator is 
aware of such an occurrence and require additional detailed information to be collected 
and entered in the study database.  
 
Based on the available data, and consideration of mechanism of action of MK-3475, 
potential immune-related adverse events (irAEs) are the primary ECI. Given that 
immune-related events can involve different organ systems, following section provides 
information on the major potential target organs that could be affected by MK-3475 and 
other molecules that function via an immune mechanism. It is possible that irAEs other 
than those listed in this document may be observed in patients receiving MK-3475; 
therefore, all adverse events (AEs) of unknown etiology associated with drug exposure 
should be evaluated to determine if it is possibly immune-related. 
 
Table 10 provides the list of terms and reporting requirements for ECIs for MK-3475 
protocols. 
Table 10 
Colitis (reported as ECI if ≥ Grade 2) 
Bowel Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
GI Perforation 
Necrotizing Colitis 
 
 
 
Diarrhea (report as ECI if ≥ Grade 3 or any grade resulting in dose modification) 
 
Endocrine (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid Disorder 
Thyroiditis 
 
 
 
Eye 
Uveitis (report as ECI if ≥ Grade 2 or any grade resulting in dose modification) 
 
Hepatic (reported as ECI if ≥ Grade 2 or any grade requiring dose modification) 
Hepatitis 
Hepatitis, Autoimmune 
 
 
Pneumonitis (reported as ECI if ≥ Grade 2) 
Acute Interstitial Pneumonitis 
Interstitial Lung Disease 
Pneumonitis 
 

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See also Section 6.3.1.1 for detailed description of the management of these irAEs.  
Dose Modification/Discontinuation 
The treatment guidance suggests when to hold and/or discontinue MK-3475 
 
2. ECI REPORTING GUIDELINES 
ECIs are selected non-serious and serious adverse experiences that must be reported to 
Principal Investigator within 72 hours regardless of attribution to trial treatment.  Any event 
that meets the ECI criteria in Table 1 or in the respective protocol (event term and Grade) 
must be reported regardless of investigator-determined causality with study medication or if 
considered 
immune-related 
(unless 
otherwise 
specified). 
 
 
Investigators/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. 
 
 
 
Renal (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification)  
Nephritis 
Nephritis Autoimmune 
Renal Failure 
Renal Failure, Acute 
 
 
 
Skin (always reported as ECI regardless of grade) 
Dermatitis Exfoliative 
Erythema Multiforme 
Stevens-Johnson Syndrome 
Toxic Epidermal Necrolysis 
 
 
 
Skin (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
Vitiligo 
 
 
Other (The following should always be reported as an ECI, regardless of grade) 
Autoimmune Neuropathy 
Demyelinating Polyneuropathy 
Guillain-Barre 
Myasthenia Gravis like syndrome 
Non-infectious myocarditis 
Non-infectious pericarditis 
Pancreatitis 
Rapid onset of Grade 3 fatigue in 
the absence of disease progression 
 

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3. ECI CATEGORIES AND TERMS 
This section describes the ECI categories and outlines subject management guideline when 
an event is reported.       
3.1 Colitis 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be 
reported to the Principal Investigator within 72 hours of the event:  
– Bowel obstruction  
– Colitis  
– Colitis microscopic 
– Enterocolitis 
– Enterocolitis hemorrhagic  
– GI perforation 
– Necrotizing colitis 
 
Diarrhea should be reported as an ECI if it is ≥ Grade 3.  
 
The following signs and symptoms may be associated with any of the above diagnosis.  The 
signs and symptoms below may represent one of the included adverse events, but do not need 
to be reported as an ECI unless the investigator suspects one of the ECI events listed above. 
 
Symptoms 
Symptoms may include (but not limited to): 
– Abdominal pain, cramping and/or bloating 
– Blood and/or mucus in stool with or without fever 
– Constipation 
– Diarrhea 

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– Ileus 
– Nausea and/or vomiting 
– Peritoneal signs consistent with bowel perforation 
– Rectal bleeding 
– With or without fever 
 
Differential Diagnosis 
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, and a Clostridium difficile titer.  
Course of Action 
Grade 1 diarrhea:  
– Treat symptomatically (loperamide, oral hydration, electrolyte substitution and 
ADA colitis diet). 
– Endoscopy is recommended if symptoms persist. 
Grade 2 diarrhea (or persistent Grade 1):   
– Hold MK-3475. 
– GI consultation and endoscopy is recommended to confirm or rule out colitis for 
Grade 2 diarrhea that persists >1 week or Grade 1-2 diarrhea with rectal bleeding 
(additional guidelines for the treatment of persistent colitis are provided below).   
– Grade 1 events that persist for >1 week or Grade 2 events should be treated with 
the addition of oral diphenoxylate hydrochloride and atropine sulfate four times 
daily and budesonide 9 mg daily.  
– Grade 2 diarrhea with diffuse ulceration and bleeding seen on endoscopy may 
require oral steroids with prolonged taper and represent an increased risk for the 
development of bowel perforation. 
– When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 

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Grade 3-4 diarrhea (or Grade 2 diarrhea that persist after initial steroid treatment): 
– Hold/Discontinue MK-3475. 
– Rule out bowel perforation.  Imaging with plain films or CT can be useful. 
– Consider consultation with Gastroenterologist and confirmation biopsy with 
endoscopy 
– Treat with intravenous steroids (methylprednisolone 125 mg) followed by high 
dose oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg 
every 4 hours)  When symptoms improve to Grade 1 or less, steroid taper should 
be started and continued over no less than 4 weeks.  Taper over 6 to 8 weeks in 
patients with diffuse and severe ulceration and/or bleeding. 
– If IV steroids followed by high dose oral steroids does not reduce initial 
symptoms within 48 to 72 hours, consider treatment with infliximab at 5 mg/kg 
once every 2 weeks. Discontinue infliximab upon symptom relief and initiate a 
prolonged steroid taper over 45 to 60 days. If symptoms worsening 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 infliximab.  CAUTION: 
infliximab is contraindicated in patients with bowel perforation or sepsis [12]. 
– If symptoms persist despite the above treatment a surgical consult should be 
obtained. 
3.2 Endocrine 
The following AE terms, if considered ≥ Grade 3 or if ≥ Grade 2 and require 
holding/discontinuation of MK-3475, are considered ECIs and should be reported to the 
Principal Investigator within 72 hours of the event:   
– Adrenal insufficiency 
– Hyperthyroidism 
– Hypophysitis 
– Hypopituitarism  
– Hypothyroidism 
– Thyroid disorder  
– Thyroiditis  

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The following signs and symptoms may be associated with any of the above diagnoses.  The 
occurrence of the signs and symptoms listed below do not require reporting as an ECI unless 
the investigator suspects one of the ECI events listed above. 
Symptoms 
Symptoms may include (but not limited to): 
– Abdominal pain 
– Abnormal thyroid function tests and/or serum chemistries 
o TSH increased (decreased),  
o Free Thyroxine increased,  
o Tri-iodothyronine increased.   
– Arrhythmias* 
– Cold or heat intolerance 
– Fatigue  
– Fever 
– Headache 
– Hypotension* 
– Loss of appetite 
– Mental status and/or behavior changes 
– Nausea and/or vomiting  
– Unusual bowel habits 
– Vision disturbances 
– Weakness 
*If symptoms indicate possible new or worsening cardiac abnormalities additional testing 
and/or a cardiology consultation should be considered.  

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Differential Diagnosis 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection.  An endocrinology consultation is recommended. 
 
Course of Action 
Grade 1-2 events: 
– Monitor thyroid function or other hormonal level tests and serum chemistries 
more frequently until returned to baseline values. 
– If hypophysitis is considered, pituitary gland imaging should be considered (MRIs 
with gadolinium and selective cuts of the pituitary can show enlargement or 
heterogeneity and confirm the diagnosis). 
– Thyroid hormone and/or steroid replacement therapy to manage adrenal 
insufficiency. 
 
Symptomatic pan-hypopituitarism and any Grade 3-4 events 
– Hold/discontinue MK-3475. 
– Consider Endocrine consultation. 
– 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.  
– Hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and 
hyperkalemia) constitutes adrenal crisis. Hospitalization and intravenous 
methylprednisolone should be initiated.  
3.3 Eye 

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The following AE term, if considered Grade ≥2, is considered an ECI and should be reported 
to the Principal Investigator within 72 hours of the event: 
– Uveitis 
 
The following signs and symptoms may be associated with the above diagnosis.  The 
occurrence of the signs and symptoms listed below do not require reporting as an ECI unless 
the investigator suspects the ECI event listed above. 
Symptoms 
Symptoms may include (but not limited to): 
– Blurred vision 
– Diffuse erythema and a prominent blush on the sclerae 
– Dryness of the eyes 
– Pain 
– Photophobia 
 
Differential Diagnosis 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other ocular disease (e.g. glaucoma or cataracts). 
 
Course of Action 
Grade 1-2 events:  
– Evaluation by an ophthalmologist is strongly recommended. 
– Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
– Discontinue MK-3475 if symptoms persist despite treatment with topical 
immunosuppressive therapy. 
 

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Grade 3-4 events: 
– Discontinue MK-3475. 
– 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. 
 
3.4 Hepatic 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be 
reported to the Principal Investigator within 72 hours of the event:   
– Hepatitis  
– Hepatitis, Autoimmune 
 
The following signs and symptoms may be associated with any of the above diagnoses.  The 
signs and symptoms below may represent one of the included adverse events, but do not need 
to be reported as an ECI unless the investigator suspects one of the ECI events listed above. 
 
Symptoms 
Symptoms may include (but not limited to): 
– Elevations in: 
o AST >2.5 times upper limit of normal (ULN) 
o ALT >2.5 times ULN 
o Total bilirubin >1.5 times ULN 
– Fever 
– Malaise 
– Upper quadrant abdominal pain 
 

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Differential Diagnosis 
All attempts should be made to rule out other causes such as metastatic disease, progressive 
liver disease, viral hepatitis, alternative drug toxicity, infectious causes and/or myositis. 
 
Course of Action 
Grade 1 events: 
– Monitor liver function tests more frequently until returned to baseline values. 
 
Grade 2 events: 
– Monitor liver function tests more frequently until returned to baseline values. 
 
Grade 3-4 events: 
– Discontinue MK-3475 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.  
– 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 [12]. 
– Several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased. 
 
Note: in the event of a drug-induced liver injury (DILI) adverse event (as outlined in the 
study protocol), please follow the DILI guidance outlined in the site Administrative Binder.   
 

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3.5 Pneumonitis 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be 
reported to the Principal Investigator within 72 hours of the event: 
– Pneumonitis 
– Interstitial lung disease 
– Acute interstitial pneumonitis  
 
The following signs and symptoms may be associated with any of the above diagnoses.  The 
signs and symptoms represent one of the included adverse events, but do not need to be 
reported as an ECI unless the investigator suspects one of the ECI events listed above. 
 
Symptoms 
Symptoms may include (but not limited to): 
– Abnormal breath sounds 
– Chest pain and/or tightness* 
– Dyspnea* 
– Dry cough 
– Fatigue 
– Fever 
– Hemoptysis 
*If symptoms indicate possible new or worsening cardiac abnormalities additional testing 
and/or a cardiology consultation should be considered.  
 
Differential Diagnosis 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
viral infection.  

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Course of Action 
Grade 1 events:  (asymptomatic with radiographic findings only): 
– MK-3475 may be continued with close monitoring. 
– Radiologic findings should be followed on serial imaging studies.  
– Consider pulmonary consultation and/or bronchoscopy if clinically indicated. 
Grade 2 events: 
– Hold MK-3475 as specified in the protocol. 
– Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– Consider pulmonary function tests. 
– 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.   
– Treatment with MK-3475 may be resumed if the event improves to grade 0 or 1 
within 12 weeks and corticosteroids have been reduced to the equivalent of 
methylprednisolone 10 mg po daily or less.  Repeat chest imaging monthly as 
clinically indicated. 
– Second episode of pneumonitis – discontinue MK-3475 if upon rechallenge the 
patient develops a second episode of Grade 2 or higher pneumonitis. 
Grade 3 and 4 events: 
– Permanently Discontinue MK-3475. 
– Consider pulmonary function tests with pulmonary consult. 
– Bronchoscopy with biopsy and/or BAL is recommended. 
– Treat with intravenous steroids (methylprednisolone 125 mg). 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 infliximab at 5 mg/kg once every 2 
weeks. Discontinue infliximab upon symptom relief and initiate a prolonged 
steroid taper over 45 to 60 days. If symptoms worsening during steroid reduction, 

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initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed 
by a more prolonged taper and administer infliximab.   
3.6 Renal 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Principal 
Investigator within 72 hours of the event: 
– Nephritis 
– Nephritis autoimmune 
– Renal failure 
– Renal failure, Acute 
 
The following signs and symptoms may be associated with any of the above diagnosis.  The 
occurrence of the signs and symptoms listed below do not require reporting as an ECI unless 
the investigator suspects one of the ECI events listed above. 
 
Symptoms 
Symptoms may include (but not limited to): 
– Fatigue  
– High blood pressure  
– Increased serum creatinine 
– Swelling 
 
Differential Diagnosis 
All attempts should be made to rule out other causes such as obstructive uropathy, 
progression of disease, or injury to other chemotherapy agents.  A renal consultation is 
recommended. 
 
Course of Action 

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Grade 1 events: 
– Mild (Grade 1) irAEs – provide symptomatic treatment. 
 
Grade 2 events: 
– Moderate (Grade 2) or Grade 1 irAEs that do not improve with symptomatic 
treatment – consider withholding MK-3475.  Systemic corticosteroids may be 
indicated. 
 
Grade 3-4 events: 
– Clinically significant or severe (≥ Grade 3) irAEs 
– Discontinue MK-3475 
– 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 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.   
 
Discontinue MK-3475 if unable to reduce corticosteroid dose for irAEs to ≤10 mg.    
MK-3475 treatment may be restarted and the dose modified as specified in the protocol 
3.7 Skin 
The following AEs should always be reported as ECIs, regardless of CTCAE grade, and 
should be reported to the Principal Investigator within 72 hours of the event:  
– Dermatitis Exfoliative 
– Erythema Multiforme 
– Stevens-Johnson Syndrome 

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– Toxic Epidermal Necrolysis 
 
The following AE terms should only be reported as an ECI if they are considered to be 
immune related, ≥ Grade 3 or result in dose modification or discontinuation:   
– Pruritus 
– Rash 
– Rash generalized 
– Rash maculo-papular 
– Vitiligo 
 
Differential Diagnosis 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
allergic dermatitis. 
 
Course of Action with MK-3475  
Grade 1-2 events: 
– Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in 
combination with oral antipruritics (e.g., diphenhydramine HCl or hydroxyzine 
HCl).  
– Treatment with oral steroids is at investigator discretion for Grade 2 events. 
Grade 3 events: 
– Hold MK-3475. 
– 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. 

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Grade 4 events: 
– Permanently discontinue MK-3475. 
– 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. 
 
3.8 Other 
The following AEs are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
– Autoimmune Neuropathy 
– Demyelinating Polyneuropathy 
– Guillain-Barre 
– Myasthenia Gravis-like Syndrome 
– Non-infectious myocarditis 
– Non-infectious pericarditis 
– Pancreatitis 
– Rapid onset of Grade 3 fatigue in the absence of disease progression 
Differential Diagnosis 
All attempts should be made to rule out other causes.  Therapeutic specialists should be 
consulted as appropriate. 
 
Course of Action 
– Mild (Grade 1) irAEs – provide symptomatic treatment. 

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– Moderate (Grade 2) or Grade 1 irAEs that do not improve with symptomatic 
treatment – consider withholding MK-3475.  Systemic corticosteroids may be 
indicated. Consider biopsy for confirmation of diagnosis. 
– Clinically significant or severe (≥Grade 3) irAEs –discontinue MK-3475 and treat 
with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day.  Report as ECI.  
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.   
 
Discontinue MK-3475 if unable to reduce corticosteroid dose for irAEs to ≤10 mg.    
MK-3475 treatment may be restarted and the dose modified as specified in the protocol. 
 
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 
 

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5. 
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 
2012; 366:2443-2454. 
 
6. 
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–
PD-L1 Antibody in Patients with Advanced Cancer.  N Engl J Med 2012; 366:2455-2465. 
 
7. 
Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-
controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered 
with or without prophylactic budesonide in patients with unresectable stage III or IV 
melanoma. Clin Cancer Res 15:5591-5598, 2009 
 
8. 
Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma 
and the Management of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 
53–66 
 
9. 
Phan GQ, Weber JS, and Sondak VK.  CTLA-4 Blockade with Monoclonal 
Antibodies in Patients with Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 
15(11):3014–3021 
 
10. 
Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated 
adverse reactions—YERVOY Risk Evaluation and Mitigation Strategy (REMS). 
http://www.yervoy.com/hcp/rems.aspx 
 
11. 
Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised 
March 2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf 
 
12. 
Janssen Biotech, Inc.: REMICADE (Infliximab) prescribing information revised 
September 2011.  
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_
ApprovalHistory#labelinfo