Conditions: Unresectable Malignant Neoplasm Melanoma Metastatic Melanoma Stage IV Melanoma Stage III Melanoma
Keywords: immunotherapy PD-1 inhibitor programmed death 1 inhibitor neoadjuvant pembrolizumab MK-3475
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
This study is being done to see if using the study drug, pembrolizumab, can shrink down melanoma tumors enough so that they will be small enough to cut out, so that there will be no cancer left in the body.

Eligible participants include those who have not received any systemic melanoma therapies (i.e. participants do not have to fail ipilimumab or BRAF inhibitor) and those who have failed all available systemic options (if the participant meets other inclusion / exclusion criteria).

Detailed description:
This study is being done to see if using the study drug, pembrolizumab, can shrink down melanoma tumors enough so that they will be small enough to cut out, so that there will be no cancer left in the body.

Eligible participants include those who have not received any systemic melanoma therapies (i.e. participants do not have to fail ipilimumab or BRAF inhibitor) and those who have failed all available systemic options (if the participant meets other inclusion / exclusion criteria).

For most melanoma cases, surgery is the recommended treatment. Until recently surgery was not used for patients with advanced melanoma (melanoma that has spread to lymph nodes or melanoma that has spread to other organs like the lung, liver, brain) because it was thought that surgery wouldn't help patients live longer when the melanoma tumors had spread beyond the skin. Recent studies have shown that patients with advanced melanoma who have surgery as one of their treatments may live longer than patients who only have systemic therapy (IV drugs or pills) and do not have surgery at all.

Unfortunately, when patients with advanced melanoma come to the doctor, surgery is not a good choice for most patients because they have 'unresectable' melanoma. 'Unresectable' melanoma means they have melanoma tumors in the body that are too big or too close to important parts in the body (like big blood vessels) to be cut out safely. We are studying if we can use a drug to shrink tumors down to make them small enough to cut out; this is called a "neoadjuvant" approach to treating melanoma. By removing all of the cancer from body by using the combination of drug and surgery, we think this could help people live longer.

Pembrolizumab is a drug that is given in the veins and can make the immune system stronger so that it can fight cancer cells. Pembrolizumab is in the class of drugs called immunotherapy.

Immunotherapy uses parts of a person's immune system to fight the disease. Pembrolizumab is designed to restore the natural ability of the immune system to recognize and target melanoma cells to be attacked. In addition to possibly shrinking tumors, it may change your immune system so that it can fight melanoma in the future.

We are also trying to learn more about how pembrolizumab works in the body. In this study, we will look at the skin, blood, and bone marrow to see if we can see any signs to tell doctors whether pembrolizumab is working or tell us which patients it may work on.

Arms:
arm 1: Open-label non-randomized trial. All subjects will receive active drug (pembrolizumab).

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: At the Treatment Initiation Visit (Baseline/Day 1), subjects will begin treatment with IV pembrolizumab 200 mg infusions every 3 weeks. As in previous pembrolizumab trials, eligible subjects will receive at least 24 weeks of therapy and may receive up to 2 years of pembrolizumab therapy depending on response to treatment.

Protocol document:
Prot_SAP_000.pdf: 
COVER PAGE 
 
Study Title:   Phase 2B single-site, open-label, nonrandomized study evaluating the efficacy of  
                        neoadjuvant MK-3475 for unresectable Stage III and unresectable Stage IV melanoma 
 
NCT02306850  
Responsible Party:  John Richart, MD 
Documents:  Study Protocol and Statistical Analysis Plan 
Date of Study Protocol document:  1.8.19 
 


Product:  MK-3475  
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Protocol/Amendment No.:  4 
John M. Richart, M.D. 
Saint Louis University 
Confidential 
SPONSOR:  
John M. Richart, M.D. (Principal Investigator) and Melinda B. Chu, M.D. 
Saint Louis University 
TITLE:  
Phase 2B single-site, open-label, nonrandomized study evaluating the efficacy of 
neoadjuvant MK-3475 for unresectable Stage III and unresectable Stage IV melanoma 
IND NUMBER: pending 
EudraCT NUMBER: 
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Product:  MK-3475  
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Protocol/Amendment No.:  4 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
1.0 TRIAL SUMMARY 
Abbreviated Title 
 Neo MK-3475 for unresectable melanoma 
Trial Phase 
 2B 
Clinical Indication 
 Melanoma 
Trial Type 
 single-site, open-label, nonrandomized 
Type of control 
 n/a 
Route of administration 
 intravenous 
Trial Blinding 
 n/a 
Treatment Groups  
 All subjects 
Number of trial subjects 
 15 
Estimated duration of trial 
 24-36 months after study start 
Duration of Participation 
 20-24 months 
 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a Phase 2B single-site, open-label, nonrandomized 24-week study of the efficacy of 
neoadjuvant MK-3475 (200 mg every 3 weeks) in improving resectability rates in subjects 
with unresectable Stage III or unresectable Stage IV melanoma.  Patients with unresectable 
Stage IV melanoma will be eligible for study entry if the investigators think that complete 
metastectomy would be possible if the anatomic site(s) of metastasis that are precluding 
curative resection at the time of study entry decreased in size by up to 50%.   
A total of 15 subjects will be enrolled in the study.   
At the Treatment Initiation Visit (Baseline/Day 1), eligible subjects will begin treatment with 
IV MK-3475 200 mg infusions every 3 weeks.  Clinical assessments will be performed every 
3 weeks during treatment.  Imaging to assess initial response will be performed at Week 12 
(after 4 cycles).   
There are 5 types of response in this neoadjuvant trial: 
- Complete Response (CR) 
- Resectable Partial Response (rPR):  
        - partial response amenable to curative resection in all affected sites 
- Unresectable Partial Response (uPR):  
        - partial response not yet amenable to curative resection 
- Stable Disease (SD) 
- Progressive disease (PD) 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
Patients with stable disease or any response at Week 12 will receive at least 24 weeks of 
treatment (8 cycles) and undergo repeat imaging at Week 24.  Patients with no evidence of 
disease (CR or rPR after complete metastectomy) at Week 24 will be eligible to discontinue 
treatment (at Week 24 or Week 30 depending on time of response) enter the observation period 
with follow-up visits every 12 weeks for 1 year. 
Complete responders at Week 12 will receive 4 additional cycles to complete 24 weeks of 
treatment (8 cycles).  If CR is confirmed on Week 24 imaging, patients who achieved CR at 
Week 12 will discontinue treatment and enter the observation period.  Patients who exhibit rPR 
at Week 12 assessment will undergo complete metastectomy and receive 4 additional cycles 
of MK-3475 to complete 24 weeks of treatment (8 cycles).  If no evidence of disease is 
observed on Week 24 imaging, patients who achieved rPR at Week 12 will discontinue 
treatment and enter the observation period.   
Subjects who display SD or uPR at Week 12 will continue MK-3475 for 12 additional weeks 
(4 cycles) with repeat imaging and resectability evaluation at Week 24.   
If PD is noted on Week 12 imaging, repeat imaging will be performed 4 weeks later (Week 
16).  If PD is confirmed, the subject will exit the study.  If stable disease or partial response is 
observed on Week 16 imaging, the patient will continue MK-3475 and be reassessed at Week 
24 (after 8 cycles). 
Patients who achieve CR at Week 24 (and who did not demonstrate CR at Week 12 assessment) 
will receive 2 additional cycles of MK-3475 (10 cycles total) before entering the observation 
period.  At Week 24, complete metastectomy will be performed in patients with rPR; after 
surgery, these patients (rPR after complete metastectomy) will receive 2 additional cycles of 
therapy (10 cycles total) before entering the observation period.   
Subjects who display SD or uPR at Week 24 will continue MK-3475 infusions every 3 weeks 
until disease progression or completion of 24 months of treatment. 
If PD is observed on Week 24 imaging, repeat imaging will be performed 4 weeks later (Week 
28).  If PD is confirmed, the subject will discontinue MK-3475 treatment and exit the study.  
If stable disease or partial response is observed on Week 28 imaging, the patient will continue 
MK-3475 infusions every 3 weeks until disease progression or completion of 24 months of 
treatment. 
The rationale for using 24-week treatment schedule for primary endpoint analysis (increase in 
‘resectability rate’) is based on previous data from pilot studies.  Data from a previous trial of 
135 subjects with metastatic melanoma, demonstrated that 84.5% (44 of 52) of responders 
responded by 24 weeks. (Hamid et al 2013) 
Tissue, blood and bone marrow aspirate specimens will be collected to further understand the 
immunomodulatory effects of MK-3475 and to identify any biomarkers of response.  
Histopathologic evaluation of affected and unaffected tissue will be performed during the study 
to characterize any differences in cellular profiles. 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
At the baseline visit, skin biopsy of melanoma tissue (if applicable), non-sun-exposed 
unaffected skin, and any nevi on non-sun-exposed skin will be performed.  These specimens 
will be examined along with the metastatic specimen for pre-treatment immunohistochemical 
(IHC) evaluation. 
Histopathologic evaluation from unaffected skin and nevi in non-sun-exposed skin will be 
conducted at Week 12 and Week 24. 
Post-treatment tissue histopathologic evaluation will be performed after curative resection on 
both responding and nonresponding tissue where possible.  In complete responders, skin 
biopsies of non-sun-exposed unaffected skin and nevi will be performed. 
In addition, flow cytometry of blood and bone marrow aspirates will be followed during the 
study to determine if MK-3475 induces any host immune response. 
Safety assessments including adverse event (AE) monitoring will be performed at every visit 
and assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
 
 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
2.2 
Trial Diagram 
 
Treatment Algorithm 
All enrolled subjects will receive 4 cycles of IV MK-3475 infusions (200 mg) every 3 weeks. At Week 12, imaging to 
assess initial response will be performed.  There are 5 types of response in this neoadjuvant trial:  
    
1.)  Complete response (CR) 
2.)  Resectable partial response (rPR)  
3.)  Unresectable partial response (uPR)  
4.)  Stable disease (SD)  
5.)  Progressive disease (PD) 
 
Week 12: 
Subjects that display CR, uPR, or SD at Week 12 will continue MK-3475 with reassessment at Week 24 (after 8 cycles).  
Patients with rPR at Week 12 will undergo complete metastectomy and continue MK-3475 with re-evaluation at Week 
24.  If PD is observed on Week 12 imaging, the subject will continue MK-3475 and repeat imaging will be performed in 
4 weeks (Week 16).  If PD is confirmed, the patient will stop MK-3475 and exit the study.  If SD or uPR is seen on Week 
16 imaging, the patient will continue MK-3475 for 4 additional cycles and imaging to reassess response will be 
performed at Week 24. 
Week 24: 
Subjects who, at Week 12, either attained CR or demonstrated rPR and underwent complete metastectomy, will 
discontinue MK-3475 after Week 24 (after 8 cycles) and enter the observation period if no evidence of disease is seen 
on Week 24 imaging.  Patients that achieve CR at Week 24 (and did not exhibit CR at Week 12) or those that 
demonstrate rPR and undergo complete metastectomy at Week 24 will receive 2 additional cycles of MK-3475 (10 
cycles total) before entering the observation period.  Subjects who display SD or uPR at Week 24 will continue MK-
3475 infusions every 3 weeks until disease progression or completion of 24 months of treatment.  If PD is observed on 
Week 24 imaging, the subject will continue MK-3475 and repeat imaging will be performed in 4 weeks (Week 28).  If PD 
is confirmed, the patient will stop MK-3475 and exit the study.  If SD or uPR is seen on Week 28 imaging, the patient 
will continue MK-3475 infusions every 3 weeks until disease progression or completion of 24 months of treatment.  
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypothesis:  
Resectability Rate 
Objective:  
To evaluate the efficacy of intravenous MK-3475 as a neoadjuvant therapy in unresectable 
Stage III and unresectable Stage IV melanoma 
Hypothesis:   
Our hypothesis is that treatment with MK-3475 will result in a 20% increase in 
“resectability rate” in the study cohort compared to 0% (baseline before treatment) in 
melanoma, defined as 20% of study subjects becoming eligible for curative resection after 
treatment with MK-3475 
3.2 
Secondary and Exploratory Objectives & Hypotheses: 
(1) Response by RECIST criteria 
Objective: 
 
To evaluate intravenous MK-3475 for response by RECIST criteria 
 
Hypothesis: 
 
Our hypothesis is that subjects treated with MK-3475 in this study have similar rates of 
response as demonstrated in previous studies by Hamid et al 2013. 
 
(2) Immunomodulatory effects and biomarkers of response 
Objective: 
To further understand the immunomodulatory effects of MK-3475 and to identify any 
biomarkers of response by evaluating uninvolved skin tissue and blood/bone marrow 
aspirates 
Hypothesis: 
Our hypothesis is that uninvolved skin and blood/bone marrow aspirate will demonstrate 
changes in T-cell expression that can serve as a biomarker(s) of response and help to 
explain the systemic immune response during MK-3475 treatment 
 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
(3) Cellular profiles of responding and nonresponding tissue  
Objective: 
To evaluate differences in cellular or immunohistochemical (IHC) profiles of responding 
and nonresponding tissue 
Hypothesis: 
 
Our hypothesis is that the density of infiltration with CD8 T-cells in tumor tissue will 
correspond to the magnitude of response (amount tumor decreases after treatment) 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 8].  The structure 
of murine PD-1 has been resolved [9].  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade [7; 10; 11; 12].  The mechanism by which PD-1 down modulates T-cell 
responses is similar to, but distinct from that of CTLA-4 as both molecules regulate an 
overlapping set of signaling proteins [13; 14].  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells [15; 16].  Expression has also been shown during thymic development on CD4-CD8- 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
(double negative) T-cells as well as subsets of macrophages and dendritic cells [17].  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety 
of cell types, including non-hematopoietic tissues as well as in various tumors [18; 19; 20; 13].  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains 
in the extracellular region and contain short cytoplasmic regions with no known signaling 
motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-
L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves 
to dampen unwarranted T-cell function in peripheral tissues [13].  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels 
of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion 
in subjects with melanoma (MEL) [21].  This suggests that the PD-1/PD-L1 pathway plays a 
critical role in tumor immune evasion and should be considered as an attractive target for 
therapeutic intervention. 
MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2.   
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
When melanoma presents at an early stage (Stage I or II) as in the majority of patients, it is a 
highly curable cancer.  When diagnosed at an advanced stage, melanoma has a poor prognosis 
with reported 10 year survival rates of 24-43% in Stage IIIB/C melanoma and 5 year survival 
rates of 10-15% in Stage IV melanoma [22].  Surgery is the treatment of choice or a part of 
standard management in nearly all cases of melanoma (for both Stage I and II and most Stage 
III cases) [23].  In contrast, traditionally, for melanoma that has metastasized to any distant 
site, whether it be soft tissue, visceral, or a distant lymph node, the prevailing orthodoxy has 
been that systemic therapy alone was the only option.  Surgery and locoregional management 
were thought to be futile as the development of multiple distant metastases was considered 
inevitable in any patient with metastatic disease, even in those with a solitary metastasis or 
oligometastases [24]. 
Currently, the paradigm is shifting and metastectomy now has a more prominent role in the 
management of advanced melanoma as there is increasing data to suggest that surgical 
resection may help to prolong survival.  Sub-group analysis of data from the First Multicenter 
Selective Lymphadenectomy Trial (MSLT-1) revealed that those who received surgical 
management of their Stage IV disease only (no systemic therapy) had the longest median 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
overall survival duration (22.0 months), while those who received systemic therapy before 
surgery had the next longest median overall survival duration (17.0 months).  By comparison, 
patients who received systemic therapy alone (no surgery) had a median overall survival 
duration of 6.9 months [25].   
Though not completely understood, there are several theoretical biologic mechanisms that may 
explain the therapeutic benefit of surgery in advanced melanoma.  The most commonly held 
belief is that tumor resection is immediately advantageous because it decreases the effects of 
tumor-induced immunosuppression [24].  It has also been suggested that surgical resection 
may interrupt the metastatic cascade that leads to hematogenous seeding or trigger the 
augmentation of the patient’s own immune system [25].  One practical explanation that may 
account for the favorable disease course seen in those who undergo curative resection is that 
since metastases themselves can metastasize, removal of a metastasis limits the potential 
growth of future systemic tumor burden by making it physically impossible for the metastasis 
to spread [26, 24]. 
Despite the potential benefit of curative resection, unfortunately, the majority (78.6%) of 
patients with Stage IV disease are ineligible for complete metastectomy at initial presentation 
due to anatomic location or size of the metastatic lesion(s) [27].  On the other hand, in Stage 
III disease, complete surgical resection and lymph node dissection is almost always achievable; 
in only a small minority of cases, is it not feasible due to size and location of the primary tumor 
or lymph nodes.  For both groups – unresectable Stage III and unresectable Stage IV 
melanoma, it has been proposed that a “neoadjuvant” approach, using a systemic therapy to 
decrease tumor burden before curative resection would be beneficial. 
Neoadjuvant treatment in melanoma has been studied for decades, initially with chemotherapy 
and biochemotherapy, but is underutilized and still not commonly employed in routine clinical 
practice [28]. Data available are from retrospective analyses where ‘resectability rate’ was not 
the primary endpoint [29].   
Recently, neoadjuvant vemurafenib has been shown to lead to rapid impressive tumor bulk 
reduction, within a few weeks in some cases [30].  However, while vemurafenib was effective 
in maintaining local disease control, it did not decrease the risk of metastatic relapse [31].  
Immunotherapies may be a better option for use as a neoadjuvant agent compared to 
chemotherapy or molecular targeted therapies, which target tumor cells only.  In theory, 
immunotherapies provide not only the possibility of tumor size reduction and resection, but 
also offer the prospect of inducing a systemic immune response, which may delay or prevent 
future metastatic relapse. There have been some preliminary studies with ipilimumab as a 
neoadjuvant therapy, but further studies of immunotherapies with a neoadjuvant approach are 
still needed [32]. 
MK-3475 is an intravenously administered programmed death (PD-1) receptor inhibitor which 
is pending FDA approval for metastatic melanoma that may be useful as a neoadjuvant therapy 
in melanoma [33]. 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted by Merck, Inc. to evaluate the 
safety and clinical activity of single agent MK-3475.  The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors.  All three dose levels were well tolerated and 
no dose-limiting toxicities were observed.  This first in human study of MK-3475 showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 
mg/kg Q2W, the highest dose tested in PN001, will be the dose and schedule utilized in 
Cohorts A, B, C and D of this protocol to test for initial tumor activity.  Recent data from 
other clinical studies within the Merck MK-3475 program has shown that a lower dose of 
MK-3475 and a less frequent schedule may be sufficient for target engagement and clinical 
activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a 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. 
 
 
 
 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
A novel primary endpoint, ”resectability rate”, was developed for this trial.  Resectability rate 
is defined as the proportion of subjects in the trial that were unresectable at baseline who after 
treatment with MK-3475 are now eligible for curative resection with complete metastectomy. 
Using resectability rate as the primary endpoint by definition makes those with resectable Stage 
III/IV disease ineligible for study entry.  This decision was deliberate.  Patients with resectable 
Stage III/IV disease were excluded; in non-responders delaying surgery may unnecessarily 
endanger the patient possibly allowing their melanoma to progress to an unresectable state 
which could potentially negatively affect their clinical outcome.   
Ideally, the goal of any advanced melanoma treatment is to lead to complete response.  For 
systemic therapies, it has been demonstrated that complete response is associated with 
increased overall survival [34].  In addition, it has been established that complete metastectomy 
in Stage IV melanoma improves survival for all M stages [25]. 
Thus, taken together, the goal of a neoadjuvant trial should be the ability of the treatment to 
lead to curative resection.  This approach, should not only improve the duration of overall 
survival for patients, but also allows for the most tissue to be collected for histopathologic 
evaluation to further understand the mechanism of action and response of MK-3475. 
The decision to use an increase in resectability rate as the endpoint was also based on our 
institutional experience and the inadequacy of current response criteria.   
It is common practice at our institution (Saint Louis University) to perform curative resection 
when possible in Stage IV melanoma after systemic therapy.  Though systemic therapy was 
not utilized initially to be a “neoadjuvant” therapy, we have found that performing curative 
resection after high-dose interleukin-2 (HD IL-2) has favorable results on both median duration 
of response and overall survival.  Out of 55 evaluable patients with melanoma who underwent 
HD IL-2 at our institution, 8 achieved complete response (14.5%) and 6 achieved partial 
response, 3 of whom had “resectable partial response” and 3 of whom who had “unresectable 
partial response” [35]. 
 
 
 
 
 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
In patients that were able to achieve “resectable partial response” or a decrease in tumor burden 
rendering a patient’s disease amenable to complete metastectomy, a longer median duration of 
response (9.1 months) than reported rates (~6 months) for partial response to HD IL-2 was 
seen [36]. In addition, the overall survival of these patients was much longer than would have 
been expected by their M stage if they received systemic therapy alone based on data from 
MSLT-1 trial [25]. 
 
The RECIST criteria, designed to evaluate the benefit of systemic therapies, which measure 
response by assessing the measurement of overall tumor burden, are not well suited for use as 
an endpoint or the deciding factor in whether to perform surgery in a neoadjuvant trial. [37].  
Using partial response by RECIST criteria as the deciding factor at the very least may be 
incongruent with clinical reality and may possibly prohibit surgery where it is in the best 
interest of the patient. 
There are situations where a minimal response to systemic therapy may permit curative 
resection, which theoretically should improve survival.   In the example below, the 
retroperitoneal tumor is unresectable making curative resection unattainable, but this site is 
potentially resectable with a small decrease in size, which if it occurred would make the patient 
eligible for complete metastectomy. 
 
 
 
 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
If the retroperitoneal tumor did decrease in size to 4.8 cm and even if the other sites did not 
respond to treatment, the patient would be eligible for curative resection in this study.  
However, by RECIST criteria, which measures overall tumor burden, this patient would be 
considered stable disease and not eligible for complete metastectomy, since overall tumor 
burden has only decreased in size by 14%. 
 
 
Even though partial response by RECIST criteria, which requires a decrease in the 
measurement of overall tumor burden by 30%, appears to be a higher standard for undergoing 
surgery, there are situations when achieving partial response by RECIST criteria may be an 
inaccurate determinant in resectability as detailed below.  Even though in this example, the 
patient had remarkable response including resolution of brain metastasis, the patient’s Stage 
IV disease is still unresectable. 
 
For these reasons, an increase in resectability rate was selected as the most appropriate primary 
endpoint for this neoadjuvant trial. 
4.2.3.2 Biomarker Research 
Tissue (primary cutaneous melanoma and/or metastatic specimen), blood and bone marrow 
aspirate specimens will be collected before treatment and at Weeks 12 and 24 for T-cell subset 
analyses and functional assays to further understand the immunomodulatory effects of MK-
3475.  
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Saint Louis University 
 
Confidential 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1.   
4. Has a diagnosis of unresectable Stage III or Stage IV melanoma with anatomic site(s) 
of metastasis that could be amenable to curative resection if the site(s) decreased in 
size by up to 50% (at the investigators’ discretion).   
 
5. Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine clearance 
(GFR can also be used in place of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Coagulation 
International Normalized Ratio (INR) or Prothrombin 
Time (PT) 
 
Activated Partial Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
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Saint Louis University 
 
Confidential 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
8. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
9. 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.  
10. 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. 
 
5.1.3 Subject 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 or 
using an investigational device within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has 
not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier.  
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy 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.   
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Saint Louis University 
 
Confidential 
5. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy.   
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.   
7. Has an active automimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a 
syndrome that requires systemic steroids or immunosuppressive agents.  Subjects with 
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  
Subjects that require intermittent use of bronchodilators or local steroid injections 
would not be excluded from the study.  Subjects with hypothyroidism stable on 
hormone replacement or Sjorgen’s syndrome will not be excluded from the study. 
8.   “Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.Has an active infection requiring systemic therapy. 
9. 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.   
10. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
11. 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. 
12. 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). 
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
15. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
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Saint Louis University 
 
Confidential 
16. Is currently being treated with ipilimumab (defined as ipilimumab treatment less than 
6 weeks before first dose of MK-3475). 
 
5.2 
Trial Treatments 
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 
Regimen/ 
Treatment Period 
Use 
MK-3475 200mg 
every 3 
weeks 
IV infusion 
24 weeks to 24 
months 
regimen granted 
FDA’s ‘Breakthrough 
Therapy’ designation 
– pending approval 
 
 
The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.2.1.2. 
 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
5.2.1.2 Dose Modification  
MK-3475 will be withheld for drug-related Grade 4 hematologic toxicities, non-hematological 
toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-threatening AEs as 
per Table 3 below. 
Table 3: Dose modification guidelines for drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
Hematological Toxicity 
 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
*Excluding 
Grade 3 
neutropenia, 
anemia, and 
thrombocytopenia 
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 
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Saint Louis University 
 
Confidential 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
Non-hematological toxicity 
 
Note:  Exception to be 
treated similar to grade 1 
toxicity  
 Grade 2 alopecia 
 Grade 2 fatigue 
 
For additional information 
regarding Adverse Events 
with a potential Immune-
Etiology reference Section 
5.6.1.1. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks:  Same 
dose and 
schedule 
(reference 
Section 5.6.1.2 
for 
recommendations 
regarding 
pneumonitis) 
Clinical AE does 
not resolve 
within 4 weeks:  
May increase the 
dosing interval 
by  1 week for 
each occurrence 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
3, 4 
 
Yes 
 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
 
May increase the 
dosing interval 
by 1 week for 
each occurrence 
 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued.  Subjects with a laboratory adverse event still at Grade 2 after 12 weeks 
may continue treatment in the trial only if asymptomatic and controlled.  For information on 
the management of adverse events, see Section 5.6.1.   
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of MK-3475 should be discontinued from trial treatment. 
 
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Saint Louis University 
 
Confidential 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
MK-3475 will be administered as a 30 minute IV infusion (treatment cycle intervals may be 
increased due to toxicity as described in Section 5.2.1.2).  Every effort will be made to target 
infusion timing to be as close to 30 minutes as possible.  However, given the variability of 
infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min). 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 
5.3 
Randomization or Treatment Allocation 
Not applicable.  This is an open-label trial. 
5.4 
Stratification 
Not applicable.  This is an open-label trial. 
5.5 
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.   
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Anti-cancer systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than MK-3475 
 Radiation therapy  
o Note:  Radiation therapy to symptomatic lesions or to the brain may be allowed. 
 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 if the investigator deems it to be medically necessary..  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
 Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without 
fever) and of bowel perforation (such as peritoneal signs and ileus).  In symptomatic 
subjects, infectious etiologies should be ruled out, and if symptoms are persistent 
and/or severe, endoscopic evaluation should be considered. 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
o In subjects with severe enterocolitis (Grade 3), MK-3475 will be permanently 
discontinued and treatment with systemic corticosteroids should be initiated at 
a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and continued 
over at least 1 month. 
o In subjects with moderate enterocolitis (Grade 2), MK-3475 should be withheld 
and anti-diarrheal treatment should be started.  If symptoms are persistent for 
more than one week, systemic corticosteroids should be initiated (e.g., 0.5 
mg/kg/day of prednisone or equivalent).  When symptoms improve to Grade 1 
or less, corticosteroid taper should be started and continued over at least 1 
month.  Regarding guidelines for continuing treatment with MK-3475, see 
Section 5.2. 
o All subjects who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. 
 Nausea/vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Subjects 
should be strongly encouraged to maintain liberal oral fluid intake. 
 Anti-infectives: Subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard institutional 
practice. 
 Immune-related adverse events: Please see Section 5.6.1.1 below and Appendix 12.4 
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. 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of MK-3475. 
 
 
 
 
Table 5  Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
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. 
 
No subsequent dosing 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Subject is permanently discontinued 
from further trial treatment 
administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.  irAEs may be predicted based on the nature of the MK-3475 
compound, its mechanism of action, and reported experience with immunotherapies that have 
a similar mechanism of action.  Special attention should be paid to AEs that may be suggestive 
of potential irAEs.  An irAE can occur shortly after the first dose or several months after the 
last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes prior to labeling an adverse event as an irAE.  Information on 
how to identify and evaluate irAEs has been developed and is included in the Event of Clinical 
Interest and Immune-Related Adverse Event Guidance Document located in the 
Administrative Binder.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 6. 
Table 6  General Approach to Handling irAEs 
irAE 
Withhold/Discontinue MK-
3475? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold MK-3475 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold MK-3475 
Discontinue if unable to reduce 
corticosteroid dose to < 10 mg 
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. 
 
5.6.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving MK-3475 and have 
an evaluation.  The evaluation may include bronchoscopy and pulmonary function tests to rule 
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Saint Louis University 
 
Confidential 
out other causes such as infection.  If the subject is determined to have study drug associated 
pneumonitis, the suggested treatment plan is detailed in Table 7. 
Table 7  Recommended Approach to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue MK-
3475? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold MK-3475, may 
return to treatment if improves 
to Grade 1 or resolves within 
12 weeks 
Systemic corticosteroids are indicated.  Taper if 
necessary. 
Grade 3 and Grade 4 
Discontinue MK-3475 
Systemic corticosteroids are indicated. The use of 
infliximab may be indicated as appropriate.  Refer to 
the Event of Clinical Interest and Immune-related 
Adverse Event Guidance Document for additional 
recommendations. 
 
For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules 
should apply: 
 First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
 Second episode of pneumonitis – permanently discontinue MK-3475 if upon 
rechallenge subject develops pneumonitis  Grade 2 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 
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John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in section 7.2.2-Reporting of Pregnancy 
and Lactation to the Investigator’s Institutional Review Board (IRB) and to Merck.  If there is 
any question that a subject will not reliably comply with the requirements for contraception, 
that subject should not be entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with MK-3475, the subject will 
immediately be removed from the study.  The site will contact the subject at least monthly and 
document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to 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 record 
the condition of the fetus or newborn.   If a male subject impregnates his female partner the 
study personnel at the site must be informed immediately and the pregnancy reported to the 
Investigator’s IRB and to Merck and followed as described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether MK-3475 is excreted in human milk.  Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.3 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
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Protocol/Amendment No.:  4 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
 Confirmed radiographic disease progression 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Completed 24 months of treatment with MK-3475 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop MK-3475 after 24 months 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.4 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up.  After documented disease progression each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
5.9 
Subject Replacement Strategy 
5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
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Protocol/Amendment No.:  4 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
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Protocol/Amendment No.:  2 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
 
Confidential 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
Observation 
Treatment Cycle/Title: 
Screening 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Week 24 
(up to 4 visits) 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Every 12 weeks 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Trial Treatment Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
(X) 
 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone marrow aspirate (9 subjects) 
 
X 
 
 
 
X 
 
 
 
X 
 
Surgical Assessment 
X 
 
 
 
 
X 
 
 
 
X 
 
Cutaneous evaluation and skin biopsy 
 
X 
 
 
 
X 
 
 
 
X 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCG 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
and LDH 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T3, FT4 and TSH 
X 
 
 
 
X 
 
 
 
X 
 
 
Efficacy Measurements 
Tumor Imaging and Resectability 
Evaluation 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
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Protocol/Amendment No.:  2 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
 
Confidential 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
Observation 
Treatment Cycle/Title: 
Screening 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Week 24 
(up to 4 visits) 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Every 12 weeks 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
 
X 
 
 
 
X 
 
 
 
X 
 
Correlative Studies Blood and Bone 
Marrow Aspirate Collection (9 subjects) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Investigator for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially 
sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that 
additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to Investigator’s IRB/ERC requirements, applicable laws 
and regulations. 
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 12.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
All AEs of unknown etiology associated with MK-3475 exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE).  See Section 5.6.1.1 and the separate guidance document in the administrative 
binder regarding the identification, evaluation and management of AEs of a potential 
immunological etiology.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
7.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.  After Cycle 8 assessment of ECOG status will be 
performed every other cycle in conjunction with the directed or full physical exam. 
 
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.1.2.5 Tumor Imaging and Assessment of Disease 
The investigators will review imaging at screening to confirm that the subject meets criteria 
for study entry.  The investigators will assess response after Cycle 4 and Cycle 8 for primary 
endpoint analysis (increase in ‘resectability rate’).  Depending on the subject’s response after 
Cycle 8, the subjects may receive additional cycles of MK-3475.  After Cycle 8, repeat 
response assessment will be performed every 12 weeks. 
7.1.2.6 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Tumor tissue and blood and bone marrow aspirate sampling will be obtained at baseline, Week 
12, Week 24.  Tumor tissue will be collected if accessible via skin, subcutaneous, or lymph 
node biopsy. 
7.1.2.7 Laboratory Safety Evaluations (Hematology, Chemistry) 
Laboratory tests for hematology, chemistry, and others are specified in Table 9.  Laboratory 
tests for screening should be performed within 10 days prior to the first dose of treatment.  
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.  
Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment.  
.  
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
Table 9  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Urine pregnancy test † 
Total thriiodothyronine (T3) 
Hemoglobin 
Alkaline phosphatase 
 
Free thyroxine (T4) 
Platelet count 
Alanine aminotransferase (ALT) 
 
Thyroid stimulating hormone (TSH) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
 
  
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
 
  
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
 
  
 
  (CO2 or bicarbonate) 
 
  
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
Phosphorus 
 
 
 
Potassium   
 
 
 
Sodium 
 
 
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
 
 
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.1.3 Other Procedures 
7.1.3.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  All subjects may receive up to 24 months of therapy during the course of the 
study. 
Subjects who meet all of the following criteria may discontinue treatment prior to completing 
24 months of therapy: 
 
1. CR or rPR with complete metastectomy has been confirmed. 
 
2. Patient has received at least 24 weeks (8 cycles) of MK-3475 therapy. 
 
3. Patient has received at least 2 cycles of MK-3475 after CR or rPR with complete  
 
      metastectomy is documented.   
After discontinuing treatment following assessment of CR or rPR with complete 
metastectomy, these subjects should return to the site for a Safety Follow-up Visit (described 
in Section 7.1.4.5.4) and then proceed to the Observation Period (aka Follow-Up Period) of 
the study (described in Section 7.1.4.6). 
7.1.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.4.1 Screening 
Subjects will be screened prior to the first dose of MK-3475 (Baseline/Day 1) to confirm that 
they meet the entrance criteria for the study.  The Screening visit may occur up to 4 weeks 
prior to initiation of study drug.   
The study investigator or qualified designee will discuss the following with each subject the 
nature of the study, its requirements, and its restrictions. Written informed consent must be 
obtained prior to performance of any protocol-specific procedures.   
The following procedures will be performed at the Screening visit 
 Confirmation that subject meets all inclusion criteria and exclusion criteria, excluding 
evaluation of whether tumor burden is potentially amenable to curative resection. 
 Recording of medical history. (Medical history is defined as a disease or syndrome that 
is ongoing at or stopped before Informed Consent.) 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
 Recording of current medications and all other drugs (including non-prescription drugs, 
vitamins, and dietary supplements) taken within 4 weeks prior to Screening. 
 Complete physical examination 
 Physical examination includes: general appearance, skin, HEENT (head, eyes, ears, 
nose and throat), heart (auscultation), lungs (auscultation), abdomen (palpation and 
auscultation), lower extremities (peripheral edema),  
 Vital signs [blood pressure (BP); heart or pulse rate; and oral, tympanic, or temporal 
temperature], height and weight. 
 Urine pregnancy test only for women who are of childbearing potential. 
 Review of imaging to assess baseline metastatic tumor burden 
 
7.1.4.2 Screening Period 
7.1.4.2.1 Pre-treatment Surgical Assessment Visit 
The following procedures will be performed at the Pre-Treatment Surgical Assessment visit: 
 Review of medical history and concomitant medications 
 Physical examination 
o Physical examination includes: general appearance, skin, HEENT (head, eyes, 
ears, nose and throat), heart (auscultation), lungs (auscultation), abdomen 
(palpation and auscultation), lower extremities (peripheral edema),  
 Vital signs [blood pressure (BP); heart or pulse rate; and oral, tympanic, or temporal 
temperature], weight. 
 Review of imaging to assess baseline metastatic tumor burden 
 
7.1.4.2.2 Pre-treatment Resectability Evaluation 
As part of the screening process, evaluation of the patient’s tumor burden to verify that it meets 
criteria to be potentially amenable to curative resection (defined below) will be performed. 
7.1.4.2.2.1 Tumor burden potentially amenable to curative resection: 
Anatomic site(s) of metastasis that could be amenable to curative resection if the site(s) 
decreased in size by up to 50%.   
If it is determined that the patient’s tumor burden is potentially amenable to curative resection 
and the patient meets all other study criteria, the subject will enter the study. 
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.1.4.2.3 Pre-treatment Cutaneous Evaluation 
The Pre-treatment Cutaneous Evaluation will be performed after it has been determined that 
patient meets the requirements for study entry.   
The following procedures will be performed at the Pre-Treatment Cutaneous Evaluation visit.  
 Review of medical history and concomitant medications 
 Skin examination and photography 
 Skin biopsy of melanoma tissue (if applicable), non-sun-exposed unaffected skin, and 
any nevi on non-sun-exposed skin 
 
7.1.4.3 Treatment Period 
7.1.4.3.1 Treatment Initiation Visit 
The objective of this visit is to ensure that subjects who will enter the study continue to meet 
all inclusion and exclusion criteria.  The Treatment Initiation visit should take place within 4 
weeks of Screening visit.   
The following procedures will be performed at Treatment Initiation Visit (Baseline/Day 1) 
after confirmation that the subject has met all inclusion criteria and has no exclusion criteria 
present: 
 Assessment of any changes (deletions, additions, or dose modifications) to 
medications. 
 Adverse Event (AE) Monitoring. 
 Physical examination  
 Vital signs (BP; heart or pulse rate; and oral, tympanic, or temporal temperature), 
weight. 
 Urine pregnancy test (β-hCG) for women who are of childbearing potential.  
 Administration of MK-3475 (200 mg infusion) 
 
 
 
 
 
 
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.1.4.4 Interval Visits 
The objective of the interval visits is to monitor subject safety while ensuring continued 
compliance with study procedures.  The Interval Visits will be performed every 3 weeks.  
Every attempt should be made to have individual subject assessments performed by the same 
physician (investigator or equally qualified physician listed on FDA form 1572). 
The following procedures will be performed at all visits during treatment: 
 Assessment of any changes (deletions, additions, or dose modifications) to 
medications. 
 Adverse Event (AE) Monitoring. 
 Physical examination  
 Vital signs (BP; heart or pulse rate; and oral, tympanic, or temporal temperature), 
weight. 
 Urine pregnancy test (β-hCG) for women who are of childbearing potential.  
 Administration of MK-3475 (200 mg infusion) 
 
After 4 cycles of MK-3475 (Week 12), the subject will undergo imaging to assess response to 
MK-3475.  The subject will also undergo repeat Surgical Assessment and Cutaneous 
Evaluation at Week 12 (see below). 
At Week 12, blood and bone marrow specimens will be collected for T-cell subset analysis 
and functional assay testing. 
7.1.4.4.1 Week 12 - Surgical Assessment Visit 
The following procedures will be performed at the Week 12 - Surgical Assessment visit after 
4 cycles of MK-3475. 
 Review of medical history and concomitant medications 
 Physical examination 
o Physical examination includes: general appearance, skin, HEENT (head, eyes, 
ears, nose and throat), heart (auscultation), lungs (auscultation), abdomen 
(palpation and auscultation), lower extremities (peripheral edema),  
 Vital signs [blood pressure (BP); heart or pulse rate; and oral, tympanic, or temporal 
temperature], weight. 
 Review of imaging to assess metastatic tumor burden 
 
 
 
 
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.1.4.4.2 Week 12 - Cutaneous Evaluation 
The following procedures will be performed at the Week 12 - Cutaneous Evaluation after 4 
cycles of MK-3475. 
 Review of medical history and concomitant medications 
 Skin examination and photography 
 Skin biopsy of melanoma tissue (if applicable), non-sun-exposed unaffected skin, and 
any nevi on non-sun-exposed skin 
 
7.1.4.4.3 Week 12 - Resectability Evaluation 
Initial imaging will be performed at Week 12 (after 4 cycles) to assess whether tumor burden 
is amenable to curative resection.   
Complete responders at Week 12 will continue MK-3475 for 12 additional weeks with repeat 
imaging to confirm CR at Week 24.  Patients who exhibit rPR at Week 12 assessment will 
undergo complete metastectomy and continue MK-3475 for 12 additional weeks with repeat 
imaging at Week 24.   
Subjects who display SD or uPR at Week 12 will continue MK-3475 for 12 additional weeks 
(4 cycles) with repeat imaging and resectability evaluation at Week 24.   
If PD is noted on Week 12 imaging, repeat imaging will be performed 4 weeks later (Week 
16).  If PD is confirmed, the subject will exit the study.  If stable disease or partial response is 
observed on Week 16 imaging, the patient will continue MK-3475 and be reassessed at Week 
24 (after 8 cycles). 
 
7.1.4.5 Week 24 Visits 
At Week 24, assessments will be performed in a similar manner as those performed at Week 
12 (e.g. Resectability Evaluation, Surgical Assessment, and Cutaneous Evaluation). 
 
7.1.4.5.1 Week 24 - Surgical Assessment Visit 
The following procedures will be performed at the Week 24 - Surgical Assessment visit after 
8 cycles of MK-3475. 
 Review of medical history and concomitant medications 
 Physical examination 
o Physical examination includes: general appearance, skin, HEENT (head, eyes, 
ears, nose and throat), heart (auscultation), lungs (auscultation), abdomen 
(palpation and auscultation), lower extremities (peripheral edema),  
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
 Vital signs [blood pressure (BP); heart or pulse rate; and oral, tympanic, or temporal 
temperature], weight. 
 Resectability evaluation 
 
7.1.4.5.2 Week 24 - Cutaneous Evaluation 
The following procedures will be performed at the Cutaneous Evaluation visit after 8 cycles of 
MK-3475. 
 Review of medical history and concomitant medications 
 Skin examination and photography 
 Skin biopsy of melanoma tissue (if applicable), non-sun-exposed unaffected skin, and 
any nevi on non-sun-exposed skin 
 
 
7.1.4.5.3 Week 24 - Resectability Evaluation 
Imaging to assess response will be performed at Week 24 (after 8 cycles).   
In a similar manner as was performed at week 12, imaging will be performed at Week 24 (after 
8 cycles) to assess whether tumor burden is amenable to curative resection.   
Subjects who achieved CR at Week 12 will discontinue treatment after Week 24 (after 8 cycles) 
and enter the observation period if CR is confirmed on Week 24 imaging.  Subjects who 
exhibited rPR at Week 12 and subsequently underwent complete metastectomy will 
discontinue treatment after Week 24 (after 8 cycles) and enter the observation period if no 
evidence of disease is observed on Week 24 imaging.  
Patients who achieve CR at Week 24 (and who did not demonstrate CR at Week 12 assessment) 
will receive 2 additional cycles of MK-3475 (10 cycles total) before entering the observation 
period.  At Week 24, complete metastectomy will be performed in patients with rPR; after 
surgery, these patients (rPR after complete metastectomy) will receive 2 additional cycles of 
therapy (10 cycles total) before entering the observation period.   
Subjects who display SD or uPR at Week 24 will continue MK-3475 infusions every 3 weeks 
until disease progression or completion of 24 months of treatment. 
If PD is observed on Week 24 imaging, repeat imaging will be performed 4 weeks later (Week 
28).  If PD is confirmed, the subject will discontinue MK-3475 treatment and exit the study.  
If stable disease or partial response is observed on Week 28 imaging, the patient will continue 
MK-3475 infusions every 3 weeks until disease progression or completion of 24 months of 
treatment. 
 
 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
7.1.4.5.4  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.   
7.1.4.6 Observation Period 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Observation Period (aka Follow-Up Phase) and should be assessed every 12 weeks (84 
± 7 days) by radiologic imaging to monitor disease status.  Every effort should be made to 
collect information regarding disease status until the start of new anti-neoplastic therapy, 
disease progression, death, or end of the study.  Information regarding post-study anti-
neoplastic treatment will be collected if new treatment is initiated. 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
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Protocol/Amendment No.:  3 
 
 
John M. Richart, M.D. 
Saint Louis University 
 
Confidential 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in section 7.2.3.1. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-3475 by 20% over the prescribed dose. No specific information is available on 
the treatment of overdose of MK-3475. In the event of overdose, MK-3475 should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 3 working 
days to the Investigator’s IRB per institutional guidelines and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation to the Investigator’s IRB 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, 
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Saint Louis University 
 
Confidential 
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 7 working days to the Investigator’s IRB per institutional 
guidelines and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
7.2.3 Immediate Reporting of Adverse Events to the Investigator’s IRB and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is a new cancer (that is not a condition of the study); 
 Is associated with an overdose; 
 Is another important medical event  
Refer to Table 10 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 3 working days to the Investigator’s IRB per institutional guidelines and within 
2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Investigator’s IRB and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
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Saint Louis University 
 
Confidential 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and 
reported within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; 
FAX 215 993-1220) 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Investigator’s IRB, that is not associated with 
clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent). 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to Merck Global Safety within 2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.”  This document provides guidance 
regarding identification, evaluation and management of ECIs and irAEs.  Additional ECIs are 
identified in this guidance document and also need to be reported to Merck Global Safety 
within 2 working days of the event.   
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Saint Louis University 
 
Confidential 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes.  If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes.  If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following cessation 
of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not 
related to the Merck’s product, must be reported to Merck Global Safety within 2 working 
days. 
7.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
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Saint Louis University                                                                                Confidential                             
 
 
 
Table 10  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 
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Saint Louis University                                                                                Confidential                             
 
 
 
 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 
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7.2.5 Investigator Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
It was decided that if half of partial responders to MK-3475 could be amenable to curative 
resection after treatment, that this would be an acceptable rate to use as a benchmark for 
comparison.  Based on available data from Hamid et al, the overall response rate was 44% and 
the partial response rate was 33.3 % [33]. If half of the responders from available data were 
amenable to curative resection, the benchmark would be 16.7%. 
By definition all subjects enrolled in the trial have unresectable disease or 0% resectability rate 
at baseline. 
Therefore, a 20-percentage point increase from the expected rate of 0% resectability rate 
exceeds the benchmark of 16.7 % and was deemed appropriate for use in the estimation of 
sample size requirements. 
A sample size of 15 would provide 95% power to detect a statistically significant improvement 
of 20%-points over the expected resectability rate of 0%.  This sample size estimation is based 
on an alpha 0.025 employing customary calculations for the normal approximation of the 
binomial distribution.  
Descriptive statistics will be reported for all other measures collected as part of the study 
protocol. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
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9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Investigator and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the 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. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Clinical data will be collected at the time of enrollment from the patient’s medical record.  
Data will be entered into the study electronic database. The Study Coordinator will also use 
hard copy forms as worksheets.  The paper worksheets will be retained at the Hematology and 
Oncology Clinic in a locked file cabinet within a locked office until the study is complete and 
all study analyses and publications have been accomplished. These paper worksheets will be 
subject to site safety monitoring reviews. 
When the subject is enrolled in the study, a study number will be automatically provided. The 
research team will recode the dates of enrollment and birth to calculate the subject’s age, in 
days, and the resulting analytical database fulfills the definition of a de-identified database 
according to HIPAA definitions. 
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Saint Louis University 
Confidential 
 
 
10.2 Compliance with Financial Disclosure Requirements 
In accordance with institutional, state and federal regulations, all investigators will disclose 
their participation in this trial. 
 
10.3 Compliance with Law, Audit and Debarment 
The investigator and other members of the research team will adhere to state and federal 
regulatory requirements during the course of the trial 
 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
10.5 Quality Management System 
Quality assurance activities undertaken during this study include monitoring and source data 
validation by the study team. 
 
10.6 Data Management 
Data will be collected on hard-copy paper forms and electronically and will be stored and 
secured as detailed below. 
Hard-Copy Data Forms  
The investigators have a dedicated, locked research room within the Hematology and 
Oncology offices, and the building has 24 hour on-site security guards. Data forms will be kept 
in research binders in a locked cabinet. 
Electronic Data 
User authentication is maintained with user/group domain-level security, centralized to 
desktop computers that are password-protected. There will be no transfer of data over public 
networks.  
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The de-identified electronic database, which contains raw research data will also be pass-word 
protected and maintained on the Saint Louis University Hematology and Oncology 
department’s secured server. Once the data is ready for analyses, it will be coded and locked. 
Analytical files will contain no identifiers and will contain accumulated data for report of 
findings. 
Confidentiality Security Plan 
The investigators and research staff are fully committed to the security and confidentiality of 
all data collected this study. All personnel involved in this study have signed confidentiality 
agreements concerning all data encountered in the study clinic. All personnel involved with 
this study have completed Human Subjects Protection and HIPAA education. 
 
 
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Saint Louis University 
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Saint Louis University 
Confidential 
 
 
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Saint Louis University 
Confidential 
 
 
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Saint Louis University 
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John M. Richart, M.D. 
Saint Louis University 
Confidential 
 
 
12.0 APPENDICES 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
12.2 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) 
12.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
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John M. Richart, M.D. 
Saint Louis University 
Confidential 
 
 
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. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
 
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John M. Richart, M.D. 
Saint Louis University 
Confidential 
 
 
12.4 MK-3475 Event of Clinical Interest Guidance Document 
Separate attachment 
NCT02306850
Jan 8, 2019