Conditions: Metastatic Non Small Cell Lung Cancer
Keywords: Metastatic, Lung Cancer, Switch, Maintenance, Pembrolizumab.
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 48
Healthy volunteers: no

Brief summary:
Single arm one stage Phase II study: post 4-6 cycles platinum doublet chemotherapy for patients with metastatic Non Small Cell Lung Cancer (NSCLC) offering Pembrolizumab as maintenance therapy to non-progressors with primary endpoint: Immune Related Progression Free Survival (irPFS) at 1 year. Aim to show that this is at least 25% (compared to an expected 12% 1 year PFS based on the Pemetrexed and Erlotinib maintenance trials).

Detailed description:
Rationale:

There are currently no data on maintenance therapy with PD1/ PDL1 inhibitors in NSCLC. After an initial response / stable disease to first line chemotherapy, non-progressors / candidates for maintenance treatment, represent an ideal setting / patient group to test the efficacy of Pembrolizumab given that chemotherapy results in antigen release, hence it has the potential to augment immune checkpoint blockade, and following disease cytoreduction, this represents a lower disease burden setting, that may suit checkpoint inhibition better given the recent studies in Prostate cancer with Ipilimumab and Melanoma with Pembrolizumab(suggesting better outcomes for patients with less extensive disease).

Primary endpoint: percentage of patients that have not progressed at 1 year using immune related radiological criteria.

All patients to be treated with fixed dose 200mg iv Pembrolizumab until unacceptable toxicity, disease progression or completion of 2 years therapy.

Statistical Analysis Plan Summary The study employs a one stage phase II Fleming's design using irPFS at 1 year as primary endpoint. Using response hypotheses of H0 \< 12 % and Ha\> 25% i.e. that the irPFS at 1 year for the maintenance Pembrolizumab arm is 25%, compared to 12% in the normal chemotherapy maintenance arm, with a significance level (i.e., the probability of rejecting H0 when it is true) α=0.05 and the power (i.e. the probability of deciding the regimen is active) is 0.8 when true response rate is 25%, 48 patients are required to be entered into this study.

Entry Criteria Diagnosis/Condition for Entry into the Trial In order to be eligible for trial entry, patients must have a diagnosis of metastatic Non Small Cell Lung Cancer, and should not have progressed after first line palliative chemotherapy with a platinum doublet. They should have received no more than six (6) cycles of a platinum doublet chemotherapy, and should be able to receive treatment within three (3) to six (6) weeks from the last chemotherapy administration.

Arms:
arm 1: experimental treatment with maintenance pembrolizumab

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Switch maintenance pembrolizumab treatment

Protocol document:
Prot_SAP_000.pdf: 
 
 
SPONSOR:  Bank of Cyprus Oncology Centre 
 
COLLABORATOR: Merck Sharp & Dohme (MSD) 
 
TITLE: A Phase II study of SWItch Maintenance PEmbrolizumab in patients with non 
small cell lung cancer who do not progress after first line platinum doublet 
chemotherapy (SWIPE). 
 
IND NUMBER: 3475-449 
 
EudraCT NUMBER: 2016-000857-11 
 
NCT 02705820 
 
 
 
Study Principal 
Investigator 
 
Dr Haris Charalambous BM MRCP FRCR 
 
Consultant Clinical Oncologist 
 
Bank of Cyprus Oncology Centre 
 
32 Acropoleos Avenue 
 
2006 Strovolos 
 
Nicosia – Cyprus 
 
Phone: 00357 22 847403 (secretary)  
 
Fax:     00357 22841388 
 
E-mail: haris.charalambous@bococ.org.cy 
 
 
 
 
 
 
Protocol Version 
Date of Regulatory 
Approval 
Amendment Reference 
1.0 - dated February, 2016 
27 May, 2016 
- 
1.1- dated 16 June, 2017 
10 July, 2017 
No. 1    Scientific 
 
 
 


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TRIAL SUMMARY 
Abbreviated Title 
Maintenance Pembrolizumab in patients with Non Small Cell Lung 
Cancer (NSCLC) 
Trial Phase 
Phase II 
Clinical Indication 
For patients with no disease progression after first line chemotherapy 
Trial Type 
Single arm, one stage, Phase II trial 
Type of control 
Non randomized 
Route of administration 
Intravenous 
Trial Blinding 
Not applicable 
Treatment Groups  
Single group 
Number of trial subjects 
Forty eight (48) 
Estimated enrollment period 
April 2016- October 2017 
Estimated duration of trial 
Three and a half (3 ½) years 
Duration of Participation 
Two (2) years 
Estimated average length of 
treatment per patient 
6 cycles 
 
 
 
 
1.0 TRIAL DESIGN 
1.1 
Trial Design 
Single arm one stage Phase II study: post 4-6 cycles platinum doublet chemotherapy for 
patients with metastatic Non Small Cell Lung Cancer (NSCLC) offering Pembrolizumab as 
maintenance therapy to non-progressors with primary endpoint: Immune Related Progression 
Free Survival (irPFS) at 1 year. Aim to show that this is at least 25% (compared to an 
expected 12% 1 year PFS based on the Pemetrexed and Erlotinib maintenance trials).  
1.2 
Trial Diagram 
 
 
 
 
Metastatic NSCLC 
4-6 cycles of platinum 
doublet chemotherapy 
PS0-2 
By RECIST: CR/PR/SD 
Consider Maintenance 
Pembrolizumab study 
Pembrolizumab 
200mg iv q 3 wks 
until DP 
By RECIST PD 
Not 
eligible 
for 
Maintenance 
Pembrolizumab study 


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2.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
2.1 
Primary Objective(s) & Hypothesis(es) 
Objective: The main objective of this trial is to provide efficacy data for Pembrolizumab 
as maintenance therapy after first line therapy for NSCLC. Especially relevant would be 
evidence of a higher percentage of patients being progression free at 1 year (primary 
endpoint), increased response rates, increased Progression free and Overall Survival (OS) 
compared to the results from other chemotherapy maintenance studies.   
Hypothesis:  Pembrolizumab can provide superior outcomes in terms of disease control 
(% of patients Progression Free at 1 year using Immune Related response criteria) 
compared to other maintenance treatments (specifically pemetrexed  continuation 
maintenance for non-squamous NSCLC and erlotinib switch maintenance for squamous 
NSCLC). 
2.2 
Secondary Objective(s) & Hypothesis 
Objective:  Pembrolizumab can provide superior outcomes in terms of disease control / 
survival compared to its use in other lines of therapy. 
Hypothesis:  The secondary study hypothesis is that Pembrolizumab is going to have its 
biggest impact in patients with metastatic NSCLC, if used in the maintenance setting, i.e. 
potentially superior outcomes to being used either as first line or last line therapy (as has 
been tested until now). 
2.3 
Exploratory Objective 
Objective: Document change in PDL1 expression on CTCs, plasma and histology, prior 
and during first line chemotherapy as well as during immunotherapy with 
Pembrolizumab, in patients with non progressive disease, and determine patterns of 
change suggestive of benefit to Pembrolizumab.  
3.0 BACKGROUND & RATIONALE 
3.1 
Background 
Based on the GLOBOCAN data, Lung Cancer is the commonest cancer worldwide with 1.8 
million cases being diagnosed in 2012, as well as the most common cause of cancer death 
with 1.6 million deaths worldwide¹.  There are two main subdivisions of Lung Cancer; small 
cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). This study is focused in 
the treatment of NSCLC, which accounts for approximately 80% of all lung cancers. 
Although over the last few years there have been a number of new drugs (EGFR / ALK 
Tyrosine Kinase Inhibitors) and technology developments (e.g. stereotactic ablative 
radiotherapy and intensity modulated and image guided radiotherapy) in the treatment of 
NSCLC and there are now a wide range of different treatments available to patients with 


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NSCLC, survival still remains very poor with only approximately about 10% of patients 
being alive five year after the initial diagnosis¹.  There is therefore an urgent need to 
introduce new innovative treatments for patients with NSCLC in order to improve outcomes 
in this disease. 
3.1.1 Therapeutic Background 
Information for metastatic Non Small Cell Lung Cancer (NSCLC) 
Routine molecular testing is currently being carried out for patients with metastatic NSCLC: 
predominantly checking for EGFR mutations and ALK translocations. Patients with such 
genetic alterations are candidates to receive either EGFR Tyrosine Kinase Inbitors (TKIs) i.e. 
Erlotinib, Gefitinib or Afatinib, if they harbour an EGFR mutation or Crizotinib if they have 
an ALK translocation².  
For patients with metastatic NSCLC and good performance status (WHO PS 0-2), without 
EGFR mutations or ALK translocations, the ESMO guidelines recommend first line 
treatment with a platinum doublet². A phase III trial suggested superior outcomes for the 
combination of pemetrexed cisplatin versus gemcitabine cisplatin in patients with non-
squamous NSCLC, whilst for patients with squamous cancers gemcitabine cisplatin provided 
better outcomes³.  More specifically overall survival was statistically superior for 
cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 
12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 
months, respectively), whilst in patients with squamous cell histology, there was a significant 
improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 
10.8 v 9.4 months, respectively). Equally in the ECOG 4599 trial⁴, the addition of 
Bevacizumab (Avastin) in combination with carboplatin and paclitaxel showed a significant 
improvement in overall survival to 12.3 months compared to 10.3 months with the same 
regimen without Bevacizumab (hazard ratio for death, 0.79; P=0.003) in patients with non 
squamous NSCLC (also excluding patients with significant haemoptysis and brain 
metastases). Other large phase III trials comparing different platinum based regimens in the 
first line setting or non platinum versus platinum doublets, or addition of molecularly 
targeted drugs , e.g. the EGFR inhibitors such as Iressa (gefitinib) in the INTACT1 and 2 
trials and Tarceva (erlotinib) in the TALENT and TRIBUTE trials to chemotherapy failed to 
show an improvement in overall survival compared to cytotoxic chemotherapy alone².  
As a result of these studies, first line chemotherapy for patients with non-squamous 
metastatic NSCLC without EGFR mutations or ALK translocations is either pemetrexed 
platinum chemotherapy (preferred in Europe) or Carboplatin Paclitaxel and Bevacizumab 
(preferred in the USA). For squamous cancers a non- pemetrexed / non- bevacizumab 
platinum doublet, often platinum gemcitabine, is used worldwide.  
In the second line setting Docetaxel was the first drug to be approved following a landmark 
randomized control study versus best supportive care showing an improvement in median 
survival from 4.6 to 7 months⁵. However this was at considerable toxicity especially in terms 
of severe neutropaenia and malaise. The next step to second line therapy was the randomized 


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controlled study of Docetaxel versus pemetrexed, which showed similar response rates and 
overall survival for the two agents⁶. It was also noted that pemetrexed had significantly less 
toxicity than Docetaxel, especially in terms of severe neutropaenia, febrile neutropaenia, 
deaths due to neutropaenia and hospitalization rates.  
The next agent to gain approval both for second and third line use was Erlotinib (Tarceva) 
based on the BR21 trial; a randomized controlled versus placebo study  showing an 
improvement in survival from 4.7 to 6.7 months⁷.  In this trial eligible patients were those 
that had either already received first and second line therapy, or had received only first line 
therapy but were not deemed fit to receive further palliative chemotherapy.   
More recently in the last two years, data have supported the use of two novel anti-angiogenic 
agents, nintedanib and ramucirumab, both in conjunction with docetaxel, as second line 
treatment for metastatic NSCLC. In the LUME-Lung I trial⁸, 1314 patients were randomized 
to docetaxel with or without nintedanib, with the combination improving overall survival in 
adenocarcinoma patients with a median of 12.6 versus 10.3 months respectively. In the 
REVEL trial⁹, 1253 patients were randomized to docetaxel with or without ramucirumab, 
with the combination improving overall survival from a median of 9.1 months to 10.5 
months. In this study with ramucirumab the benefit was also seen in patients with squamous 
histology; this is the first evidence of benefit of an antiangiogenic monoclonal antibody for 
patients with squamous Lung Cancer. 
3.1.2 Background data: Maintenance Chemotherapy in NSCLC:  
With the understanding that we have reached a therapeutic plateau with platinum doublet 
first line chemotherapy in NSCLC, there has been renewed interest in “maintenance” therapy 
in metastatic NSCLC in the last few years ¹º ¹¹.  Maintenance therapy is applied after 4-6 
cycles of chemotherapy to patients who have not progressed after the initial chemotherapy. 
Distinction needs to be made between continuation and switch maintenance. According to 
the NCCN (National Comprehensive Cancer Network) guidelines, continuation maintenance 
refers to the use of at least one of the agents used in first line, whilst switch maintenance 
refers to the initiation of a different agent, not included as part of the first line regimen. 
Given that the main toxicity from platinum doublet chemotherapy is due to the platinum 
agent (especially cisplatin), a number of investigators have looked at the possibility of 
continuing with the non platinum agent¹º. Such trials include continuation of Paclitaxel 
(Belani 2003¹²), Gemcitabine (Brodowicz 2006¹³, Belani 2010¹⁴ and Perol 2010¹⁵), and 
Pemetrexed (Paz Arez 2011¹⁶). The design of all these trials is that they randomized non 
progressors after 4 cycles (or 16 weeks in the case of the paclitaxel trial) of chemotherapy to 
continuing with the non platinum agent until progression. From these trials only the 
continuation maintenance Pemetrexed trial by Paz Ares showed a statistically significant 
overall survival difference (from 11.0 to 13.9 months; 22% reduction of risk of death with 
HR=0.78 and 95% Cl: 0.64 to 0.96; P=.0195) for patients with non-squamous NSCLC.   


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In terms of continuation maintenance of targeted agents, the licensing studies for both 
Bevacizumab (ECOG 4599 by Sandler⁴) and Cetuximab (the FLEX trial by Pirker¹⁷) 
specified continuation of both agents until progression, and beyond the initial chemotherapy 
doublet treatment period, hence both cetuximab and bevacizumab if used with the initial 
chemotherapy doublet, need to be continued until disease progression (although no 
randomization to a continuation versus no continuation Bevacizumab or Cetuximab was 
tested in these trials). 
In terms of switch maintenance, there have been six (6) randomized trials in the last five 
years. The common theme in these trials, is that they randomized non progressors after four 
cycles of first line platinum doublet chemotherapy to immediate treatment with one of four 
agents already licensed for use as second line therapies in NSCLC, i.e. pemetrexed¹⁸, 
docetaxel¹⁹, gefitinib²º, erlotinib alone²¹ and erlotinib in combination with bevacizumab²² in 
patients receiving bevacizumab as part of their first line treatment, versus treatment at 
progression, and also to vinorelbine²³. From the chemotherapy switch maintenance trials, 
there was only one positive trial for overall survival with pemetrexed. In the Pemetrexed / 
JMEN trial¹⁸, Ciuleanu et al,  randomized 663 patients with advanced  NSCLC who had not 
progressed after four cycles of platinum-based chemotherapy (which did not include 
pemetrexed) to Pemetrexed versus placebo, showing an improvement in PFS (4 vs. 2 months; 
p < .00001) and OS (median 13.4 versus 10.6 months, p = .012). As the trial was enacted 
prior to the understanding of the treatment interaction by histology for pemetrexed, 
squamous cell cancers were also included. Patients with squamous histology however 
derived no benefit from pemetrexed, and subset analysis looking at patients with 
nonsquamous histology showed a large, 5.2 month survival benefit for maintenance 
Pemetrexed versus placebo. The main criticism about this trial was that 33% of the patients 
in the observation arm did not receive second-line chemotherapy, whilst only 19% of the 
patients who received chemotherapy  received pemetrexed at the time of progression.  
From the switch maintenance trials with targeted agents, there was only one positive trial; the 
SATURN trial²¹ by Capuzzo, which tested the benefit of immediate Erlotinib for patients 
who had not progressed after four cycles of platinum-based first-line chemotherapy. Erlotinib 
maintenance therapy significantly improved progression free and overall survival although 
the absolute difference in median OS was modest of only one month from 11 to 12 months. 
Both patients with EGFR mutations and wild type patients appeared to benefit. Further 
analysis of this trial, showed that the main benefit was seen in patients with stable disease 
(SD) after first line chemotherapy, who had a 2.3 month improvement in median survival. 
These results led to the approval for Erlotinib for switch maintenance to be limited to patients 
with SD after induction treatment2. Similar to the Pemetrexed trial, there is criticism that only 
21% of patients on the placebo arm ever got an EGFR inhibitor like Erlotinib.  


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As a result of these studies recently there is more interest in providing maintenance therapy 
to patients with advanced NSCLC, especially for patients with non-squamous histology 
(where both Pemetrexed as continuation and switch maintenance can be used). For patients 
with squamous histology, this approach is less commonly applied given the limited benefit 
seen in the randomized studies (small benefit found for patients with stable disease after first 
line chemotherapy, by using erlotinib in the SATURN trial²¹). The most common clinical 
practice pattern in Europe regarding maintenance therapy is the use of continuation 
maintenance therapy for patients with non-squamous histology with Pemetrexed  trial (Paz 
Ares et al¹⁶). Equally clinically meaningful improvement in survival has been seen with the 
switch maintenance trial for Pemetrexed (starting with a non-Pemetrexed containing 
regimen) again for patients with non-squamous cancers (Ciulianu T et al¹⁸), however this 
approach is not commonly used.  
Despite the use of various lines of chemotherapy, including maintenance chemotherapy, the 
benefit seen with these treatments is modest, with median survival for patients with 
metastatic NSCLC remaining approximately 1 year²⁴. There is therefore an urgent unmet 
need to provide new / innovative therapies to patients with metastatic NSCLC, that are going 
to have a bigger impact and more specifically that are going to be able to provide them with 
more durable responses and lasting disease control. Immunotherapy checkpoint inhibitors 
have shown very promising results in a number of different cancer types, including Non 
Small Cell Lung Cancer, and are coming to the forefront to address this need, which is 
the reason for this study. 
3.1.3 Immune surveillance and the PD1 pathway 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control25.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  
The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 


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for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors.  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor immune evasion and should be considered as an attractive target 
for therapeutic intervention. 
3.1.4 Pembrolizumab: Preclinical and Clinical Trial Data 
KeytrudaTM Pembrolizumab is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 
and its ligands, PD-L1 and PD-L2.  By blocking the binding of PDL-1 and 2 with the PD- 1 
receptor on the surface of activated T-cells, and consequently increase T-cell activation by 
removing the inhibitory signaling of PD-1²⁵.  
KeytrudaTM (pembrolizumab) has been approved in the United Stated for the treatment of 
patients with unresectable or metastatic melanoma and disease progression following 
ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor, and has also received 
accelerated approval to treat patients with advanced (metastatic) non-small cell lung cancer 


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(NSCLC) whose disease has progressed after other treatments and with tumors that express 
PD-L1. 
In the recent publication of the KEYNOTE-001 trial²⁶, including 495 patients, both 
treatment-naïve and previously treated advanced NSCLC patients, the overall response rate 
(ORR) was 19.4% and the median duration of response was 12.5 months.  The median 
duration of progression-free survival was 3.7 months, and the median duration of overall 
survival was 12.0 months.  Patients who were treatment naïve had better response rates 
(RRs): 24.8% compared to 18.0% for the previously treated paients. Equally median PFS was 
higher in untreated patients: 6 months versus 3 months for the previously treated patients. 
Finally for patients with greater than 50% PDL1 expression on immunohistochemistry the 
RR was 42.5%, median progression-free survival was 6.3 months, whilst median overall 
survival was not reached. 
Similar to the KEYNOTE -001 data with Pembrolizumab, clinical trials with other anti-PD-1 
and anti-PD-L1antibodies show similar efficacy producing durable responses in 
approximately 20% of unselected patients with advance NSCLC26. 
Refer to the Investigator’s Brochure for further Preclinical and Clinical data²⁷. 
3.2 
Rationale 
3.2.1 Rationale for the Trial and Selected Subject Population 
There are currently no data on maintenance therapy with PD1/PDL1 inhibitors in NSCLC. 
After an initial response / stable disease to first line chemotherapy, non progressors / 
candidates for maintenance treatment, represent an ideal setting / patient group to test the 
efficacy of Pembrolizumab for the following reasons:  
1. Chemotherapy results in antigen release, which results in T-cell activation hence facilitates 
immune system activation, hence it has the potential to augment immune checkpoint 
blockade ²⁸ ²⁹, thus PD1 inhibition is more likely to be active immediately after 
chemotherapy compared to using this prior to first line chemotherapy. 
2. Equally there is evidence from a randomized phase II study with Ipilimumab that phased / 
sequential administration of a checkpoint inhibitor compared to concurrent use is more 
effective³⁰.  
3. Immune responses with PD1 inhibitors occur faster compared with CTLA-4 inhibitors, 
however about half occur around two (2) months for Nivolumab and Pembrolizumab, and 
some may occur as late as 8 months from initiation of treatment³¹. Hence there are potential 


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concerns that for some patients that progress quickly, there may not be enough time to 
receive the full benefit of this treatment. In the maintenance setting, given that there is 
already disease response or stabilization of disease following the first line chemotherapy, 
there is a time window for the immune response to occur, compared to using PD1 inhibition 
in patients after 2nd - 3rd line therapy, where there is usually rapidly progressing disease, 
which may not allow the time for this approach to work.  
4. Equally after the initial disease response / cytoreduction of the disease, this represents a 
lower disease burden setting, that again may suit checkpoint inhibition better given the recent 
studies in Prostate cancer with Ipilimumab and Melanoma with Pembrolizumaba³² ³³, 
suggesting better outcomes for patients with less extensive disease. 
With this study, looking at efficacy and tolerability of Pembrolizumab as maintenance 
therapy after first line therapy for NSCLC, it is hoped that evidence of better efficacy is 
going to be generated compared to other chemotherapy maintenance studies and compared to 
the use of Pembrolizumab in other lines of therapy.  This should lead to further studies to 
establish the role of Pembrolizumab as maintenance therapy in NSCLC, potentially providing 
better treatments and outcomes for patients with advanced NSCLC. 
Finally, it is worth reflecting on the reality of access to innovative new drugs for Lung 
Cancer patients in Cyprus, whilst maintenance Pemetrexed is also not available due to 
funding restrictions.  As a result, this study provides access to Pembrolizumab, a very 
important checkpoint inhibitor  in NSCLC, as a maintenance treatment, where no other 
treatment options are available for patients with advanced NSCLC, in Cyprus. 
3.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) has being conducted to evaluate the safety and 
clinical activity of single agent MK-3475 (Pembroliumab).  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 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.   


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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. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 


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3.2.3 Rationale for Endpoints 
3.2.3.1 Efficacy Endpoints 
Primary endpoint:  percentage of patients that have not progressed at 1 year using immune 
related radiological criteria (see section 11.3). The 1 year timing relates to the time from trial 
enrollement and initiation of pembrolizumab as maintenance therapy. This is the most 
clinically relevant endpoint in a maintenance study. Prolongation of disease control is a very 
worthwhile endpoint, towards the realization of the goal to obtain long term disease control 
for patients with metastatic NSCLC, similar to the results seen with checkpoint inhibition for 
patients with melanoma. The timing of assessment at 1 year is based on the durable nature of 
responses seen with Pembrolizumab so far, suggesting that at 1 year there is going to be a 
large difference in disease progression between patients on Pembrolizumab compared to the 
historical data from the maintenance studies.   
Secondary Endpoints: These would include 
• 
Response rates (RECIST) 
• 
Response Rates with immune related Response Criteria (irRC)  
• 
Radiological Progression Free Survival (PFS) using RECIST criteria 
• 
Immune-related PFS using irRC:  irPFS is the progression free survival (PFS) 
measured applying immune related radiological criteria. PFS (RECIST) at 6 months 
and 1 year from initiation of Pembrolizumab. 
• 
Overall survival  
• 
1, 2 and 3 year OS rate. 
• 
Best overall response rate and disease control rate using both RECIST and irRC in 
patients with squamous and non-squamous NSCLC and 
• 
Immune-related toxicities (IRAEs) 
 
3.2.3.2 Biomarker Research 
From the recent publication of the KEYNOTE-001 trial²⁸, including 495 treatment-naïve and 
previously treated advanced NSCLC patients, PDL1 status emerges as a potential predictive 
factor for response to Pembrolizumab based on the fact that the ORR (irRC) was 45.2% in 


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patients with strong PD-L1 expression (≥50% staining) statistically higher than for patients 
with expression of 1-49%, or for those less than 1% (p<0.0001).  
In this study we propose to undertake PDL1 testing from the histological sample available at 
diagnosis of metastatic disease (pre- first line chemotherapy sample) and to compare this 
from a new biopsy after first line chemotherapy and prior to study entry with the aim to 
undertake PDL1 status again and compare with pre-chemotherapy initial Bx.  PDL1 testing is 
going to be undertaken by QualTek Molecular Laboratories in the United States 
(http://www.qmlabs.com/About-QualTek.html). 
In this study, we aim to investigate the prognostic and predictive value of PD-L1 and Ki67 
on CTCs and plasma, to patients receiving first line platinum doublet chemotherapy and 
patients receiving Pembrolizumab.   
Aims are:  
1. 1. To investigate the spatial change in PDL1 status with Immunohistochemistry on 
tumour biopsy pre and after chemotherapy and to correlate responses / clinical benefit to 
Pembrolizumab with PDL1 status (from initial biopsy prior to chemotherapy and from 
biopsy after first line chemotherapy).  
2. To ascertain whether pre-chemo or post-chemo PDL-1 status is the better predictor of 
response to Pembrolizumab and whether the pre-chemo Bx is still reliable as a predictive 
marker, making unnecessary a new Bx after 4-6 cycles of first line chemotherapy. 
3. Investigate the differences between membranous, cytoplasmic and nuclear expression of 
PD-L1 on CTCs using the two different antibodies.  
4. Investigate the concordance between the PD-L1 expression analysed with IHC on the 
initial tumour biopsy compared to PD-L1 expression on CTCs and plasma at baseline 
prior to starting platinum based chemotherapy. 
5. Investigate the prognostic and predictive role of Ki67 expression and PD-L1 expression 
on CTCs and plasma at baseline to platinum based chemotherapy and Pembrolizumab 
immunotherapy. 
6. Investigate the temporal change of these biomarkers during chemotherapy and 
immunotherapy, and how this relates to outcomes (e.g. change of CTC number during 
treatment relating to response to chemotherapy and whether the change in expression has 
predictive function: comparing patients with PD-L1(+) and PD-L1(-) CTCs, plus change 
in soluble PD-L1). 


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7. Finally investigate of all the different methods of assessing PD-L1 (e.g. tissue biopsy 
immunohistochemistry, soluble PD-L1 and PD-L1 on CTCs) which one, is the most 
accurate predictive factor to Pembrolizumab immunotherapy.  
 
 
4.0 METHODOLOGY 
4.1 
Entry Criteria 
4.1.1 Diagnosis/Condition for Entry into the Trial 
In order to be eligible for trial entry, patients must have a diagnosis of metastatic Non Small 
Cell Lung Cancer, and should not have progressed after first line palliative chemotherapy 
with a platinum doublet. They should have received no more than six (6) cycles of a platinum 
doublet chemotherapy, and should be able to receive treatment within three (3) to six (6) 
weeks from the last chemotherapy administration. 
4.1.2 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. Be willing to provide tissue from a newly obtained core or excisional biopsy of a 
tumor lesion.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on Day 1.  Subjects for whom newly-obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may submit 
an archived specimen only upon agreement from the Principle Investigator. 
5. Have a performance status of 0 to 2 on the ECOG Performance Scale. 
6. 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 


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Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
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 
Albumin 
>2.5 g/L 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
7. 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.   
8. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception,  for 
the course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
9. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
4.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 


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1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Have completed more than six (6) cycles of first line platinum doublet chemotherapy 
or more than six (6) have elapsed from the last chemotherapy administration of the 
first line chemotherapy with platinum doublet. 
3. 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. 
 
4. Has a known history of active TB   (Bacillus Tuberculosis) 
 
5. Hypersensitivity to pembrolizumab or any of its excipients. 
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
7. 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.   
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment.  This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability.   
10. Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 


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physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
11. Has known history of, or any evidence of active, non-infectious pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. 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.   
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
15. 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. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
19. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
4.2 
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 
Pembrolizumab 200 mg  
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
 
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated/assigned. 


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4.2.1 Dose Selection/Modification 
4.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
4.2.1.2 Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per 3 below. See Section 5.6 for 
supportive care guidelines, including use of corticosteroids. 
Table 3 Dose Modification Guidelines for Drug-Related Adverse Events 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b 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; 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
4.2.2 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. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible.  However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution. 
4.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 


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4.3 
Randomization or Treatment Allocation 
Not applicable 
4.4 
Stratification 
Not applicable 
4.5 
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.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
4.5.1 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 administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
4.5.2 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: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   


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• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
4.6 
Rescue Medications & Supportive Care 
4.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made 
to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 


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o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
▪ Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 


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and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
▪ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
▪ Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Increase monitoring of vital signs as medically 
None 


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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
4.7 
Diet/Activity/Other Considerations 
4.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
4.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   


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For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 
  
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  


SWIPE Protocol Version: 1.1  June, 2017 
 
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Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
 ‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
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 subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
4.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 


SWIPE Protocol Version: 1.1  June, 2017 
 
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subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 
4.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
4.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 11.3 
• 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 uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 


SWIPE Protocol Version: 1.1  June, 2017 
 
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additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.5.5 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for 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. 
4.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of 
the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Subjects will resume therapy at the same dose and schedule at 
the time of initial discontinuation.  Additional details are provided in Section 7.1.5.5. 
4.9 
Subject Replacement Strategy 
No patients are going to be replaced in the event of patient withdrawal. 
4.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 


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Page 30 of 57 
 
5.0 TRIAL FLOW CHART 
5.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsb 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 9 
weeks post 
discon 
Every 
12 
weeks  
Administrative Procedures 
Pre-screening Consent 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
√ 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Trial Treatment Administration 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
√ 
√ 
√ 
Survival Status 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Clinical Procedures/Assessments 
Review Adverse Events 
 
 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Full Physical Examination 
√ 
√ 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
 
 
Directed Physical Examination 
 
 
 
√ 
 
√ 
 
√ 
 
√ 
√ 
√ 
 
 


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Trial Period: 
Screening Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsb 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 9 
weeks post 
discon 
Every 
12 
weeks  
Vital Signs and Weight 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
ECOG Performance Status 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCG 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
PT/INR and aPTT 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
CBC with Differential 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Comprehensive Serum Chemistry Panel 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Urinalysis 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
 
Efficacy Measurements 
Tumor Imaging 
 
√ 
 
 
√ 
 
 
√ 
 
 
√ 
 
√ 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
 Newly Obtained Tissue Collection 
 
√ 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.0 TRIAL PROCEDURES 
6.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
6.1.1 Administrative Procedures 
6.1.1.1 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 IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 


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6.1.1.2 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.  
6.1.1.3 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.   
6.1.1.4 Prior and Concomitant Medications Review 
6.1.1.4.1 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.  
6.1.1.4.2 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. 
6.1.1.5 Disease Details and Treatments 
6.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
6.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
6.1.1.5.3 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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6.1.1.6 Assignment of Screening Number 
Register of all patients invited to participate and screened is going to be held. 
6.1.1.7 Assignment of Trial Identification Number 
Each patient is going to be registered with a number for confidentiality purposes. No 
randomization is going to take place. 
6.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Trial compliance is going to be monitored via scheduled visits. 
6.1.2 Clinical Procedures/Assessments 
See trial flow chart (section 6.0). 
6.1.2.1 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 11.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is possibly an 
event of clinical interest (ECI) of a potentially immunologic etiology (termed immune-
related adverse events, or irAEs); see the separate ECI guidance document in Appendix 4 
regarding the identification, evaluation and management of potential irAEs.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
6.1.2.2 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,  
6.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   


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6.1.2.4 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. 
6.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
6.1.2.6 Tumor Imaging and Assessment of Disease 
CT scan imaging to be undertaken every 9 weeks (3 cycles of treatment) for the first year and 
every 12 weeks (4 cycles) from the second year onwards for patients whilst on treatment, or 
for patients who discontinue trial treatment for reasons other than disease progression. 
6.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 PDL1 status to be undertaken from histological sample available at diagnosis of metastatic 
disease (pre- first line chemotherapy sample) and also from a new biopsy after first line 
chemotherapy and prior to study entry.  
 
6.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   


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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
FBC 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Absolute Neutrophil Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Free thyroxine (T4) 
Absolute Lymphocyte Count 
Uric Acid 
results are noted 
Thyroid stimulating hormone (TSH) 
 
Calcium 
Urine pregnancy test † 
ACTH 
 
Chloride 
 
Cortisol (morning sample) 
 
Glucose 
 
 
 
Phosphorus 
 
 
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
 
 
 


SWIPE Protocol Vesion: 1.1  June, 2017 
 
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Laboratory tests for screening or entry into the Second Course Phase 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.  
6.1.3.1 Pharmacokinetic/Pharmacodynamic Evaluations 
No pharmacokinetic or pharmacodynamic evaluations are going to be carried out. 
6.1.3.1.1 Blood Collection for Serum Pembrolizumab 
Not applicable 
6.1.3.1.2 Blood Collection for Anti-Pembrolizumab Antibodies  
Not applicable 
6.1.4 Other Procedures 
6.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.5.  After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.4). 
6.1.4.2 Blinding/Unblinding 
Not applicable. 
6.1.5 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. 
6.1.5.1 Screening 
Patients with metastatic NSCLC who have not progressed after first line chemotherapy, are 
going to be identified by the treating oncologists, Dr Haris Charalambous, Dr Flora Kyriakou 


SWIPE Protocol Vesion: 1.1  June, 2017 
 
Page 38 of 57 
 
and Dr George Orphanos. Following initial discussion about proposed study, patients are 
going to be referred to the Clinical Trials Unit staff, to undertake screening for the study. 
6.1.5.1.1 Screening Period 
Aim to start in January  2016 and finish once all forty-eight (48) patients have been enrolled, 
with a target date to finish accrual in July 2017. 
6.1.5.2 Treatment Period 
Aim to start treatment in January  2016. Patients to receive treatment until either progressive 
disease or until they have received two (2) years of continuous Pembrolizumab treatment. 
6.1.5.3 Post-Treatment Visits 
See flow chart (section 6.0). 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  Subjects who are eligible for retreatment 
with pembrolizumab (as described in Section 7.1.5.5) may have up to two safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase. 
6.1.5.4 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 9 weeks (63 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 12 weeks (84 ± 7 days). Every effort should be made to collect information regarding 
disease status until the start of new anti-neoplastic therapy, disease progression, death, end of 
the study or if the subject begins retreatment with pembrolizumab as detailed in Section 
7.1.5.5.  Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.     


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6.1.5.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  
6.1.5.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
• Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 to 2 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 


SWIPE Protocol Vesion: 1.1  June, 2017 
 
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Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
6.2 
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 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded 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. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome. 


SWIPE Protocol Vesion: 1.1  June, 2017 
 
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6.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
6.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 


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6.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
6.2.3.1 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 another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details)  that occurs to any subject must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the 
subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Merck product, must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 


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All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
6.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to Merck product, must be reported within 24 hours to the Sponsor and 
within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  


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6.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE. 
 
6.2.4 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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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); 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) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. 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 to the Sponsor and to 
Merck within 2 working days.. 
 
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 


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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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that 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 Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to 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 
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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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 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 Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to 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) Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is 
reasonable.  The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated 
AE.) 


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6.2.5 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
6.3 
Procedures for filing complaints 
Patients will e able to communicate directly with the doctor / researcher or with the research 
nurses of the study (by phone or by visiting the centre) for any grievance, complaint or any 
clarification they need, in relation to the study.  All patients are going to receive a card with 
all the necessary contact details for the participating doctors and research nurses.  The same 
information is going to be available on the consent form. 
Complaints can also be submitted in person or anonymously to the Chief Executive Officer 
of the Bank of Cyprus Oncology Centre (BOCOC), Mr. Panos Ergatoudes.  Finally, 
complaints can be posted in a complaints box located in the main entrance of the building at 
the BOCOC. 
7.0 STATISTICAL ANALYSIS PLAN 
7.1 
Statistical Analysis Plan Summary 
The study employs a one stage phase II Fleming’s design using irPFS at 1 year as primary 
endpoint.  
Using response hypotheses of H0 < 12 % and Ha> 25% i.e. that the irPFS at 1 year for the 
maintenance Pembrolizumab arm is 25%, compared to 12% in the normal chemotherapy 
maintenance arm, with a significance level (i.e., the probability of rejecting H0 when it is 
true) α=0.05 and the power (i.e. the probability of deciding the regimen is active) is 0.8 when 
true response rate is 25%, 48 patients are required to be entered into this study. 
7.2 
Statistical Analysis Plan 
Comparator data regarding patients’ outcomes receiving maintenance therapy can be 
obtained from the Pemetrexed continuation and Erlotinib switch maintenance studies. 
The best available data for maintenance treatment of non-squamous NSCLC patients come 
from the continuation Pemetrexed trial (Pas Ares¹⁶). This trial enrolled good performance 
status patients (PS 0-1), with non-squamous histology, who did not progress after 4 cycles of 
Pemetrexed / Cisplatin, and continued Pemetrexed chemotherapy, resulting in a 1-year PFS 
of  18.6%, whilst in the placebo arm the 1 year PFS was 5%.  


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For the squamous patients, the best available data come from the switch maintenance 
Erlotinib trial²¹ (SATURN), given that Erlotinib is the only agent approved for maintenance 
treatment in patients with squamous cancers. The 1-year PFS for the erlotinib arm is slightly 
above placebo, around 6%. 
Hence for the comparator arm by using:  
• data from the Pemetrexed continuation study for non squamous histology: 1-year PFS 
of 18% for non squamous on Pemetrexed maintenance,   
• data from the erlotinib arm in the SATURN trial for patients with squamous histology 
and estimating 1-year PFS  of 6% for squamous patients  
• whilst assuming a ratio of 1:1 adenocarcinomas to squamous,  
• provides us a weighted average of 12% of 1-year PFS 
Assume irPFS at 1 year for the maintenance Pembrolizumab arm to be 25%, compared to 
12% in the normal chemotherapy maintenance arm.  
Sample size for Fleming one stage Phase II trials 
Probability of Type I Error (α) = 0.05 
Power (1 - β) = 0.8 
Lower proportion for rejection (p0) = 0.12 
Higher proportion for acceptance (pn) = 0.25 
Sample size required = 48 
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
8.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 


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Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
8.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
8.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
8.4 
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. 
8.5 
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. 
9.0 ADMINISTRATIVE AND REGULATORY DETAILS 
9.1 
Confidentiality 
Confidentiality standards are going to be maintained by coding each patient enrolled in the 
study through assignment of a unique patient identification number. This would mean that 


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patient names are not going to be included in any data sets that are going to be transferred to 
the sponsor. 
Patient medical information obtained by this study remains confidential and may only be 
disclosed to a patient’s personal physician / or other appropriate medical personnel 
responsible for the patient, for treatment purposes. 
9.2 
Compliance with Financial Disclosure Requirements 
Investigators are going to be responsible to provide information on financial interests during 
the course of the study and for 1 year after completion of the study, to the appropriate health 
authorities and in accordance with local regulations. 
9.3 
Compliance with Law, Audit and Debarment 
This study is going to be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice, the EU Clinical Trial Directive (2001/20/EC) and the principles of the 
Declaration of Helsinki, as well as the laws and regulations of the republic of Cyprus. Ethics 
committee approval is going to be sought from the Cyprus National Bioethics committee. 
Study data (including patients’ medical records and CRFs) are going to be available for 
inspection and audit from either the sponsor or the Regulatory Bodies. 
9.4 
Compliance with Trial Registration and Results Posting Requirements 
This 
trial 
is 
going 
to 
be 
submitted 
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, as well as provide them information regarding the 
results, when those become available.     
9.5 
Quality Management System 
The primary investigator is going to be responsible for data management of this study, 
including quality checking of the data. Study monitors should be carried out intermittently to 
confirm that critical protocol data entered into the CRFs and the Electronic Data Collection 
(EDC) system by authorized study personnel are accurate, complete and verifiable from 
source documents. 
9.6 
Data Management 
Data collected manually on CRFs are going to be entered electronically into the Electronic 
Data Collection (EDC) system. System backups for data stored electronically are going to be 
carried out, whilst paper records are going to be retained in the Clinical Trials Unit at the 
BOCOC (as with the conduct of other studies in the centre). 


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10.0 APPENDICES 
10.1 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. 
 
10.2 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) 


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10.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
Both RECIST version 1.1³⁴ and immune related Response Criteria³⁵ (irRC) 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. 
The use of irRC is to correct for the possibility of pseudo-progression / deal with the altered 
patterns of response seen with ipilimumab and potentially other immunotherapies [Wolchok 
JD al³⁵, table 8). 
The decision to discontinue treatment is going to be based on irRC assessment. The irRC 
assessment considers the patient's "total tumour burden" and requires confirmation of 
suspected disease progression with a subsequent CT scan, four weeks later. 
Table 8. Immune related response rates: 
Immune-related complete response 
Complete 
resolution 
of 
all 
measureable 
and 
nonmeasurable lesions, with no new lesions. Complete 
response must be confirmed by a second, consecutive 
assessment at least four weeks later. 
Immune-related partial response 
A decrease in the total tumor burden of 50 percent or 
more compared to baseline, which must be confirmed 
by a second, consecutive assessment at least four 
weeks later. This category allows for the inclusion of 
progression of some lesions or the appearance of new 
lesions as long as the total tumor burden meets the 
response criterion. 
Immune-related stable disease 
Not meeting the criteria for either a partial or complete 
response or for progressive disease. 
Immune-related progressive disease 
An increase in tumor burden of 25 percent or more 
relative to the minimum recorded tumor burden. This 
must be confirmed by a second, consecutive 
assessment no less than four weeks after the initial 
documentation of an increase in tumor 
 
 
 


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11.0    REFERENCES: 
1. Ferlay J, Soerjomataram I, Ikshit R et al.  Cancer incidence and mortality worldwide: 
Sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 2015: 136, E359–
E386. 
2. M. Reck, S. Popat, N. Reinmuth,et al. Metastatic Non Small Cell Lung Cancer: ESMO 
Clinical Guidelines Ann Oncol (2014) 25 (suppl 3): iii27-iii39. 
3. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III Study Comparing Cisplatin Plus 
Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With 
Advanced-Stage Non–Small-Cell Lung Cancer J Clin Oncol 2008 vol. 26 no. 21 3543-3551. 
4. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for 
non-small cell lung cancer. N Engl J Med 2006; 355: 2542-50. 
5. Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus 
best supportive care in patients with non-small cell lung cancer previously treated with 
platinum chemotherapy. J Clin Oncol 2000; 18: 2095-103. 
6. Hanna N, Shepherd FA, Fosella FV, et al. Randomized phase III trial of pemetrexed versus 
docetaxel in patients with non-small cell lung cancer previously treated with chemotherapy. J 
Clin Oncol 2004; 22: 1589-97. 
7. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-
small cell lung cancer. N Engl J Med 2005; 353: 123-32. 
8. Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus 
placebo in patients with previously treated non-small-cell lung cancer (LUME Lung 1): a 
phase 3, double blind, randomized controlled trial. Lancet Oncol; 2014: 15. 143-155. 
9. Garon EB, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus 
docetaxel for second line treatment of stage IV non small cell lung cancer after disease 
progression on platinum based therapy (REVEL): a multicentre, double-blind, randomized 
phase III trial. Lancet 2014; 384:665-673.  
10. Charalambous H, Kopitopoulou A, Syrigos K. Maintenance Chemotherapy in Non Small 
Cell Lung Cancer.  (Chapter 38, p 471-489). Edited by K Syrigos, Y Giozos, A Harpidou. 
Atlas of Thoracic Oncology (2011) ISBN 978-960-394-838-4. 
11. Gerber DE, Schiller JH. Maintenance chemotherapy for advanced non-small-cell lung 
cancer: new life for an old idea. J Clin Oncol 2013; 31: 1009-20. 
12. Belani, C.P., Barstis, J., Perry, M.C., et al. (2003) Multicenter, randomized trial for stage 
IIIB or IV non-small-cell lung cancer using weekly paclitaxel and carboplatin followed by 
maintenance weekly paclitaxel or observation. J Clin Oncol 21: 2933–2939. 


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13. Brodowicz, T., Krzakowski, M., Zwitter, M., et al. (2006) Cisplatin and gemcitabine 
first-line chemotherapy followed by maintenance gemcitabine or best supportive care in 
advanced non-small cell lung cancer: a phase III trial. Lung Cancer 52: 155–163. 
14. Belani, C.P., Waterhouse, D.M., Ghazal, H., et al. (2010) Phase III study of maintenance 
gemcitabine (G) and best supportive care (BSC) versus BSC, following standard combination 
therapy with gemcitabine-carboplatin (G-Cb) for patients with advanced non-small cell lung 
cancer (NSCLC). J Clin Oncol(Meeting Abstracts) 28(15 Suppl.): 7506. 
15. Perol, M., Chouaid, C., Milleron, B.J., et al (2010) Maintenance with either gemcitabine 
or erlotinib versus observation with predefined second-line treatment after cisplatin-
gemcitabine induction chemotherapy in advanced NSCLC: IFCT-GFPC 0502 phase III 
study. J ClinOncol (Meeting Abstracts)28(15 Suppl.): 7507. 
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