Phase II, Open Label, Single Arm Study of PembrolizumAb combiNeD With Cisplatin or carbOplatin and Etoposide in Treatment naïve Advanced meRkel Cell cArcinoma (MCC) (PANDORA Trial)
Phase: PHASE2
Conditions: Merkel Cell Carcinoma
Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

 
 
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CLINICAL STUDY PROTOCOL 
 
TITLE: Phase II, open label, single arm study of PembrolizumAb combiNeD with 
cisplatin or carbOplatin and etoposide in treatment naïve advanced meRkel cell 
cArcinoma (MCC) (PANDORA Trial). 
 
 
 
Acronym 
PANDORA Trial 
EudraCT number 
EudraCT 2022-500988-12-00 
Version Number 
3.0  
Sponsor 
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 
Phase: 
II 
Indication: 
Advanced, naïve, Merkel cell carcinomas 
 
 
 
Principal Investigator: 
Dott.ssa Sara Pusceddu 
Medical Oncology and Hematology Department,  
Fondazione IRCCS Istituto Nazionale dei Tumori,  
Via G. Venezian 1 
20133 Milano, Italy 
 
 
Investigator’s signature 
 
 
 
 
 
            Date 
 
 
07/09/2023

 
 
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Writing committee: 
 
Dott.ssa Sara Pusceddu 
Medical Oncology Department, 
Fondazione IRCCS Istituto Nazionale dei Tumori,  
Via G. Venezian 1 
20133 Milano, Italy 
Email: sara.pusceddu@istitutotumori.mi.it 
 
Prof. Filippo de Braud 
Medical Oncology and Hematology Department,  
Fondazione IRCCS Istituto Nazionale dei Tumori,  
Via G. Venezian 1 
20133 Milano, Italy 
Email: debraud_studiclinici@istitutotumori.mi.it 
 
Responsible biological studies: 
 
Dott. Massimo Milione 
Department of Diagnostic Pathology and Laboratory 
Fondazione IRCCS Istituto Nazionale dei Tumori,  
Via G. Venezian 1 
20133 Mil 
ano, Italy 
Email: massimo.milione@istitutotumori.mi.it 
 
Dott.ssa Roberta Mortarini 
Experimental Oncology And Molecular Medicine Department  
Fondazione IRCCS Istituto Nazionale dei Tumori,  
Via G. Venezian 1 
20133 Milano, Italy 
Email: roberta.mortarini@istitutotumori.mi.it 
 
 
Responsible biometry:  
 
Dott. Luca Porcu 
Methodology for Clinical Research Laboratory, Oncology Department, 
IRCCS Istituto di Ricerche Farmacologiche Mario Negri,  
Via Mario Negri 2  
20156 Milan, Italy 
Email: luca.porcu@marionegri.it 
 
 

 
 
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Responsible Pharmacovigilance:  
 
Dott. Vito Ladisa  
Pharmacy 
Fondazione IRCCS Istituto Nazionale dei Tumori  
via Giacomo Venezian 1 
20133 Milan, Italy 
Email: vito.ladisa@istitutotumori.mi.it 
 
 

 
 
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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 9 
2.0 
LIST OF ABBREVIATIONS .................................................................................. 16 
3.0 
BACKGROUND & RATIONALE .......................................................................... 19 
3.1 
Background ........................................................................................................... 19 
3.1.1 Pharmaceutical and Therapeutic Background .................................................... 19 
3.1.2 Preclinical and Clinical Trial Data ...................................................................... 20 
3.2 
Rationale ................................................................................................................ 20 
3.2.1 Rationale for the Trial and Selected Population ................................................. 20 
3.2.2 Justification for Dose .......................................................................................... 22 
3.2.3 Rationale for Endpoints ...................................................................................... 23 
3.2.4 Potential Risks and Benefits ............................................................................... 26 
3.2.5 GCP Study Conduct Statement ........................................................................... 26 
4.0 
OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) ............................... 28 
4.1 
Primary Objective(s), Hypothesis(es), and Endpoint(s) .................................... 28 
5.0 
TRIAL DESIGN........................................................................................................ 29 
5.1 
Trial Design ........................................................................................................... 29 
5.2 
Trial Schema ......................................................................................................... 30 
5.3 
Schedule of Activities ............................................................................................ 31 
5.3.1 Table 1 Study Schedule of Activities .................................................................. 31 
5.3.2 Table 2 Study Schedule of Activities: Survival Status ....................................... 34 
5.3.3 Table 3 Study Schedule of Activities: Tumor Imaging ...................................... 35 

 
 
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*Radiological assessment will be performed by CT scan every 6 weeks (± 7 days) for the first 
year, After completion of the first year, tumor assessments will be required every 12 
weeks (± 7 days) ......................................................................................................... 35 
6.0 
METHODOLOGY ................................................................................................... 36 
6.1 
Study Population ................................................................................................... 36 
6.1.1 Participant Inclusion Criteria .............................................................................. 36 
6.1.2 Participant Exclusion Criteria ............................................................................. 38 
6.1.3 Lifestyle Considerations ..................................................................................... 39 
6.1.4 Pregnancy ............................................................................................................ 41 
6.2 
Trial Intervention(s) ............................................................................................. 42 
6.2.1 Preparation, Handling and Storage of Drug ........................................................ 42 
6.2.2 Packaging and Labeling Information .................................................................. 42 
6.2.3 Clinical Supplies Disclosure ............................................................................... 42 
6.2.4 Drug Administration and Dosage Schedule ........................................................ 42 
6.2.5 Timing of Dose Administration .......................................................................... 43 
6.2.6 Dose Modification and toxicity management for immune-related AEs associated with 
Pembrolizumab and combination therapy .......................................................... 44 
6.2.7 Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab ................................................................................................... 51 
6.2.8 Second Course .................................................................................................... 53 
6.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 54 
6.3.1 Acceptable Concomitant Medications ................................................................ 57 
6.3.2 Prohibited Concomitant Medications.................................................................. 57 
6.3.3 Rescue Medications & Supportive Care ............................................................. 58 
6.4 
Participant Discontinuation Criteria .................................................................. 59 
6.5 
Participant withdrawal From Study ................................................................... 60 

 
 
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6.6 
Clinical Criteria for Early Trial Termination ................................................... 60 
7.0 
TRIAL ASSESSMENTS AND PROCEDURES .................................................... 61 
7.1 
Trial Procedures ................................................................................................... 61 
7.1.1 Administrative and General Procedures ............................................................. 61 
7.1.2 Clinical Procedures/Assessments ........................................................................ 63 
7.1.3 Clinical Safety Laboratory Assessments............................................................. 64 
7.1.4 Tumor Imaging and Assessment of Disease ....................................................... 65 
7.1.5 Tumor Tissue Collection and Correlative Studies Blood Sampling ................... 70 
• 
Tissue collection ................................................................................................. 70 
• 
Blood immunophenotype .................................................................................... 70 
7.1.6 Other Procedures ................................................................................................. 70 
7.1.7 Visit Requirements .............................................................................................. 71 
7.2 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety 
Events ..................................................................................................................... 72 
7.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information ......................................................................................................... 73 
7.2.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events ............. 74 
7.2.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information .......... 74 
7.2.4 Sponsor Responsibility for Reporting Adverse Events ...................................... 74 
7.2.5 Pregnancy and Exposure During Breastfeeding ................................................. 75 
7.2.6 Events of Clinical Interest (ECIs) ....................................................................... 75 
7.3 
Suspected unexpected serious adverse reactions (SUSARs) ............................. 75 
7.3.1 Reporting of SUSARs by the sponsor to the EudraVigilance database .............. 76 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 76 
8.1 
Statistical Analysis Plan Summary ..................................................................... 76 

 
 
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8.2 
Statistical Analysis Plan ....................................................................................... 77 
9.1 
Compliance with law and regulation .................................................................. 78 
9.2 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and    
Competent Authority (CA) .................................................................................. 78 
9.3 
Informed consent .................................................................................................. 78 
9.4 
Confidentiality and Privacy ................................................................................. 78 
9.5 
Financial disclosure .............................................................................................. 79 
9.6 
Premature Closure of the Study .......................................................................... 79 
10.0 
DATA MANAGEMENT .......................................................................................... 79 
10.1 
Data Quality Assurance ........................................................................................ 79 
10.2 
Electronic case report forms ................................................................................ 79 
10.3 
Source data documentation.................................................................................. 80 
11.0 
QUALITY CONTROL ............................................................................................. 80 
11.1 
Responsibilities of the investigators .................................................................... 80 
11.2 
Study Monitoring .................................................................................................. 80 
11.3 
Retention of Records ............................................................................................ 81 
11.4 
Site Discontinuation (if applicable): .................................................................... 81 
12.0 
STUDY CONDUCTION .......................................................................................... 81 
12.1 
Administrative Structure ..................................................................................... 81 
12.2 
Training of study site personnel .......................................................................... 82 
12.3 
Study timetable and end of study ........................................................................ 82 
12.4 
Data Handling ....................................................................................................... 82 
12.5 
Data Breach Management .................................................................................... 83 
12.5.1 Management of data breaches occurring within the Promoter or Data Owner's facility.
 ............................................................................................................................. 83 

 
 
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12.5.2 Data breach at third-party data processors acting on behalf of the Foundation. . 83 
12.6 
Publication of Data ............................................................................................... 84 
12.7 
FINANCING AND INSURANCE ....................................................................... 84 
13.0 
References .................................................................................................................. 84 
14.0 
APPENDICES ........................................................................................................... 89 
14.1 
Appendix 1: ECOG Performance Status ............................................................ 89 
14.2 
Appendix 2: Clinical Laboratory Tests .............................................................. 90 
14.3 
Appendix 3: Contraceptive Guidance and Pregnancy Testing ........................ 91 
14.4 
Appendix 4:  Description of the iRECIST Process for Assessment of Disease 
Progression ............................................................................................................ 94 
14.5 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .................................................................................... 98 
 

 
 
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1.0 TRIAL SUMMARY 
 
 
TITLE 
Phase II, open label, single arm study of PembrolizumAb combiNeD 
with cisplatin or carbOplatin and etoposide in treatment naïve 
advanced meRkel cell cArcinoma (MCC) (PANDORA Trial) 
SPONSOR 
Fondazione IRCCS Istituto Nazionale dei Tumori- 
Via G. Venezian 1 
20133 Milano 
PRINCIPAL 
INVESTIGATOR: Dott.ssa Sara Pusceddu 
PHASE: 
II 
BACKGROUND 
AND 
RATIONALE 
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the 
skin with a very aggressive clinical course and high propensity for 
locoregional recurrence and metastasis. Although still relatively rare 
the incidence of MCC has tripled over the past 20 years. The 
Surveillance of Rare Cancers in Europe (RARECARE) project 
reported an incidence rate of 0.13 MCC cases per 100,000 between 
1995 and 2002. The incidence of MCC increases with age. The mean 
age at diagnosis is approximately 75 years. The development of MCC 
can be associated with integrated Merkel cell polyomavirus (MCPyV) 
and/or with ultraviolet light (UV) exposure or immunosuppression. 
The natural evolution of MCC is usually poor with a reported 5-year 
overall survival (OS) for metastatic disease of 14%. For these patients, 
the therapeutic options are scant, mainly based on immunotherapy or 
chemotherapy. 
MCC is generally considered a chemosensitive tumor. The great part 
of chemotherapy regimens used in MCC are also used in small cell 
lung cancer (SCLC), and comprise multiple agents such as 
cyclophosphamide, doxorubicin, vincristine, etoposide, cisplatin, and 
carboplatin. However, current literature regarding the management of 
MCC are poor. Due to the rarity of this disease, there are no 
randomized trials comparing different chemotherapy regimens, and 
the available data are still insufficient to completely assess the effect 
of chemotherapy on patient survival. Overall, response to 
chemotherapy in metastatic disease ranges from 20 to 61%, but the 
duration of the response is short, and most patients experience relapse 
within 8 months. In addition to the unclear benefit in OS, 
chemotherapy is associated with numerous toxicities (i.e., fatigue, 
gastrointestinal diseases and renal toxicity, hematological toxicity).  
Immunotherapy 
is 
the 
most 
important 
new 
approach 
in 
advanced/metastatic MCC. A recent study with the PD-L1 inhibitor, 
avelumab, showed an ORR of 62% in chemotherapy-naive 

 
 
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participants and 32% in participants with chemotherapy-refractory 
metastatic disease. Responses occurred in patients with both PD-L1 
positive and negative tumors and were independent of Merkel cell 
polyomavirus 
status. 
Furthermore, 
a 
phase 
2 
trial 
with 
pembrolizumab, a PD-1 inhibitor, showed objective response rate of 
56% in participants with metastatic or recurrent MCC not amenable 
to definitive surgery or radiation therapy. Based on these results, 
NCCN guidelines recommend pembrolizumab and avelumab as 
possible treatment option for patients with recurrent or advanced 
disease. 
Chemotherapy has always been seen as immunosuppressive due to its 
direct cytotoxicity, however emerging data suggest that some 
chemotherapies may induce immunogenic cell death, eliminate 
immune-suppressive cells or sensitize tumor cells to immune effector 
cells. Some chemotherapy agents can impact both on the tumor and 
on the host immune system, which provides strong rationale for their 
combination with immunotherapeutic agents. In particular, platinum 
agents have demonstrated immunogenic effects. 
Therefore, based on all this rationale, to test this hypothesis in vivo, 
we propose a phase II study for naïve advanced/metastatic MCC 
patients, that will include the administration of pembrolizumab plus 
platinum-based chemotherapy, followed by maintenance with 
immunotherapy alone. 
PATIENT 
POPULATION 
Advanced/metastatic MCC 
OBJECTIVES 
AND 
ENDPOINTS 
To assess the safety and antitumor activity of pembrolizumab 
combined with cisplatin/carboplatin and etoposide as first line 
treatment in MCC. 
 
Primary objective 
- 
To 
assess 
efficacy 
of 
pembrolizumab combined 
with chemotherapy as first 
line treatment in patients 
with MCC 
Primary endpoint  
- 
ORR, that will be defined as 
the percentage of patients 
achieving 
complete 
response (CR) or partial 
response (PR) according to 
RECIST 1.1 criteria 
 
Secondary objectives 
- 
To 
assess 
safety 
and 
efficacy of pembrolizumab 
combined 
with 
chemotherapy as first line 
treatment in patients with 
MCC 
Secondary endpoints  
- 
Incidence 
of 
Serious 
Adverse Events (SAE)  
- 
Incidence and severity of 
Immune-mediated Adverse 
Events (imAE) 

 
 
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- 
Incidence and severity of 
Adverse 
Events 
(AEs) 
according to NCI Common 
Terminology 
criteria 
Adverse Event (CTCAE), 
version 5.0 
- 
Overall Survival (OS) that 
will be measured from the 
date of starting therapy to 
the date of death by any 
cause 
- 
Progression Free Survival 
(PFS) that will be measured 
from the date of starting 
therapy to the date of 
disease 
progression 
or 
death. 
- 
Duration 
of 
Response 
(DOR) 
that 
will 
be 
measured from the date of 
the first response to disease 
progression or death in 
those patients who achieved 
a CR o PR during study 
treatment 
 
Exploratory objectives 
- 
To identify immune and 
molecular biomarkers that 
may 
be 
indicative 
of 
clinical 
response/resistance, safety, 
and/or the mechanism of 
action of pembrolizumab 
and other treatments. 
 
- 
To 
assess 
efficacy 
of 
pembrolizumab 
plus 
cisplatin/carboplatin 
and 
etoposide 
according 
to 
iRECIST. 
 
 
- 
To assess Health-Related 
Quality 
of 
Life 
of 
Exploratory Endpoints 
- 
Molecular determinants of 
response or resistance to 
treatments, using blood and 
tumor tissue 
 
 
 
 
- 
Efficacy parameters such as 
OS 
and PFS will be 
evaluated 
according 
to 
iRECIST using investigator 
response assessments.  
 
 
- 
Evaluations will included, 
changes in EQ-5D and 
FACT-M 
scores 
and 

 
 
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pembrolizumab 
plus 
cisplatin/carboplatin 
and 
etoposide in participants 
with 
advanced/metastatic 
MCC. 
correlation of the HR-PRO 
scores to tumor responses 
during the treatment period. 
 
STUDY DESIGN 
This is an open label, multicenter, phase II study evaluating the 
activity 
and 
safety 
of 
pembrolizumab 
combined 
with 
cisplatin/carboplatin and etoposide as first line treatment in patients 
with advanced MCC. 
The induction treatment will consist of four cycles of pembrolizumab 
plus chemotherapy. Each cycle will be administered every 21 days (3 
weeks). On Day 1 of each cycle, all eligible patients will receive drug 
infusions in the following order:  
• pembrolizumab (200 mg flat dose, administered intravenously) 
• carboplatin (AUC 5 mg per milliliter per minute, administered 
intravenously) or cisplatin (75 mg per square meter of body-
surface area, administered intravenously)  
• etoposide (100 mg per square meter of body-surface area, 
administered intravenously on days 1 through 3 of each cycle).  
On days 2 and 3 of each cycle, patients will receive etoposide alone at 
the same dosage.  
After the induction phase, patients will start maintenance therapy with 
pembrolizumab 400 mg flat dose intravenously every 6 weeks. 
Overall, treatment with pembrolizumab will be continued until disease 
progression, unacceptable toxicity, Investigator’s decision or consent 
withdrawal, for a maximum of 24 months. 
Palliative radiation will be also allowed as per clinical practice. 
Subjects will attend clinic visits at regular intervals to receive trial 
treatment and for efficacy and safety assessments. All subjects will be 
continuously monitored for any adverse event (AE) according to NCI 
Common Terminology Criteria for Adverse Event (CTCAE), version 
5.0 while on study treatment. Treatment will be continued until 
disease progression, unacceptable toxicity, Investigator’s decision or 
consent withdrawal. Radiological assessment will be performed by 
CT scan every 6 weeks (± 7 days) for the first year and every 12 weeks 
(± 7 days) thereafter. Disease response to treatment will be assessed 
by the Investigator using RECIST v1.1 and irRECIST. Treatment 
should be discontinued in all patients who exhibit evidence of disease 
progression per RECIST v1.1. However, if there is a clinical benefit 
patient may be considered for treatment beyond radiologic disease 
progression per RECIST v1.1, at discretion of the investigator and 
after appropriate discussion with the patient and the Sponsor. Patients 
who continue treatment after radiographic disease progression 

 
 
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according to RECIST v 1.1 criteria should undergo careful clinical 
monitoring and radiographic re-evaluation after 4-6 weeks 
(investigator choice), or sooner in case of symptomatic worsening. 
NUMBER 
OF 
PATIENTS 
35 patients in 3 National Cancer Centers 
INCLUSION 
CRITERIA 
Patients must meet all of the following criteria to be eligible for study 
entry: 
• Patients must be capable of giving signed informed consent 
• Ability to comply with protocol requirements 
• Patients must be ≥18 years of age at the time of signing the 
ICF 
• Locally advanced, relapsed or metastatic MCC stage IIIB-IV 
according to American Joint Committee on Cancer (AJCC) 
TNM Staging Classification for Merkel Cell Carcinoma (8th 
ed. 2017) 
• Histologically confirmed diagnosis of MCC. 
• Availability of tumor sample (obtained from core biopsy or 
surgical specimen) is mandatory for PD L1 expression 
assessment and biomolecular characterization.  
• Life expectancy ≥ 3 months 
• Measurable disease per Response Evaluation Criteria in Solid 
Tumors, version 1.1 (RECIST v1.1) 
• Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) of 0 to 1 
• No previous systemic therapy for advanced disease  
• Patients with treated or asymptomatic brain metastases may be 
enrolled.  
• Women of childbearing potential must use 2 effective methods 
of contraception with a failure rate of less than 1% per year, 
during the entire study treatment period and for a period of 5 
months after the last dose of study drug, or agree to practice 
true abstinence, when this is in line with the preferred and us 
usual lifestyle of the subject. They must have a negative serum 
pregnancy test during the screening period. 
• Adequate haematological function defined by white blood cell 
(WBC) count ≥2,500/mm 3 with absolute neutrophil count 
(ANC) ≥1,500/mm 3, platelet count ≥ 100,000/mm 3 and 
haemoglobin ≥9 g/dL 
• Adequate hepatic function defined by a total bilirubin ≤ 1.5 x 
the upper limit of normal (ULN) range (except subjects with 
Gilbert Syndrome), serum alanine aminotransferase (ALT) 
and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 if liver 
function test elevations are due to liver metastases) 

 
 
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• Adequate renal function defined by a serum creatinine ≤ 1.5 x 
ULN or an estimated creatinine clearance of ≥ 30 mL/minute 
for patients with creatinine levels above institutional limits (if 
using the Cockcroft Gault formula) 
• Stable medical condition, including the absence of acute 
exacerbations of chronic illnesses, serious infections, or major 
surgery within 4 weeks before registration, and otherwise 
noted in other inclusion/exclusion criteria 
EXCLUSION 
CRITERIA 
Patients who meet any of the following criteria will be excluded from 
study entry: 
• Prior treatment with pembrolizumab or any other immunotherapy 
agents (anti PD 1, anti PD L1, anti PD L2, anti CD137, anti CTLA 
4 antibodies, or any other antibody or drug specifically targeting 
T cell costimulatory immune checkpoint pathways) 
• Prior treatment with chemotherapy for advanced MCC, with the 
exception for subjects who received adjuvant or neoadjuvant 
therapy. They are eligible if the adjuvant/neoadjuvant therapy was 
completed at least 12 months prior to the onset of metastatic 
disease. 
• Adjuvant radiotherapy is permitted if ended ≥ 6 months before 
trial enrollment 
• Known hypersensitivity to pembrolizumab, carboplatin, cisplatin 
and/or etoposide 
• Concurrent anticancer treatment, immune therapy, or cytokine 
therapy, except for erythropoietin 
• Major surgery for any reason within 4 weeks from registration 
and/or if the subject has not fully recovery from the surgery within 
4 weeks of treatment start 
• Subjects receiving immunosuppressive agents such as steroids for 
any reason should be tapered of these drugs before initiation of the 
trial treatment. Low dose corticosteroid therapy will be allowed.  
• Known severe hypersensitivity reactions to chimeric or 
monoclonal antibodies, fusion proteins  
• Patients with untreated, symptomatic and/or progressive brain 
metastases, or with carcinomatous meningitis. Subjects with brain 
metastases are eligible if metastases have been treated and there is 
no clinical evidence of progression  
• History of active autoimmune diseases. Subjects with diabetes 
mellitus type I, hypothyroidism only requiring hormone 
replacement or controlled hyperthyroidism, skin disorders (such 
as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, 
or conditions not expected to recur in the absence of an external 
trigger are permitted to enroll. 

 
 
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• Other concurrent neoplasms requiring active treatment 
• Prior organ transplantation, including allogenic stem cell 
transplantation 
• Any medical condition, within 6 months before receiving the first 
dose of study drug, considered relevant by Investigator.  
• Known human immunodeficiency virus (HIV) infection or 
acquired immunodeficiency syndrome (AIDS) 
• Serious infection within 14 days before the first dose of study drug 
• History of idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g., bronchiolitis obliterans), drug induced pneumonitis, 
idiopathic pneumonitis, or evidence of active pneumonitis on 
screening chest computed tomography (CT) scan 
• Active tuberculosis 
• Pregnancy or breastfeeding 
• Vaccination within 4 weeks of the first dose and while on trial is 
prohibited except for administration of inactivated vaccines 
• Unwilling or unable to comply with the protocol or cooperate fully 
with the investigator and site personnel 
STUDY 
DURATION 
• Estimated enrollment period: 24 monts 
• Estimated duration of trial: 48 monts 
STATISTICAL 
METHODS, 
DATA 
ANALYSIS 
A minimax Simon two-stage design will be applied. Assuming an 
unsatisfactory ORR of 56%, a valuable ORR of 71%, 24 and 11 
patients will be enrolled in the first and second stage, respectively 
(total number of patients: 35, one-sided alpha: 0.15, power: 0.78). If 
complete or partial response is assessed in at least 15 patients in the 
first stage, the second stage will be performed, otherwise the study 
will be closed, and study failure declared. If complete or partial 
response is assessed in at least 23 patients at the end of the second 
stage, the experimental treatment will be considered promising and 
worthy of further investigation. 
Only eligible patients who receive at least one dose of experimental 
treatment will be considered for the primary analysis. Objective 
response and disease control will be evaluated with point estimates 
and 95% CIs on the basis of the exact binomial method. DOR, PFS, 
and OS will be estimated using the Kaplan-Meier method for censored 
data. In order to detect selection bias, the number of eligible and 
consecutive patients participating or not to the study will be collected 
by center. Reasons of participation failure will be collected too. 
Participant flow through the trial, baseline characteristics, and adverse 
events will be summarized by descriptive statistics. Data will be 
analyzed using SAS version 9.4 (SAS Institute, Cary, NC). 
 
 
 

 
 
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2.0 LIST OF ABBREVIATIONS 
Abbrevia
tion 
Definition 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase  
AUC 
Area Under the Curve  
CT 
Computerised Tomography  
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTLA-4  Cytotoxic T-Lymphocyte Antigen 4  
CR 
Complete Response  
CrCl 
Creatinine Clearance 
CV 
Cardiovascular Disease 
CTCAE 
Common Terminology Criteria for Adverse Events  
DNA 
Deoxyribonucleic Acid  
DOR 
Duration Of Responce 
EC 
Ethics Committees 
ECG 
Electrocardiogram  
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form  
EGFR 
Epidermal Growth Factor Receptor  
EOT 
End of treatment 
EUDRA
CT 
European Clinical Trials Database  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate  
GLP 
Good Laboratory Practice 
HBV  
Hepatitis B Virus  
HCV  
Hepatitis C Virus  
HIV  
Human Immunodeficiency Virus  
HLA 
Human Leukocyte Antigen  
IB 
Investigator brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
IHC 
Immunohistochemistry  
IL 
Interleukin 
INR 
International normalized ratio 
irAE 
Immun-mediated Adverse Event  
IRB 
Institutional review board 

 
 
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Abbrevia
tion 
Definition 
iRECIST immune-mediate Response evaluation criteria in solid tumors 
IV 
Intravenous  
Kg 
Kilogram 
LDH 
Lactate Dehydrogenase  
m2 
square meters 
Mb 
Megabase 
MCC 
Merkel Cell Carcinoma 
mcL 
microliter 
MCPyV 
Merkel cell polyomavirus 
mg 
Milligram 
MHC 
Major Histocompatibility Complex 
MDSC 
myeloid-derived suppressor cells 
min 
minute 
mL 
milliliter 
mmol 
millimole 
MRI 
magnetic resonance imaging 
NCCN 
National Comprensive Cancer Network 
NCI 
National Cancer Institute 
NK 
natural killer 
NSCLC 
Non-small Cell Lung Cancer  
ORR 
Objective Response Rate  
OS 
Overall Survival  
PBMCs 
Peripheral blood mononuclear cells 
PD-1 
Programmed-death 1 
PD-L1 
Programmed Death-ligand 1  
PE 
Platinum and Etoposide 
PFS 
Progression-free Survival  
PK 
Pharmacokinetic  
PS 
Performance Status  
PT 
Prothrombin Time 
Q3W 
every 3 weeks  
Q6W 
every 6 weeks 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic Acid  
Treg 
regulatory T 
SAE 
Serious adverse event 
SCLC 
Small Cell Lung Cancer  
SNVs 
Single Nucleotide Variants 
SD 
Stable Disease 
SUSAR 
Suspected unexpected serious adverse reaction 
TAM 
tumor-associated macrophages 

 
 
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Abbrevia
tion 
Definition 
TGF-b 
Transforming Growth Factor-b 
TMB 
Tumor Mutational Burden 
TNFa 
Tumor Necrosis Factor-a 
ULN 
Upper Limit of Normal 
UV 
Ultraviolet 
WOCBP 
Woman Of Childbearing Potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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3.0 BACKGROUND & RATIONALE 
3.1 
Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with 
high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction 
with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an 
intravenous (IV) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications because of its mechanism of action to bind 
the PD-1 receptor on the T cell.  For more details on specific indications refer to the Investigator brochure 
(IB). 
3.1.1  Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes 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 (T-regs) correlates with improved prognosis and long-term survival in solid 
malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant 
melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can be expanded ex vivo and 
reinfused, inducing durable objective tumor responses in cancers such as melanoma [Dudley et al., 2005; 
Hunder et al., 2008]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to 
cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that 
has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 
and/or PD-L2) [Greenwald et al., 2005; Okazaki et al., 2001]. 
The structure of murine PD-1 has been resolved [Zhang et al., 2004].  PD-1 and its family members are 
type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch motif.  Following T-cell stimulation, 
PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor tyrosine-based 
switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as 
CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase 
(ZAP70), which are involved in the CD3 T-cell signaling cascade [Okazaki et al., 2001; Chemnitz et al., 
2004; Sheppard et al., 2004; and Riley, 2009].  The mechanism by which PD-1 down-modulates T-cell 
responses is similar to, but distinct from, that of CTLA-4, because both molecules regulate an 

 
 
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overlapping set of signaling proteins [Parry et al., 2005; Francisco, 2010].  As a consequence, the 
PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in MCC. 
3.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
3.2 Rationale 
3.2.1 Rationale for the Trial and Selected Population 
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin with a very aggressive clinical 
course and high propensity for locoregional recurrence and metastasis [Lemos BD et al., 2010]. Although 
still relatively rare the incidence of MCC has tripled over the past 20 years [Hodgson NC, 2005]. The 
Surveillance of Rare Cancers in Europe (RARECARE) project reported an incidence rate of 0.13 MCC 
cases per 100,000 between 1995 and 2002 [van der Zwan JM et al., 2013]. The incidence of MCC 
increases with age [Banks PD et al., 2016; Schadendorf D et al., 2017]. The mean age at diagnosis is 
approximately 75 years [Albores-Saavedra J et al., 2010]. The development of MCC can be associated 
with integrated Merkel cell polyomavirus (MCPyV) [Feng H et al., 2008] and/or with ultraviolet light 
(UV) exposure [Agelli M et al., 2003] or immunosuppression [Lanoy E et., 2009; Lanoy E et al., 2010]. 
The prognosis of MCC is extremely poor with lower survival rates compared with melanoma or other skin 
malignancies. The 5-year survival rates for patients with MCC are 75% for primary localized tumors, 59% 
for tumors with regional lymph node metastases (or local recurrence) and 25% for the metastatic disease 
[Becker et al., 2010].  
Surgery  potentially followed by radiation therapy represents the  standard of care for local-regional 
disease however relapse is common [Fields et al., 2011]. For  the metastatic disease, the therapeutic 
options are scant, mainly based on immunotherapy or chemotherapy. 
Historically, metastatic MCC has been treated with platinum-based chemotherapy regimens that provided 
high initial response rates but no survival advantage [Lebbe et al., 2015].  Overall, response to 
chemotherapy in metastatic disease ranges from 20 to 61%, but the duration of the response is short, and 
most patients experience relapse within 8 months [Nghiem P et al., 2017]. In recent years, immunotherapic 
agents, such as pembrolizumab and avelumab, showed promising results both in chemotherapy-naïve and 
chemotherapy-refractory metastatic patients [Nghiem et al., 2016; Kaufamn et al., 2016; D’Angelo et al., 
2018]. In these phase 2 trials, objective response rate was 56% for pembrolizumab and 62.1% for 
avelumab  in previously untreated patients and it was independent from PD-L1 expression or MCPyP 
status. Based on these results, NCCN guidelines recommend pembrolizumab and avelumab as a treatment 
option for patients with advanced disease [NCCN 2021]. 
Although the results obtained with checkpoint inhibitors are encouraging, there is still a group of patients 
not responsive to this treatment.  
Currently a single-arm, open-label, multicenter, efficacy, and safety study of pembrolizumab in adult and 
pediatric participants with previously untreated advanced MCC KEYNOTE-913 trial (NCT03783078)  is 
still ongoing. As with other systemic cancer therapies, resistance to immunotherapy may lead to 
therapeutic failure. Tumor cells are known to evade immune surveillance by a variety of mechanisms 
[Mittal D et al., 2014] (i.e. downregulation of tumor antigens, MHC class I and II proteins, and other 
molecules involved in antigen processing and presentation; intratumoral accumulation of immune 
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derived suppressor cells (MDSC), and tumor-associated macrophages (TAM); expression of PD-L1 by 
tumor cells and high levels of immune-suppressive cytokines within the tumor microenvironment, 
including transforming growth factor-b (TGFb), tumor necrosis factor-a (TNFa), and IL10 with the 
consequent block of the tumor-specific immune responses [Mittal D et al., 2014; 23. 
Pardoll 
DM, 
2012]. 
Moreover, recently the immunosuppressive characteristic of tumor microenvironments has been identified 
as one mechanism for the low therapeutic efficacy of targeted chemotherapy in clinical evaluations. These 
recent findings have not only initiated a new era of intelligently designed immunotherapies but have also 
demonstrated a direct or indirect immunostimulatory effect of chemotherapeutic drugs [Motz GT et al., 
2013], contrary to their current use, which involves a one-dimensional, cytotoxic interaction with cancer 
cells. Various chemotherapies can indirectly activate the immune system by inducing immunogenic cell 
death, which allows dying tumor cells to initiate an immune response [Krysko DV et al., 2012; Galluzzi 
L et al., 2017]. Furthermore, several chemotherapeutic drugs have been reported to directly affect various 
immune cells, such as dendritic cells (DCs), macrophages, myeloid-derived suppressor cells (MDSCs), 
T-cells and natural killer (NK) cells [Galluzzi L et al., 2012]. Consequentially, successful clinical 
translation of immunotherapy and findings about the immune-modulatory effects of chemotherapeutic 
drugs have fostered investigations into the combination of chemo- and immunotherapies for the treatment 
of cancer [ 
Gomez GG et al., 2001]. In particular, platinum agents have demonstrated immunogenic 
effects [Hato et al., 2014]. 
 
We believe that the combination of pembrolizumab plus cisplatin or carboplatin and etoposide may 
improve the clinical outcome of patients with MCC compared to monotherapy. 
Studies that have evaluated the combination of these drugs in other cancers (especially NSCLC and 
SCLC) showed a safety profile consistent with the defined toxic effects of the individual agents and an 
improvement in PFS and OS.  
 
Pembrolizumab is being studied as a single agent in the advanced cancer, as well as in combination with 
chemotherapy. Pembrolizumab has been generally well tolerated. 
Safety and anti-tumoral activity of pembrolizumab in association with platinum-based chemotherapy have 
been evaluated in several clinical trials. 
The phase 3 KEYNOTE-189 study evaluated efficacy (OS and PFS) and safety of the combination 
treatment with pemetrexed and platinum-based chemotherapy plus pembrolizumab for 4 cycles followed 
by pembrolizumab plus pemetrexed as maintenance therapy (arm 1, n= 410) vs pemetrexed and platinum-
based chemotherapy plus placebo for 4 cycles followed by placebo plus pemetrexed maintenance therapy 
(arm 2, n=206) in naïve metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations. 
The 12-month OS was 69.2% in arm1 vs 49.4% in arm2  (P<0.001).  
Median PFS was 8.8 months  arm1 vs  in arm2 (P<0.001). Adverse events of grade 3 or higher occurred 
in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in 
the placebo-combination group [Gandhi L et al., 2018]. 
In phase 3 KEYNOTE-604 study the investigator evaluated the safety and efficacy of pembrolizumab plus 
platinum and etoposide (PE) vs placebo + PE, in patients with naïve, extensive-stage SCLC. Overall, 453 
patients were included in the study and of these, 228 patients were randomly assigned to the 
pembrolizumab group. The two primary end points were PFS and OS. 
The 12-month PFS was 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. The 24-
month OS was 22.5% with pembrolizumab plus EP and 11.2% with placebo plus EP (significance 

 
 
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threshold was not met). ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo 
plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 
3.3%, respectively [Rudin CM et al., 2020]. 
 
Based on these observations, the benefit/risk for pembrolizumab in combination with cisplatin or 
carboplatin plus etoposide, as derived from the participation to the present study, should also be safe and 
potentially effective. 
 
3.2.2 Justification for Dose  
In the introduction phase, the planned dose of pembrolizumab for this study is 200 mg every 3 weeks 
(Q3W).  Based on the totality of data generated in the Keytruda development program, 200 mg Q3W is 
the appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications demonstrating flat 
dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 mg/kg  Q2W, representing an 
approximate 5- to 7.5-fold exposure range (refer to IB, Section 5.2.2) 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides similar 
control of PK variability with considerable overlap in the distributions of exposures, supporting 
suitability of 200 mg Q3W 
• Clinical data showing meaningful improvement in benefit-risk including overall survival at 200 
mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] analysis) 
at 200 mg Q3W. 
In the maintenance phase, the planned dose of pembrolizumab for this study is 400 mg every 6 weeks 
(Q3W). A 400 mg Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk 
profile as 200 mg Q3W, in all treatment settings where 200 mg Q3W pembrolizumab is currently 
approved. Specifically, the dosing regimen of 400 mg Q6W is considered adequate, given the following 
rationale: 
• PK simulations demonstrated that in terms of pembrolizumab exposures 
- Cavg (or AUC) over the dosing interval at 400 mg Q6W are similar to those at the approved 200 
mg Q3W dose, thus bridging efficacy between dosing regimens. 
- Ctrough at 400 mg Q6W is ~12% lower at a mean level compared with that at the lowest clinically 
tested dose of 2 mg/kg Q3W, at steady state. In most (>99%) patients, however, Ctrough at 400 mg Q6W 
is generally within the range of clinical experience of Ctrough achieved with 2 mg/kg or 200 mg Q3W. 
- Cmax and concentrations over the entire dosing interval at 400 mg Q6W are well below those 
for the highest clinically tested dose of 10 mg/kg Q2W. Clinically, the observed safety profiles were 
similar among 2 mg/kg Q3W, 10 mg/kg Q3W, and 10 mg/kg Q2W dosing regimens in multiple tumor 
types based on randomized dose comparisons. Since the Cmax, and Cavg (or AUC) over the dosing 

 
 
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interval expected at 400 mg Q6W lies within the range of those achieved at these clinically tested doses, 
the safety profile is expected to be comparable to the established safety profile of pembrolizumab. 
- The exposure-response relationship for pembrolizumab has been shown to be flat across multiple 
indications, in the dose/exposure range of 2 mg/kg Q3W or 200 mg Q3W to 10 mg/kg Q2W. Since the 
Ctrough and Cavg exposures over the dosing interval at 400 mg Q6W lie within the range of those 
achieved at the Q3W doses with established clinical efficacy, the dosing regimen of 400 mg Q6W is 
expected to be efficacious across indications where 200 mg (or 2 mg/kg) Q3W has demonstrated efficacy, 
given the generally similar PK and flat exposure-response relationship for pembrolizumab across tumor 
types.  
The observed PK data from the analysis of Cohort B of KN555 in subjects treated with pembrolizumab at 
400 mg Q6W showed that in terms of pembrolizumab exposures through Cycle 1 (ie, the first 6 weeks of 
treatment) and steady state (Cycle 4, post 18 weeks of treatment): 
The observed concentrations for 400 mg Q6W were well within the 90% prediction interval of simulated 
concentrations using the model.  
- The geometric mean of the observed Ctrough, at Week 6 at 400 mg Q6W is ~18% lower than the 
geometric mean of Ctrough, at Week 6 at 200 mg Q3W and ~10% higher than the geometric mean of 
Ctrough at Week 6 at 2 mg/kg Q3W, ie, the lowest clinically tested dose shown to be efficacious. 
- The geometric mean of the observed Cmax at Week 6 at 400 mg Q6W is ~42% lower than the geometric 
mean of Cmax at Week 6 at 10 mg/kg Q2W, ie, the highest clinically tested dose shown to be safe. 
- The geometric mean of the observed Ctrough, at steady state at 400 mg Q6W is ~22% lower than the 
geometric mean of Ctrough, at steady state at 200 mg Q3W and ~4% higher than the geometric mean of 
Ctrough at steady state 6 at 2 mg/kg Q3W. 
- The geometric mean of the observed Cmax at steady state at 400 mg Q6W is ~65% lower than the 
geometric mean of Cmax at steady state at 10 mg/kg Q2W, ie, the highest clinically tested dose shown to 
be safe. 
 
 
 
 
3.2.3 Rationale for Endpoints 
3.2.3.1 Endpoints 
Primary 

 
 
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ORR, defined as the percentage of patients achieving complete response (CR) or partial response (PR) 
according to RECIST 1.1 criteria, is an endpoint commonly accepted for phase II trials. 
Secondary 
Safety will be assessed by the number, frequency, duration and severity of AEs /irAE /SAEs and  changes 
in vital signs and laboratory values. Adverse events will be assessed as defined by CTCAE, Version 5.0. 
OS, defined as the time from the date of enrolment to the date of death by any cause or last follow-up for 
alive patients, has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies. 
PFS, defined as the time from the date of enrolment until disease progression, or death due to any cause,  
will be assessed per RECIST 1.1. 
 
DOR, defined as the time from an initial objective response (CR or PR) according to RECIST 1.1 until 
disease progression, or death due to any cause, is a common endpoint in oncology trials. 
 
3.2.3.2 Exploratory Endpoints 
Translational assessments 
Translational assessments have been included in the Protocol to explore the relationships between tumor 
and host factors and clinical outcomes. These studies will also help to further understanding of the 
pathogenesis and drug resistance mechanisms. Investigations may include but are not limited to: 
 
Merkel Cell Polyomavirus (MCPyV) and tumor microenvironment immunophenotypic characterization: 
for each patient, will be performed direct assessment of MCPyV in tumor tissue sections by 
immunohistochemistry (IHC) on FFPE samples. In addition, in order to evaluate content and quality of 
tumor microenvironment the inhibitory receptors and ligands (PD-1, PD-L1), the HLA molecules antigens 
(HLA-DR and HLA-Class I), the T cell markers (CD3, CD4, CD8), the myeloid markers (CD33 and 
CD163), the fibroblast phenotypes (with morphology and α-SMA) and the vascularity (with morphology 
and CD31) will be evaluate. PD-L1 will be assessed by 22C3 (DAKO) pharm DX. The evaluations will 
be carried out in the malignant cells and, importantly, in the stroma cells near and distant from the tumor. 
 
Mutational analysis and determination of Tumor Mutational Burden (TMB): The IonTorrent technology 
will be used to screen major alterations for 500 genes in all FFPE samples enrolled. A custom-built 
bioinformatics pipeline will be used to identify putative somatic mutations and copy number variations. 
TMB will be estimated and mutational spectrum for each sample was evaluated using the Oncomine TML 
5.10 plugin available on IonReporter software. TML is calculated using a specific algorithm of the Ion 
Reporter software and is expressed as the number of mutations per megabase (muts/Mb), where the 
number of mutations include nonsynonymous (missense and nonsense single nucleotide variants (SNVs), 
plus insertion and deletion variants (InDels) detected per megabase (Mb) of exonic sequences. 
 

 
 
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Gene expression profile and identification of transcriptional networks: the expression of about 20800 
genes (canonical transcript) will be evaluated for all samples using IonTorrent platform. Data obtained 
will be compared to expression profiles of non-neoplastic samples (N). 
 
Fusion transcript identification on tumor tissue: Fifty fusion genes with unknown partner will be 
investigated using Archer FusionPlex Technologies able to identified de-novo fusion transcript starting 
fromFFPEsample. 
 
Peripheral blood Immunophenotyping: to longitudinally monitor the frequency and the phenotype of 
circulating immune cells at baseline and during treatment, we will perform multiparametric flow 
cytometry analysis. PBMCs from pts will be stained with HLA-DR, CD14, CD16, CD15, CD66, c-kit and 
CD33 antibodies to define the subsets of myeloid-derived suppressor cells. CD8+ and CD4+ T cell 
frequency will be calculated on the whole CD45+/CD3+ lymphocytes. CD4+ T cell will be characterized 
with different Abs including CD127, CD25, FOXP3, CTLA-4, OX40, ICOS, PD-1, CD45RA, CCR10, 
CCR7, CCR4, CCR6, CXCR5, Ki67, IL-17, IFN-g and IL-10. In addition, we will investigate the 
expression of co-stimulatory and co-inhibitory molecules such as OX40, ICOS, CD69, CTLA-4, PD-1, 
TIM3 and LAG3.  
 
 
iRECIST assessment 
An exploratory endpoint is to assess efficacy of pembrolizumab plus cisplatin/carboplatin and etoposide 
according to iRECIST. 
Indeed, immunotherapeutic agents may manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. 
Standard RECIST v1.1 may not provide a fully accurate response assessment of immunotherapeutic 
agents. Therefore, the general principles of a modified version of RECIST v1.1 for immune-based 
therapeutics, termed iRECIST, will be used in the evaluation of participant response (Seymour et al 2017) 
in an exploratory capacity and guide treatment decisions for discontinuation of therapy due to disease 
progression. 
Response per iRECIST should be assessed at each post-baseline imaging timepoint. The use of iRECIST 
accounts for the response patterns of immunotherapies and includes a requirement for the confirmation of 
progression to rule out or confirm pseudoprogression. 
 
Health-Related Quality of Life 
Health-related PRO assessments are scheduled to align with tumor response assessments. The FACT-M 
and EQ-5D questionnaires are validated PRO tools that will be used to assess health-related quality-of-
life criteria and evaluate correlations between HR-PRO and clinical observations. 
The Functional Assessment of Cancer Therapy – Melanoma (FACT-M) is a validated questionnaire 
specific to melanoma, a disease that shares many similarities with MCC. 
The EQ-5D is a self-administered, generic, utility questionnaire. Participants will rate their current health 
state based on the following criteria: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. 
 
 

 
 
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3.2.4 Potential Risks and Benefits 
Treatment directed at the PD-1/PD-L1 axis is a promising approach to MCC. Phase 2 results with 
avelumab and pembrolizumab show efficacy in terms of durable tumor response with preservation of 
health-related quality of life. MCC is also a chemosensitive tumor with an ORR ranging from 20 to 61% 
but with a short duration of the response. Preclinical evidence suggests that chemotherapy has 
immunomodulatory effects, supporting the use of chemotherapy plus immunotherapy combination as a 
potential effective treatment strategy. 
Anti-tumoral activity of pembrolizumab has been demonstrated in both preclinical and clinical trial in a 
wide variety of malignancies.  Pembrolizumab is being studied as a single agent in the advanced cancer, 
as well as in combination with chemotherapy. Pembrolizumab has been generally well tolerated. 
Safety and anti-tumoral activity of pembrolizumab in association with platinum-based chemotherapy have 
been evaluated in several clinical trials. 
In phase 3 KEYNOTE-604 study the investigator evaluated the safety and efficacy of pembrolizumab plus 
platinum and etoposide (PE) vs placebo + PE, in patients with naïve, extensive-stage SCLC. Overall, 453 
patients were included in the study and of these, 228 patients were randomly assigned to the 
pembrolizumab group. The two primary end points were progression-free survival (PFS) and OS. 
The 12-month PFS was 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP.  The 24-
month OS was 22.5% with pembrolizumab plus EP and 11.2% with placebo plus EP (significance 
threshold was not met). ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo 
plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 
3.3%, respectively [Rudin CM et al 2020]. 
We believe that the combination of pembrolizumab plus cisplatin/carboplatin and etoposide may improve 
the clinical outcome of patients with MCC compared to monotherapy. 
Studies that have evaluated the combination of these drugs in other cancers (especially SCLC) showed a 
safety profile consistent with the defined toxic effects of the individual agents and an improvement in PFS 
and OS.  
Based on these observations, the benefit/risk for pembrolizumab in combination with cisplatin/carboplatin 
plus etoposide, as derived from the participation to the present study, should also be favorable. 
3.2.5 GCP Study Conduct Statement  
The study will be conducted in compliance with Study Protocol, Declaration of Helsinki, current ICH-
GCP and GLP guidelines and other applicable International and National Regulatory Requirements. 
3.2.5.1 Clinical Investigator’s 
Every Clinical Investigator must be a medical doctor qualified according to the regulations in the region 
where the study is being conducted. The Clinical Investigator agrees to conduct the study as outlined in 
the approved protocol, and in accordance with all applicable regulations for clinical studies on medicinal 
products in human beings. The Clinical Investigator agrees that all information provided by Sponsor, 
including study-related pre-clinical data, protocols, case report forms, verbal and written information, will 
be kept strictly confidential and will be disclosed only to the personnel involved in conduct of the study. 
It is recognized this information may be given in confidence to the Institutional Ethics Committee and 
regulatory authorities.  

 
 
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3.2.5.2 Protocol Amendments 
Changes in any part of the protocol must be documented in the Study Protocol Amendment. All 
amendments that would increase the risk to the subject or may alter the results of the study must be re-
submitted to the Ethics Committee and to regulatory authorities and must be approved before their 
implementation.  
If an amendment to Study Protocol substantially alters the study design or the potential risks to the 
subjects, the Clinical Investigator will decide whether a new subject’s consent to continued participation 
will be needed.  
If the changes in Study Protocol involve only logistical or administrative aspects of the trial [e.g. change 
of monitor(s), telephone number(s)], written approvals are necessary from Sponsor, but not from the 
Ethics Committee and the Regulatory Authorities before their implementation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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4.0 OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) 
This study will evaluate the safety and efficacy of pembrolizumab in combination with cisplatin or 
carboplatin plus etoposide in patients non-previously treated for unresectable locally advanced or 
metastatic MCC.  
Specific objectives, hypothesis and corresponding endpoints for the study are outlined below.  
 
4.1 
Primary Objective(s), Hypothesis(es), and Endpoint(s) 
Objectives 
Endpoints 
Primary 
objectives: 
To 
assess 
activity 
of 
pembrolizumab combined with chemotherapy as first 
line treatment in patients with MCC. 
 
Hypothesis: combination of pembrolizumab plus 
cisplatin/carboplatin and etoposide may improves the 
ORR in participants with advanced MCC. 
• 
Objective Response Rate (ORR) will be defined as 
the percentage of patients achieving complete 
response (CR) or partial response (PR) according 
to RECIST 1.1 criteria. 
 
Secondary objectives: To assess safety and efficacy 
of pembrolizumab combined with chemotherapy as 
first line treatment in patients with MCC. 
 
Hypothesis: combination of pembrolizumab with 
cisplatin/carboplatin and etoposide is safe and may 
improve the PFS and OS in participants with advanced 
MCC. 
 
• 
Incidence of Serious Adverse Events (SAE)  
• 
Incidence and severity of Immune-related 
Adverse Events (irAE). 
• 
Incidence and severity of Adverse Events (AEs) 
according to NCI Common Terminology criteria 
Adverse Event (CTCAE), version 5.0. 
• 
Overall Survival (OS) will be measured from the 
date of starting therapy to the date of death by any 
cause. 
• 
Progression Free Survival (PFS) will be measured 
from the date of starting therapy to the date of 
disease progression or death. 
• 
Duration of Response (DOR) will be measured 
from the date of the first response to disease 
progression or death in those patients who 
achieved a CR o PR during study treatment. 
Exploratory objectives: To identify immune and 
molecular biomarkers that may be indicative of clinical 
response/resistance, safety, and/or the mechanism of 
action of pembrolizumab and other treatments. 
 
To assess efficacy of pembrolizumab plus 
cisplatin/carboplatin and etoposide according to 
iRECIST. 
 
To assess Health-Related Quality of Life of 
pembrolizumab 
plus 
cisplatin/carboplatin 
and 
etoposide in participants with advanced/metastatic 
MCC. 
• 
Molecular determinants of response or resistance 
to treatments, using blood and tumor tissue. 
 
• 
Efficacy parameters such as OS and PFS will be 
evaluated according to iRECIST using investigator 
response assessments.  
 
• 
Evaluations will included, changes in EQ-5D and 
FACT-M scores and correlation of the HR-PRO 
scores to tumor responses during the treatment 
period. 

 
 
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5.0 TRIAL DESIGN 
5.1 Trial Design 
This is an open label, multicenter, phase II study evaluating the activity and safety of pembrolizumab 
combined with cisplatin or carboplatin and etoposide as first line treatment in patients with advanced 
MCC. 
The induction treatment will consist of four cycles of pembrolizumab 200 mg flat dose, intravenously 
every 3 weeks (Q3W) plus cisplatin or carboplatin and etoposide at standard dose (see below). Each cycle 
will be administered every 21 days (3 weeks). After the induction phase, patients will start maintenance 
therapy with pembrolizumab 400 mg flat dose intravenously every 6 weeks (Q6W), for a maximum of 16 
cycles. Overall, treatment with pembrolizumab (Q3W + Q6W pembrolizumab combined) will be 
administered for a maximum of 24 months. 
Subjects will attend clinic visits at regular intervals to receive trial treatment and for efficacy and safety 
assessments. All subjects will be continuously monitored for any adverse event (AE) according to NCI 
Common Terminology Criteria for Adverse Event (CTCAE), version 5.0 while on study treatment. 
Treatment will be continued until disease progression, unacceptable toxicity, Investigator’s decision or 
consent withdrawal, for a maximum of 24 months.  
Radiological assessment will be performed by CT scan every 6 weeks (± 7 days) for the first year, 
following Cycle 1, Day 1, regardless of treatment dose delays. After completion of the first year, tumor 
assessments will be required every 12 weeks (± 7 days) thereafter, regardless of treatment dose delays. 
Disease response to treatment will be assessed by the Investigator using RECIST 1.1 and irRECIST.  
Treatment should be discontinued in all patients who exhibit evidence of disease progression per RECIST 
1.1. However, given the limited therapeutic options in MCC patients progressing to a first line of 
treatment, patients may be considered for treatment beyond radiographic disease progression, at the 
discretion of the investigator, after appropriate discussion with the patient and after obtaining informed 
consent if: 
- 
there is a clinical benefit  
- 
there is absence of decline in ECOG Performance Status and/or absence of symptoms and signs 
(including laboratory values) indicating unequivocal progression of disease  
Patients who continue treatment after radiographic disease progression according to RECIST 1.1 criteria 
should undergo careful clinical monitoring and radiographic re-evaluation after 4-6 weeks (investigator 
choice), or sooner in case of symptomatic worsening. Treatment should be discontinued if clinical 
deterioration due to disease progression occurs at any time, or if persistent disease growth (disease 
progression) is confirmed in a follow-up scan. In addition, patients should be discontinued for 
unacceptable toxicity or for any other signs or symptoms of deterioration attributed to disease progression 
as determined by the investigator after an integrated assessment of radiographic data and clinical status. 
Patients who discontinue treatment for reasons other than radiographic disease progression per RECIST 
1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor assessments at the same 
frequency as would have been followed if the patient had remained on study treatment. 
 
The primary endpoint of the trial is the Objective Response Rate (ORR), defined as the percentage of 
patients achieving complete response (CR) or partial response (PR) according to RECIST 1.1. Secondary 
endpoints include Progression Free Survival (PFS), Overall Survival (OS), Duration of Response (DOR) 

 
 
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and safety as assessed by a variety of AE parameters.  Exploratory analyses include translational 
assessments evaluation of effectiveness according to iRECIST and Quality of life assessments. 
 
The duration of the study is expected to be a maximum of 48 months. The study recruitment period is 
expected to be approximately 24 months. The study will end at the conclusion of additional survival 
follow-up. The survival follow-up will continue until 6 months after the last subject receives the last dose 
 
5.2 Trial Schema 
The trial design is depicted in Figure 1. 
 
Induction phase: Cisplatin (75 mg/sqm on day 1)  or carboplatin (AUC 5 on day 1), etoposide (100 
mg/sqm on day 1-3), pembrolizumab (200 mg flat dose on day 1). Mainteinance phase: pembrolizumab 
(400 mg flat dose Q6W). 
Overall, pembrolizumab will be administered for a maximum of 24 months. 
PD= progression disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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5.3 Schedule of Activities 
5.3.1 Table 1 Study Schedule of Activities 
Study Period: 
Screening 
Treatment cycles 
EOT 
Notes 
Treatment Cycle Screening 
(Visit 1) 
1 
2 
3 
4 
5 
6 
7 to 
24 
month
s 
 
Discon 
 
Scheduled  Window (days) 
-28 to -1 
+3 
±3 
±3 
±3 
±3 
±3 ±3 
At time of 
discon  
 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
Participant Identification Card 
X 
. 
 
 
 
 
 
 
 
. 
Medical History (includes 
substance usage and Family 
history of premature CV disease) 
X 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tumor tissue collection 
X 
 
 
 
 
 
 
 
 
 
Study drug administration 
Treatment 
• 
Pembrolizumab 
+ 
cisplatin/carboplatin 
+ 
etoposide 
(induction phase)# 
 
X 
X 
X 
X 
 
 
 
 
 
Treatment  
• 
Pembrolizumab 
(maintenance phase)## 
 
 
 
 
 
X 
X 
X 
 
 

 
 
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Study Period: 
Screening 
Treatment cycles 
EOT 
Notes 
Treatment Cycle Screening 
(Visit 1) 
1 
2 
3 
4 
5 
6 
7 to 
24 
month
s 
 
Discon 
 
Scheduled  Window (days) 
-28 to -1 
+3 
±3 
±3 
±3 
±3 
±3 ±3 
At time of 
discon  
 
Clinical Procedures 
/assessments 
 
 
 
 
 
 
 
 
 
 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full physical examination 
including, ECOG PS, height and 
weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs (heart rate, blood 
pressure) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
Laboratory Procedure / assessments: analysis performed by local laboratory 
Hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
X 
 
X 
 
 
 
X 
 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid Function Tests (TSH, 
T3, free T4; periodically) 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy test urine or serum b-
HCG* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X** 
PT and aPTT (baseline only) 
X 
 
 
 
 
 
 
 
 
 
Blood Immunophenotyping 
X 
 
X 
 
 
 
 
 
X 
 
Patient Reported Outcomes (PRO) 
EuroQoL (EQ)-5D 
X 
 
X 
 
X 
 
 
 
X 
 
FACT- M  
X 
 
X 
 
X 
 
 
 
X 
 
# Cycles every 3 weeks  
## Clycles every 6 weeks 
* Only for Woman of Childbearing Potential (WOCBP) 

 
 
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 ** Additional pregnancy testing should be conducted for the time required to eliminate systemic exposure after the last dose of each study intervention (120 days 
after last dose of pembrolizumab and 180 days after last dose of chemotherapy) 
 

 
 
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5.3.2 Table 2 Study Schedule of Activities: Survival Status 
Study Period 
Screening 
Phase 
Treatment Cycles 
 
EOT 
Post Treatment Visits 
Notes 
Treatment Cycle 
Screening 
(Visit 1) 
1 
2 
3 
4 
5** 6 to 24 
months DC 
Safety 
Follow-
up 
Efficacy 
Follow-
up 
Survival 
Follow-
up# 
Scheduling 
Window (Days): 
-28 to -1 
+3 ±3 
±3 ±3 ±3 
±3 
Time 
of 
DC  
30 Days 
from the 
last dose 
(+7 
days) 
Every 
6* 
Weeks 
(±7 
days) 
Every 
12 
Weeks 
(±7 
days) 
Administrative Procedures 
Survival Status 
 
 
X 
After investigator 
determined disease 
progression or start of 
new anticancer 
treatment. 
* After completion of the first year, tumor assessments will be required every 12 weeks 
# Telephone contacts are allowed 
** From cycle 5, every 6 weeks.

 
 
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5.3.3 Table 3 Study Schedule of Activities: Tumor Imaging 
Study Period:  
Screening 
Phase   
Treatment Cycles  
End of 
Treatment  
Post-Treatment  
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1  
2  
3  
4* 
Discon  
Safety 
Follow-Up  
Follow-
Up Visits  
Survival 
Follow-Up 
Scheduling Window (Days):  -28 to -1 
+3 
±3 
±3 
±3 
At time of 
discon  
30 days 
post discon 
Every 12 
weeks 
post 
discon 
Every 12 weeks 
Tumor imaging 
X 
X 
X 
X 
*Radiological assessment will be performed by CT scan every 6 weeks (± 7 days) for the first year, After completion of the first year, tumor assessments will be required every 12 
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6.0 METHODOLOGY 
6.1 Study Population 
6.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
1. Male/female subjects with histologically confirmed diagnosis of MCC, who have not received 
prior systemic treatment for their advanced or metastatic MCC, are at least 18 years of age on the 
day of signing informed consent, will be enrolled in this study. 
 
2. Male participants: 
A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol 
during the treatment period and for at least 120 days, corresponding to time needed to eliminate 
any study treatments (e.g. 5 terminal half-lives for pembrolizumab and/or any active 
comparator/combination) plus an additional 90 days (a spermatogenesis cycle) after the last dose 
of study treatment and refrain from donating sperm during this period. 
 
Female participants: 
 
3. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 120 days (corresponding to time needed to eliminate any study 
treatments (pembrolizumab and/or any active comparator/combination) plus 30 days (a 
menstruation cycle)  after the last dose of study treatment. 
 
4. The participant (or legally acceptable representative if applicable) provides written informed 
consent for the trial.   
 
5. Unresectable and locally advanced, relapsed or metastatic MCC stage IIIB-IV according to 
American Joint Committee on Cancer (AJCC) TNM Staging Classification for Merkel Cell 
Carcinoma (8th ed. 2017) 
 
6. No prior systemic treatment for metastic MCC. Subjects who received adjuvant or neoadjuvant 
therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior 
to the onset of metastatic disease. 
 
7. Have a life expectancy of at least 3 months. 
 
 
8. Have measurable disease based on RECIST 1.1.  Lesions situated in a previously irradiated area 
are considered measurable if progression has been demonstrated in such lesions. 

 
 
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9. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a 
tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded (FFPE) tissue blocks 
are preferred to slides.  Newly obtained biopsies are preferred to archived tissue. 
 
10. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.  Evaluation 
of ECOG is to be performed within 7 days prior to the first dose of study intervention.   
11. Have adequate organ function as defined in the following table (Table 4).  Specimens must be 
collected within 10 days prior to the start of study intervention. 
Table 4. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks. 
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
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6.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see 
Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. 
 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).  
 
3. Has received prior systemic anti-cancer therapy, with the exception for subjects who received 
adjuvant or neoadjuvant therapy. They are eligible if the adjuvant/neoadjuvant therapy was 
completed at least 12 months prior to the onset of metastatic disease. 
 
4. Has received prior radiotherapy within 2 weeks of start of study intervention.  Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not have had 
radiation pneumonitis.  A 1-week washout is permitted for palliative radiation (≤2 weeks of 
radiotherapy) to non-CNS disease. 
 
5. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of 
study drug.  Administration of killed vaccines is allowed. 
 
6. Is currently participating in or has participated in a study of an investigational agent or has used 
an investigational device within 4 weeks prior to the first dose of study intervention. 
 
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of study drug.  
8. Has a known additional malignancy that is progressing or has required active treatment within 
the past 2 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, transitional cell carcinoma of urothelial cancer or carcinoma in situ (eg, breast 
carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not 
excluded. 
9. Has known active CNS metastases and/or carcinomatous meningitis.  Participants with previously 
treated brain metastases may participate provided they are radiologically stable, i.e. without 
evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging 

 
 
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should be performed during study screening),  clinically stable and without requirement of steroid 
treatment for at least 14 days prior to first dose of study intervention. 
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
11. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.  
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has 
current pneumonitis/interstitial lung disease. 
13. Has an active infection requiring systemic therapy. 
14. Has a known history of Human Immunodeficiency Virus (HIV) infection.   
15. Has a known history of active Hepatitis B (defined as HBV DNA is detected) or known active 
Hepatitis C virus (defined as HCV RNA quantitative is detected) infection.  
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the participant’s participation for the full duration 
of the study, or is not in the best interest of the participant to participate, in the opinion of the 
treating investigator.   
17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
18. Is pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose of trial 
treatment. 
19. Has had an allogenic tissue/solid organ transplant. 
 
6.1.3 Lifestyle Considerations  
6.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea or vomiting. 
6.1.3.2 Contraception 
 Study drugs  may have adverse effects on a fetus in utero.   
For this study, male participants 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).   

 
 
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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.  
Sexually active fertile subjects and their partners must agree to use medically accepted methods of 
contraception with a failure rate of < 1% per year during the study and contraception in both males and 
females should be used until 120 days after last dose of pembrolizumab and 180 days after last dose of 
chemotherapy that corresponding to time needed to eliminate systemic exposure after the last dose of each 
study intervention. 
• practice abstinence from heterosexual activity; 
OR 
• 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 
➢ 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) 

 
 
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• hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection 
In order to participate in the study, subjects (both male and female) 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 last dose of pembrolizumab and 180 days after last dose of chemotherapy that 
corresponding to time needed to eliminate systemic exposure after the last dose of each study intervention. 
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. 
Refer to Appendix 3 for more details. 
6.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the participant 
will be immediately discontinued from study intervention(s).  The site will contact the participant at least 
monthly and document the participant’s status until the pregnancy has been completed or terminated.  
The outcome of the pregnancy will be reported to the Promoter within 2 working days 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 Promoter.  If a male participant impregnates his female partner, the study personnel at the site must 
be informed immediately and the pregnancy must be reported to the Promoter and followed as described 
in Section 7.2. 
 
 

 
 
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6.2 Trial Intervention(s) 
6.2.1 Preparation, Handling and Storage of Drug 
Refer to the Pharmacy Manual (V. 8.0 28 April 2021) for guidance on preparation, handling and storage 
information for Pembrolizumab.  
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. 
At the end of the study, the Promoter will ensure the correct destruction of the remaining drug according 
to applicable laws and regulations. 
Pembrolizumab will be provided by MSD as summarized in Table 10. 
Table 10. Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
All other supplies not indicated in Table 10 above will be used locally.  
6.2.2 Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
6.2.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; 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. 
6.2.4 Drug Administration and Dosage Schedule 
The intervention(s) to be used in this trial is outlined below in: 

 
 
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Table 5  Trial Intervention(s) 
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 
Pembrolizumab 400 mg 
   Q3W 
IV infusion 
Day 1 of each 6-week 
cycle 
Experimental 
Cisplatin 
75 mg/m2 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle 
Treatment of 
cancer 
Carboplatin 
AUC 5 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle 
Treatment of 
cancer 
Etoposide 
100 mg/m2 
Q3W 
IV infusion 
Day 1-3 of each 3-
week cycle 
Treatment of 
cancer 
 
 
6.2.5 Timing of Dose Administration 
Trial interventions should be administered on Day 1 of each cycle after all procedures/assessments have 
been completed as detailed on the Schedule of Activities, Section 5.3.  Trial interventions may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
All trial interventions will be administered on an outpatient basis. 
On Day 1 of each cycle, all eligible patients will receive drug infusions in the following order: 
Induction phase: 
Pembrolizumab (200 mg flat dose, administered intravenously) → cisplatin (75 mg/ per square meter of 
body-surface area, admistered intravenously) or carboplatin (AUC 5 mg per milliliter per minute, 
administered intravenously) → etoposide (100 mg per square meter of body-surface area, administered 
intravenously on days 1 through 3 of each cycle). 
On Days 2 and 3, patients will receive etoposide alone. 
Manteinance phase: 
Pembrolizumab (400 mg flat dose, administered intravenously). 
Pembrolizumab 200/400 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). 

 
 
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The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab infusion 
fluid and administration of infusion solution. 
Concomitant standard chemotherapeutic agents will be prepared and administered as per the approved 
product label at the doses indicated below: 
• Cisplatin: 75 mg/m2 
• Carboplatin: AUC 5 (using Calvert formula). Carboplatin dose not to exceed 750mg 
Calvert Formula 
Total Dose (mg) = (target AUC) x (CrCl + 25) 
The estimated CrCl used in the Calvert formula should not exceed 125 mL/min 
Maximum carboplatin dose (mg) = target AUC 5 (mg•min/mL) x (125 + 25) = 5 x150 mL/min 
= 750 mg 
• Etoposide: 100 mg/m2 
 
6.2.6 Dose Modification and toxicity management for immune-related AEs associated with 
Pembrolizumab and combination therapy 
AEs associated with pembrolizumab exposure, including coadministration with additional compounds, 
may represent an immunologic aetiology. These immune-related AEs (irAEs) may occur shortly after 
the first dose or several months after the last dose of pembrolizumab/combination treatment and may 
affect more than one body system simultaneously. Therefore, early recognition and initiation of treatment 
is critical to reduce complications.  Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin 
biopsy may be included as part of the evaluation. Dose modification and toxicity management guidelines 
for irAEs associated with pembrolizumab/combination treatment are provided in Table 6. 
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be interrupted or 
discontinued due to toxicity. 
Chemotherapy dose reductions are permitted (Table 5.1). If a dose reduction for toxicity occurs with any 
agent, the dose may not be re-escalated. Subjects can have a maximum of 2 dose modifications (if 
applicable) to each of the components of study therapy throughout the course of the study for toxicities. 
If a subject experiences several toxicities and there are conflicting recommendations, the most 
conservative dose adjustment recommended should be followed (dose reduction appropriate to the most 
severe toxicity). Subjects who require a 3rd dose modification to any particular component will have that 
agent discontinued. Reduction of one chemotherapy agent and not the other agent is appropriate if, in the 
opinion of the Investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of the 
Investigator, the toxicity is related to the combination of both chemotherapy agents, both drugs should 
be reduced according to recommended dose modifications. If the toxicity is related to the combination 
of three agents, all three agents should be reduced (if applicable), interrupted, or discontinued according 
to the recommended dose modifications. Subjects may have chemotherapy discontinued and continue on 
pembrolizumab alone. Similarly subjects may discontinue pembrolizumab and continue on 
chemotherapy alone if appropriate.  

 
 
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Chemotherapy may be interrupted for a maximum of 6 weeks from last dose; pembrolizumab may be 
interrupted for a maximum of 12 weeks from last dose. The Common Terminology Criteria for Adverse 
Events version 5.0 (CTCAE 5.0) must be used to grade the severity of adverse events. All dose 
modifications should be based on the AE requiring the greatest dose modification.  
 
Table 5.1. Dose Modifications for Trial Medications 
 
 
Dose Level 0 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Cisplatin 
75 mg/m2 
56 mg/ m2 
38 mg/ m2 
Discontinue 
Carboplatin 
AUC 5 
Maximum dose 
750mg 
AUC 3.75 
Maximum dose 
562.5mg 
AUC 2.5 
Maximum dose 
375mg 
 
Discontinue 
Etoposide 
100 mg/m2 
75 mg/m2 
50 mg/m2 
Discontinue 
Pembrolizumab 
200/400 mg fixed 
dose 
Dose reductions 
are not permitted 
Dose reductions 
are not permitted 
Dose reductions 
are not permitted 
 
 
Attribution of Toxicity: 
The investigator may attribute a toxicity event to the combination,  to chemotherapy alone or to 
pembrolizumab alone, for adverse events listed in Table 6.  Interventions must be held according to the 
criteria in Table 6.   
Holding Study Interventions: 
If the AE is considered immune-related interventions should be held according to recommended dose 
modifications. 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of pembrolizumab in 
this study, as described in Table 6. 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant must 
be discontinued from all study interventions. 
• If the toxicities do resolve and conditions are aligned with what is defined in Table 6, the combination 
of cisplatin or carboplatin and etoposide plus pembrolizumab may be restarted at the discretion of 
the investigator.In the cases where the toxicity is attributed to the chemotherapy re-initiation of 
pembrolizumab as a monotherapy may be considered at the principal investigator’s discretion. 
 

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Table 6. Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab 
monotherapy and IO Combinations  
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics for 
opportunistic infections 
•  Monitor participants for signs and symptoms of 
pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
 
and of bowel perforation (ie, peritoneal signs 
and ileus) 
•  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
•  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion 
AST or ALT 
Elevation 
or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM 
or 
Hyperglycemia 
New 
onset 
T1DM 
or  
Grade 3 or 4 
hyperglycemia 
Withhold d 
•  Initiate insulin replacement therapy for 
participants with T1DM 
•  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
associated with 
evidence 
of 
-cell failure 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
•  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
•  Monitor for signs and symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
•  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 2, 3 or 4 
or 
clinical 
suspicion* 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 3 
Withhold 
or 
discontinue based 
on the event e  
Recurrent 
Grade 3 
or 
Grade 4  
Permanently 
discontinue 
*In case of asymptomatic cardiac enzyme elevation with clinical suspicion of Myocarditis the treatment dosing should be withheld 
 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 

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6.2.7 Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab 
associated infusion reaction are provided in Table 7. 
Table 7. Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within 1 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 participant should be premedicated for the next 
scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug intervention 
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of study intervention 
with: 
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine). 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 
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: 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
Hospitalization may be indicated. 
No subsequent dosing 

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Life-threatening; pressor 
or ventilatory support 
indicated 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further 
study drug intervention. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov 
 
Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / 
surgical events and/or unforeseen circumstances not related to study intervention. However, intervention 
is to be restarted within 3 weeks of the originally scheduled dose and within 42 days of the previously 
administered dose, unless otherwise discussed with the Sponsor. The reason for study intervention 
interruption is to be documented in the patient's study record. 
 
 
Dose Modification for Chemotherapy 
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 5.2 and Table 
5.3. These serve as a guide and do not replace investigator judgment and applicable local label 
recommendations if more stringent. 
 
Table 5.2. Recommended Dose Modifications for Chemotherapy Hematological Toxicity 
 
 
Etoposide 
Cisplatin/Carboplatin 
Platelets 
ANC 
Dose level (DL) from Table 5.1 
≥50,000/mcL AND 
≥ 500/mcL 
DL 0 
DL 0 
≥50,000/mcL AND 
< 500/mcL 
DL -1 
DL -1 
<50,000/mcL without 
bleeding AND 
ANY 
DL -1 
DL -1 
<50,000/mcL with Grade ≥ 
2bleeding AND 
ANY 
DL -2 
DL -2 
ANY AND 
< 1,000/mcL +  fever ≥ 38.5°C 
(101°F) 
DL -1 
DL -1 
 
 
 
 
 

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Table 5.3. Recommended Dose Modifications for Chemotherapy Non-Hematological Toxicity 
 
 
Etoposide 
Cisplatin 
Carboplatin 
 
CTC Grade 
Dose level (DL) from Table 5.1 
Nausea or vomiting 
Grade 3or 4 
DL 0 
DL 0 
DL 0 
Diarrhea 
Grade 3or 4 
DL -1 
DL -1 
DL 0 
Mucositis 
Grade 3or 4 
DL -2 
DL 0 
DL 0 
Neurotoxicity 
Grade 2 
DL 0 
DL -2 
DL 0 
Grade 3or 4 
DL -1 
Discontinue 
DL -1 
Transaminase elevation 
Grade 3 
DL -1 
DL -1 
DL -1 
Grade 4 
Discontinue 
Discontinue 
Discontinue 
Other non-hematological 
toxicity 
Grade 3 or 4 
DL -1 
DL -1 
DL -1 
 
 
6.2.8 Second Course  
All participants who stop study intervention with SD or better may be eligible for up to an additional 
17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping study 
treatment from the initial treatment phase.  This retreatment is termed the Second Course Phase of this 
study and is only available if the study remains open and the participant meets the following conditions: 
Either 
• Stopped initial study intervention after attaining an investigator-determined confirmed CR based 
on RECIST 1.1, and 
o Was treated with at least 8 cycles of study treatment before discontinuing treatment, and 
o Received at least 2 treatments with pembrolizumab beyond the date when the initial CR was 
declared 
OR 
• Had SD, PR, or CR and stopped study intervention after completion of 35 administrations 
(approximately 2 years) of study intervention for reasons other than disease progression or 
intolerability 
AND 

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• Experienced an investigator-determined radiographic disease progression by RECIST 1.1 after 
stopping initial treatment, and 
o No new anticancer treatment was administered after the last dose of study treatment, and 
o The participant meets all of the safety parameters listed in the inclusion criteria and none of 
the safety parameters listed in the exclusion criteria, and 
o The study is ongoing 
An objective response or disease progression that occurs during the Second Course Phase for a participant 
will not be counted as an event for the primary analysis of either endpoint in this study. 
Participants who have experienced an initial disease progression by RECIST 1.1 and have an iSD, iPR,or 
iCR per iRECIST after completion of 35 administrations of study intervention for reasons other than 
disease progression or intolerability may be considered for the Second Course Phase after consultation 
with the Sponsor. 
6.3 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 final decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician. However, the decision to continue the participant on study intervention 
requires the mutual agreement of the investigator, the Sponsor, and the participant. 
Below are summarized the most relevant interactions with other drugs  and other forms of 
interactions including drugs that are prohibited or should be used with caution for cisplatin, 
carboplatin etoposide and pembrolizumab. 
CISPLATIN  
    
Nephrotoxic substances 
   Concomitant administration of nephrotoxic (e.g. cephalosporins, aminoglycosides, amphotericin B or 
contrast media) or ototoxic (e.g. aminoglycosides) medicinal products potentiates the renal toxic effect of 
cisplatin. During or after cisplatin therapy caution is advised with the use of predominantly renally 
eliminated substances, eg cytostatic agents such as bleomycin and methotrexate, due to reduced renal 
elimination. 
The renal toxicity of ifosfamide may be greater when used with cisplatin or in patients previously treated 
with cisplatin. 
 In some cases, a reduction in blood lithium values has been observed after treatment with cisplatin in 
combination with bleomycin and etoposide. It is therefore recommended to monitor lithium levels. 
The manifestations of nephrotoxicity caused by cisplatin may be intensified by concomitant therapy with 
antihypertensives containing furosemide, hydralazine, diazoxide and propranolol. The dosage of 
allopurinol, colchicine, probenecid or sulfinpyrazone may need to be adjusted when used concomitantly 
with cisplatin, since cisplatin induces an increase in serum uric acid concentrations. 

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Forced diuresis with loop diuretics should not be induced with loop diuretics due to possible renal tract 
damage, except in patients receiving doses of cisplatin greater than 60 mg/m2 and whose urine secretion 
is less than 1000 ml in 24 hours. . Simultaneous use of ifosfamide causes increased protein excretion. 
 
Ototoxic substances 
Concomitant administration of ototoxic medicinal products (e.g. aminoglycosides, loop diuretics) 
potentiates the toxic effect of cisplatin on hearing function. Forced diuresis with loop diuretics should not 
be induced with loop diuretics due to possible renal tract damage, except in patients receiving doses of 
cisplatin greater than 60 mg/m2 and whose urine secretion is less than 1000 ml in 24 hours. and ototoxicity. 
Ifosfamide may increase hearing loss due to cisplatin. 
Live attenuated virus vaccines Yellow fever vaccine is strictly contraindicated due to the risk of a fatal 
systemic vaccine reaction. 
 In view of the risk of generalized reaction, it is advisable to use an inactivated vaccine, if available. The 
use of live virus vaccines is not recommended within three months of stopping cisplatin therapy. 
 
Oral anticoagulants 
In case of concomitant administration of oral anticoagulants, it is advisable to check the INR regularly. 
Antihistamines, phenothiazines and others Simultaneous use of antihistamines, buclizine, cyclizine, 
loxapine, meclozine, phenothiazines, thioxanthenes or trimethobenzamides may mask the symptoms of 
ototoxicity (such as dizziness and tinnitus). Anticonvulsant drugs Serum concentrations of anticonvulsant 
drugs may remain at subtherapeutic levels during treatment with cisplatin. Cisplatin may reduce the 
absorption of phenytoin, resulting in impaired epilepsy control when phenytoin is given as existing 
treatment. It is absolutely contraindicated to start a new phenytoin-based anticonvulsant treatment during 
cisplatin therapy. 
Pyridoxine + altretamine combination In a randomized study on the treatment of advanced ovarian cancer, 
response time to therapy was negatively affected when pyridoxine was used in combination with 
altretamine (hexamethylmelamine) and cisplatin. Paclitaxel Treatment with cisplatin prior to a paclitaxel 
infusion can reduce paclitaxel clearance by 33%, thereby enhancing its neurotoxicity. 
Other the simultaneous use of myelosuppressive agents or radiotherapy potentiates the effects of the 
myelosuppressive activity of cisplatin. 
Cisplatin given in combination with bleomycin and vinblastine can cause Raynaud's phenomenon. In a 
study of cancer patients with advanced or metastatic tumors, docetaxel in combination with cisplatin 
induced more severe neurotoxic effects (dose-dependent and sensory) than either agent taken individually 
at similar doses. 
Chelating agents, such as penicillamine, can reduce the effectiveness of cisplatin. In case of concomitant 
use of cisplatin and cyclosporine, excessive immunosuppression with risk of lymphoproliferation should 
be considered. 
 
CARBOPLATIN  
 
Carboplatin is mostly used in combination with antineoplastic drugs having similar cytotoxic effects. 
Additive toxicity may occur under these circumstances. 
Concomitant use of carboplatin and other myelosuppressive agents or radiotherapy may potentiate 
haematological toxicity. 

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An increased incidence of emesis has been reported when carboplatin was administered concomitantly 
with other emesis-inducing drugs, or in patients who had previously received emetic therapy. 
Concomitant administration of carboplatin and aminoglycosides carries an increased risk of 
nephrotoxicity and/or ototoxicity, so these drugs should be used concomitantly with caution. 
Use of other nephrotoxic drugs results in potentiation of the renal effects of carboplatin. Carboplatin 
interacts with aluminum, forming a black precipitate of platinum and decreasing potency. Needles, 
syringes, catheters, or IV administration sets containing aluminum should not be used for carboplatin 
administration. 
Due to the increased thrombotic risk, in the case of tumor pathologies, the use of anticoagulants is frequent. 
During diseases, the variability of individual coagulability, and the possibility of interaction between oral 
anticoagulants and anticancer chemotherapy, require an increase in the frequency of INR (prothrombin 
time) monitoring monitoring, if it is decided to treat the patient with oral anticoagulants. 
Concomitant use contraindicated - Yellow fever vaccine: risk of fatal generalized vaccinal disease. 
 
Concomitant use not recommended 
- Live attenuated vaccines (except yellow fever): risk of a systemic, potentially fatal disease. This risk is 
increased in people who are already immunosuppressed due to the disease. Where it exists it is necessary 
to use an inactivated vaccine (poliomyelitis). 
   - Phenytoin, fosphenytoin due to risk of exacerbation of seizures caused by decreased gastric absorption 
of phenytoin due to cytotoxic drug or due to risk of enhanced toxicity or loss of efficacy of cytotoxic drug 
due to increased hepatic metabolism by phenytoin. Concomitant use to be considered 
- Cyclosporine (and by extrapolation tacrolimus and sirolimus): excessive immunosuppression with risk 
of lymphoproliferation. 
- Aminoglycosides: Concomitant use of carboplatin with aminoglycoside antibiotics should be considered 
due to cumulative nephrotoxicity and toxicity, particularly in patients with renal insufficiency. - Loop 
diuretics: Concomitant use of carboplatin with a loop diuretic should be considered due to cumulative 
nephrotoxicity and ototoxicity. 
 
ETOPOSIDE  
 
Effects of other medicinal products on the pharmacokinetics of etoposide 
High doses of cyclosporine, resulting in plasma concentrations above 2,000 ng/mL, co-administered with 
oral etoposide, resulted in an 80% increase in etoposide exposure (AUC) with a 38% decrease in total 
body clearance of etoposide versus etoposide monotherapy. 
Concomitant cisplatin-based therapy is associated with a reduction in the total body clearance of 
etoposide. 
Concomitant phenytoin therapy is associated with increased etoposide clearance and decreased efficacy, 
and other enzyme-inducing antiepileptic therapies may be associated with increased etoposide clearance 
and decreased efficacy. Plasma protein binding in vitro is 97%. 
Phenylbutazone, sodium salicylate and acetylsalicylic acid can displace etoposide from plasma protein 
binding. 
 
Effect of etoposide on the pharmacokinetics of other medicinal products 
Co-administration of antiepileptic medicinal products and etoposide and associated names may result in 
decreased seizure control due to pharmacokinetic medicinal product interactions. 

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Co-administration of warfarin and etoposide may cause an increase in international normalized ratio 
(INR). Careful monitoring of INR is recommended. 
 
Pharmacodynamic interactions 
There is an increased risk of fatal systemic vaccination disease following administration of yellow fever 
vaccine. Live vaccines are contraindicated in immunosuppressed patients. 
 Prior or concomitant use of other medicinal products with myelosuppressive action similar to etoposide 
may cause additive or synergistic effects. 
Cross-resistance between anthracyclines and etoposide has been reported in preclinical studies. 
 
PEMBROLIZUMAB 
 
No formal pharmacokinetic interaction studies have been performed with pembrolizumab.  
Since pembrolizumab is cleared from the bloodstream by catabolism, no metabolic drug-drug interactions 
are expected. The use of systemic corticosteroids or immunosuppressants prior to initiating 
pembrolizumab therapy should be avoided due to their possible interference with the pharmacodynamic 
activity and efficacy of pembrolizumab. However, corticosteroids or other systemic immunosuppressants 
may be used after initiation of pembrolizumab therapy to treat immune-related adverse reactions (see 
section 6.2.7). Corticosteroids may also be used as premedication, when pembrolizumab is used in 
combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related 
adverse reactions. 
 
 
6.3.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’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 prior to the first dose of trial intervention and up to 
30 days after the last dose of trial intervention should be recorded.  If participants experience an SAE or 
ECI, concomitant medications administered30 days after the last dose of trial intervention are to be 
recorded as defined in Section 7.2. 
6.3.2 Prohibited Concomitant Medications 
Participants 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 

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• Investigational agents other than pembrolizumab 
• Radiation therapy  
Note:  Radiation therapy to a symptomatic lesion or to the brain may be allowed at the investigator’s 
discretion.   
• Live vaccines within 30 days prior to the first dose of study treatment and while participating in 
the study.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.  
• 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. 
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  All treatments that the 
Investigator considers necessary for a participant’s welfare may be administered at the discretion of the 
Investigator in keeping with the community standards of medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study.  If there is a clinical indication for any medication or vaccination specifically prohibited 
during the study, discontinuation from study therapy or vaccination may be required.  The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the participant's primary 
physician.  However, the decision to continue the participant on study treatment requires the mutual 
agreement of the investigator, the Sponsor and the participant. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.3.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined along with the dose modification guidelines in Section 6.2.6, [Table 
6]. Where appropriate, these guidelines include the use of oral or IV 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 of the event, it is determined not to be related to pembrolizumab, the 
Investigator does not need to follow the treatment guidance.  

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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  
6.4 Participant Discontinuation Criteria 
Discontinuation of study intervention does not represent withdrawal from the study. 
As certain data on clinical events beyond study intervention discontinuation may be important to the 
study, they must be collected through the participant’s last scheduled follow-up, even if the participant 
has discontinued study intervention.  Therefore, all participants who discontinue study intervention prior 
to completion of the protocol-specified treatment period will still continue to be monitored in this study 
and participate in the study visits and procedures as specified in Section 5.3 unless the participant has 
withdrawn from the study (Section 6.6). 
Participants may discontinue study intervention at any time for any reason or be discontinued from the 
study intervention at the discretion of the investigator should any untoward effect occur.  In addition, a 
participant may be discontinued from study intervention by the investigator or the Sponsor if study 
intervention is inappropriate, the study plan is violated, or for administrative and/or other safety reasons.   
A participant must be discontinued from study treatment but continue to be monitored in the study for 
any of the following reasons: 
• The participant or participant’s legally acceptable representative requests to discontinue study 
intervention 
• After prolonged study intervention interruption that prohibits restarting study intervention if 
agreed upon with the Sponsor 
• Radiographic disease progression outlined in Section 7.1.4. 
• Any progression or recurrence of any malignancy, or any occurrence of another malignancy that 
requires active treatment 
• Any study intervention-related toxicity specified as a reason for permanent discontinuation as 
defined in the guidelines for dose modification due to AEs in Section 6.2.6. 
• The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
Completion of pembrolizumab Q3W monotherapy consists of 35 treatments (approximately 2 years).  
Discontinuation of treatment may be considered for participants who have attained a confirmed 
complete response (CR) and have been treated for at least 24 weeks, receiving beyond the date when 
the initial CR was declared. These participants may be eligible for second course treatment described in 
Section 6.2.8 

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Note: The number of treatments is calculated starting with the first dose.  Participants who stop the 
combination or pembrolizumab after receiving 35 doses may be eligible for retreatment if they progress 
after stopping study intervention provided they meet the requirements detailed in Section 6.2.8. 
Participants may be retreated in the Second Course Phase (Retreatment) for up to an additional 17 cycles 
(approximately 1 year). 
6.5 Participant withdrawal From Study 
A participant must be withdrawn from the study if the participant or the participant’s legally acceptable 
representative withdraws consent from the study. 
If a participant withdraws from the study, they will no longer receive study intervention or be followed 
at scheduled protocol visits. 
Specified details regarding procedures to be performed at the time of withdrawal from the study are 
outlined in Section 7.1.6.1. 
6.6 
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 participants 
4. Plans to modify or discontinue the development of the study drug 
In the event of MSD decision to no longer supply study drug, adequate notification will be provided so 
that appropriate adjustments to participant treatment can be made. 

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7.0 TRIAL ASSESSMENTS AND PROCEDURES 
7.1 Trial Procedures 
• Study procedures and their timing are summarized in The Schedule of Activities, Section 5.3.   
• Adherence to the study design requirements, including those specified in the Schedule of Activities 
is essential and required for study conduct. 
• The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (by education, training, and experience) staff. 
• All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria 
• All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
7.1.1 Administrative and General Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant or each participant’s 
legally acceptable representative prior to participating in a clinical trial. If there are changes to a 
participant’s status during the study (e.g. health requirements) the investigator must ensure appropriate 
consent is in place. 
7.1.1.2 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’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 participant before participation in the 
trial. 
The initial informed consent form, any subsequent revised written informed consent form and any written 
information provided to the participant must receive the IRB/ERC’s approval/favorable opinion in 
advance of use.  The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’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 
participant’s dated signature or by the participant’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.   

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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and Sponsor 
requirements. 
If the investigator recommends continuation of study intervention beyond disease progression, the 
participant or his/her legally acceptable representative will be asked to sign consent. 
7.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the participant qualifies for the trial.  
7.1.1.4 
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 participant has 
enrolled in this study will be recorded separately and not listed as medical history.   
7.1.1.5 
Prior and Concomitant Medications Review 
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 participant within 28 days before starting 
the trial.  Treatment for the disease for which the participant has enrolled in this study will be recorded 
separately and not listed as a prior medication.  
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant during the 
trial.  In addition, new medication started during the Second Course should be recorded. All medications 
related to reportable SAEs and ECIs should be recorded as defined in Section 7.2. 
7.1.1.6 
Disease Details and Treatments 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
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 participant initiates a new anti-cancer therapy within 30 days after the last 

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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 participant will move into survival follow-
up.  
7.1.1.7 
Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify the subject 
for all procedures that occur prior to treatment allocation. Each subject will be assigned only one screening 
number. Screening numbers must not be re –used for different subjects. Any subject who is screened 
multiple times will retain the original screening number assigned at the initial screening visit. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant 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 5.0 (see Appendix 2).  Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.   
7.1.2.2 
Full Physical Exam 
A complete physical examination will be conducted by an investigator or medically qualified designee 
(consistent with local requirements) as per institutional standard systems . Height and weight will also be 
measured and recorded. 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.  The time points for full physical exams are described in Section 5.3.  After the first dose of study 
intervention, new clinically significant abnormal findings should be recorded as AEs.  Investigators should 
pay special attention to clinical signs related to previous serious illnesses. 
7.1.2.3 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of each 
dose of trial treatment and at treatment discontinuation as specified in the Schedule of Activities (Section 
5.3).  Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure.  Height 
will be measured at screening only. 
7.1.2.4 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified in the 
Schedule of Activities (Section 5.3). 
 

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7.1.2.5 
Electrocardiograms 
A standard 12-lead ECG will be obtained and reviewed by an investigator or medically qualified designee 
(consistent with local requirements) as outlined in the SoA (see Appendix X) using an ECG machine that 
automatically calculates the HR. 
 
7.1.3 Clinical Safety Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for the timing 
and frequency. 
• The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF. The laboratory reports must be filed 
with the source documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
• All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the SoA. 
• If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the appropriate CRF (eg, SLAB). 
• For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every attempt 
should be made to perform repeat assessments until the values return to normal or baseline or if 
a new baseline is established as determined by the investigator. 
Details regarding specific laboratory procedures/assessments to be performed in this study are provided 
below. The total amount of blood/tissue to be drawn/collected over the course of the study (from prestudy 
to poststudy visits), including approximate blood/tissue volumes drawn/collected by visit and by sample 
type per participant can be found in the Study Procedures Manual. Refer to the Study Flow Chart (Section 
5.3) for the timing of laboratory assessments. 
7.1.3.2 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2. 
 
7.1.3.3 
Pregnancy Testing 
All women who are being considered for participation in the study, and who are not surgically sterilized 
or postmenopausal, must be tested for pregnancy at each cycle. If a urine test is positive or not evaluable, 

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a serum test will be required. Participants must be excluded/discontinued from the study in the event of a 
positive test result.  
 
7.1.4 Tumor Imaging and Assessment of Disease 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  For the abdomen and 
pelvis, contrast-enhanced magnetic resonance imaging (MRI) may be used when CT with iodinated 
contrast is contraindicated, or when local practice mandates it.  MRI is the strongly preferred modality for 
imaging the brain.  The same imaging technique regarding modality, ideally the same scanner, and the use 
of contrast should be used in a participant throughout the study to optimize the reproducibility of the 
assessment of existing and new tumor burden and improve the accuracy of the assessment of response or 
progression based on imaging. Brain imaging is required for all participants at screening.  MRI is 
preferred; however, CT imaging will be acceptable according to the investigator decision. Local site 
investigator/radiology confirmation of measurable disease based on RECIST 1.1 at Screening should be 
used to determine participant eligibility.  Confirmation that the participant’s imaging shows at least 1 
lesion that is appropriate for selection as a target lesion per RECIST 1.1 is highly recommended prior to 
participation allocation.   
7.1.4.1    Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of allocation.  The 
site study team must review screening images to confirm the participant has measurable disease per 
RECIST 1.1.  Brain imaging, if performed to document the stability of existing metastases, should be by 
MRI if possible.  If MRI is medically contraindicated, CT with contrast is an acceptable alternative. 
7.1.4.2 Tumor Imaging During the Study 
The first on-study imaging assessment should be performed at 6 weeks (±7 days) from the date of 
allocation. Subsequent tumor imaging should be performed every 6 weeks (±7 days) or more frequently 
if clinically indicated.  After the first years, participants who remain on treatment will have imaging 
performed every 12 weeks (±7 days).  Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts.  Imaging should continue to be performed until disease progression is 
identified by the Investigator.  
Per iRECIST (Section 7.1.4.6), disease progression should be confirmed by the site 4 to 8 weeks after first 
radiologic evidence of PD in clinically stable participants. Participants who have unconfirmed disease 
progression may continue on treatment at the discretion of the investigator until progression is confirmed 
by the site provided they have met the conditions detailed in Section 7.1.4.6.  Participants who receive 
confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point, if clinically stable.  
Participants who have confirmed disease progression by iRECIST, as assessed by the site, will discontinue 
study treatment.  Exceptions are detailed in Section 7.1.4.6. 

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7.1.4.3 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the time of 
treatment discontinuation (±4 week window).  If previous imaging was obtained within 4 weeks prior to 
the date of discontinuation, then imaging at treatment discontinuation is not mandatory.  In participants 
who discontinue study treatment due to documented disease progression and the investigator elects not to 
implement iRECIST, this is the final required tumor imaging. 
For participants who discontinue study treatment without documented disease progression, every effort 
should be made to continue monitoring their disease status by tumor imaging using the same imaging 
schedule used while on treatment (every 6 weeks in Year 1 or every 12 weeks after Year 1) to monitor 
disease status until the start of a new anticancer treatment, disease progression, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
7.1.4.4 Second Course (Retreatment) Tumor Imaging 
Tumor imaging must be performed within 28 days prior to restarting treatment with pembrolizumab.  
Local reading (Investigator assessment with site radiology reading) will be used to determine eligibility. 
The first on-study imaging assessment should be performed at 6 weeks (±7 days) after the restart of 
treatment.  Subsequent tumor imaging should be performed every 6 weeks (±7 days) or more frequently, 
if clinically indicated. 
Per RECIST 1.1 (Section 7.1.4.5), if tumor imaging shows initial PD, tumor assessment should be repeated 
4 to 8 weeks later in order to confirm PD with the option of continuing treatment while awaiting radiologic 
confirmation of progression with the option of continuing treatment while awaiting radiological 
confirmation of progression in clinically stable patients.  Participants who obtain confirmatory imaging 
do not need to undergo scheduled tumor imaging if it is less than 4 weeks later and may wait until the next 
scheduled imaging time point, if clinically stable. 
Imaging should continue to be performed until disease progression, the start of a new anticancer treatment, 
withdrawal of consent, death, or notification by the Sponsor, whichever occurs first.  Disease progression 
may be confirmed 4 to 8 weeks after the first tumor imaging indicating PD, by the investigator using 
iRECIST, in clinically stable participants. 
In participants who discontinue study treatment, tumor imaging should be performed at the time of 
treatment discontinuation (±4 week window).  If previous imaging was obtained within 4 weeks prior to 
the date of discontinuation, then imaging at treatment discontinuation is not mandatory.  For participants 
who discontinue study treatment due to documented disease progression, this is the final required tumor 
imaging. 
For participants who discontinue study treatment without documented disease progression, every effort 
should be made to continue monitoring their disease status by radiologic imaging every 12 weeks (±7 
days) until either the start of a new anticancer treatment, disease progression, pregnancy, death, or the end 
of the study, whichever occurs first. 

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7.1.4.5 RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease 
progression, and as a basis for all protocol guidelines related to disease status (eg, discontinuation of study 
treatment).  Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, the 
Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a 
broader sampling of tumor burden.  
7.1.4.6 iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen with 
immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor response and 
progression and make treatment decisions. When clinically stable, participants should not be discontinued 
until progression is confirmed by the investigator, working with local radiology, according to the rules 
outlined in Appendix 4. This allowance to continue treatment despite initial radiologic disease progression 
takes into account the observation that some participants can have a transient tumor flare in the first few 
months after the start of immunotherapy, and then experience subsequent disease response. This data will 
be captured in the clinical database.  
Clinical stability is defined as the following: 
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status 
• No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care  
Any participant deemed clinically unstable should be discontinued from study intervention at central 
verification of site-assessed first radiologic evidence of disease progression, and is not required to have 
repeat tumor imaging for confirmation of disease progression by iRECIST.  
If the investigator decides to continue treatment, the participant may continue to receive study intervention 
and the tumor assessment should be repeated 4 to 8 weeks later to confirm disease progression by 
iRECIST, per investigator assessment.  
If repeat imaging does not confirm disease progression per iRECIST, as assessed by the investigator, and 
the participant continues to be clinically stable, study intervention may continue and follow the regular 
imaging schedule. If disease progression is confirmed, participants will be discontinued from study 
intervention.  
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 4, study 
intervention should be discontinued; however, if the participant is achieving a clinically meaningful 
benefit, an exception to continue study intervention may be considered. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the intervals as 
outlined in Section 7. 

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A description of the adaptations and iRECIST process is provided in Appendix 4.  A summary of imaging 
and treatment requirements after first radiologic evidence of progression is provided in Table 8 and 
illustrated as a flowchart in Figures 2. 
Table 8. Imaging and Treatment After First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of disease 
progression by 
RECIST 1.1  
Repeat imaging 
at 4 to 8 weeks 
to confirm 
disease 
progression. 
May continue 
study intervention 
at the 
investigator’s 
discretion after the 
participant’s 
consent while 
awaiting 
confirmatory 
tumor imaging by 
iRECIST. 
Repeat imaging at 
4 to 8 weeks to 
confirm disease 
progression per 
investigator’s 
discretion only. 
Discontinue 
treatment 
Repeat tumor 
imaging confirms 
disease progression 
(iCPD) by iRECIST 
per investigator 
assessment. 
No additional 
imaging 
required. 
Discontinue 
treatment 
(exception is 
possible at 
investigator’s 
discretion). 
No additional 
imaging required. 
Not applicable 
Repeat tumor 
imaging shows iUPD 
by iRECIST per 
investigator 
assessment. 
Repeat imaging 
at 4 to 8 weeks 
to confirm 
disease 
progression. 
May occur at 
next regularly 
scheduled 
imaging visit. 
Continue study 
intervention at the 
investigator’s 
discretion. 
Repeat imaging at 
4 to 8 weeks to 
confirm disease 
progression per 
investigator’s 
discretion only. 
Discontinue 
treatment 
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
investigator 
assessment. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
Continue study 
intervention at the 
investigator’s 
discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart study 
intervention if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule. 

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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified 
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable 
disease; iUPD=iRECIST unconfirmed progressive disease; RECIST 1.1=Response Evaluation Criteria in 
Solid Tumors 1.1; VOP=verification of progression. 
 
 
 
Figure 2. Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 
 
 
 
 
 
 

 
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7.1.5 Tumor Tissue Collection and Correlative Studies Blood Sampling 
• Tissue collection 
As mandatory inclusion criteria, the tissue submitted will be used to assess exploratory biomarkers. The 
tissue submitted should be a formalin-fixed, paraffin-embedded (FFPE) tumor specimen or 10 serial, 
freshly cut, unstained slides accompanied by an associated pathology report. Cytological samples are not 
acceptable. Representative FFPE tissue samples will be collected from the primary tumor and/or any 
previous metastatic tissue specimens, so that further analysis may be performed on that/those tissue 
sample(s) as appropriate. The samples will be received, processed and centrally analysed by the 
Department of Pathology of Fondazione IRCCS Istituto Nazionale dei Tumori. 
Analysis on biomarkers is exploratory by nature and will be performed retrospectively after the main study 
analysis is completed. Tissue received in excess to that required by this study will be returned to the 
histopathology department from where it was originally requested.  Tumor tissue (archival or recently 
biopsied) obtained at enrollment will be used to explore potentially pathway components or modulators 
associated with the mechanism of action of the chemo-immunotherapy combination as predictive 
biomarkers.  
 
• Blood immunophenotype 
PBMCs and plasma will be obtained from fresh blood of patients at baseline (before treatment initiation), 
at the first radiological evaluation and at the end of treatment. The samples will be processed locally in 
each center and subsequently collected and centrally analyzed at Fondazione IRCCS Istituto Nazionale 
dei Tumori. We will perform multiparametric flow cytometry analysis. PBMCs from patients will be 
stained with HLA-DR, CD14, CD16, CD15, CD66, c-kit and CD33 antibodies to define the subsets of 
myeloid-derived suppressor cells. CD8+ and CD4+ T cell frequency will be calculated on the whole 
CD45+/CD3+ lymphocytes. CD4+ T cell will be characterized with different Abs including CD127, 
CD25, FOXP3, CTLA-4, OX40, ICOS, PD-1, CD45RA, CCR10, CCR7, CCR4, CCR6, CXCR5, Ki67, 
IL-17, IFN-g and IL-10. In addition, we will investigate the expression of co-stimulatory and co-inhibitory 
molecules such as OX40, ICOS, CD69, CTLA-4, PD-1, TIM3 and LAG3.  
 
7.1.6 Other Procedures 
7.1.6.1 Discontinuation and withdrawal 
Participants who discontinue study intervention prior to completion of the treatment period should be 
encouraged to continue to be followed for all remaining study visits as outlined in the SoA and Section 
7.2. 
Participants who withdraw from the study should be encouraged to complete all applicable activities 
scheduled for the final study visit at the time of withdrawal. Any AEs that are present at the time of 
withdrawal should be followed in accordance with the safety requirements outlined in Section 7.2. 

 
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7.1.7 Visit Requirements 
Visit requirements are outlined in Section 5.3 – Schedule of Activities. Specific procedure-related details 
are provided above in Section 7.1 - Trial Procedures. 
7.1.7.1 
Screening 
7.1.7.1.1 
Screening Period 
Approximately 28 days prior to allocation, potential subjects will be evaluated to determine that they fulfill 
the entry requirements as set forth in Section 6.1. Written consent must be obtained prior to performing 
any protocol specific procedure. Screening procedures (i.e., vital signs and full physical exam) and results 
of a test performed prior to the subject signing consent as part of routine clinical management are 
acceptable in lieu of a screening test if performed within the specified time frame. Screening procedures 
are to be completed within 28 days prior to the first dose of trial treatment except for the following: 
• Laboratory tests are to be performed within 10 days prior to the first dose of trial treatment. 
• For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior 
to first dose of trial treatment. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test, performed by the local study site laboratory, will be required. 
• Tumor imaging must be performed within 28 days prior to the first dose of trial treatment. 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. Results from 
assessments performed during the initial screening period are acceptable in lieu of repeating a screening 
test if performed within the specified time frame and the results meet the inclusion/exclusion criteria. 
7.1.7.2 
Treatment Period 
Visit requirements are outlined in Section 5.3. Specific procedure-related details are provided above in 
Section 7 – Trial assessment and procedures. 
7.1.7.3 
Post-Treatment Visits 
Subjects will be followed for up to 2 years. If the subject experienced a CR, PR, or SD during the 
Treatment Phase on pembrolizumab, and then experiences PD at any time during that two year follow-up 
period, he/she will be eligible to receive up to 12 months of therapy with pembrolizumab in the Second 
Course Phase according to the criteria in Section 6.2.8. After the Second Course Phase, subjects should 
be followed for up to two years, with no option for retreatment with pembrolizumab on study. Subjects 
who discontinue trial treatment for a reason other than disease progression will still be considered as on 
study and should continue with regularly scheduled assessments  including collecting subject information 
on the start of new antineoplastic therapy, disease progression, and death. 

 
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7.1.7.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of 
study intervention or before the initiation of a new anti-cancer treatment, whichever comes first.  
Participants who are eligible for retreatment with pembrolizumab (as described in Section 6.2.8) may have 
up to two safety follow-up visits, one after the Initial Treatment Period and one after the Second Course 
Treatment. 
7.1.7.3.2 Efficacy Follow-up Visits 
Participants who complete the protocol-required cycles of study intervention of who discontinue study 
intervention for a reason other than disease progression will begin the Efficacy Follow-Up Phase and 
should be assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease status.  After 1 
year, the imaging time point will occur every 12 weeks (± 7 days). Every effort should be made to collect 
information regarding disease status until the start of new anti-cancer therapy, disease progression, death, 
end of the study or if the participant begins retreatment with pembrolizumab . Information regarding post-
study anti-cancer treatment will be collected if new treatment is initiated.  Participants who completed all 
efficacy assessments and/or will  not have further efficacy assessments must enter the Survival Follow-up 
Phase. 
Participants who are eligible to receive retreatment with pembrolizumab according to the criteria in 
Section 6.2.8 will move from the Efficacy Follow-up Phase to the Second Course Phase when they 
experience disease progression.  Details are provided in the SoA (Section 5.3) for retreatment with 
pembrolizumab. 
7.1.7.3.3 Survival Follow-up Contacts 
Participant survival follow-up status will be assessed approximately every 12 weeks by visit or by 
telephone contact,  to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
The first survival follow-up assessment should be scheduled as described below: 
• For participants who discontinue treatment intervention and who will not enter the Efficacy 
Follow-up Phase, the first survival follow-up contact will be scheduled 12 weeks after the 
discontinuation visit and/or safety follow-up visit (whichever is last). 
7.2 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing causality 
of AE and SAE and the procedures for completing and transmitting AE, SAE, and other reportable safety 
event reports can be found in Appendix 5.   
Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 

 
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The investigator and any designees are responsible for detecting, documenting, and reporting events that 
meet the definition of an AE or SAE as well as other reportable safety events. Investigators remain 
responsible for following up AEs, SAEs, and other reportable safety events for outcome, for 90 days after 
EOT. 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE or 
SAE as well as other reportable safety events with respect to seriousness, intensity/toxicity and causality. 
7.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but before 
intervention allocation must be reported by the investigator if the event cause the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, or a procedure. 
• All AEs from the time of intervention allocation through 30 days following cessation of study 
intervention must be reported by the investigator. 
• All AEs meeting serious criteria, from the time of intervention allocation through 90 days 
following cessation of study intervention or 30 days following cessation of study intervention if 
the participant initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator. 
• All pregnancies and exposure during breastfeeding, from the time of intervention allocation 
through 120 days following cessation of study intervention, or 30 days following cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by the 
investigator. 
• Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately if the event is considered drug-related. 
 
All initial and follow-up SAEs and other reportable safety events occurring in all centers participating in 
the clinical trial, will be recorded and reported to the Promoter's Pharmacovigilance 
(farmacovigilanza.studispontanei@istitutotumori.mi.it) within the time frames as indicated in Table 
9. The Promoter will inform MSD about SAEs that occurred during the study. 
Table 9. Reporting Time Periods and Time Frames for Adverse Events and Other Reportable Safety 
Events 
Type of Event 
Reporting Time 
Period: 
Consent to 
Allocation 
Reporting Time 
Period: 
Allocation 
through Protocol-
specified Follow-
up Period 
Reporting Time Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame to Report 
Event and Follow-up 
Information to 
Promoter’s 
Phamacovigilance: 
Serious Adverse 
Event (SAE) 
Report if: 
- due to protocol-
Report all 
Report if: 
- drug/vaccine related. 
Within 2 business days 
but no longer than 3 

 
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Type of Event 
Reporting Time 
Period: 
Consent to 
Allocation 
Reporting Time 
Period: 
Allocation 
through Protocol-
specified Follow-
up Period 
Reporting Time Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame to Report 
Event and Follow-up 
Information to 
Promoter’s 
Phamacovigilance: 
including Cancer 
and Overdose 
specified intervention 
- causes exclusion 
- participant is 
receiving placebo 
run-in or other run-in 
treatment 
(Follow ongoing to 
outcome) 
calendar days of learning 
of event 
Pregnancy/Lactation 
Exposure 
Report if: 
- due to intervention 
- causes exclusion 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 2 business days 
but no longer than 3 
calendar days of learning 
of event 
Event of Clinical 
Interest (require 
regulatory 
reporting) 
Report if: 
- due to intervention 
- causes exclusion 
Report 
- potential drug-
induced liver 
injury (DILI) 
- require regulatory 
reporting 
Not required 
Within 2 business days 
but no longer than 3 
calendar days of learning 
of event 
 
7.2.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable safety 
events. Open-ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrence. 
7.2.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs, SAEs, and other reportable safety events including pregnancy and 
exposure during breastfeeding, events of clinical interest (ECIs), cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost to follow-
up.. In addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
allocated or randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 5. 
7.2.4 Sponsor Responsibility for Reporting Adverse Events  
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable country specific regulatory requirements, global laws and regulations.  

 
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7.2.5 Pregnancy and Exposure During Breastfeeding 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any pregnancy or 
infant exposure during breastfeeding in a participant (spontaneously reported to the investigator or their 
designee) that occurs during the study are reportable to the Promoter. 
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. 
7.2.6 Events of Clinical Interest (ECIs) 
Selected nonserious and SAEs are also known as ECIs and must be reported to Promoter's 
Pharmacovigilance. The Promoter will inform MSD about selected nonserious and SAEs that occurred 
during the study. 
Events of clinical interest for this study include:  
1. 
An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results. For purposes of this study, 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. In the event of overdose, the participant 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 
MSD product, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met. 
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.  
7.3 
Suspected unexpected serious adverse reactions (SUSARs)  
Unexpected adverse reactions are SUSARs if the following three conditions are met:  
 
• The event must be serious;  
 

 
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• There must be a certain degree of probability that the event is a harmful and an undesirable 
reaction to the medicinal product under investigation, regardless of the administered dose;  
 
• The adverse reaction must be unexpected, that is to say, the nature and severity of the adverse 
reaction are not in agreement with the product information as recorded in the reference safety 
information. 
7.3.1 Reporting of SUSARs by the sponsor to the EudraVigilance database  
The sponsor will keep detailed records of all AEs which are reported to him/her by the investigator or 
investigators (CTR: Article 41(3)).  
 
The sponsor will report electronically and without delay to EudraVigilance database all relevant 
information about any SUSAR (CTR: Article 42).  
 
The period for the reporting of SUSARs by the sponsor to EudraVigilance will take account of the 
seriousness of the reaction and will be as follows:  
 
• In the case of fatal or life-threatening SUSARs, as soon as possible and in any event not later 
than 7 days after the sponsor became aware of the reaction (CTR: Article 42(2(a)));  
 
• In the case of non-fatal or non-life-threatening SUSARs, not later than 15 days after the sponsor 
became aware of the reaction (CTR: Article 42(2(b)));  
 
• In the case of a SUSARs which was initially considered to be non-fatal or nonlife threatening but 
which turns out to be fatal or life-threatening, as soon as possible and in any event not later than 
7 days after the sponsor became aware of the reaction being fatal or life-threatening (CTR: 
Article 42(2(c))).  
 
Where necessary to ensure timely reporting, the sponsor may, in accordance with section 2.4 of Annex 
III, submit an initial incomplete report followed up by a complete report (CTR: Article 42(2)). 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 Statistical Analysis Plan Summary 
Objective Response Rate (ORR) according to RECIST 1.1 will be the primary endpoint. A minimax 
Simon two-stage design will be applied. Assuming an unsatisfactory ORR of 56%, a valuable ORR of 
71%, 24 and 11 patients will be enrolled in the first and second stage, respectively (total number of 
patients: 35, one-sided alpha: 0.15, power: 0.78). If complete or partial response is assessed in at least 15 
patients in the first stage, the second stage will be started, otherwise the study will be closed, and study 
failure declared. If complete or partial response is assessed in at least 23 patients at the end of the second 
stage, the experimental treatment will be considered promising and worthy of further investigation. 
Sample size and minimax thresholds were calculated using R version 4.1.0 (R Core Team, 2021) and the 

 
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clinfun version 1.0.15 package [Venkatraman E. Seshan (2018). clinfun: Clinical Trial Design and Data 
Analysis Functions. R package version 1.0.15. https://CRAN.R-project.org/package=clinfun] in R 
statistical software. 
8.2 Statistical Analysis Plan 
Only eligible patients who receive at least one dose of experimental treatment will be considered for the 
primary analysis. A consecutive enrollment of eligible patients will be performed in order to better control 
selection bias in this single arm study. Number and reasons of participation failure from consecutive 
enrollment will be collected by center and reported in a flow-chart. Consecutive enrollment will not be 
interrupted between the first and second stage. Study enrollment will be interrupted in the following cases: 
- 
study failure could be prematurely declared 
- 
the planned number of patients with an assessed objective tumor response has been enrolled.   
In case of success at the end of the second stage, according to the chosen type I error probability (i.e. the 
probability of incorrectly rejecting the null hypothesis), an exact one-sided 85%CI will be estimated for 
the primary endpoint. Objective response and disease control rates will be evaluated with point estimates 
and 95% CIs on the basis of the exact binomial method. Treatment administration will be summarized by 
starting dose, number of cycles, number, type and reason of dose modification and dose intensity. Protocol 
violations of treatment administration and reasons for ending treatment will be summarized too. Type of 
adverse events and SAE will be tabulated using the last updated MedDRA dictionary. For each type of 
AE and SAE, the maximum grade observed in each patient will be used as summary statistic. For time-
to-event endpoints the median and interquartile range of follow-up will be estimated using the reverse 
Kaplan-Meier estimator. The survival function will be estimated using the Kaplan-Meier estimator. The 
95%CI of median survival times will be estimated using the robust non-parametric method due to 
Brookmeyer and Crowley [Brookmeyer, R. and Crowley, J. (1982), "A Confidence Interval for the Median 
Survival Time," Biometrics, 38, 29-41]. Participant flow through the trial, baseline characteristics and 
adverse events will be summarized by non-parametric descriptive statistics (i.e. absolute and percentage 
frequencies for categorical variables and median and range for continuous variables). Data will be 
analyzed using SAS version 9.4 (SAS Institute, Cary, NC). 
 

 
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9.0 ETHICAL CONSIDERATIONS 
9.1 
Compliance with law and regulation  
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical Practice 
and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. 
 
9.2 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and    Competent 
Authority (CA) 
Before initiating the trial, the Investigators must obtain a written favourable opinion from the IRB/IEC 
and CA for the study protocol, the written informed consent form, the subject recruitment procedures and 
any other written information to be provided to subjects. All the correspondence with the IRB/IEC and 
CA must be retained in the Investigator File. 
 
9.3 
Informed consent 
The Sponsor's Informed Consent Form (and ancillary sample Informed Consent Forms (if applicable) will 
be provided to each site. The Sponsor or its designee must review and approve any proposed deviations 
from the Sponsor's Informed Consent Forms or any alternate consent forms proposed by the site before 
IRB/EC submission.  The final IRB/EC−approved Consent Forms must be provided to the Sponsor for 
health authority submission purposes according to local requirements. The investigator or authorized 
designee will explain to each patient the objectives, methods, and potential risks associated with each 
optional procedure. Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason. 
The Consent Forms must be signed and dated by the patient or the patient's legally authorized 
representative before his or her participation in the study. The case history or clinical records for each 
patient shall document the informed consent process and that written informed consent was obtained prior 
to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient. 
Patients must be re-consented to the most current version of the Consent Forms (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/EC policy) during their 
participation in the study. For any updated or revised Consent Forms, the case history or clinical records 
for each patient shall document the informed consent process and that written informed consent was 
obtained using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's legally authorized 
representative. All signed and dated Consent Forms must remain in each patient's study file or in the site 
file and must be available for verification by study monitors at any time 
 
9.4 
Confidentiality and Privacy 
All information provided to the Investigator by the Sponsor, information produced during the clinical trial 
including, but not limited to the protocol, e-CRF, IB, and the results obtained during the course of the trial 
is confidential. The members of the research team agree not to discuss such information in any way 

 
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without prior written permission from the Sponsor. Subject names will remain confidential and will not 
be supplied to the Sponsor. The subject’s personal data, i.e. name and contact information and date of 
birth will be replaced by a code (so called pseudonymized). The Investigator will maintain a personal 
subject identification list (subject and treatment numbers with the corresponding subject names) to enable 
records to be identified. The ICF will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy legislation. 
Patients will give explicit permission for the Sponsor or its designee, regulatory authorities, and the 
relevant IRB/IEC  to inspect their medical records to verify the information collected. Patients will be 
informed that all personal information made available for inspection will be handled in the strictest 
confidence and in accordance with local data protection/privacy laws.  
 
9.5 
Financial disclosure 
Investigators will provide sufficient, accurate financial information in accordance with local regulations 
to allow the Sponsor to submit complete and accurate financial certification or disclosure statements to 
the appropriate health authorities.  
 
9.6 
Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator, there is sufficient 
reasonable cause. Written notification documenting the reason for study termination will be provided to 
the investigator by the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend or discontinue the development of the drug 
 
10.0 DATA MANAGEMENT 
10.1 Data Quality Assurance 
The Sponsor will be responsible for data management of this study, including quality check of the data. 
Data will be collected through use of electronic case report for (e-CRFs). Sites will be responsible for data 
entry into the e-CRFs. 
e-CRFs and correction documentation will be maintained in the CRF system's audit trail. 
System backups for data stored by the sponsor and records retention for the study data will be consistent 
with the sponsor's standard procedures. 
 
10.2 Electronic case report forms   
Sites will receive training for appropriate e-CRF use. All e-CRFs should be completed by designated, 
trained site staff. e-CRFs should be reviewed and electronically signed and dated by the investigator. At 

 
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the end of the study, the investigator will receive patient data for his or her site in a readable format that 
must be kept with the study records. Acknowledgement of receipt of the data is required. 
 
10.3 Source data documentation  
Source documents (paper or electronic) are those in which patient data are recorded and documented for 
the first time. They include, but are not limited to, hospital records, clinical and office charts, laboratory 
notes, memoranda, patient-reported outcomes, checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media,  X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be defined.  
Source documents that are required to verify the validity and completeness of data entered into the e-CRFs 
must not be obliterated or destroyed and must be retained per the policy for retention of records. 
To facilitate source data verification and review, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related monitoring, Sponsor 
audits, and IRB/EC review. The study site must also allow inspection by applicable health authorities. 
 
 
 
11.0 QUALITY CONTROL 
11.1 Responsibilities of the investigators 
The Investigators undertake to perform the study in accordance with Good Clinical Practice. The 
Investigator is required to ensure his compliance to the procedures required by the protocol with respect 
to the investigational drug schedule and visit schedule. The Investigator agrees to provide all information 
requested in the Case Report Form in an accurate and legible manner according to the instructions 
provided. The Investigator has responsibilities to take all reasonable steps to ensure the proper conduct of 
the study as regards ethics, protocol adherence, integrity and validity of the data recorded on the case 
report forms. 
 
11.2 Study Monitoring  
Monitoring activities will be done in order to verify that the data are authentic, accurate, and complete; 
that the safety and rights of the subject are being protected; and that the study is conducted in accordance 
with the currently approved protocol, GCP, and all applicable regulatory requirements. At regular intervals 
during the study, the center will be contacted by a representative of the Sponsor (internal and/or external 
staff authorized and duly appointed by the Sponsor), through site visits and/or remote visit and/ or 
telephone calls, to review the study progress, the investigators and subjects’ adherence to protocol 
requirements.  
 
The following points will be scrutinized:  
• subject informed consent 
• subject recruitment and follow-up 

 
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• study drug allocation  
• subject compliance to the study treatment 
• study treatment accountability  
• Adverse Event documentation and reporting 
According to the guidelines on ICH Good Clinical Practice, the monitor of the study will check the case 
report form entries against the source documents.  
 
Data will be collected by e-CRF and data will be systematically checked by representative of the Sponsor 
(internal and/or external staff authorized and duly appointed by the Sponsor) for consistency, 
completeness and accuracy. 
 
11.3 Retention of Records 
Records and documents pertaining to the conduct of this study, including e-CRFs, ICFs, Investigator Site 
File (ISF) must be retained by the Principal Investigator for at least 25 years after completion or 
discontinuation of the study, or for the length of time required by relevant national or local health 
authorities, whichever is longer. After that period, the documents may be destroyed, according to local 
regulations.  
 
11.4 Site Discontinuation (if applicable): 
The Sponsor has the right to close a site at any time.  
Reasons for closing a site may include, but are not limited to, the following: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with the International Council for Harmonisation (ICH) guideline for Good 
Clinical Practice 
• No study activity (i.e., all patients have completed the study and all obligations have been fulfilled 
 
12.0 STUDY CONDUCTION 
12.1 Administrative Structure 
This trial will be sponsored by Fondazione IRCCS Istituto Nazionale dei Tumori di Milano. 
The Sponsor will provide clinical operations oversight, data management, and medical monitoring. 
3 National Cancer Centers will participate to enroll approximately 35 patients.  
Central facilities will be used for certain study assessments throughout the study (e.g., specified laboratory 
tests, biomarker and PK analyses).. 
As mandatory inclusion criteria, the tissue submitted will be used to assess exploratory biomarkers. The 
tissue submitted should be a formalin-fixed, paraffin-embedded (FFPE) tumor specimen or 20 serial, 
freshly cut, unstained slides accompanied by an associated pathology report. Cytological samples are not 
acceptable. Representative FFPE tissue samples will be collected from the primary tumor and/or any 
previous metastatic tissue specimens, so that further analysis may be performed on that/those tissue 

 
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sample(s) as appropriate. The samples will be received, processed and centrally analysed by the 
Department of Pathology of Fondazione IRCCS Istituto Nazionale dei Tumori under the responsibility of 
Dr. Massimo Milione, Director of Pathology Division 1. Tissue received in excess to that required by this 
study will be returned to the histopathology department from where it was originally requested. For 
information on tumor tissue assessments see the section 3.2.3.2. 
 
To longitudinally monitor the frequency and the phenotype of circulating immune cells at baseline and 
during treatment, we will perform multiparametric flow cytometry analysis on peripheral blood. 
The blood samples collected will be sent to the Promoter and processed and centrally analysed by the 
Experimental Oncology And Molecular Medicine Department of Fondazione IRCCS Istituto Nazionale 
dei Tumori under the responsibility of Dr.ssa Roberta Mortarini. 
 
12.2 Training of study site personnel 
The Principal Investigator will ensure that appropriate training relevant to the study is given to all 
investigational staff, and that any new information relevant to the performance of this study is forwarded 
to the staff involved. 
 
12.3 Study timetable and end of study 
The duration of the study is expected to be a maximum of 48 months. The study recruitment period is 
expected to be approximately 24 months. The end of the study is defined as the conclusion of survival 
follow-up. The survival follow-up will continue until 6 months after the last subject receives the last dose. 
 
The study is expected to start in Oct 2023  and patient enrollment should be completed by September 
2027 . The study may terminate prematurely if concerns for safety arise. All patients will receive follow-
up care in accordance with standard local clinical practice.  
Any SAE or non-serious AE that is ongoing at the time of this data cut-off must be followed up to 
resolution unless the event is considered unlikely to resolve by the investigator, or the patient is lost to 
follow-up.  
 
 
12.4 Data Handling 
According to the ICH Guidelines on Good Clinical Practice the sponsor of a study is the owner of the data 
resulting there from. All centers and investigators participating in the study should be made aware of such 
circumstance and invited not to disseminate information or data without the Institution’s prior express 
consent. Source documents are where data is first recorded. These include, but are not limited to, hospital 
records, clinical and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, and 
correspondence. Direct access to source data will be granted to authorized representatives to permit trial-
related monitoring, audits and inspections. Data Management will be carried out by Clinical Trial Center 
of Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133, Milan, Italy. 
 

 
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12.5 Data Breach Management 
In case of a data breach, the Data Protection Officer (DPO) and the legal team of the National Cancer 
Institute must be informed of all personal data breaches as soon as possible. 
12.5.1 Management of data breaches occurring within the Promoter or Data Owner's facility. 
To manage a personal data breach, the following six steps, two of which are optional, need to be followed: 
• Reporting; 
• Preliminary investigation, risk assessment, response & recovery; 
• Notification to the Supervisory Authority (if applicable); 
• Communication to the affected parties (if applicable); 
• Documentation of the breach. 
The Data Protection Officer (DPO) must record the breaches and collaborate with the responsible clinical 
data member (the "data owner") to assess the likely impact of the breach. A breach is considered notifiable 
unless it is unlikely to result in a risk to the rights and freedoms of individuals. 
The notification should include the nature of the personal data breach, including, where possible: the 
approximate number of data subjects affected, and the approximate number of personal data records 
involved. 
12.5.2 Data breach at third-party data processors acting on behalf of the Foundation. 
During the contractual phase of acquiring services and/or technologies involving data processing on behalf 
of the Data Owner, the Foundation has appointed suppliers, individuals, or legal entities as data processors 
(Article 28 GDPR). As soon as the Data Processor becomes aware of a data breach within its organization, 
or the Data Processor becomes aware of a potential breach involving personal data for which the 
Foundation is the data controller, the breach must be reported following the instructions specified in the 
appointment agreement. The communication includes the relevant documentation to enable the 
Foundation to report the breach to the Supervisory Authority, if necessary, and to inform the affected 
parties if required. 
If the Foundation is the data controller for sensitive data and becomes aware of a breach, it must inform 
the Data Owner without undue delay, through the Data Protection Officer (DPO), in accordance with the 
instructions received in the appointment agreement. If precise instructions have not been provided, INT 
undertakes to inform the Data Owner of the data breach, providing all necessary information for 
evaluation, within 24 hours of becoming aware of the breach. 
In the event of difficulties with computer systems or computer crashes, internal procedures within the 
Foundation may also be conducted in writing. The notification to the Supervisory Authority is exclusively 
carried out online; therefore, in the event of email service issues, an alternative email address will be used 
by INT to minimize communication delays. 
Written communication with the affected individual may be conducted via postal mail. 
 

 
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12.6 Publication of Data 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and as required 
in EudraCT.  
This trial is intended for publication, even if terminated prematurely. Publication may include any or all 
of the following: posting of a synopsis online, abstract and/or presentation at a scientific conference, or 
publication of a full manuscript. In addition, after study completion and finalization of the study report, 
results of this trial will be submitted for publication and posted in a publicly accessible database of clinical 
trial results, as well as in Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.) 
 
12.7 FINANCING AND INSURANCE 
Financing is addressed in a separate agreement. 
Sponsor as a holder of the insurance policy will cover the liability to all subjects in the case of any study 
related injury or death and provide indemnity for the Clinical Investigators, except for claims resulting 
from malpractice and/or negligence.  
 
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cancers among persons with AIDS in the United States. AIDS. 2009  

 
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21.  
Lanoy E, Costagliola D, Engels EA. Skin cancers associated with HIV infection and 
solid-organ transplantation among elderly adults. Int J Cancer. 2010  
22.  
Becker JC. Merkel cell carcinoma. Ann Onc 2010; Oct;21 Suppl 7:vii81-5 
23.  
Fields RC, Busam K J, Chou J F, Panageas KS, Pulitzer MP, Allen PJ, Kraus DH, Brady 
MS, Coit DG. Recurrence after complete resection and selective use of adjuvant therapy 
for stage I through III Merkel cell carcinoma. Cancer 2012 Jul 1;118(13):3311-20. 
24.  
Lebbe C, Becker JC, Grob JJ,  et al. Diagnosis and treatment of Merkel Cell Carcinoma. 
European consensus-based interdisciplinary 
guideline. Eur J Cancer 2015; 
Nov;51(16):2396-403. 
25.  
Nghiem P, Kaufman HL, Bharmal M, et al. Systematic literature review of efficacy, 
safety and tolerability outcomes of chemotherapy regimens in patients with metastatic 
Merkel cell carcinoma. Future Oncol. 2017. 
26.  
Nghiem PT, Bhatia S, Lipson E J. PD-1 Blockade with Pembrolizumab in Advanced 
Merkel-Cell Carcinoma. N Engl J Med 2016; 374(26):2542-52. 
27.  
Kaufman HL, Russell J, Hamid O, et al. Avelumab in patient with chemotherapy-
refractory metastatic Merkel cell carcinoma: a multicenter, single-group, open-label, 
phase 2 trail. Lancet Oncol 2016.  
28.  
D'Angelo SP, Russell J, Lebbé C, et al. Efficacy and Safety of First-line Avelumab 
Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned 
Interim Analysis of a Clinical Trial. JAMA Oncol. 2018. 
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NCCN Guidelines 2021. 
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Mittal D, Gubin MM, Schreiber RD, et al. New insights into cancer immunoediting and 
its three component phases—elimination, equilibrium, and escape. Curr Opin Immunol 
2014 
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Pardoll DM. The blockade of immune checkpoints in cancer therapy. Nat Rev Cancer 
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32.  
Motz GT, Coukos G. Deciphering and reversing tumor immune suppression, Immunity 
2013. 
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Krysko DV, Garg AD, Kaczmarek A. Immunogenic cell death and DAMPs in cancer 
therapy. Nat. Rev. Cancer 2012. 
34.  
Galluzzi L, Buqué A, Kepp O et al. Immunogenic cell death in cancer and infectious 
disease, Nat. Rev. Immunol. 2017 

 
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35.  
Galluzzi L, Senovilla L, Zitvogel L, et al. The secret ally: immunostimulation by 
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Gomez GG, Hutchison RB, Kruse CA. Chemo-immunotherapy and chemo- adoptive 
immunotherapy of cancer. Cancer Treat. Rev. 2001. 
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Hato SV, Khong A, de Vries IJM et al. Molecular pathways: the immunogenic effects of 
platinum-based chemotherapeutics. Clin Cancer Res 2014; 20(11):2831-7. 
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Gandhi L, Rodríguez-Abreu D, Gadgeel S et al. Pembrolizumab plus Chemotherapy in 
Metastatic Non–Small-Cell Lung Cancer. N Engl J Med 2018; 378:2078-2092 
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Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or Placebo Plus Etoposide and 
Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: 
Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol. 2020 
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Venkatraman E. Seshan (2018). clinfun: Clinical Trial Design and Data Analysis 
Functions. R package version 1.0.15. https://CRAN.R-project.org/package=clinfun 
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Brookmeyer, R. and Crowley, J. (1982), "A Confidence Interval for the Median Survival 
Time," Biometrics, 38, 29-41 
42.  
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet 
Oncol. 2017;18(3):e143-e152. Epub 2017 Mar 2. 
43.  
Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or Placebo Plus Etoposide and 
Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: 
Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol. 2020 
44.  
D. Lgs. n. 200 del 6.11.2007 “Attuazione della direttiva 2005/28/CE recante principi e 
linee guida dettagliate per la buona pratica clinica relativa ai medicinali in fase di 
sperimentazione a uso umano, nonche' requisiti per l'autorizzazione alla fabbricazione o 
importazione di tali medicinali”, G.U. n. 261 del 09.11.07, Supplemento ordinario n. 228 
45.  
ICH Gudeline for Good Clinical Practice E6 (R2) 14.06.2017 
46.  
REGOLAMENTO (UE) N. 536/2014 DEL PARLAMENTO EUROPEO E DEL 
CONSIGLIO del 16 aprile 2014 sulla sperimentazione clinica di medicinali per uso 
umano e che abroga la direttiva 2001/20/CE 

 
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47.  
Regolamento generale per la protezione dei dati personali n. 2016/679 (General Data 
Protection Regulation o GDPR) 

 
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14.0 APPENDICES 
14.1 Appendix 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. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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14.2 Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 11 will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 6.1 of 
the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 11. Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Chemistry 
BUN 
Potassium 
AST/SGOT 
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above the 
ULN) 
 
Albumin 
Bicarbonate 
Chloride 
Phosphorous 
 
Creatinine 
Sodium 
ALT/SGPT 
Total Protein 
 
Glucose fasting 
Calcium 
Alkaline 
phosphatase 
 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
Testing 
• 
Highly sensitive serum or urine hCG pregnancy test (needed only for WOCBP) 
Other Screening 
Tests 
• 
HBsAg, and hepatitis C virus antibody 
 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; hCG=human chorionic gonadotropin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; 
ULN=upper limit of normal; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential 
 
The investigator (or medically qualified designee) must document their review of each laboratory safety 
report. 

 
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14.3 Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical records, 
medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
hormonal highly effective contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they agree to 
one of the following during the protocol defined time frame in section 6.1.1:  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long 
term and persistent basis) and agree to remain abstinent 
● Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year as 
described in Table 12 when having penile-vaginal intercourse with a woman of childbearing potential 
who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration. 
 
 

 
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Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 12 during the protocol-
defined time frame in Section 6.1.1. 
 
 
 
 
Table 12. Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
● Combined (estrogen- and progestogen- containing) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency . 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 

 
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a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least (120 days after last dose of pembrolizumab and 180 days after last dose of chemotherapy)  
corresponding to time needed to eliminate systemic exposure after the last dose of each study 
intervention.   
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use one of the 
contraception methods described in Table 14 consistently and correctly during the protocol-defined time 
frame in Section 6.1.1. 
Table 13 . Contraceptive Methods 
Acceptable Contraceptive Methods   
● Male or female condom with or without spermicide 
● Cervical cap, diaphragm or sponge with spermicide 
Highly Effective Contraceptive Methods That Are User Dependent a  
● Combined (estrogen- and progestogen- containing ) hormonal contraception b 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  

 
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Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least (120 days after last dose of pembrolizumab and 180 days after last dose of chemotherapy)  
corresponding to time needed to eliminate systemic exposure after the last dose of each study 
intervention.   
  
 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
 
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test and in 
accordance with local requirements.  When applicable this test should be repeated a maximum of 24-hours 
before the first dose/vaccination. Following initiation of treatment additional pregnancy testing will be 
performed at each cycle during the treatment period and should be conducted for the time required to 
eliminate systemic exposure after the last dose of each study intervention (120 days after last dose of 
pembrolizumab and 180 days after last dose of chemotherapy) and as required locally. 
14.4 Appendix 4:  Description of the iRECIST Process for Assessment of Disease Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. In 
participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide whether 
to continue a participant on study treatment until repeat imaging 4 to 8 weeks later is obtained (using 
iRECIST for participant management (see Table 8 and Figures  2).  This decision by the Investigator 
should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  

 
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• No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at site-assessed 
first radiologic evidence of PD and is not required to have repeat tumor imaging for confirmation of PD 
by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study treatment 
and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by iRECIST, per 
Investigator assessment.   
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and ≥ 5 mm 
from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD 
(confirmed progressive disease).  For purposes of iRECIST assessment, the first visit showing progression 
according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors 
caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds and rules 
as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 5 lesions total (up 
to 2 per organ), may be selected as New Lesions – Target.  The sum of diameters of these lesions will be 
calculated and kept distinct from the sum of diameters for target lesions at baseline.  All other new lesions 
will be followed qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an overall 
response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), 
or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occurs: 

 
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• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, compared 
to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared to a 
prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
▪ An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time point  
▪ Visible growth of new non-target lesions  
▪ The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which iUPD is 
seen.  This may correspond to the next visit in the original visit schedule.  The assessment of the 
subsequent confirmation scan proceeds in an identical manner, with possible outcomes of iCPD, iUPD, 
and iSD/iPR/iCR. 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR 
if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, whenever it 
occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response 
of iCPD can be assigned. 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule.  
If PD is confirmed, participants will be discontinued from study treatment. 

 
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NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment may be 
considered.  In this case, if study treatment is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Section 7. 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by any of the 
following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) either for 
the first time, or after resolution of previous pseudo-progression.  The nadir is always the 
smallest sum of diameters seen during the entire trial, either before or after an instance of 
pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this progression has not 
resolved, iUPD results from any significant further growth of non-target lesions, taken as a 
whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion sum of 
diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation 
process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression must be confirmed 
before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one respect. 
If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the burden of new lesions 
has increased from its smallest value (for new target lesions, their sum of diameters is ≥5 mm increased 
from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the 
new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication [Seymour et al, 2017]. 

 
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14.5 Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting 
Definition of AE 
• An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a study intervention. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. 
• For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term 
should reflect the clinical symptoms or abnormal test result. An overdose without any associated 
clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect.” 
     
Events NOT meeting the AE definition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 

 
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• Surgery planned prior to informed consent to treat a pre-existing condition that has not worsened. 
 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
• The term “life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
d. 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 an SAE.  
e. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
f. Is a congenital anomaly/birth defect 
• In offspring of participant taking the product regardless of time to diagnosis. 
g. Other important medical events 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. 
These events should usually be considered serious. 

 
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• Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
Recording AE and SAE 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory, and diagnostics reports) related to the event. 
• The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at each 
examination. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
Assessment of intensity/toxicity 
• An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, not when it is rated as severe. 
1. 
The investigator will make an assessment of intensity for each AE and SAE (and other reportable 
safety event) according to the NCI Common Terminology for Adverse Events (CTCAE), version 
5. Any AE that changes CTCAE grade over the course of a given episode will have each change 
of grade recorded on the AE CRFs/worksheets. 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
• Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• Grade 4: Life threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
Assessment of causality 
1. 
Did a product cause the AE? 

 
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2. 
The determination of the likelihood that a product caused the AE 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 product and the AE 
based upon the available information. 
3. 
The following components are to be used to assess the relationship between a product and the 
AE; the greater the correlation with the components and their respective elements (in number 
and/or intensity), the more likely product caused the AE: 
• Exposure: Is there evidence that the participant was actually exposed to a product such as: 
reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
• Time Course: Did the AE follow in a reasonable temporal sequence from administration of 
the product? Is the time of onset of the AE compatible with a drug-induced effect (applies to 
studies 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. 
• Dechallenge: Was the 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. 
 
• Rechallenge: Was the participant re-exposed to the 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. 
4. 
Consistency with study intervention profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding the product or drug class pharmacology or 
toxicology? 

 
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5. 
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. 
6. 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of the product relationship). 
• Yes, there is a reasonable possibility of the product relationship: 
• There is evidence of exposure to the product. The temporal sequence of the AE onset relative 
to the administration of the product is reasonable. The AE is more likely explained by the 
product than by another cause. 
• No, there is not a reasonable possibility of the product relationship: 
• Participant did not receive the product OR temporal sequence of the AE onset relative to 
administration of the product is not reasonable OR the AE is more likely explained by another 
cause than the  product. (Also entered for a participant with overdose without an associated 
AE.) 
7. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
8. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Promoter's Pharmacovigilance . However, it is very 
important that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to Promoter's Pharmacovigilance  .The Promoter will 
inform MSD about SAEs that occurred during the study. 
9. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
10. 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
11. 
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent of 
the combination. In general, causality attribution should be assigned to the combination regimen 
(ie, to all agents in the regimen). However, causality attribution may be assigned to a single agent 
if in the investigator’s opinion, there is sufficient data to support full attribution of the AE to the 
single agent. 
Follow-up of AE and SAE 

 
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• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.  
• New or updated information will be recorded in the CRF.  
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Promoter's 
Pharmacovigilance 
All serious adverse events occurring during the clinical study, in all centers participating, will be reported 
to the Pharmacovigilance Unit of the study sponsor Institution (Fondazione IRCCS Istituto Nazionale dei 
Tumori) by the Investigator or a delegate member of investigational staff, using the Serious Adverse Event 
Form, which must be signed by a member of the investigational staff,  within the time frames as indicated 
in Table 9, section 7.2.1. 
Pharmacovigilance e-mail: farmacovigilanza.studispontanei@istitutotumori.mi.it. 
The Promoter will inform MSD about SAEs that occurred during the study, according to the established 
deadlines.