Adjuvant Immunotherapy With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo After Complete Resection of High-risk Stage III Melanoma: A Randomized, Double- Blind Phase 3 Trial of the EORTC Melanoma Group
Phase: PHASE3
Conditions: Melanoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02362594 
Document Date: 
28-Feb-2018
Adjuvant immunotherapy with anti-PD-1 monoclonal 
antibodyPembrolizumab (MK-3475) versus placebo after 
complete resection of high-risk Stage III melanoma: A 
randomized, double-blind Phase 3 trial of the EORTC 
Melanoma Group

 
EORTC 
Avenue E. 
Mounierlaan 83/11 
Brussel 1200 
Bruxelles 
België – Belgique 
e-mail: eortc@eortc.be
www.eortc.org
EORTC Melanoma Group 
Adjuvant immunotherapy with anti-PD-1 monoclonal antibody Pembrolizumab 
(MK-3475) versus placebo after complete resection of high-risk Stage III 
melanoma: A randomized, double- blind Phase 3 trial of the EORTC Melanoma 
Group 
EORTC protocol 1325-MG/ KEYNOTE 054 
Sponsor: 
Merck protocol MK-3475-054-03 
EudraCT number 2014-004944-37 
(NCT02362594) 
Study Coordinator: 
Study Chair: 
EORTC Protocol 
versions 
Date of EORTC PRC 
approval/notification 
Final Protocol Version 
Approved by the Sponsor 
EORTC Amendment reference 
N° 
Classification 
Outline 
Amended 
April 29, 2014 
December 12, 2014 
n/a 
---- 
---- 
1.0 
December 17, 2014 
MK-3475-054-00 
---- 
---- 
2.0 
May 19, 2015 
n/a 
1 
Scientific 
2.1 
June 12, 2015 
n/a 
4 
Administrative 
3.0 
July 07, 2015 
MK-3475-054-01 
5 
Scientific 
4.0 
January 21, 2017 
n/a 
8 
Scientific 
5.0 
March 28, 2017 
n/a 
9 
Scientific 
6.0 
October 02, 2017 
MK-3475-054-02 
12 
Scientific 
7.0 
February 28, 2018 
MK-3475-054-03 
13 
Scientific 
EORTC v7.0/ MK-3475-054-03 
Copyright EORTC 2018
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Contact addresses 
Writing Committee: 
 
 
  
 
EORTC Headquarters Team, Brussels, Belgium. 
Study Coordinator:  
Study Chair: 
Merck Representative: 
 
 
 
Merck Research Laboratories  
Phone: 
 
 
 
 
Merck Research Laboratories 
Phone: 
 
 
 
 
Merck Research Laboratories  
Phone: 
 
 
Clinical Research 
Physician: 
Clinical Scientist: 
Project Manager: 
Data Manager: 
 
 
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Immunotherapy with anti-PD in stage III melanoma 
EORTC v7.0/MK-3475-054-03 
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Statistician: 
Pharmacovigilance 
Unit: 
CRO Representative: 
 
 
 
Covance Inc. 
210 Carnegie Center, New Jersey 
08540-6233 
Phone: 
 
 
 
 
 
 
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March 30th 2018 
 
 
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EORTC v7.0/MK-3475-054-03 
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Table of contents: 
 
Protocol summary 
16 
1 
Background and introduction 
28 
1.1 
Disease background information 
28 
1.1.1 Risk of relapse in patients with stage III melanoma 
28 
1.1.2 Surgical management of regional lymph nodes 
28 
1.1.3 Adjuvant Therapy in high risk melanoma patients 
29 
1.1.3.1 Adjuvant trials 
29 
1.1.3.1.1 Interferon-α trials 
29 
1.1.3.2 Adjuvant trial with anti-CTLA-4 monoclonal antibody ipilimumab 
30 
1.1.3.3 Summary of rationale for observation as comparator 
30 
1.2 
Rationale for trial proposal 
30 
1.2.1 Immunotherapy and melanoma 
30 
1.2.2 Immunomodulation and breaking immune tolerance 
31 
1.2.2.1 Recent developments with anti-CTLA4 and Anti-PD1/PDL1 immune 
checkpoint blockers 
31 
1.2.2.2 Durability of response: hall mark of immune checkpoint blockers 
31 
1.2.2.2.1 Combinations 
32 
1.2.3 Background data for anti-PD-1 and PD-L1 
32 
1.2.4 Pembrolizumab characteristics and clinical data overview 
33 
1.2.4.1 Non-Clinical Toxicology Summary of Results 
33 
1.2.4.2 Clinical development 
34 
1.2.4.2.1 Initial pembrolizumab clinical development 
34 
1.2.4.2.2 Pembrolizumab melanoma clinical trials 
35 
1.2.4.2.3 Relationship of response to pembrolizumab depends on PD-L1 
expression as evaluated by immunohistochemistry 
36 
1.2.4.2.4 Pembrolizumab clinical trials in non-melanoma indications 
37 
2 
Objectives of the trial 
38 
2.1 
Primary objective 
38 
2.2 
Secondary objectives 
38 
2.3 
Exploratory objectives 
38 
2.4 
End-points 
38 
 
 
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2.4.1 Primary endpoint 
39 
2.4.2 Secondary endpoints 
39 
2.4.3 Exploratory endpoints 
39 
3 
Patient selection criteria 
39 
3.1 
Registration- step 1 (ORTA Step 1) 
39 
3.2 
Central confirmation of PD-L1 expression - step 2 
40 
3.3 
Enrollment and Randomization - step 3 (ORTA Step 2) 
40 
4 
Trial Design 
44 
4.1 
Part 1: Adjuvant therapy 
44 
4.1.1 Multi step process for enrollment 
44 
4.1.1.1 Registration - step 1 (ORTA Step 1) 
45 
4.1.1.2 Central confirmation of PD-L1 expression- step 2 
45 
4.1.1.3 Enrollment and Randomization - step 3 (ORTA Step 2) 
45 
4.1.2 Sample size and stratification factors 
46 
4.2 
Part 2: after the first recurrence (Cross-over or Re-challenge treatment) 
47 
4.2.1 Crossover for patients in the placebo arm with documented recurrence 
47 
4.2.1.1 Crossover qualifications 
47 
4.2.1.2 Crossover Assessments and Procedures 
48 
4.2.2 Rechallenge for patients in the pembrolizumab arm with documented recurrence 
>6 months after completion of one year of adjuvant therapy 
48 
4.2.2.1 Rechallenge qualifications 
48 
4.2.2.2 Rechallenge Assessments and Procedures 
48 
4.3 
Unblinding data 
49 
5 
Therapeutic regimens, expected toxicity, dose modifications 
50 
5.1 
Placebo 
50 
5.2 
Pembrolizumab (MK-3475) 
50 
5.2.1 Selected dose 
50 
5.3 
Drug supply 
50 
5.3.1 Placebo 
51 
5.3.2 Pembrolizumab 
51 
5.3.2.1 Initial drug supply 
51 
5.3.2.2 Drug resupply by IVRS 
51 
5.3.3 Packaging, labeling, handling and storage 
51 
5.3.3.1 Packaging 
51 
5.3.3.2 Labeling 
51 
 
 
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5.3.3.3 Dosage and Administration 
51 
5.3.3.4 Storage 
51 
5.3.4 Drug accountability 
52 
5.3.5 Return of investigational product 
52 
5.3.6 Destruction of investigational product 
52 
5.3.7 Standard Policies 
52 
5.4 
Treatment schedule 
53 
5.4.1 Part 1: Adjuvant therapy schedule, duration and withdrawal 
53 
5.4.1.1 Adjuvant treatment duration 
53 
5.4.1.2 Withdrawal criteria for Part 1 adjuvant treatment 
53 
5.4.2 Part 2: After the First Recurrence (Cross-over or Re-challenge treatment) 
54 
5.4.2.1 Crossover from placebo to pembrolizumab 
54 
5.4.2.2 Administration of pembrolizumab after the first recurrence (Re-challenge)55 
5.4.2.3 Treatment duration for pembrolizumab 
55 
5.4.2.4 Withdrawal criteria for Part 2 treatment (Cross-over or Re-challenge 
treatment) 
55 
5.5 
Management of Toxicity 
56 
5.6 
Concomitant medications 
56 
5.6.1 Prohibited medications, therapies and procedures 
56 
6 
Clinical evaluation, laboratory tests and follow-up 
57 
6.1 
General considerations 
57 
6.1.1 Subject Identification Card 
57 
6.2 
Before treatment start 
57 
6.2.1 Within 8 weeks prior to randomization 
57 
6.2.2 Within 6 weeks prior to randomization 
58 
6.2.3 Within 14 days (+/- 3 days) prior to treatment initiation 
58 
6.2.4 Within 72 hours prior to treatment initiation 
59 
6.2.5 Within 24 hours prior to treatment initiation 
59 
6.3 
During treatment 
59 
6.3.1 Part 1: Adjuvant Therapy 
59 
6.3.1.1 Every 6 weeks (+/- 3 days) 
60 
6.3.1.2 Every 12 weeks (+/- 7 days) 
60 
6.3.2 Translational research 
61 
6.3.3 Pharmacokinetic and anti-pembrolizumab antibody 
61 
6.3.4 End of adjuvant treatment (Part 1) 
61 
 
 
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6.3.4.1 Discontinuation due to recurrence 
61 
6.3.4.2 Discontinuation in absence of recurrence 
62 
6.3.4.2.1 Treatment discontinuation due to adverse event or ECI 
63 
6.3.4.2.2 Treatment discontinuation due to patient's decision 
63 
6.3.4.3 HRQoL evaluation 
63 
6.3.4.4 Translational research 
63 
6.3.4.5 Pharmacokinetic and anti-pembrolizumab antibody 
63 
6.3.5 Follow-up (after end of adjuvant treatment - Part 1) 
63 
6.3.5.1 For patients who discontinued treatment due to recurrence but are not 
eligible for re-challenge or cross-over 
64 
6.3.5.2 For patients who discontinued due to patient's decision and are not eligible 
for re-challenge or cross-over 
64 
6.3.5.3 For patients who discontinued in absence of recurrence 
64 
6.3.6 Part 2: cross-over or re-challenge treatment after the 1st recurrence 
65 
6.3.6.1 Translational research 
65 
6.3.6.2 Evaluations for patients receiving pembrolizumab 
65 
6.3.7 End of treatment (Part 2) 
66 
6.3.7.1 Discontinuation due to progression or 2nd recurrence 
66 
6.3.7.2 Discontinuation in absence of recurrence 
67 
6.3.8 Follow-up (after end of pembrolizumab in Part 2) 
67 
6.3.8.1 For patients who discontinued Part 2 due to progression or recurrence or 
completion of treatment 
68 
6.3.8.2 Treatment discontinuation due to adverse event or ECI 
68 
6.3.8.3 Treatment discontinuation due to patient’s decision 
68 
6.4 
Summary Tables 
69 
6.4.1 Part 1: Evaluations during adjuvant treatment (Part 1) 
69 
6.4.1.1 Overview EOT for adjuvant treatment (Part 1) 
71 
6.4.1.2 Follow-up evaluation Part 1: for patients who discontinue due to recurrence 
but do not cross-over/re-challenge or due to patient’s decision 
73 
6.4.1.3 Follow-up evaluation Part 1: for patients who discontinued in absence of 
recurrence 
74 
6.4.2 Part 2: Cross-over or rechallenge after the 1st recurrence 
75 
6.4.2.1 Evaluations during cross-over or re-challenge with pembrolizumab 
75 
6.4.2.2 Overview EOT (Part 2) 
76 
6.4.2.3 Follow-up evaluation for patients who discontinue Part 2 
77 
6.4.3 Blood, serum and tumor samples 
78 
 
 
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7 
Criteria of evaluation 
79 
7.1 
Evaluation of efficacy 
79 
7.1.1 Recurrence 
79 
7.1.1.1 Definition 
79 
7.1.1.2 Methods of measurements 
80 
7.1.1.3 Date of recurrence 
81 
7.1.2 Progression During Part 2 (Cross-over/Re-challenge) 
81 
7.1.3 Time to event endpoints 
82 
7.1.3.1 Recurrence-free survival 
82 
7.1.3.2 Distant metastasis-free survival 
82 
7.1.3.3 Duration of overall survival 
82 
7.1.3.4 Duration of progression/recurrence-free survival 2 
82 
7.2 
Evaluation of safety 
83 
7.2.1 Adverse events 
83 
7.2.2 General evaluation of adverse events 
83 
7.2.3 Serious adverse events and Events of Clinical Interest 
83 
7.2.4 Toxic deaths 
83 
7.2.5 Evaluability for safety 
83 
8 
Statistical considerations 
84 
8.1 
Statistical design 
84 
8.1.1 Sample size 
84 
8.1.2 Randomization and stratifications 
93 
8.2 
Statistical analysis plan 
94 
8.2.1 Primary and secondary endpoints 
94 
8.2.2 Analysis populations 
94 
8.2.3 Statistical methods 
94 
8.2.3.1 Analysis methods for efficacy endpoints 
94 
8.2.3.2 Analysis methods for safety endpoints 
95 
8.2.4 Pre-planned sensitivity or exploratory analyses 
95 
8.2.4.1 Sensitivity analyses for efficacy endpoints (RFS, DMFS, OS) 
95 
8.2.4.2 Exploratory analyses for primary and secondary efficacy endpoints (RFS, 
DMFS, OS) 
96 
8.2.4.3 Exploratory analyses for exploratory efficacy endpoint (PRFS2) 
98 
8.2.5 Prognostic factor analyses 
98 
8.2.6 Data recoding and display 
99 
 
 
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8.3 
Interim analyses 
99 
8.4 
End of study 
101 
9 
Data Monitoring 
101 
9.1 
Safety data monitoring 
101 
9.2 
Efficacy data monitoring 
101 
10 Quality of life assessment 
102 
10.1 
Rationale 
102 
10.2 
Objective 
102 
10.3 
HRQoL instrument 
102 
10.4 
Study design 
103 
10.4.1 HRQoL schedule 
103 
10.5 
Statistical considerations 
104 
10.5.1 Missing data 
105 
10.6 
Health outcomes evaluation 
105 
10.6.1 EQ-5D-3L instrument 
105 
11 Pharmacokinetic/Pharmacodynamic Evaluations 
106 
11.1 
Timepoints 
106 
11.2 
PK Blood Collection for Serum MK-3475 
106 
11.3 
Blood Collection for Anti-Pembrolizumab Antibodies 
106 
12 Translational research 
106 
12.1 
Objectives 
106 
12.2 
Patient selection criteria 
107 
12.3 
Biological material 
107 
12.4 
Data storage, transfer and development of technical appendices 
107 
12.5 
General principles for human biological material (HBM) collection 
107 
13 Investigator authorization procedure 
109 
14 Patient registration and randomization procedure 
110 
14.1 
General procedure 
110 
14.2 
Registration - step 1 (ORTA Step-1) 
110 
14.3 
Central confirmation of PD-L1 expression testing - step 2 
111 
14.4 
Enrollment and Randomization - step 3 (ORTA Step-2) 
111 
14.5 
Description of the blind procedure 
112 
14.6 
Stock management process 
112 
14.7 
Unblinding procedure 
112 
 
 
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14.7.1 Emergency unblinding 
112 
14.7.2 Unblinding by investigator after first disease recurrence 
113 
14.7.3 Unblinding at final analysis 
114 
14.7.4 Other unblinding during the course of the study 
114 
15 Forms and procedures for collecting data 
114 
15.1 
Case report forms and schedule for completion 
114 
15.2 
Data flow 
115 
15.3 
HBM* sample registration and tracking 
116 
16 Reporting of Serious Adverse Events 
116 
16.1 
Definitions 
116 
16.2 
Exceptions 
118 
16.3 
Severity assessment 
119 
16.4 
Causality assessment 
119 
16.5 
Expectedness assessment 
120 
16.6 
Reporting procedure for investigators 
120 
16.7 
Reporting responsibilities of the Sponsor 
122 
16.8 
Pregnancy reporting 
123 
17 Quality assurance 
123 
17.1 
Control of data consistency 
123 
17.2 
On-site quality control 
123 
17.3 
Audits 
123 
18 Ethical considerations 
124 
18.1 
Patient protection 
124 
18.2 
Subject identification 
124 
18.3 
Informed consent 
125 
19 Administrative responsibilities 
125 
19.1 
The study coordinator 
125 
19.2 
The EORTC Headquarters 
126 
19.3 
The EORTC group 
126 
20 Trial sponsorship and financing 
127 
21 Administrative and regulatory details 
127 
21.1 
Confidentiality 
127 
21.1.1 Confidentiality of Data 
127 
21.1.2 Confidentiality of Subject Records 
127 
 
 
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21.1.3 Confidentiality of Investigator Information 
128 
21.1.4 Confidentiality of IRB/IEC Information 
128 
21.2 
Compliance with Financial Disclosure Requirements 
128 
21.3 
Compliance with Law, Audit and Debarment 
129 
21.4 
Compliance with Trial Registration and Results Posting Requirements 
130 
21.5 
Quality Management System 
131 
21.6 
Data Management 
131 
21.7 
Calibration of Critical Equipment 
131 
22 Trial insurance 
131 
23 Publication policy 
132 
 
 
List of tables: 
Table 1: Overall response rate by PD-L1 positivity by dose and schedule 
36 
Table 2: Adequate Organ Function Laboratory ValuesPrior treatment for melanoma 
42 
Table 3: Evaluations during adjuvant therapy 
70 
Table 4: Evaluations for EOT 
72 
Table 5: Follow up evaluations for patients who discontinue Part 1due recurrence (but no 
cross-over or rechallenge) or patient's decision 
73 
Table 6: Follow-up evaluations for patients discontinued in absence of recurrence 
74 
Table 7: Evaluations during cross-over or re-challenge with pembrolizumab 
75 
Table 8. Evaluation for EOT visit 
76 
Table 9: Follow up evaluations for patients who discontinue Part 2 
77 
Table 10: Timeschedule for blood, serum and tumor samples collection 
78 
Table 11: Estimations of RFS events 
85 
Table 12: Estimations of RFS events in PD-L1+ Subgroup 
87 
Table 13: Estimations of DMFS events 
88 
Table 14: Estimations of DMFS events in PD-L1+ Subgroup 
89 
Table 15: Estimations of OS events 
91 
Table 16: Estimations of OS events in PD-L1+ Subgroup 
92 
Table 17: Sensitivity analyses 
96 
Table 18: Prevalence PD-L1+/Prevalence PD-L1- in the entire cohort 
97 
Table 19: Operating Characteristics of the Interim Analysis 
100 
 
 
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Immunotherapy with anti-PD in stage III melanoma 
EORTC v7.0/MK-3475-054-03 
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Table 20: HRQoL schedule 
104 
Table 21: Relationship to the protocol treatment 
119 
Table 22: Reporting schedule 
121 
Table 23: Dose Modification Guidelines for Drug-Related Adverse Events 
158 
Table 24: Infusion Reaction Treatment Guidelines 
162 
Table 25: Events of Clinical Interest 
165 
Table 26: Pneumonitis 
167 
Table 27: Colitis 
169 
Table 28: Hypophysitis or other symptomatic endocrinopathy other than hypo- or 
hyperthyroidism 
170 
Table 29: Hyperthyroidism and Hypothyroidism 
172 
Table 30: Hematologic ECIs 
174 
Table 31: Hepatic adverse ECIs 
176 
Table 32: Neurologic ECIs 
177 
Table 33: Ocular ECIs 
178 
Table 34: Renal ECIs 
179 
Table 35: Skin ECIs 
180 
Table 36: Other ECIs 
182 
Table 37: Infusion reactions ECIs 
185 
Table 38: Integration of Target, non-Target and New lesions into response assessment: 203 
 
List of figures: 
Figure 1: PFS and OS based on tumor PD-L1 expression (Central Review, RECIST v.1.1) 37 
Figure 2. Multi step process for enrollment 
46 
Figure 3: Trial design 
49 
Figure 4: Treatment schedule 
53 
Figure 5: Graphical approach 
93 
 
 
 
 
 
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Table of appendices: 
Appendix A: References 
133 
Appendix B: Abbreviations 
139 
Appendix C: ECOG performance status scale 
142 
Appendix D: EORTC Quality of Life evaluation: guidelines for administration of 
questionnaires 
143 
Appendix E: AJCC 2010 for Melanoma 
146 
Appendix F: Surgical and pathological considerations for melanoma 
150 
Appendix G: Guidelines for management of toxicity 
154 
Appendix H: Guidelines for Management of Adverse Events (AE) and Events of clinical 
interest (ECI) 
163 
Appendix I: Past Medical History Related to Dermatologic Event 
187 
Appendix J: Presentation of the Dermatologic Event 
189 
Appendix K: Focused Skin Examination 
191 
Appendix L: Merck Code of Conduct for Clinical Trials 
192 
Appendix M: EQ-5D-3L – Health Questionnaire 
195 
Appendix N: Recommendations for Contraception in United Kingdom, Portugal, 
Scandinavian countries and Other Applicable Countries 
198 
Appendix O: Guidelines for RECIST 1.1 
200 
 
 
 
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Protocol summary 
Title of the 
Study 
Adjuvant immunotherapy with anti-PD-1 monoclonal antibody 
Pembrolizumab (MK-3475) versus placebo after complete resection of 
high-risk Stage III melanoma: A randomized, double-blind Phase 3 trial 
of the EORTC Melanoma Group. 
Objective(s) 
To prospectively assess whether post-operative adjuvant therapy with 
pembrolizumab improves recurrence-free survival (RFS) as compared to 
placebo in high-risk patients with complete resection of Stage IIIA (> 1 
mm metastasis), IIIB and IIIC melanoma. 
To prospectively assess whether in the subgroup of patients with PD-
L1-positive tumor expression, pembrolizumab improves recurrence-free 
survival as compared to placebo. 
Methodology 
This is an international, double-blinded, placebo-controlled randomized 
phase III trial.  
Enrollment will be a multi-step process. 
Randomization (placebo vs. pembrolizumab) will be performed 
centrally and will be stratified for the following factors: stage (IIIA (> 1 
mm metastasis) vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC  4 
positive lymph nodes) and region (North America, European countries, 
Australia and other countries as designated)). 
Data will be unblinded in case of recurrence and at any time during the 
trial in case of a safety concern affecting an individual patient. 
Number of 
patients  
Number 
planned 
(Statistical 
design) 
Number 
analyzed 
A total of approximately 900 eligible patients will be randomized into 
two equal-sized, double-blind treatment arms (approximately 450 
patients each). 
The RFS final analysis will require 409 RFS events (loco-regional 
recurrences, distant metastases or deaths); all patients will have been 
followed for approximately a minimum of 1 year at approximately 3 
years from the start of the trial. 
One interim analysis is planned for assessing whether pembrolizumab is 
superior to placebo with respect to the improvement of RFS in the 
overall population. The interim analysis will occur after approximately 
330 RFS events have been reported, and will be based on the primary 
efficacy analysis on the primary efficacy population (ITT population). 
The stopping boundaries for the interim analysis will be based on the 
O’Brien-Fleming spending function. 
The Distant metastases-free survival (DMFS) final analysis will require 
423 DMFS events (distant metastases or deaths); it will be done 
approximately 5 years from the trial inception. 
 
 
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The OS final analysis will require 380 deaths; it will be done 
approximately 8-8.5 years from the trial inception. 
The "graphical approach" to testing the hypotheses that the 
Pembrolizumab and placebo groups differ with respect to RFS, RFS in 
the PD-L1+ subgroup, DMFS, and DMFS in the PD-L1+ subgroup, OS, 
OS in the PD-L1+ subgroup, will be adopted.  
Objective 
HR 
1-sided alpha 
%† 
Power % 
RFS in the overall 
population 
0.7 
2.5 (1.4) 
95 (92) 
RFS in the PD-L1+ 
subgroup (if 205/409 
events are PD-L1+) 
0.55 
2.5 (1.54) 
99 (98) 
0.60 
2.5 (1.54) 
95 (93) 
DMFS in the overall 
population (if both RFS 
null hypotheses are 
rejected) 
0.725 
2.5 (1.4) 
91 (87) 
DMFS in the PD-L1+ 
subgroup (if both RFS null 
hypotheses are rejected and 
if 212/423 events are PD-
L1+) 
0.55 
2.5 (1.54) 
99 (99) 
0.60 
2.5 (1.54) 
99 (94) 
OS (if both DMFS and 
both RFSs null hypotheses 
are rejected) 
0.75 
2.5 (1.4) 
80 (73) 
OS in the PD-L1+ 
subgroup (if both RFSs and 
both DMFS null 
hypotheses are rejected and 
if 190/380 of events are 
PD-L1+) 
0.65 
2.5 (1.54) 
84 (79) 
0.7 
2.5 (1.54) 
69 (62) 
† According to the multiplicity strategy (Bonferroni-Holm), the 
hypothesis for the overall population will first be tested at 
alpha=1.4%. If the hypothesis for the PD-L1+ subgroup is rejected 
at the allocated alpha (alpha in parentheses), then the hypothesis for 
the overall population will be tested at alpha=2.5%. Similarly, the 
hypothesis for the PD-L1+ subgroup will first be tested at the 
allocated alpha (alpha in parentheses). If the hypothesis for the 
overall population is rejected at alpha=1.4% (alpha in parentheses), 
then the hypothesis for the PD-L1+ subgroup will be tested at 
 
 
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alpha=2.5%.  
The "graphical approach" (see Figure 5 below) to testing the hypotheses 
that the Pembrolizumab and placebo groups differ with respect to RFS, 
DMFS, OS and these endpoints in the PD-L1+ subgroup, will be 
adopted.  
The initial 1-sided alpha allocation to RFS, DMFS and OS, will be 
0.025, 0 and 0, respectively. This indicates that RFS, DMFS and OS 
will be tested sequentially. Both hypotheses (for the overall population 
and for the PD-L1+ subgroup) must be rejected to proceed to the next 
endpoint. 
For each endpoint, alpha allocation was determined as follows. For the 
overall population, 1-sided alpha=0.014. For the PD-L1+ subgroup, the 
allocated alpha will be calculated as a function of the event ratio 
(number of observed events in the PD-L1+ subgroup: total number of 
observed events) using a method by Spiessens and Debois. Several 
scenarios are discussed in the sample size calculation (above). 
This "graphical approach" guarantees a 1-sided significance level of 
0.025 for the study, as a whole. No multiplicity adjustment for other 
secondary analyses will be made. 
 
Figure 5: Graphical approach 
At the time of OS final analysis, an assessment of the long term 
treatment impact on RFS and DMFS will be evaluated as well. 
 
 
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Diagnosis 
and main 
criteria for 
inclusion 
Patient enrollment will follow a three steps procedure as illustrated in 
Section 4 (step 1 registration, step 2 central confirmation of PD-L1 
expression, step 3 enrollment and randomization through IVRS). 
Patients must meet all of the criteria described in Section 3 to be eligible 
for enrollment . 
1) Registration- step 1 (ORTA Step 1) 
Before patient registration, written informed consent for tumor 
testing must be given according to ICH/GCP, and national/local 
regulations. 
Note: if a patient signs the Registration Informed Consent before 
the complete lymph node dissection (CLND) was performed, please 
contact the medical monitor to assess eligibility before registering in 
ORTA. 
♦ At least 18 years of age. 
♦ No mucosal or ocular melanoma. 
♦ Melanoma with unknown origin of the primary is eligible. 
♦ Complete resection of Stage III melanoma (AJCC R0) with 
histologically confirmed cutaneous melanoma metastatic to lymph 
node, classified as (AJCC, 2010): Stage IIIA with metastasis > 1 
mm; any Stage IIIB or IIIC. No past or current in-transit metastases 
or satellitosis. 
♦ Patient population IIIA (> 1 mm metastasis) is capped at a 
maximum of 20% of the total patient population. 
♦ Mandatory to ship tumor sample for evaluation of PD-L1 
expression. A tumor sample obtained at resection or tissue obtained 
from the biopsy must not be previously irradiated. During the 
screening period, the tumor sample must be sent to the central 
pathology laboratory for PD-L1 expression testing. Patients will be 
eligible to participate regardless of the level of PD-L1 expression. 
♦ PD-L1 testing is mandatory: tumor material will be collected 
from positive lymph nodes (LN) embedded in paraffin. If the 
resection samples from LNs are not adequate for PD-L1 testing, 
the primary melanoma must be collected. Patients whose 
samples are inadequate for PD-L1 determination will not be 
enrolled.  
♦ In addition the primary melanoma may also be collected if 
available to evaluate the PD-L1 expression.  
2) Central confirmation of PD-L1 expression - step 2 
This central confirmation through EORTC is required for enrolling the 
patient in step 3. 
 
 
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3) Enrollment and randomization -step 3 (ORTA Step 2) 
Before patient enrollment, written informed consent to participate 
in the trial must be given according to ICH/GCP, and national/local 
regulations. 
♦ The resection of Stage III lymph nodes must have been performed in 
complete compliance with the Criteria for adequate surgical 
procedures for CLND that is displayed in Appendix F. This must be 
documented in the medical file (including pathology report); 
patients without documentation of adequate resection are not 
eligible. 
♦ To be considered as adequate, the surgical and pathological 
procedures should have included at least the following: 
♦ Head and Neck 
♦ Minimum of 15 pathologically investigated nodes 
♦ Face, ear, and anterior scalp: parotidectomy plus modified 
radical neck dissection 
♦ Posterior scalp: modified radical neck dissection plus 
suboccipital nodes. For this specific localization, a CLND 
will be considered as adequate if at least 5 LN have been 
investigated 
♦ Upper Extremity 
♦ Minimum of 10 pathologically investigated nodes 
♦ Axillary node dissection included at least 10 nodes taken 
from Levels I and II  
♦ Level III nodes dissected if they were clinically involved 
♦ Pectoralis minor muscle may be divided or sacrificed with 
the specimen at the discretion of the surgeon 
♦ Lower Extremity 
♦ Minimum of 5 pathologically investigated nodes 
♦ Superficial inguinal node dissection was performed for non-
palpable nodal involvement 
♦ If Cloquet’s node was positive, a deep inguinal node 
dissection was performed 
♦ Lymph Node Dissection for Nodal Recurrence 
♦ Regional node recurrence was treated using the appropriate 
lymphadenectomy as above 
♦ Diagnosis of regional node recurrence was made by fine 
needle aspiration technique to avoid contaminating the 
 
 
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region with tumor, followed by CLND as above 
♦ The maximum duration from surgery to first study drug treatment is 
13 weeks. Treatment should start only after complete wound healing 
from the surgery. 
Note: if there is a delay of 1-7 days exceeding 13 weeks due to 
extreme unforeseen circumstances, the eligibility should be 
discussed with the medical monitor. 
♦ Disease status for the post-surgery baseline assessment must be 
documented by full Chest/Abdomen/Pelvis CT and/or MRI with 
Neck CT and/or MRI (for Head and Neck primaries) and complete 
clinical examination after the informed consent and prior to 
enrollment.  
Note: if a patient had laboratory/imaging tests as part of local 
routine guidelines (standard of care) prior to signing informed 
consent, the procedures will be acceptable for screening purposes if 
they are within the window required by the protocol. 
♦ Disease-free (no loco-regional relapse or distant metastasis); no 
clinical evidence for brain metastases. 
♦ BRAF mutation status (known or not done). 
♦ ECOG performance status of 0 or 1. 
♦ Patient demonstrates adequate organ function as defined in Table 2, 
all screening labs should be performed within 14 days (+/- 3 days) 
prior to treatment initiation.  
System 
Laboratory Value 
Hematological 
Absolute neutrophil count 
(ANC) 
≥ 1,500 /mcL 
Platelets 
≥ 100,000 / mcL 
Hemoglobin 
≥ 9 g/dL or ≥ 5.6 mmol/L  
Renal 
Creatinine or 
Measured or calculated 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
Creatinine clearance should be 
calculated per institutional 
standard. 
≤ 1.5xULN or 
≥ 60 mL/min for patient with  
creatinine levels > 1.5x institutional 
ULN 
Note: For patients entering Part 2  
≥ 30 mL/min for patient with  
creatinine levels > 1.5x institutional 
 
 
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ULN 
Hepatic 
Total bilirubin 
≤ 1.5xULN or 
Direct bilirubin ≤ ULN for patients 
with total bilirubin levels > 
1.5xULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5xULN 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤ 1.5xULN unless patient is 
receiving anticoagulant therapy as 
long as PT or PTT is within 
therapeutic range of intended use of 
anticoagulants 
≤ 1.5xULN unless patient is 
receiving anticoagulant therapy as 
long as PT or PTT is within 
therapeutic range of intended use of 
anticoagulants 
Table 2: Adequate Organ Function Laboratory Values 
♦ Prior treatment for melanoma 
♦ In case of an indication for post lymph node dissection 
radiotherapy, this must have been completed within the 13 
weeks post-surgery period and prior to treatment start. 
Note: radiotherapy may alter the process of wound healing. If 
the wound healing is not complete patient will not be eligible. 
♦ No prior therapy for melanoma except surgery for primary 
melanoma lesions; patients who have previously received IFN 
for thick primary melanomas without evidence of lymph node 
involvement are eligible. 
♦ No history of (non-infectious) pneumonitis that required steroids or 
current pneumonitis. No history of or current interstitial lung 
disease.  
♦ No history of another malignancy or a concurrent 
malignancy. Exceptions include patients who have been disease-free 
for 5 years, or patients with a history of completely resected non-
melanoma skin cancer or successfully treated in situ carcinoma are 
eligible, for example cervical cancer in situ. 
♦ No active autoimmune disease that has required systemic treatment 
in past 2 years (i.e. with use of disease modifying agents, 
 
 
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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.  
♦ No active infection requiring therapy. 
♦ Patients with hyperthyroidism or hypothyroidism but that are stable 
on hormone replacement will not be excluded. 
♦ No diagnosis of immunodeficiency, no systemic steroid therapy or 
any other form of immunosuppressive therapy within 7 days prior to 
the first dose of study treatment 
♦ No known history of human immunodeficiency virus (HIV), active 
Hepatitis B or Hepatitis C. 
♦ Patients who received treatment with live vaccines within 30 days 
prior to the first dose of study medication are not eligible. Examples 
of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, shingles, yellow fever, 
seasonal flu, H1N1 flu, rabies, BCG and typhoid vaccine. 
♦ Patient must not have received prior treatment with any anti-CTLA4 
monoclonal antibody or anti-PD-1, or PD-L1 or PD-L2 agent. 
Examples of PD-1 inhibitors (include, but are not limited to): 
pembrolizumab (Merck); Nivolumab (also known as BMS-936558, 
MDX-1106, ONO-4538) (Bristol-Myers Squibb); Pidilizumab (CT-11) 
(Cure-Tech/Teva); and AMP-224 (Amplimmune). 
Examples of PD-L1 inhibitors (include, but are not limited to): BMS-
936559 (also known as MDX-1105) (Bristol-Myers Squibb); 
MPDL3280A (also known as RG7446) (Roche Genentech); and 
MEDI4736 (MedImmune). 
♦ Patient is not currently participating and receiving study therapy or 
has not participated in a study of an investigational agent and 
received study therapy or used an investigation device within 4 
weeks prior to the first dose of treatment 
♦ Women of child bearing potential (WOCBP) must have a negative 
serum (or urine) pregnancy test within 72 hours prior to the first 
dose of study treatment. 
♦ Patients of childbearing / reproductive potential should use adequate 
birth control methods, as defined by the investigator, during the 
study treatment period and for a period of 120 days after the last 
dose of study drug. A highly effective method of birth control is 
defined as those which result in low failure rate (i.e. less than 1% 
per year) when used consistently and correctly.  
♦ Note: abstinence is acceptable if this is established and preferred 
 
 
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contraception for the patient and is accepted as a local standard. 
♦ Appendix N is to be used where applicable for specific countries 
and sites adhering to Clinical Trial Facilitation Group guidelines 
for clinical trials (e.g. United Kingdom, Norway, Sweden, 
Portugal, etc). 
♦ Female patients who are breast feeding should discontinue nursing 
prior to the first dose of study treatment and until 120 days after the 
last dose of study drug . 
♦ Absence of any condition hampering compliance with the study 
protocol and follow-up schedule; those conditions should be 
discussed with the patient before registration in the trial. 
♦ Patient will not be eligible: if patient is or has an immediate family 
member (e.g., spouse, parent/legal guardian, sibling or child) who is 
investigational site or Sponsor staff directly involved with this trial, 
unless prospective IRB approval (by chair or designee) is given 
allowing exception to this criterion for a specific subject.  
Once eligibility has been verified, the treatment arm will be 
randomly allocated to the patient.  
Important note: All eligibility criteria must be adhered to. 
Treatment 
Test product, 
dose and 
mode of 
administration 
1) Adjuvant therapy: Pembrolizumab 200 mg fixed dose OR Placebo, 
will be administered by IV, every 3 weeks. 
2) After 1st recurrence:  
Upon documented recurrence patients are eligible for cross-over/re-
challenge and if patients fulfill criteria as per Sections 4.2.1.1 (cross-
over) and 4.2.2.1 (re-challenge) : 
a) Patients assigned to the placebo adjuvant arm who experience disease 
recurrence may be treated with pembrolizumab 200 mg IV every 3 
weeks if clinically indicated. 
b) Patients assigned to the pembrolizumab adjuvant arm who experience 
disease recurrence more than six months after completing one year of 
therapy may be re- challenged with pembrolizumab 200 mg IV every 3 
weeks if clinically indicated. 
Duration of 
treatment 
1) Adjuvant treatment: 
Study drugs will be administered for 1 year unless one of the 
withdrawal criteria applies (Section 5.4.1.2) 
2) After 1st recurrence: 
 
Treatment in Part 2 will be administered up to 1 year (local recurrence) 
or 2 years treatment period unless occurrence of a withdrawal criterion 
 
 
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(see Section 5.4.2.4). 
For patients with local recurrence, the treatment may stop at 1 year at 
the discretion of the investigator. 
Reference 
therapy, dose 
and mode of 
administration 
1) Adjuvant therapy 
Placebo will be administered by IV, every 3 weeks. 
2) After 1st recurrence: 
Upon documented recurrence, eligible patients will be offered to receive 
pembrolizumab at 200 mg fixed dose, administered by IV, every 3 
weeks if they fulfill criteria as per Section 4.2.1.1 
Criteria for 
evaluation 
 
Efficacy 
Primary endpoint:  
♦ Recurrence-free survival (RFS) 
♦ RFS for patients with PD-L1-positive expression 
Secondary endpoints:  
♦ Distant metastases-free survival (DMFS) 
♦ DMFS for patients with PD-L1-positive expression 
♦ Overall survival (OS)  
♦ OS for patients with PD-L1-positive expression 
♦ Pharmacokinetics (PK) of pembrolizumab 
Safety 
Exploratory 
Adverse events will be scored according to the CTCAE version 4.0  
♦ Quality of life  
♦ Health outcomes evaluation 
♦ Predictive biomarkers (e.g. immune-related gene signatures, 
genetic variation, SPDL1) for treatment difference in outcome 
♦ Progression/recurrence-free survival 2 (PRFS2) 
Statistical 
methods 
All the main analyses of the efficacy endpoints (RFS, DMFS, OS) will 
be performed on the intent-to-treat (ITT) population using the ITT 
principle: patients will be considered in the treatment group as indicated 
at randomization, regardless the “treatment” duration, cause of going 
off-protocol treatment, possible switch to another treatment before the 
1st relapse, etc. 
The Kaplan-Meier technique will be used to obtain estimates of the 
survival-type distributions (RFS, DMFS, OS), and the standard error of 
the estimates will be computed using the Greenwood formula. Medians 
- if reached - will be presented with a 95% confidence interval based on 
 
 
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the non-parametric method of Brookmeyer and Crowley. 
The comparison of the time-to-event distributions (RFS, DMFS, OS) 
between the two treatment arms will be done using the log-rank test 
stratified by stage (IIIA (> 1 mm metastasis) vs. IIIB vs. IIIC 1-3 nodes 
vs. IIIc 4 nodes) as indicated at randomization. The HR, and its 2-sided 
(1-alpha)*100% confidence interval, of Pembrolizumab to placebo, will 
be estimated using a Cox proportional hazards (PH) model (using 
Efron’s tie-handling method), stratified by stage (IIIA (> 1 mm 
metastasis) vs. IIIB vs. IIIC 1-3 nodes vs. IIIc 4 nodes) as indicated at 
randomization, with treatment as the single covariate. 
Predictive importance of a factor i.e. its impact on the treatment 
difference regarding the time to event end point (RFS, DMFS, OS) will 
be investigated for exploratory purposes. Consistency of treatment 
comparisons among subgroups of variables will be investigated using 
the Forest plot techniques.  
In addition, possible interactions between a factor and treatment effect 
will be assessed in a Cox model, in a bi-variate setting (i.e. treatment, 
variable, treatment x variable) and a multivariate one, i.e. adding in the 
model those factors which appear to be of independent prognostic 
importance. 
The prognostic/predictive importance of the following variables will be 
considered for the efficacy endpoints (RFS, DMFS, OS): 
♦ PD-L1 expression (negative vs positive). 
♦ Variables considered in the AJCC Staging: 
♦ LN involvement: micro vs. macro- involvement 
♦ Ulceration: absent vs. present vs. unknown 
♦ Number of lymph-nodes positive: 1 vs. 2-3 vs. 4+ 
♦ Breslow thickness (< 2 mm vs 2-<4 mm vs 4 mm) 
♦ BRAF-mutation status (negative vs positive vs unknown) 
♦ Sex (Male vs. Female) 
♦ Age (at randomization <65 vs. 65 yrs) 
For efficacy endpoints, several sensitivity analyses are foreseen (see 
protocol, Section 8.2.4.1). 
 
 
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Pharmaco-
kinetic and 
pharmaco-
dynamic 
evaluations 
To further evaluate pembrolizumab immunogenicity and 
pembrolizumab exposure in this indication, and also to evaluate 
exposure of the proposed dosing regimen, sample collections for 
analysis of anti-drug antibodies (ADA) and PK are currently planned.  
For sampling refer to Sections 6.2.5, 6.3.3, 6.3.4.5 and 6.4.3. 
If ongoing ADA and/or PK results continue to be consistent with 
existing ADA and/or PK data from other pembrolizumab clinical 
trials, it may be decided to discontinue further sample collection or 
analysis in this study. 
Translational 
research 
Tumor material, blood and serum samples will be collected for future 
research.  
For sampling refer to Sections 6.2.2, 6.3.4.4 and 6.4.3. 
Quality of 
Life 
HRQoL is an exploratory endpoint testing the hypothesis of no 
clinically relevant differences between the two treatment arms using the 
global QoL scale during the first two years. To meet this objective, the 
QLQ-C30 (v3) and the EQ-5D-3L will be administered at baseline and 
every 12 weeks for the first two years and every 6 months up to 4th year 
(included), regardless of recurrence/progression or treatment status, 
unless patient withdraws from this part of the study. 
 
 
 
 
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1 Background and introduction 
1.1 
Disease background information 
1.1.1 
Risk of relapse in patients with stage III melanoma 
The increase in incidence of melanoma has led to an increased number of patients with 
regional positive lymph nodes (stage III) being diagnosed each year, across the globe, but 
especially in the western world (Ref. 1). Breslow thickness of primary melanoma is the 
strongest prognostic factor in terms of likelihood of micrometastatic disease at the regional 
lymph node level. Likelihood of systemic metastatic disease in patients with regional lymph 
node metastasis (stage III) correlates closely with microscopic vs palpable nodal disease and 
with number of positive nodes. Stage III melanoma patients are at high risk of relapse. 
According to the data of the most recent AJCC staging committee relapse rates at 5 years for 
Stage IIIA, Stage IIIB and Stage IIIC are about 35%, 75% and 90% respectively (Ref. 2,  
Ref. 3). Because of sentinel node (SN) staging there is tremendous heterogeneity within the 
sentinel node positive (microscopic only) patient population. Depending on tumor load in the 
sentinel node defined by diameter of the micrometastasis(es) according to the Rotterdam 
Criteria, prognosis rapidly deteriorates from equal to a sentinel node negative status in case 
of metastasis < 0.1 mm to equal to having 1 palpable positive node in case of metastasis > 1 
mm (Ref. 4, Ref. 5, Ref. 6). Patients with a metastasis > 1 mm have a highly significant 
higher risk of relapse and death than patients with a metastasis < 1 mm (Ref. 6).  
In the conduct of adjuvant trials in stage III disease, it is important to be able to have a timely 
read out of the impact of the drug on relapse- free survival (RFS) and overall survival (OS) 
and to be able to achieve that goal one should not dilute the stage III patient population by 
including the very large numbers of SN-positive patients with metastasis < 1 mm, but one 
should enrich the patient population in the study by only enrolling patients with a high risk 
(stage IIIA, > 1 mm diameter of metastasis) or with multiple microscopically positive nodes 
or palpable nodes (stage IIIB and IIIC).  
There is a large unmet medical need in patients with resectable advanced stage IIIA (>1 mm 
metastasis), IIIB and IIIC melanoma, who are at high-risk of disease recurrence because of 
the marginal impact of adjuvant IFN regimens on OS as will be discussed in Section 
1.1.3.1.1 of the protocol. 
1.1.2 
Surgical management of regional lymph nodes 
Patients with operable clinically positive nodes undergo systematically full 
lymphadenectomy of the involved sites. Patients with clinically negative lymph node 
involvement are most commonly staged by sentinel lymph node biopsy, which has replaced 
the former use of elective lymph node dissection (Ref. 7).  
Patients with a negative sentinel lymph node are spared a complete lymph node dissection 
(CLND), whereas patients with a positive SN most commonly undergo a CLND (Ref. 7,  
Ref. 8). CLND may not be indicated for all patients, but differentiation regarding the 
indication for CLND is a topic under current investigation (Ref. 9). In the context of an 
adjuvant trial in stage III patients, enriched for risk of relapse, it is recommended that all 
 
 
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patients have undergone full regional lymph node dissection to avoid heterogeneity and risk 
of early locoregional relapses because of not having had optimal surgery for optimal 
locoregional control, as has been practiced in the most recent EORTC phase III trials 
(EORTC-18991 and 18071) in stage III (Ref. 10). 
1.1.3 
Adjuvant Therapy in high risk melanoma patients 
1.1.3.1 
Adjuvant trials 
Surgery alone is insufficient to achieve a cure in most patients with stage III melanoma. Thus 
systemic adjuvant therapy has been investigated over the last decades in patients with high 
risk (Tany N1,2,3 M0: microscopically or clinically node- positive patients). Up to now, 
adjuvant therapy of stage III malignant melanoma with cytostatic agents and/or nonspecific 
immunotherapy, biologic response modifiers and combinations have failed to show a clear 
clinical benefit especially in terms of survival (Ref. 1). 
1.1.3.1.1 
Interferon-α trials 
Adjuvant Therapy with Interferon 
Twenty-five years of RCTs in melanoma with interferon-alpha (IFN) are a testimony that 
efficacy of adjuvant therapy with IFN is modest at best. High-dose interferon-α is approved 
in the USA and EU for the treatment of patients with completely resected Stage IIB/ III 
melanoma.  
Many other dose regimens have been tested over the years. Meta-analyses of phase III trials 
demonstrated that IFN has a consistent effect on RFS but no or only a marginal effect on OS 
(Ref. 11, Ref. 12, Ref. 13). No relationship between dose or duration of treatment with 
outcome has been demonstrated. These findings suggest that only a minority of patients are 
sensitive to IFN and demands that we identify these patients. Based on the EORTC 18991 
trial in 1256 patients, the FDA approved pegylated interferon α-2b (Peg-IFN; Sylatron™) in 
2011 for stage III melanoma patients (Ref. 14) . The EORTC 18952 trial in 1388 stage IIB/III 
melanoma patients, compared intermediate doses of interferon α-2b (IFN) with observation 
(Ref. 15). These EORTC RCTs stratified patients by SN-staging (microscopic involvement 
only: stage III-N1) or gross macroscopic relapse (stage III-N2) as well as by presence or 
absence of ulceration in the primary tumor. Both stage and ulceration are key prognostic 
factors (Ref. 2, Ref. 3). Patients with only micrometastases have a much better prognosis 
than patients with palpable node metastases (Ref. 2, Ref. 3). Palpable nodal disease may 
represent more aggressive disease from the onset or by acquisition of additional mutations 
over time. Regarding ulceration, for the same Breslow thickness, patients with an ulcerated 
primary have a 10-25% lower survival probability at 10 years, indicating a distinct biologic 
entity (Ref. 2). 
The meta-analysis of the two largest adjuvant IFN/PEG-IFN RCTs in 2644 patients 
demonstrated that both tumor load in the lymph nodes and ulceration of the primary are 
independent predictive factors for adjuvant IFN therapy (Ref. 16). Patients with favorable 
stage (IIb/III-N1) and/or ulcerated primary tumor benefited significantly from IFN/PEG-IFN 
treatment (HRs 0.56–0.69) with regard to RFS, distant metastasis free survival (DMFS), and 
OS, whereas patients with stage III-N2 disease or non-ulcerated primary tumor did not. 
 
 
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Ulceration of the primary was the overridingly important predictive factor for IFN-
sensitivity, which was again confirmed at 7.6 years follow up of EORTC 18991 (Ref. 17). 
In a meta-analysis of 1393 patients with ulcerated melanomas reported in a variety of trials 
that did not include EORTC 18991, Wheatley et al. reported a HR of adjuvant IFN therapy 
for OS of 0.77 (99% CI 0.63–0.93); whilst there was no impact of adjuvant IFN therapy in 
the 2118 patients without ulceration (HR 0.98 [99% CI 0.87–1.17]) (Ref. 16). 
In 2012, the results of the adjuvant phase III trial of adjuvant biochemotherapy (CVD + IL2 
+ IFN) demonstrated a significant improvement on RFS but no improvement of OS. These 
results are interesting but not practice changing (Ref. 18). 
1.1.3.2 
Adjuvant trial with anti-CTLA-4 monoclonal antibody ipilimumab  
In 2014, at the annual meeting of ASCO the EORTC18071 trial results for the primary 
endpoint RFS were reported. EORTC 18071 evaluates in patients with advanced stage III 
melanoma (stage IIIA > 1 mm diameter; stage IIIB/IIIC), in a double-blind RCT the impact 
of adjuvant ipilimumab versus placebo in 951 patients (EORTC 18071; ClinicalTrials.gov, 
number NCT00636168) (Ref. 19). The results indicated a significant impact on RFS (HR 
0.75; p=0.002). Median RFS was 17 months in the placebo arm versus 26 months in the 
ipilimmab treated patients. Data on DMFS and OS were not mature and therefore not 
reported. Adverse Events (AE) were quite frequent. Most common grade 3/4 immune-related 
adverse events (irAEs) in the ipilimumab and placebo arms were gastrointestinal (15.9% vs 
0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most irAEs were managed 
and resolved using established algorithms. Of 471 patients who started ipilimumab, 245 
(52%) discontinued treatment due to AEs [182 (38.6%) within 12 weeks]. Five patients 
(1.1%) died due to drug-related AEs. The trial is being continued for DMFS and OS 
reporting in the next few years. 
1.1.3.3 
Summary of rationale for observation as comparator 
While high dose interferon is approved by the EMA, the current standard of care for locally 
advanced melanoma remains controversial. This uncertainty is reflected in current National 
Comprehensive Cancer Network (NCCN) guidelines, which support observation as one 
approach to patient management in this setting. Uncertainty about the clinical utility of 
interferon, together with a potential reluctance to expose patients who may be cured by 
surgery alone to potentially toxic regimens, has led many physicians in European countries to 
accept surgery alone as a standard of care for locally advanced melanoma. Observation was 
used as a comparator in the recent EORTC 18991 and 18071 trials.  
1.2 
Rationale for trial proposal 
1.2.1 
Immunotherapy and melanoma 
Immunologic interventions to treat cancer can potentially be achieved through the induction 
of an immune response (active immunotherapy), administration of antibodies (passive 
immunotherapy), and/or stimulation of effector cells with cytokines or antibodies. All of 
these approaches have been investigated in melanoma and have shown early promise. 
Immune-modulating agents such as IFN-α and interleukin-2 (IL-2) have shown efficacy 
 
 
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against melanoma and have been approved by the FDA for the treatment of various stages of 
melanoma. In addition to a direct cytotoxic effect, IFN-α is able to stimulate natural killer 
(NK) cell activity and to regulate the expression of histocompatibility antigens or tumor-
associated antigens and demonstrate a 10-15% response rate in metastatic melanoma with 
less than 5% complete responses. The median duration of response ranged from 6 - 12 
months. IFN-α treatment, however, is associated with significant toxicity.  
IL-2 modulates the immune system by stimulating the growth and activity of T lymphocytes, 
human lymphocyte antigen (HLA)-restricted or -non- restricted cytotoxic T cells and induces 
the production of many cytokines, such as tumor necrosis factor (TNF), IFN- α and IL-1. IL-
2 is currently approved in the USA for treatment of Stage IV melanoma; however, its usage 
is also limited due to its significant toxicities. Various combinations of IL-2, IFN- α, and 
chemotherapy drugs have failed to significantly improve survival or quality of life. 
1.2.2 
Immunomodulation and breaking immune tolerance 
1.2.2.1 
Recent developments with anti-CTLA4 and Anti-PD1/PDL1 immune 
checkpoint blockers 
Tackling immune suppression, seems to be a much more powerful intervention than short-
lived immune-activating strategies and the current axioma of “Inhibiting the inhibitor” and 
‘‘breaking tolerance’’ appears to be a particularly powerful approach. This was first 
demonstrated by the success of anti-CTLA4 molecules, resulting in the approval of 
ipilimumab for patients with advanced melanoma in 2011 (Ref. 20, Ref. 21), with similar 
results reported for renal cell cancer as early as in 2005 by the group of Steve Rosenberg at 
the NCI Surgery Branch (Ref. 22). It was observed that long lasting responses seem to 
depend on immunologic control and are rarely obtained with chemotherapy or targeted 
therapies alone. Although BRAF and MEK-inhibitors alone produce responses in up to 50% 
of patients with a BRAF-mutated melanoma, these responses are in general only short lived 
responses lasting 5-6 months (Ref. 23, Ref. 24, Ref. 25). Combinations of these targeted 
agents indicate additive effects, but resistance seems to occur in most patients and tumor 
control seems still only temporary (Ref. 26). 
1.2.2.2 
Durability of response: hall mark of immune checkpoint blockers 
In contrast to the response rates with these targeted agents in BRAF-mutated melanomas, 
response rates with ipilimumab in melanoma (mutated and non-mutated) patients are lower 
(10-15%), but of high durability of about 1.5-2 years (Ref. 20, Ref. 21). Large data sets have 
now confirmed that immunotherapy with ipilimumab is associated with 2-5 year survival 
rates in previously treated advanced melanoma patients to be close to 20% and in treatment 
naïve patients to be superior to 30% (Ref. 27).  
The efficacy indicators of the anti-PD-1 molecules nivolumab and pembrolizumab (MK-
3475 and previously lambrolizumab) appear quite superior those of ipilimumab. Response 
rates are significantly higher and range from 30-50%, while importantly the responses are 
similarly durable, if not superior to the durability of ipilimumab ones (Ref. 28, Ref. 29,  
Ref. 30). Moreover the toxicity profile is much more favorable than that of ipilimumab. At 
the annual meeting of the American Society for Clinical Oncology (ASCO) in 2013 the long 
term follow up data of patients treated with nivolumab were reported and showed 
 
 
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unprecedented 61% one-year and 44% 2-year survival rates (Ref. 29) and were confirmed by 
the update in 2014 at ASCO (Ref. 31). 
Anti-PD1 monoclonal antibodies seem to combine the best of both worlds i.e. high response 
rates and durable responses. The largest study that has been reported on anti-PD1 activity in 
patients with advanced melanoma pertain to pembrolizumab. Initial results were reported in 
2013 (Ref. 32) and in 2014 at the annual meeting of ASCO the results in 411 patients were 
reported (Ref. 33). High response rates and great durability of responses were confirmed in 
the experience with 411 patients. The overall response rate (ORR) by RECIST was 40% 
(95% CI 32%-48%) in ipilimumab-naive (IPI-N) and 28% (95% CI 22%-35%) in ipilimumab 
- treated (IPI-T) patients. Responses were durable (88% ongoing at analysis). Median PFS by 
RECIST was 24 weeks in IPI-N and 23 weeks in IPI-T patients. Median OS was not reached, 
with 1-y OS of 71% in all patients. Benefit was observed by both RECIST and irRC at all 
doses and schedules in IPI-N and IPI-T patients. Pembrolizumab demonstrated activity in all 
major subgroups irrespective of ECOG PS, LDH levels, BRAF mutation, M stage, and 
number and type of prior therapy. Overall, 12% of patients experienced drug-related grade 
3/4 AEs and only 4% of patients discontinued due to a drug-related AE. There were no drug-
related deaths. 
1.2.2.2.1 
Combinations 
The first data in 53 patients, indicate that ipilimumab and nivolumab can be used in 
combination and improve response rates even further (Ref. 34, Ref. 35). With a 62% dose 
limiting toxicity rate however, this combination may not be suited for use in the adjuvant 
setting (Ref. 34).  
All these results clearly indicate that a new era for immunotherapy has arrived and that tumor 
control and “clinical cure” are now real phenomena in the context of the observation that 
most of the patients with durable responses seem to have obtained a state of tumor control 
rather than one of complete tumor eradication. 
1.2.3 
Background data for anti-PD-1 and PD-L1  
The programmed death receptor 1 (PD-1) is another key immune checkpoint receptor 
expressed by activated T cells. 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 CD28 and CTLA-4 which 
has been shown to negatively regulate antigen receptor signaling upon engagement of its 
ligands PD-L1 and/or PD-L2 (Ref. 36, Ref. 37). The structure of murine PD-1 has been 
resolved (Ref. 38). Not only tumor cells can suppress activated-T-Cell function by expressing 
PD-1 receptor ligand, but also (and importantly) myeloid cells in the tumor-infiltrate. 
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-
type (V-type) domain responsible for ligand binding and a cytoplasmic tail responsible for 
the binding of signaling molecules. The cytoplasmic tail of PD-1 contains two tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T cell stimulation, PD-1 
 
 
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recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3, PKCθ, 
and ZAP70, which are involved in the CD3 T cell signaling cascade (Ref. 37, Ref. 39,  
Ref. 40, Ref. 41). 
The mechanism by which PD-1 down modulates T cell responses is similar to, but distinct 
from, that of CTLA-4, as both molecules regulate an overlapping set of signaling proteins 
(Ref. 42, Ref. 43). PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T cells, B cells, T regs, and natural killer cells (Ref. 44, Ref. 45). 
Expression has also been shown during thymic development on CD4-CD8- (double negative) 
T cells, as well as subsets of macrophages and dendritic cells (Ref. 46). 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types including non-hematopoietic tissues and in various tumors (Ref. 43,  
Ref. 47, Ref. 48, Ref. 49, Ref. 50). Both ligands are type 1 transmembrane receptors 
containing both IgV- and IgC-like domains in the extracellular region and contain short 
cytoplasmic regions with no known signaling motifs. Binding of either PD-L1 or PD-L2 to 
PD-1 inhibits T cell activation triggered through the T cell receptor. PD-L1 is expressed at 
low levels on various non-hematopoietic tissues, most notably on vascular endothelium; 
whereas PD-L2 is only detectably-expressed on antigen-presenting cells found in lymphoid 
tissue or chronic inflammatory environments. 
PD-L2 is thought to control immune T cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T cell function in peripheral tissues (Ref. 43). Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T cell inhibitor. High expression of PD-L1 on tumor cells 
(and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and 
survival in various cancer types, including renal cell carcinoma (Ref. 51), pancreatic 
carcinoma (Ref. 52), hepatocellular carcinoma (Ref. 53), and ovarian carcinoma (Ref. 54). 
Furthermore, PD-1 has been suggested to regulate tumor-specific T cell expansion in patients 
with melanoma (Ref. 55, Ref. 57). 
1.2.4 
Pembrolizumab characteristics and clinical data overview 
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-
1 receptor, thus inhibiting its interaction with PD-L1 and 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 being advanced for clinical 
development as an IV immunotherapy for advanced malignancies. 
1.2.4.1 
Non-Clinical Toxicology Summary of Results 
In the 1-month and 6-month toxicology study in cynomologus monkeys, pembrolizumab 
administered once a week and once every other week respectively, intravenously up to 200 
mg/kg resulted in no adverse treatment related effects. The exposure multiple based on a 
predicted AUC 0-tau of 4464 μg.day/mL at the maximum anticipated human clinical dose of 
10 mg/kg (every 2 weeks) Q2W or Q3W (every 3 weeks) is 15-fold at 200 mg/kg, the 
NOAEL for the 6-month monkey study. Additionally, in the tissue cross-reactivity study of 
pembrolizumab with human and monkey tissues demonstrated the expected on-target 
 
 
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staining of the membranes of mononuclear leukocytes in both species. Off-target cross-
reactivity staining was also noted in both species but was limited to cytoplasm of various cell 
types/tissues and the stroma (extracellular connective tissue matrix), and was considered 
related to the experimental method artifacts, i.e. tissue processing for IHC, that are well 
recognized limitations of tissue cross-reactivity studies and, thus not considered 
toxicologically relevant. 
No reproductive or developmental toxicity studies are planned with pembrolizumab. 
Therefore, inclusion of women of childbearing potential in clinical trials should be in 
accordance with the study protocol and applicable regulatory guidance (e.g., ICH M3(R2): 
Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals). 
1.2.4.2 
Clinical development 
As of September 03, 2016, about 21,036 subjects have been treated with pembrolizumab at 
several dose schedules. Pembrolizumab has been generally well tolerated, as expected based 
on preclinical findings and other anti-PD-1 monoclonal antibodies. 
Merck is studying pembrolizumab for various oncology indications (Ref. 56). These studies 
are further outlined in the Investigator's Brochure. 
1.2.4.2.1 
Initial pembrolizumab clinical development 
An open-label Phase I study (Protocol 001) is being conducted to evaluate the safety, 
tolerability, pharmacokinetics (PK) and pharmacodynamics (PD), and anti-tumor activity of 
pembrolizumab when administered as monotherapy. The dose escalation portion of this study 
evaluated three dose levels of single agent pembrolizumab (1 mg/kg, 3 mg/kg, and 10 
mg/kg), in patients with progressive locally advanced or metastatic carcinoma, melanoma 
[IPI-naïve or previously treated with IPI], and non-small cell lung carcinoma (NSCLC). As 
of 26-Jul-2013, there have been 789 patients treated with pembrolizumab as a 30-minute IV 
infusion. Of these 789 patients, preliminary data are available from 479 patients. Based upon 
this safety database consisting of patients treated up to 10 mg/kg once every two to three 
weeks, pembrolizumab has been generally well-tolerated at doses up to 10 mg/kg every other 
week without DLTs. No serious infusions reactions have been reported. One (0.002%) 
patient assayed to date had samples confirmed positive for ADA, but no impact on safety has 
been observed.Pembrolizumab pharmacokinetic results have been obtained following the 
first dose at 1, 3 and 10 mg/kg IV of pembrolizumab administered to 17 patients with solid 
tumors. The observed pharmacokinetic profile of pembrolizumab was typical of other IgG 
mAbs with a half-life (t½) of approximately 2 to 3 weeks. There was no indication of dose 
dependency of half-life in the 3 dose groups and a dose related increase in exposure was 
observed from 1 to 10 mg/kg. The long half-life supports a dosing interval of every 2 or 3 
weeks. Exposure obtained with sparse sampling after dosing melanoma and NSCLC patients 
at 2 and 10 mg/kg, every 2 or 3 weeks, is consistent with this profile. 
Pembrolizumab monotherapy induced an ORR of 25%/27% in patients with ipilimumab-
exposed melanoma by central independent RECIST and oncology review/investigator 
assessed irRC, respectively. Pembrolizumab monotherapy induced an ORR of 39%/43% in 
patients with ipilimumab-naive melanoma by central independent RECIST and oncology 
review/investigator assessed irRC, respectively. These responses are remarkably durable. The 
 
 
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preliminary 1-year survival rate for patients, many of whom have had multiple therapies, 
including ipilimumab, who receive pembrolizumab is 81%.  
The most commonly reported treatment emergent AEs experienced are fatigue (43.8%), 
nausea (26.7%), cough (25.3%), pruritus (24.6%), diarrhoea (22.3%) and rash (21.5%). irAEs 
were reported in 21.4% of melanoma patients; most of these events (15.8%) were considered 
drug-related by the investigator. The most commonly reported, irAEs across the dose-
schedules are rash (3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia 
(2.2%), diarrhoea (2.2%), and pneumonitis (1.9%).  
The organ most frequently affected by irAEs with pembrolizumab is the skin. Less frequently 
affected tissues include thyroid gland, colon, lung, kidney, and liver. 
Review of the overall benefit:risk ratio of pembrolizumab favors enrollment of eligible 
patients into clinical trials of pembrolizumab. The preliminary data suggest that a dose of 
pembrolizumab at 2 mg/kg every 3weeks is appropriate for patients with melanoma. Fixed 
dosing at 200 mg every three weeks will be discussed in Section 5.2.1. 
1.2.4.2.2 
Pembrolizumab melanoma clinical trials 
Results from a phase II registration trial (MK-3475 PN 002) comparing two doses of 
pembrolizumab versus investigator choice of standard chemotherapy in patients with 
advanced melanoma who have progressed after prior therapy (clinicaltrials.gov identifier 
NCT10704287) were reported at the Society for Melanoma Research in November, 2014 
(Ref. 67). The primary objectives were to evaluate progression free survival (PFS) or OS of 
pembrolizumab versus standard of care chemotherapy. Pembrolizumab substantially 
increased PFS at 6 months from 16% to 36% (HR = 0.53 [C.I. 0.43, 0.65]). Assessment of 
OS was immature, and will be further evaluated at later analyses. Incidence of treatment-
related AEs was lower in the pembrolizumab arms compared with the chemotherapy arm. 
Results from a Phase III registration trial (MK-3475-006 AM1) of pembrolizumab versus 
ipilimumab in ipilimumab-naive patients with advanced melanoma were recently published 
after the trial closed early due to demonstrated efficacy of pembrolizumab over ipilimumab 
(Ref. 68). This was a 3-arm study to evaluate the safety and efficacy of two dosing schedules 
of pembrolizumab compared to ipilimumab for the treatment of ipilimumab-naïve 
participants with unresectable or metastatic melanoma. Patients were randomized to receive 
pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or pembrolizumab 10 mg/kg every 
3 weeks for up to 2 years or ipilimumab 3 mg/kg for a total of 4 doses. Primary endpoints of 
this study are PFS and OS. The estimated 6-month PFS rates were 47.3% for pembrolizumab 
every 2 weeks, 46.4% for pembrolizumab every 3 weeks, and 26.5% for ipilimumab (HR for 
disease progression, 0.58; P<0.001 for both pembrolizumab regimens versus ipilimumab). 
Estimated 12-month survival rates were 74.1%, 68.4%, and 58.2%, respectively (HR for 
death for pembrolizumab every 2 weeks, 0.63; 95% CI, 0.47 to 0.83; P = 0.0005; HR for 
pembrolizumab every 3 weeks, 0.69; 95% CI, 0.52 to 0.90; P = 0.0036). 
Additional studies of pembrolizumab in advanced melanoma are ongoing. MK-3475 027 is 
evaluating efficacy and safety of pembrolizumab in melanoma and NSCLC metastatic to 
brain. MK-3475 022 is evaluating safety and efficacy of pembrolizumab in combination with 
the mutant BRAF inhibitors Trametinib and Dabrafenib. Safety and efficacy of combinations 
with ipilimumab and peg-interferon will be evaluated in MK-3475 029. MK-3475-034 is 
 
 
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evaluating the safety and efficacy of pembrolizumab in combination with talimogene 
laherperpvec. MK-3475-053 is comparing Investigator's choice of high dose interferon or 
ipilimumab to pembrolizumab. MK-3475-252 is evaluating the efficacy of pembrolizumab in 
combination with epacadostat or placebo. For these and other ongoing trial details please 
refer to the Investigator's brochure (IB). 
1.2.4.2.3 
Relationship of response to pembrolizumab depends on PD-L1 expression 
as evaluated by immunohistochemistry 
Expression of PD-L1 has been shown to be associated with tumor response and survival in 
the initial phase 1 trial KEYNOTE-001 (NCT01295827) presented at ASCO in 2014 by 
 
 Tumor response in 125 patients treated with any of the three weight-based regimens 
was assessed by RECIST 1.1 and compared to PD-L1 tumor expression in pretreatment 
biopsy specimens. Tumor PD-L1 expression was assessed by IHC and a 1% expression in 
stained cells was used to define the positive population. Tumor PD-L1 expression levels were 
associated with tumor response (Table 1). While there was a general association of response 
with PD-L1 positive status, PD-L1 negative patients responded and their responses were as 
durable as those of the PD-L1 positive patients.  
 
10 mg/kg Q2W 
n = 35 
10 mg/kg Q3W 
n = 47 
2 mg/kg Q3W 
n = 31 
PD-L1+ * 
86% 
77% 
55% 
Overall response rate 
Unselected 
51% 
32% 
39% 
PD-L1 + 
57% 
39% 
59% 
PD-L1- 
20% 
9% 
14% 
*Level of PD-L1 expression in percentage 
Table 1: Overall response rate by PD-L1 positivity by dose and schedule 
Overall and progression free survival were evaluated as well (Figure 1). It is important to 
again note that a longer PFS was generally associated with PD-L1 positivity, PD-L1 negative 
patients had prolonged benefit, and the overall survival of the PD-L1 negative patients was 
prolonged and has not crossed the median after longer than one year. 
 
 
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Figure 1: PFS and OS based on tumor PD-L1 expression (Central Review, RECIST v.1.1) 
Given the evidence that both PD-L1 positive and negative patients can benefit from 
pembrolizumab in the metastatic setting, this study will evaluate potential benefit in both the 
overall population, as well as the PD-L1 positive biomarker subgroup. 
1.2.4.2.4 
Pembrolizumab clinical trials in non-melanoma indications 
Additional clinical trials are being conducted in NSCLC, head and neck cancer, triple 
negative breast cancer, gastric cancer, bladder cancer, hematologic malignancies and a range 
of additional malignancies. For additional trial details please refer to the IB. 
A randomized, adaptively designed Phase II/III trial (Protocol 010) is being conducted to 
evaluate two dosing schedules of pembrolizumab (10 mg/kg Q3W or 2 mg/kg Q3W) versus 
docetaxel in previously treated patients with NSCLC with PD-L1 positive tumors who have 
experienced disease progression after platinum-containing systemic therapy. This protocol 
has randomized three patients with NSCLC across the 3 treatment groups: 10 mg/kg Q3W, 2 
mg/kg Q3W, and docetaxel 75 mg/m² Q3W in a 1:1:1 ratio. No safety and efficacy data are 
available. Two phase III registration trials studies of first line therapy with pembrolizumab 
are designed as pivotal tests of its efficacy in NSCLC (MK-3475 024 and 042).  
A non-randomized, multi-cohort trial (Protocol 012) is evaluating pembrolizumab 10 mg/kg 
Q2W in patients with PD-L1 positive advanced solid tumors. Cohort A has enrolled patients 
with triple negative breast cancer, Cohort B has enrolled patients with squamous cell 
carcinoma of the head and neck, Cohort C has enrolled patients with urothelial tract cancer of 
the renal pelvis, ureter, bladder, or urethra. Cohort D has enrolled patients with 
adenocarcinoma of the stomach or gastroesophageal junction. Safety and efficacy of 
pembrolizumab are being evaluated in an additional 20 tumor indications in MK-3475 028. 
 
 
 
 
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2 Objectives of the trial 
2.1 
Primary objective 
♦ To prospectively assess whether post-operative adjuvant therapy with pembrolizumab 
improves recurrence-free survival, as compared to placebo in high-risk patients with 
complete resection of Stage IIIA (>1 mm metastasis), IIIB and IIIC melanoma. 
♦ To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor 
expression, pembrolizumab improves recurrence-free survival as compared to placebo. 
2.2 
Secondary objectives 
♦ To prospectively assess whether post-operative adjuvant therapy with pembrolizumab 
improves distant metastasis free survival as compared to placebo. 
♦ To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor 
expression pembrolizumab improves distant metastasis free survival as compared to 
placebo. 
♦ To prospectively assess whether post-operative adjuvant therapy with pembrolizumab 
improves overall survival, as compared to placebo. 
♦ To prospectively assess whether in the subgroup of patients with PD-L1-positive tumor 
expression pembrolizumab improves overall survival as compared to placebo. 
♦ To compare adverse event profiles (AE and Serious Adverse Event (SAE)) between 
patients receiving pembrolizumab versus patients in the placebo arm. 
♦ To evaluate the pharmacokinetics (PK) of pembrolizumab when pembrolizumab is 
administered at 200 mg every three weeks.  
2.3 
Exploratory objectives 
♦ To compare quality of life between the two arms (pembrolizumab versus placebo). 
♦ To compare health outcomes evaluation between the two arms (pembrolizumab versus 
placebo). 
♦ To evaluate predictive biomarkers (e.g., immune-related gene signatures, genetic 
variation, SPDL1) for treatment difference in outcome. 
♦ Progression/recurrence-free survival 2 (PRFS2) 
2.4 
End-points 
Refer to Section 7 for definitions of endpoints 
 
 
 
 
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2.4.1 
Primary endpoint 
The primary endpoints are: 
♦ Recurrence free survival (RFS) 
♦ RFS in subgroup of patients with PD-L1-positive tumor expression receiving either 
pembrolizumab or placebo 
2.4.2 
Secondary endpoints 
♦ Distant metastases-free survival (DMFS) 
♦ DMFS in subgroup of patients with PD-L1-positive tumor expression receiving either 
pembrolizumab or placebo 
♦ Overall survival (OS) 
♦ OS in subgroup of patients with PD-L1-positive tumor expression receiving either 
pembrolizumab or placebo 
♦ Toxicity profile according to Common Terminology Criteria for Adverse Events 
(CTCAE) v. 4.0 
♦ To evaluate the pharmacokinetics (PK) of pembrolizumab when pembrolizumab is 
administered 200 mg every 3 weeks 
♦ To assess for development of anti-drug antibodies (ADA) 
2.4.3 
Exploratory endpoints 
♦ Quality of life  
♦ Health outcomes evaluation 
♦ To evaluate predictive biomarkers (e.g. immune-related gene signatures, genetic 
variation, SPDL1) for treatment difference in outcome  
♦ Progression/recurrence-free survival 2 (PRFS2) 
3 Patient selection criteria 
Patient enrollment will follow a three steps procedure as illustrated in Section 4 (step 1 
registration, step 2 central confirmation of PD-L1 expression, step 3 enrollment and 
randomization through IVRS). Patients must meet all of the criteria described in Section 3 to 
be eligible for enrollment. 
3.1 
Registration- step 1 (ORTA Step 1) 
Before patient registration, written informed consent for tumor testing must be given 
according to ICH/GCP, and national/local regulations. 
Note: if a patient signs the Registration Informed Consent before CLND was 
performed, please contact the medical monitor to assess eligibility before registering in 
ORTA. 
 
 
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♦ At least 18 years of age. 
♦ No mucosal or ocular melanoma. 
♦ Melanoma with unknown origin of the primary is eligible. 
♦ Complete resection of Stage III melanoma (AJCC R0) with histologically confirmed 
cutaneous melanoma metastatic to lymph node, classified as (AJCC, 2010): Stage IIIA 
with metastasis > 1 mm; any Stage IIIB or IIIC. No past or current in-transit metastases 
or satellitosis. 
♦ Patient population IIIA (> 1 mm metastasis) is capped at a maximum of 20% of the 
total patient population. 
♦ Mandatory to ship tumor sample for evaluation of PD-L1 expression. A tumor sample 
obtained at resection or tissue obtained from the biopsy must not be previously irradiated. 
During the screening period, the tumor sample must be sent to the central pathology 
laboratory for PD-L1 expression testing. Patients will be eligible to participate regardless 
of the level of PD-L1 expression. 
♦ PD-L1 testing is mandatory: tumor material will be collected from positive lymph 
nodes (LN) embedded in paraffin. If the resection samples from LNs are not adequate 
for PD-L1 testing, the primary melanoma must be collected. Patients whose samples 
are inadequate for PD-L1 determination will not be enrolled.  
♦ In addition the primary melanoma may also be collected if available to evaluate the 
PD-L1 expression.  
3.2 
Central confirmation of PD-L1 expression - step 2 
This central confirmation through EORTC is required for enrolling the patient in step 3 
3.3 
Enrollment and Randomization - step 3 (ORTA Step 2) 
Before patient enrollment, written informed consent to participate in the trial must be 
given according to ICH/GCP, and national/local regulations. 
♦ The resection of Stage III lymph nodes must have been performed in complete 
compliance with the Criteria for adequate surgical procedures for complete lymph node 
dissection (CLND) that is displayed in Appendix F. This must be documented in the 
medical file (including the pathology report); patients without documentation of adequate 
resection are not eligible.  
♦ To be considered as adequate, the surgical and pathological procedures should have 
included at least the following: 
♦ Head and Neck 
♦ Minimum of 15 pathologically investigated nodes 
♦ Face, ear, and anterior scalp: parotidectomy plus modified radical neck dissection 
♦ Posterior scalp: modified radical neck dissection plus suboccipital nodes. For this 
specific localization, a CLND will be considered as adequate if at least 5 LN have 
been investigated 
 
 
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♦ Upper Extremity 
♦ Minimum of 10 pathologically investigated nodes 
♦ Axillary node dissection included at least 10 nodes taken from Levels I and II  
♦ Level III nodes dissected if they were clinically involved 
♦ Pectoralis minor muscle may be divided or sacrificed with the specimen at the 
discretion of the surgeon 
♦ Lower Extremity 
♦ Minimum of 5 pathologically investigated nodes 
♦ Superficial inguinal node dissection was performed for non-palpable nodal 
involvement 
♦ If Cloquet’s node was positive, a deep inguinal node dissection was performed 
♦ Lymph Node Dissection for Nodal Recurrence 
♦ Regional node recurrence was treated using the appropriate lymphadenectomy as 
above 
♦ Diagnosis of regional node recurrence was made by fine needle aspiration 
technique to avoid contaminating the region with tumor, followed by CLND as 
above 
♦ The maximum duration from surgery to first study drug treatment is 13 weeks. Treatment 
should start only after complete wound healing from the surgery. 
Note: if there is a delay of 1-7 days exceeding 13 weeks due to extreme unforeseen 
circumstances, the eligibility should be discussed with the medical monitor. 
♦ Disease status for the post-surgery baseline assessment must be documented by full 
Chest/Abdomen/Pelvis CT and/or MRI with Neck CT and/or MRI (for Head and Neck 
primaries) and complete clinical examination after the informed consent and prior to 
enrollment. 
Note: if a patient had laboratory/imaging tests as part of local routine guidelines (standard 
of care) prior to signing informed consent, the procedures will be acceptable for 
screening purposes if they are within the window required by the protocol. 
♦ Disease-free (no loco-regional relapse or distant metastasis); no clinical evidence for 
brain metastases.  
♦ BRAF mutation status (known or not done).  
♦ ECOG performance status of 0 or 1. 
Patient demonstrates adequate organ function as defined in Table 2, screening labs should be 
performed within 14 days (+/- 3 days) prior to treatment initiation.  
 
 
 
 
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System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥ 1,500 /mcL 
Platelets 
≥ 100,000 / mcL 
Hemoglobin 
≥ 9 g/dL or ≥ 5.6 mmol/L  
Renal 
Creatinine or 
Measured or calculated creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
Creatinine clearance should be 
calculated per institutional standard. 
≤ 1.5xULN or 
≥ 60 mL/min for patient with  
creatinine levels > 1.5x institutional ULN 
Note: For patients entering Part 2  
≥ 30 mL/min for patient with  
creatinine levels > 1.5x institutional ULN 
 
Hepatic 
Total bilirubin 
≤ 1.5xULN or 
Direct bilirubin ≤ ULN for patients with 
total bilirubin levels >1.5xULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5xULN 
Coagulation 
International Normalized Ratio (INR) 
or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤ 1.5xULN unless patient is receiving 
anticoagulant therapy as long as PT or 
PTT is within therapeutic range of 
intended use of anticoagulants 
≤ 1.5xULN unless patient is receiving 
anticoagulant therapy as long as PT or 
PTT is within therapeutic range of 
intended use of anticoagulants 
Table 2: Adequate Organ Function Laboratory ValuesPrior treatment for melanoma 
♦ In case of an indication for post lymph node dissection radiotherapy, this must have 
been completed within the 13 weeks post-surgery period and prior to treatment start. 
Note: radiotherapy may alter the process of wound healing. If the wound healing is 
not complete patient will not be eligible. 
 
 
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♦ No prior therapy for melanoma except surgery for primary melanoma lesions; patients 
who have previously received IFN for thick primary melanomas without evidence of 
lymph node involvement are eligible. 
♦ No history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
No history of or current interstitial lung disease.  
♦ No history of another malignancy or a concurrent malignancy. Exceptions include 
patients who have been disease-free for 5 years, or patients with a history of completely 
resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, 
for example cervical cancer in situ. 
♦ No active autoimmune disease that has required systemic treatment in 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.  
♦ No active infection requiring therapy. 
♦ Patients with hyperthyroidism or hypothyroidism but that are stable on hormone 
replacement will not be excluded. 
♦ No diagnosis of immunodeficiency, no systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment 
♦ No known history of human immunodeficiency virus (HIV), active Hepatitis B or 
Hepatitis C. 
♦ Patients who received treatment with live vaccines within 30 days prior to the first dose 
of study medication are not eligible. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, chicken pox, shingles, yellow fever, 
seasonal flu, H1N1 flu, rabies, BCG and typhoid vaccine. 
♦ Patient must not have received prior treatment with any anti-CTLA4 monoclonal 
antibody or anti-PD-1, or PD-L1 or PD-L2 agent. 
Examples of PD-1 inhibitors (include, but are not limited to): pembrolizumab (Merck); 
Nivolumab (also known as BMS-936558, MDX-1106, ONO-4538) (Bristol-Myers Squibb); 
Pidilizumab (CT-11) (Cure-Tech/Teva); and AMP-224 (Amplimmune). 
Examples of PD-L1 inhibitors (include, but are not limited to): BMS-936559 (also known as 
MDX-1105) (Bristol-Myers Squibb); MPDL3280A (also known as RG7446) (Roche 
Genentech); and MEDI4736 (MedImmune). 
♦ Patient is not currently participating and receiving study therapy or has not participated in 
a study of an investigational agent and received study therapy or used an investigation 
device within 4 weeks prior to the first dose of treatment 
♦ Women of child bearing potential (WOCBP) must have a negative serum (or urine) 
pregnancy test within 72 hours prior to the first dose of study treatment. 
♦ Patients of childbearing / reproductive potential should use adequate birth control 
methods, as defined by the investigator, during the study treatment period and for a 
 
 
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period of 120 days after the last dose study drug. A highly effective method of birth 
control is defined as those which result in low failure rate (i.e. less than 1% per year) 
when used consistently and correctly. 
♦ Note: abstinence is acceptable if this is established and preferred contraception for the 
patient and is accepted as a local standard. 
♦ Please refer to Appendix N for recommendations based on Clinical Trial Facilitation 
Group guidelines for sites and countries where applicable (e.g. United Kingdom, 
Norway, Sweden, Portugal, etc). 
♦ Female patients who are breast feeding should discontinue nursing prior to the first dose 
of study treatment and until 120 days after the last dose of study drug. 
♦ Absence of any condition hampering compliance with the study protocol and follow-up 
schedule; those conditions should be discussed with the patient before registration in the 
trial. 
♦ Patient will not be eligible: if patient is or has an immediate family member (e.g., spouse, 
parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly 
involved with this trial, unless prospective IRB approval (by chair or designee) is given 
allowing exception to this criterion for a specific subject.  
Once eligibility has been verified, the treatment arm will be randomly allocated to the 
patient. 
Important note: All eligibility criteria must be adhered to. 
4 Trial Design 
This is an international, double-blinded, placebo-controlled randomized phase III trial. The 
trial design is detailed in Figure 3. 
4.1 
Part 1: Adjuvant therapy 
4.1.1 
Multi step process for enrollment 
Patients will enter the screening phase to assess their eligibility after complete resection of 
stage III melanoma.  
The surgery date is defined as the latest surgery that made the patient free of disease (AJCC 
R0). 
 
 
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4.1.1.1 
Registration - step 1 (ORTA Step 1) 
Upon consent, patient will be registered and a sample of the resected tumor material will be 
evaluated for PD-L1 expression at a central pathology lab.  
Evaluation of response in PD-L1 biomarker populations: Section 1.2.4.2.3 describes the 
potential correlation of patient response with the expression status of PD-L1 in their tumor. 
All patients will be required to submit a sample of their resected tumor for PD-L1 IHC 
expression for evaluation by a vendor designated by the Sponsor. Tumor material will be 
evaluated by the central laboratory following procedures outlined in the Procedures manual. 
Results will be recorded as positive ( 1% PD-L1 IHC), negative ( 1% PD-L1 IHC) or 
undetermined level of expression (indeterminate PD-L1 IHC) for subgroup analysis.  
Biological material for PD-L1 testing: tumor material will be collected from positive lymph 
nodes. Lymph nodes embedded in paraffin will be stained with anti-PD-L1 antibodies.  
If PD-L1 status cannot be determined from the lymph node samples, then primary melanoma 
will be screened for PD-L1 expression. Primary melanoma samples may be substituted for 
the lymph node tissues as needed. 
4.1.1.2 
Central confirmation of PD-L1 expression- step 2 
Confirmation of PD-L1 status by the central laboratory through EORTC. 
4.1.1.3 
Enrollment and Randomization - step 3 (ORTA Step 2) 
The confirmation of PD-L1 expression must be available before proceeding with the 
enrollment in the study. The patient's written informed consent to undergo screening for the 
clinical trial must be given prior to the performance of any protocol laboratory/imaging tests 
that are not part of local routine guidelines. 
Once eligibility has been verified, the treatment arm will be randomly allocated to the 
patient (see Figure 2). 
Note: if after randomization patient develops an adverse event, it has to resolve to 
Grade 0-1 before dosing. If the delay exceeds the 13 weeks interval from surgery to 
start of treatment, please contact the medical monitor. 
 
 
 
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Figure 2. Multi step process for enrollment 
4.1.2 
Sample size and stratification factors 
A total of approximately 900 eligible patients will be randomized into two equal-sized 
double blind treatment arms (approximately 450 patients each) to receive pembrolizumab vs 
placebo.  
The treatment should start no later than 13 weeks after surgery and only after complete 
wound healing from the surgery. 
Randomization will be performed centrally (see Section 14) and will be stratified for the 
following factors: 
♦ Stage (IIIA (> 1 mm metastasis) vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC 4 
positive lymph nodes) 
♦ Region (North America, European countries, Australia and other countries as designated) 
 
 
 
 
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4.2 
Part 2: after the first recurrence (Cross-over or Re-
challenge treatment) 
The main inclusion criteria previously established for Part 1 remains for Part 2 of the study 
except for the below:  
♦ Surgery, biopsy and/or radiotherapy (palliative or adjuvant) are allowed prior to Part 2. 
Radiotherapy has to be completed prior to first dose and complete wound healing is 
required prior to first dose.  
♦ Latest imaging scan date should be within 4 weeks (+/- 7 days) prior to first dose. 
♦ All lab assessments described in Table 2 should be performed within 14 days (+/- 3 days) 
prior to first dose. 
Note: For patients entering Part 2, creatinine clearance ≥ 30 mL/min for patient with 
creatinine levels > 1.5x institutional ULN 
♦ All other assessements (physical exam, AE/Conmeds, QoLs, etc) are to be performed 
within 14 days (+/- 3 days) prior to first dose 
IMPORTANT: Patients enrolled in Part 2 of the study (Cross-over or Re-challenge 
treatment) should not receive any other form of antineoplastic or adjuvant therapy. 
4.2.1 
Crossover for patients in the placebo arm with documented 
recurrence 
Patients assigned to the placebo arm who experience disease recurrence (as per Section 7.1.1) 
and meet all crossover criteria (Section 4.2.1.1), will be offered to crossover to 
pembrolizumab and receive pembrolizumab 200 mg IV Q3W.  
The primary objective of the overall study is to compare RFS of pembrolizumab versus 
placebo, while ensuring access to pembrolizumab for all patients entering the study by 
allowing crossover after recurrence. 
4.2.1.1 
Crossover qualifications 
Patients will be considered for crossover to pembrolizumab after documented recurrence as 
per Section 7.1.1. Crossover is optional and is at the discretion of the Investigator. Patients 
who meet the following criteria are eligible for crossover: 
♦ No evidence of brain metastases or any other central nervous system (CNS) disease (e.g, 
leptomeningeal disease, spinal cord, etc.). An imaging scan is required to confirm no 
brain metastasis or other CNS. 
Note : a brain MRI is required to confirm absence of brain metastasis and leptomeningeal 
disease. Additional imaging should be obtained as indicated in symptomatic patients.  
♦ After the first recurrence, if patient experiences a second recurrence or a 
progression before enrolment in part 2, he/she will not be eligible for part 2. 
♦ ECOG performance status 0-2 
♦ Documentation of recurrence as per Section 7.1.1 
 
 
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♦ Consent for the cross-over and collection of tumor material. For patients who will have a 
biopsy to confirm the recurrence or for those that will undergo surgery, they will be asked 
to consent to assess the PD-L1 status using the newly collected tumor material and to 
biobank this tumor material.  
Note: the results from PD-L1 testing for Part 2 are not needed prior to treatment start. 
4.2.1.2 
Crossover Assessments and Procedures 
All procedures and assessments completed at the time of withdrawal from adjuvant treatment 
may be used as appropriate for the start of the Crossover part of the study. 
4.2.2 
Rechallenge for patients in the pembrolizumab arm with 
documented recurrence >6 months after completion of one year 
of adjuvant therapy 
4.2.2.1 
Rechallenge qualifications 
Patients will be considered for re-treatment with pembrolizumab after documented 
recurrence if their disease recurs > 6 months after completing one year of adjuvant 
pembrolizumab treatment as per Section 7.1.1. Re-challenge is optional and is at the 
discretion of the Investigator. Patients who meet the following criteria are eligible for re-
challenge: 
♦ No evidence of brain metastases or any other central nervous system (CNS) disease (e.g, 
leptomeningeal disease, spinal cord, etc.). An imaging scan is required to confirm no 
brain metastasis or other CNS. 
Note : a brain MRI is required to confirm absence of brain metastasis and leptomeningeal 
disease. Additional imaging should be obtained as indicated in symptomatic patients.  
♦ After the first recurrence, if patient experiences a second recurrence or a 
progression before enrolment in part 2, he/she will not be eligible for part 2. 
♦ ECOG performance status 0-2 
♦ Documentation of recurrence as per Section 7.1.1 
♦ Consent for the rechallenge 
♦ Collection of tumor material. Patients who will have a biopsy to confirm the recurrence 
or patients that will undergo surgery will be asked to consent to assess tumor PD-L1 
status using newly collected tumor material and to biobank this tumor material. 
Note: the results from PD-L1 testing for Part 2 are not needed prior to treatment start. 
4.2.2.2 
Rechallenge Assessments and Procedures 
All procedures and assessments completed at the time of withdrawal from adjuvant treatment 
may be used as appropriate for the start of the re-challenge part of the study. 
 
 
 
 
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4.3 
Unblinding data 
The authorized unblinding of treatment arm will take place under the following conditions:  
♦ Emergency unblinding 
♦ Unblinding by investigator after first disease recurrence 
♦ Unblinding at final analysis 
♦ Other unblinding during the course of the study  
Please see Section 14.7 for unblinding procedures 
 
 
 
Figure 3: Trial design 
 
 
 
 
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5 Therapeutic regimens, expected toxicity, dose 
modifications 
5.1 
Placebo 
Placebo will be normal saline solution prepared by the local pharmacist, dosed and 
administered in the same manner as the investigational product. 
5.2 
Pembrolizumab (MK-3475)  
The nomenclature of pembrolizumab drug substance  
Code name: MK-3475 (Anti-PD-1) 
Chemical name: Humanized X PD-1_mAb (H409A11) IgG4 
5.2.1 
Selected dose 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic 
data (IL-2 release assay) suggested that peripheral target engagement is durable (> 21 days). 
This early PK and pharmacodynamic data provided a scientific rationale for evaluating the 
Q3W dosing schedule. 
The choice of the 200 mg Q3W as an appropriate dose for fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
Based on PK data obtained in this study as well as PK data obtained from other studies (if 
available), a population PK analysis will be performed to characterize pharmacokinetic 
parameters (Cmax, AUC, Ctrough) as endpoints and evaluate the effect of extrinsic and 
intrinsic factors to support the proposed dosing regimen. Pharmacokinetic samples will also 
be used to explore the exposure-response relationships for pembrolizumab antitumor 
activity/efficacy as well as safety in the proposed patient population, if feasible. The results 
of these analyses, if performed, will be reported separately. 
5.3 
Drug supply 
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. 
 
 
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5.3.1 
Placebo 
Placebo for this trial will be provided by investigational sites and prepared by the local 
unblinded pharmacist. 
5.3.2 
Pembrolizumab 
Pembrolizumab will be provided by Merck. 
5.3.2.1 
Initial drug supply 
Refer to Pharmacy manual. 
5.3.2.2 
Drug resupply by IVRS 
Refer to IVRS manual. 
5.3.3 
Packaging, labeling, handling and storage 
5.3.3.1 
Packaging 
Packaging and labeling of Pembrolizumab will be in accordance with Good Manufacturing 
Practice (GMP) for clinical trials.  
5.3.3.2 
Labeling 
Pembrolizumab will be affixed with a clinical label in accordance with regulatory 
requirements.  
5.3.3.3 
Dosage and Administration 
Pembrolizumab will be provided by Merck in vials of 50 mg lyophilized powder or in 100 
mg liquid vials. 
Details on the dose preparation and administration are provided in the Unblinded Pharmacist 
Manual. 
5.3.3.4 
Storage 
Investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the Investigator to ensure that investigational product is only dispensed 
to study patients. The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations. 
The Investigator should ensure that the investigational product is stored in accordance with 
the environmental conditions (temperature, light and humidity) as determined by the Sponsor 
and defined on the label. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
 
 
 
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5.3.4 
Drug accountability 
The unblinded pharmacist is responsible for investigational product accountability, 
reconciliation, and record maintenance. In accordance with all applicable regulatory 
requirements, the unblinded pharmacist or designated site staff must maintain investigational 
product accountability records throughout the course of the study. This person(s) will 
document the amount of investigational product dispensed and/or administered to study 
patients and the amount received from and returned to Merck, when applicable. 
5.3.5 
Return of investigational product 
The unblinded pharmacist is responsible for keeping accurate records of the clinical supplies 
received from the Sponsor or designee, the amount dispensed to the patients and the amount 
remaining at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return. 
5.3.6 
Destruction of investigational product 
The unblinded pharmacist is responsible for keeping accurate records of the clinical supplies 
received from the Sponsor or designee, the amount dispensed to the patients and the amount 
remaining at the conclusion of the trial. For all trial sites, the local country Sponsor personnel 
or designee will provide appropriate documentation that must be completed for drug 
accountability and return, or local discard and destruction if appropriate. Where local discard 
and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented. Unused clinical supplies can only be destroyed 
after being inspected and reconciled by the responsible study monitor. 
5.3.7 
Standard Policies 
Trial site personnel will have access to a central electronic randomization system (IVRS 
system) to allocate patients, to assign treatment to patients and to manage the distribution of 
clinical supplies. Each person accessing the IVRS system must be assigned an individual 
unique PIN. They must use only their assigned PIN to access the system, and they must not 
share their assigned PIN with anyone. 
 
 
 
 
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5.4 
Treatment schedule 
The treatment schedule is detailed in Figure 4. 
 
Figure 4: Treatment schedule  
5.4.1 
Part 1: Adjuvant therapy schedule, duration and withdrawal 
Pembrolizumab 200 mg fixed dose OR Placebo 0 mg, will be administered by IV, every 3 
weeks (+/- 3 days). 
5.4.1.1 
Adjuvant treatment duration 
Pembrolizumab/Placebo will be administered intravenously (IV), every 3 weeks, for 1 year 
or to complete total 18 doses.  
Note: if cycles are skipped and/or delayed treatment will continue beyond 1 year in 
order to complete the 18 doses. For any patient who is not able to complete the required 
18 doses, a notification to the study monitor is required to determine if it would impact 
eligibility for entry into Part 2. 
5.4.1.2 
Withdrawal criteria for Part 1 adjuvant treatment 
Patients may discontinue study treatment or withdraw their consent to participate in the study 
at any time without prejudice.  
The following conditions require patient discontinuation from study treatment: 
♦ Recurrence as defined in Section 7.1.1. Upon recurrence, the treatment will be unblinded  
♦ Normal completion of the protocol treatment (one year) 
♦ Note: one year of treatment is calculated from the date of first dose  
♦ AE or intercurrent illness that, in the opinion of the investigator, warrants the patient’s 
withdrawal from study treatment. 
 
PART 1 
ADJUVANT TREATMENT 
Pembrolizumab vs Placebo  
1 year treatment period unless 
occurrence of a withdrawal 
criterion 
PART 2 
TREATMENT AFTER 1st 
RECURRENCE 
Pembrolizumab  
Up to 1 year (local recurrence) or 
2 years treatment period 
unless occurrence of a 
withdrawal criterion  
 
Upon 
recurrence 
 
 
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♦ Specific conditions described in the Management of Adverse Events (see Appendix G 
and Appendix H). 
♦ Investigator’s decision to withdraw the patient 
♦ Noncompliance with study treatment or procedure requirements 
♦ Lost to follow up: at least 1 phone call and 2 certified letters before we can call a 
subject lost to follow up  
♦ Sexually active patients who refuse to use medically accepted adequate birth control 
methods as described in the patient selection criteria during the course of the study and 
for a period of 120 days following discontinuation of study treatment. 
♦ A female patient inadvertently becomes pregnant 
♦ Request by regulatory agencies for termination of treatment of an individual patient or all 
patients under the protocol. 
♦ Occurrence of a new malignancy. 
♦ Exceptions: 
♦ Patients with reported SAEs of non-melanoma skin cancer or in situ carcinoma 
may remain in the study at the discretion of the investigator and if discussed with 
medical monitor. 
♦ Patients with thin non-ulcerated primary melanoma 
♦ The patient or legal representative (such as a parent or legal guardian) withdraws consent 
for treatment 
♦ Administrative reasons 
5.4.2 
Part 2: After the First Recurrence (Cross-over or Re-challenge 
treatment) 
Upon documented recurrence as per Section 7.1.1, patients may undergo surgery and 
radiotherapy if indicated. For systemic treatment see Sections below. 
5.4.2.1 
Crossover from placebo to pembrolizumab 
Upon documented recurrence, adjuvant treatment will be unblinded as per Section 14.7.2. 
Patients assigned to the placebo arm that meet all crossover criteria, (as per Section 4.2.1.1) 
will be offered to crossover to pembrolizumab and receive pembrolizumab 200 mg IV Q3W, 
if clinically indicated. 
Patients will be separately consented for this part of the trial. 
 
 
 
 
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5.4.2.2 
Administration of pembrolizumab after the first recurrence (Re-
challenge) 
Upon documented recurrence, patients assigned to pembrolizumab adjuvant arm who 
experience disease recurrence more than six months after completing one year of therapy 
may be re-treated with pembrolizumab 200 mg IV Q3W, if clinically indicated and if they 
fulfill criteria as per Sections 4.2 and 4.2.2.1.  
Patients will be separately consented for this part of the trial.  
5.4.2.3 
Treatment duration for pembrolizumab  
Treatment in Part 2 will be administered up to 1 year (local recurrence) or 2 years treatment 
period unless occurrence of a withdrawal criterion (see Section 5.4.2.4). 
For patients with local recurrence, the treatment may stop at 1 year at the discretion of the 
investigator. 
 
5.4.2.4 
Withdrawal criteria for Part 2 treatment (Cross-over or Re-challenge 
treatment) 
In part 2 (Cross-over or Re-challenge treatment) of the trial, a patient must be discontinued 
from treatment for this part of the trial (but may continue to be monitored in the trial) for any 
of the following reasons: 
♦ Radiographic disease progression according to RECIST 1.1 (Appendix O) 
♦ Completed up to 1 year (local recurrence) or 2 years of treatment with pembrolizumab 
(Section 5.4.2.3) 
♦ Note: duration of study medication is calculated from the date of first dose after first 
recurrence. 
♦ AE or intercurrent illness that, in the opinion of the investigator, warrants the patient’s 
withdrawal from study treatment 
♦ Specific conditions described in the Management of Adverse Events (see Appendix G 
and Appendix H) 
♦ Investigator’s decision to withdraw the patient 
♦ Noncompliance with study treatment or procedure requirements 
♦ Lost to follow up: at least 1 phone call and 2 certified letters before we can call a 
subject lost to follow up 
♦ Sexually active patients who refuse to use medically accepted adequate birth control 
methods as described in the patient selection criteria during the course of the study and 
for a period of 120 days following discontinuation of study treatment. 
♦ A female patient inadvertently becomes pregnant 
♦ Request by regulatory agencies for termination of treatment of an individual patient or all 
patients under the protocol. 
 
 
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♦ Occurrence of a new malignancy. 
♦ Exceptions:  
♦ Patients with reported SAEs of non-melanoma skin cancer or in situ carcinoma 
may remain in the study at the discretion of the investigator and if discussed with 
medical monitor. 
♦ Patients with thin non-ulcerated primary melanoma 
♦ The patient or legal representative (such as a parent or legal guardian) withdraws consent 
for treatment 
♦ Administrative reasons 
5.5 
Management of Toxicity  
For management of toxicity and supportive care guidelines please refer to Appendix G 
and Appendix H. 
5.6 
Concomitant medications 
All treatments that the Investigator considers necessary for a patient'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 electronic case report form 
(eCRF) including all prescription, over-the-counter, herbal supplements, and IV medications 
and fluids. If changes occur during the study period, documentation of drug dosage, 
frequency, route, and date will also be included on the eCRF. 
All concomitant medications received within 30 days before the first dose of study drug 
through 30 days after the last dose of study drug should be recorded. 
5.6.1 
Prohibited medications, therapies and procedures 
♦ Any anti-cancer treatment except those permitted in this trial (pembrolizumab and 
surgery) 
♦ After the first recurrence, radiotherapy is permitted before starting part 2. 
♦ Any investigational agents other than the study drug 
♦ Immunosuppressive agents (except for patients treated for irAE) 
♦ Chronic systemic corticosteroids (except for patients which during the study developed 
endocrinopathies requiring stable doses of hormone replacement therapy such as 
hydrocortisone.) 
♦ Live vaccines within 30 days prior to the first dose of study drug and while participating 
in the study. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, shingles, yellow fever, seasonal flu, H1N1 flu, 
rabies, BCG, and typhoid vaccine. 
 
 
 
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6 Clinical evaluation, laboratory tests and follow-
up 
6.1 
General considerations 
The patient's written informed consent to undergo screening for the clinical trial must be 
given prior to the performance of any protocol laboratory/imaging tests that are not part of 
local routine guidelines. Therefore, if a patient had laboratory/imaging tests as part of local 
routine guidelines (standard of care) prior to signing informed consent, the procedures will be 
acceptable for screening purposes if they are within the window required by the protocol.  
The Trial Flow Charts - Section 6.4 summarizes the trial procedures to be performed at each 
designated visit. 
Individual trial procedures are described in detail below. It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to patient safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature and thus local regulations may require that additional 
informed consent be obtained from the patient. In these cases, such evaluations/testing will 
be performed in accordance with those regulations.  
6.1.1 
Subject Identification Card 
All patients will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the patient with a Subject Identification Card immediately after the patient 
provides written informed consent. 
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about the trial 
medication in emergency situations where the investigator is not available. 
6.2 
Before treatment start 
6.2.1 
Within 8 weeks prior to randomization 
A specific informed consent has been prepared to send the tumor sample for the level of PD-
L1 expression and must be signed by the patient before the shipment of the tumor. This is 
mandatory. 
FFPE tumor tissue will be collected from positive lymph nodes. Primary melanoma will also 
be collected if available. Samples are to be sent to central laboratory in order to check the 
PD-L1 status. For patients who consented to biobanking the tissue will thereafter be 
biobanked as per chapter 12. 
 
 
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6.2.2 
Within 6 weeks prior to randomization 
The patient's written informed consent to undergo screening for the clinical trial must be 
given prior to the performance of any protocol laboratory/imaging tests that are not part of 
local routine guidelines. 
Upon confirmation of PD-L1 status and written informed consent, the following exams will 
be performed within a maximum of 6 weeks from ICF signature until the randomization) and 
results should be known before randomization: 
♦ Eligibility criteria (see Section 3) 
♦ Demographics, medical history, height 
♦ Local testing for BRAF 
♦ Physical examination (including pulse, blood pressure, temperature and weight) 
♦ Assessment of adverse events 
♦ ECOG performance status (see Appendix C) 
♦ Urinalysis (specific gravity, pH, proteins, glucose, blood using a dipstick; elements and 
microscopic examination if needed) 
♦ Thyroid function: TSH; in case of elevated TSH to add free T3 and T4 
♦ Cardiac function: 12-lead ECG  
♦ Disease evaluation: the following imaging work up will be performed  
♦ Full Chest/Abdomen/Pelvis CT and/or MRI 
♦ Neck CT and/or MRI (for Head and Neck primaries) 
♦ Other CT and/or MRI (e.g. Brain, Deep Soft Tissue) only if clinically indicated 
♦ Concomitant medications  
♦ Health Related Quality of Life (HRQoL): within 6 weeks prior to randomization or at any 
point prior to treatment start 
♦ EORTC QLQ-C30 version 3 and EQ-5D-3L  
♦ Translational research: for patient who consented 
♦ Two tubes of whole blood samples (5 mL each) 
♦ Serum and plasma samples (9 ml tube +/- 1mL each) 
Please refer to Table 3 in Section 6.4.1. 
6.2.3 
Within 14 days (+/- 3 days) prior to treatment initiation 
♦ Hematology: WBC, ANC, differential cell count, RBC, Hgb, Hct, Platelets 
♦ Coagulation parameters: International Normalized Ratio (INR) or Prothrombin Time 
(PT), Activated Partial Thromboplastin Time (aPTT) 
 
 
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♦ Serum chemistry: creatinine, urea or BUN, bilirubin, AST, ALT, alkaline phosphatase, 
LDH, total protein, K, Na, HCO3 (Japanese and German patients are excluded from 
HCO3 testing) and Ca, albumin, glucose, CRP 
Please refer to Table 3 in Section 6.4.1. 
Note: hematology and serum chemistry are to be repeated if performed more than 14 days 
prior to the first dose of study treatment.  
6.2.4 
Within 72 hours prior to treatment initiation 
Women of child bearing potential must have a negative serum (or urine) pregnancy test 
within 72 hours prior to the first dose of study treatment. 
Note: the pregnancy test is to be repeated if performed more than 72 hours prior to the first 
dose of study treatment.  
6.2.5 
Within 24 hours prior to treatment initiation 
♦ Pharmacokinetic (PK): one blood sample of at least 3.0 mL 
♦ Anti-pembrolizumab antibody (ADA): one blood sample of 6 mL 
6.3 
During treatment 
Pregnancy testing in women of child bearing potential . This pregnancy test is to be 
renewed/repeated during protocol treatment at the criteria of the investigator according to 
national regulations/institution guidelines. 
Dosing delays  
For laboratory assessments, physical exam, adverse events assessments, concomitant 
medication assessments, HRQoL and imaging work-up, if dose administration is delayed or 
held (e.g. patient on holiday, hospitalized, etc) but occurs later, the site should: 
♦ Complete all protocol required laboratory tests, physical exam, adverse events 
assessments, concomitant medication assessments and HRQoL assessments within the 
required window prior to the new visit date of dose administration.  
♦ Follow calendar days for imaging assessment and not adjust for cycle delays. The 
reference date for imaging scans should be day 1 cycle 1. 
6.3.1 
Part 1: Adjuvant Therapy 
The visits for evaluations described below refer to study drug administrations. It's 
therefore expected that results of laboratory (hematology, serum chemistry, thyroid, 
urinalysis) and of imaging work ups are available prior to study drug administrations 
and within required timelines every 6 weeks (+/- 3 days) and every 12 weeks (+/- 7 
days) depending on the type of evaluation. 
 
Laboratory tests must be performed within maximum 3 days before study drug 
administration. 
 
 
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For imaging work ups and urinalysis it would be maximum 7 days. 
6.3.1.1 
Every 6 weeks (+/- 3 days) 
The following exams will be performed every 6 weeks: 
♦ Physical examination / ECOG performance status (see Section 6.2.2) 
♦ Assessments of adverse events  
♦ Hematology and serum chemistry (see Section 6.2.3). Results must be available prior to 
study drug administration and be drawn no longer than 3 days before study drug 
administration. 
♦ Thyroid function (see Section 6.2.2). Results must be available prior to study drug 
administration and be drawn no longer than 3 days before study drug administration. 
♦ Concomitant medications 
Please refer to Table 3 in Section 6.4.1. 
6.3.1.2 
Every 12 weeks (+/- 7 days) 
In addition to the above exams (see Section 6.3.1.1), the following exams will be performed 
every 12 weeks: 
♦ Urinalysis (see Section 6.2.2). Results must be available prior to study drug 
administration. 
♦ Imaging work up: results must be available before study drug administration. 
♦ Full chest/abdomen/pelvis CT and/or MRI 
♦ Neck CT and/or MRI (for head and neck primaries) 
♦ Other CT and/or MRI (e.g. brain, deep soft tissue) when clinically indicated, 
including and non-limited to: 
♦ Brain CT or MRI in case of headache or neurologic symptoms; chest CT in case 
of cough, dyspnea, thoracic pain; abdominal US or CT in case of abdominal pain, 
occlusive syndrome.  
PET alone will not be used for the disease assessment. Superficial cutaneous lesions: the 
neoplastic nature must be confirmed by cytology/histology. 
Deep subcutaneous lesions and lymph node lesions should be documented by ultrasound and 
cytological/histological evidence must be obtained or these can be documented by CT scan in 
absence of pathology report 
Cytology and/or histology are mandatory to confirm relapse in solitary or in doubtful lesions, 
cutaneous, subcutaneous or lymph node lesions. Histological or cytological evidence of 
recurrence should be attempted in all cases except for brain metastases. 
♦ Health Related Quality of Life (HRQoL) evaluations : EORTC QLQ-C30 version 3 and 
EQ-5D-3L 
 
 
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♦ Questionnaires are filled in every 12 weeks for the first two years and every 6 months 
up to 4th year (included). HRQoL data must be collected regardless of the patient’s 
recurrence/progression status, unless patient withdraws from this part of the study. 
In addition to above recommendations, if patients experience any adverse event or laboratory 
event during the treatment period, additional tests and/or visits will be performed as per 
recommendations in Appendix G and Appendix H. 
Please refer to Table 3 in Section 6.4.1. 
6.3.2 
Translational research  
Serial samples of plasma and serum (9 mL+/- 1 mL each) will be collected during the first 
year at week 4, week 13, 6 months and 12 months. 
Note: It is acceptable to collect the baseline TR samples after randomization but before 
treatment start. 
Please refer to Table 10 in Section 6.4.3. 
6.3.3 
Pharmacokinetic and anti-pembrolizumab antibody 
Pre-dose trough PK (3.0 mL each) and ADA (6 mL each) samples will be collected at 
baseline week 1, week 4, week 10, week 22 and at 12 months (before the last infusion N°18).  
All pre-dose blood samples should be drawn within 24 hours before infusion of 
pembrolizumab as described in the study Table 10 in Section 6.4.3. 
6.3.4 
End of adjuvant treatment (Part 1) 
6.3.4.1 
Discontinuation due to recurrence 
Please refer to Table 4 (Section 6.4.1.1), Columns A and B for discontinuation due to 
recurrence 
♦ Patients that did not complete the one year adjuvant treatment due to recurrence will be 
unblinded and will be offered to crossover if allowed per protocol qualifications in 
section 4.2. They should rapidly receive pembrolizumab after cross-over, and therefore 
the EOT visit should be done as soon as possible (site must not wait for 30 days).  
♦ Patients who are not eligible for crossover/rechallenge will have the EOT visit at 30 days 
after last treatment dose (+/- 2 weeks). 
For the EOT visit, the following exams will be performed:  
♦ Pregnancy test in women of child bearing potential 
♦ Physical examination / ECOG performance status 
♦ Assessment of adverse events 
♦ If at the time of treatment discontinuation, the patient suffers from a severe (Grade 3 
or 4) adverse event, the event must be followed until resolution or determination by 
the investigator that the event has become stable or irreversible. Any treatment related 
death occurring during and beyond this time frame must be reported to EORTC. 
 
 
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♦ Concomitant medications  
♦ Hematology and serum chemistry see Section 6.2.3 
♦ Urinalysis see Section 6.2.2 
♦ Thyroid function see Section 6.2.2 
♦ HRQoL see Section 6.3.4.3 
♦ Imaging work up: in case of discontinuation due to recurrence, the recurrence scan date 
should be used as the reference date for scheduling future imaging scans. Baseline 
imaging scan prior to first dose in Part 2 should be within 4 weeks (+/- 7 days) of planned 
EOT visit. If the recurrence scan falls outside of this window, a new scan is required as 
baseline. Imaging includes CT with contrast or MRI of brain, chest, abdomen, pelvis and 
any specific body region based on the location of the primary melanoma (e.g. 
neck).Please refer to Table 4  
6.3.4.2 
Discontinuation in absence of recurrence 
Please refer to Table 4 (Section 6.4.1.1), Columns C and D for discontinuation in absence of 
recurrence. 
For patients who complete one year of adjuvant treatment in the absence of recurrence, the 
EOT visit should be performed at 30 days after the last treatment administration. The 
following exams will be performed at 30 days +/- 2 weeks after the last treatment 
administration:  
♦ Pregnancy test in women of child bearing potential 
♦ Physical examination / ECOG performance status 
♦ Assessment of adverse events 
♦ If at the time of treatment discontinuation, the patient suffers from a severe (Grade 3 
or 4) adverse event, the event must be followed until resolution or determination by 
the investigator that the event has become stable or irreversible. Any treatment related 
death occurring during and beyond this time frame must be reported to EORTC. 
♦ Concomitant medications 
♦ Hematology and serum chemistry see Section 6.2.3 
♦ Urinalysis see Section 6.2.2 
♦ Thyroid function see Section 6.2.2 
♦ HRQoL see Section 6.3.4.3 
♦ Imaging work up as per Section 6.3.1.2. In case of discontinuation of adjuvant treatment 
in the absence of disease recurrence, the date when imaging was performed for the EOT 
visit, should be used as the new reference date for scheduling future imaging scans. 
Note: Patients discontinuing treatment in absence of recurrence, who had the last scan 
performed in the preceding 4 weeks (+/- 7 days) of planned EOT visit, may have the EOT 
scan omitted at the discretion of the investigator. In this case, for scheduling the next follow 
up visits, the date of last imaging work up will be used as reference. After EOT visit, all 
 
 
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assessments ( imaging and all other exams, safety, etc.) will be performed on the same visit 
every 12 weeks. 
Please refer to Table 4  
6.3.4.2.1 
Treatment discontinuation due to adverse event or ECI 
A patient who discontinues treatment due to an AE/ECI and presents a recurrence after 
discontinuation may be eligible to be considered for Part 2, unless when there is a 
contraindication or the patient does not meet the eligibility criteria. Please contact the 
medical monitor on a per-case basis. 
6.3.4.2.2 
Treatment discontinuation due to patient's decision 
A patient who discontinues treatment due to personal decision not described in the protocol, 
is considered permanently discontinued from treatment for the remainder of the study (Part 1 
and Part 2). 
6.3.4.3 
HRQoL evaluation 
Questionnaires (EORTC QLQ-C30 version 3 and EQ-5D-3L) will be filled in every 12 
weeks for the first two years and every 6 months up to 4th year (included). HRQoL data 
must be collected regardless of the patient’s recurrence/progression status/treatment 
completion, unless patient withdraws from this part of the study. 
6.3.4.4 
Translational research 
Translational research samples of plasma and serum (9 mL+/- 1mL each) will be collected 
every 12 months (+/- 2 weeks) at years 2, 3, 4 and 5. After the 1st recurrence, collection of 
samples will continue only for patients who will cross-over or be re-challenged with 
pembrolizumab (Part 2). During Part 2, samples are collected regardless of the patient’s 
recurrence/ progression status/treatment completion. 
Please refer to Table 10 
6.3.4.5 
Pharmacokinetic and anti-pembrolizumab antibody 
PK (3.0 mL each) and ADA (6 mL each) samples will be collected 30 days after 
discontinuation of study drug (or until another anti-cancer therapy is started). Every effort 
should be made to collect samples at these time-points. 
Please refer to Table 10 
6.3.5 
Follow-up (after end of adjuvant treatment - Part 1) 
The Sponsor may request survival status to be assessed at additional time points during the 
course of the study (not to exceed approximately 12 weeks). 
Participants in survival follow up should be contacted by telephone approximately every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.  
 
 
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In addition, upon Sponsor request, participants may be contacted for survival status at any 
time points during the course of the study. For example, survival status may be requested 
prior to the eDMC safety review, efficacy interim analyses, and final analysis. All 
participants who are in the Survival Follow-Up Phase and not known to have died prior to the 
request for these additional survival status time points will be contacted at that time. 
6.3.5.1 
For patients who discontinued treatment due to recurrence but are not 
eligible for re-challenge or cross-over 
Follow-up assessments for patients who discontinued due to recurrence but do not cross-
over/re-challenge will be performed every 12 weeks (± 2 weeks) and the following 
information will be collected: 
♦ HRQoL evaluation : EORTC QLQ-C30 version 3 and EQ-5D. Questionnaires are filled 
in every 12 weeks for the first 2 years and every 6 months up to 4th year (included). 
HRQoL data must be collected regardless of the patient’s recurrence/progression status, 
unless patient withdraws from this part of the study.  
♦ Record of further anti-cancer therapies on e-CRF and the outcomes  
♦ Survival 
♦ No imaging assessment is required for these patients during survival follow up 
Please refer to Table 5. 
6.3.5.2 
For patients who discontinued due to patient's decision and are not 
eligible for re-challenge or cross-over 
The patient will proceed to follow-up evaluations described in Table 5 for patients who 
discontinue but are not eligible for cross-over/re-challenge.  
If patient does not withdraw consent, the following information will be collected: 
♦ HRQoL evaluation : EORTC QLQ-C30 version 3 and EQ-5D. Questionnaires are filled 
in every 12 weeks for the first 2 years and every 6 months up to 4th year (included). 
HRQoL data must be collected regardless of the patient’s recurrence/progression status, 
unless patient withdraws from this part of the study.  
♦ Record of further anti-cancer therapies on e-CRF and the outcomes  
♦ Survival 
♦ No imaging assessment is required for these patients during survival follow up. 
6.3.5.3 
For patients who discontinued in absence of recurrence 
The follow-up evaluations are described in Table 6 and will be performed every 12 weeks (± 
2 weeks), unless otherwise noted below: 
♦ Pregnancy test in women of child bearing potential 
Note: pregnancy tests have to be repeated according to national regulations/institution 
guidelines. 
♦ Physical examination / ECOG performance status 
 
 
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♦ Assessment of adverse events 
♦ Concomitant medications 
♦ Hematology and serum chemistry see Section 6.2.3 
♦ Urinalysis see Section 6.2.2 
♦ Thyroid function see Section 6.2.2 
♦ Imaging work-up: follow up should still be provided for the study endpoints (RFS, 
DMFS, PRFS2 and OS). Imaging work up will be performed every 12 weeks for the first 
two years, every 6 months for the next 3 years (from year 3 to 5), and on the yearly basis 
thereafter. 
♦ HRQoL evaluation : EORTC QLQ-C30 version 3 and EQ-5D. Questionnaires are filled 
in every 12 weeks for the first 2 years and every 6 months up to 4th year (included). 
HRQoL data must be collected regardless of the patient’s recurrence/progression status, 
unless patient withdraws from this part of the study. 
Upon first recurrence, the treatment arm should be unblinded per protocol procedures 
indicated in Section 14.7.2. If the patient qualifies for Part 2 please refer to Section 6.3.6.2. If 
patient does not proceed to Part 2 of the study, patient will be followed for survival and other 
therapies, but no further imaging assessments as per Section 6.3.5.1. 
6.3.6 
Part 2: cross-over or re-challenge treatment after the 1st 
recurrence 
Upon documented recurrence, the patients will be considered for crossover to or re-challenge 
with pembrolizumab as per Sections 4.2.1.1 and 4.2.2.1 
Patients have the option to consent for participation in the Part 2 after 1st recurrence.  
6.3.6.1 
Translational research  
Patients who had previously signed consent for translational research at time of study 
registration in Part 1 of the study, will continue having research samples of plasma and serum 
(9mL+/- 1mL each) collected every 12 months (+/- 2 weeks) at years 2, 3, 4 and 5 regardless 
of the patient’s recurrence/progression status/treatment completion.  
Additionally, patients have the option to consent for Translational Research in Part 2 
after recurrence and provide tumor material, if available. 
6.3.6.2 
Evaluations for patients receiving pembrolizumab  
Please refer to Table 7 for evaluations during cross-over or re-challenge with 
pembrolizumab. 
After signing the informed consent form, the following data will be collected every 12 weeks 
(± 2 weeks) until disease progression/ second recurrence or up to the end two year treatment 
period: 
♦ Women of child bearing potential must have a negative serum (or urine) pregnancy test 
within 72 hours prior to the first dose of study treatment in Part 2 of the study. This 
 
 
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pregnancy test is to be renewed/repeated during protocol treatment at the criteria of the 
investigator according to national regulations/institution guidelines. 
♦ Physical examination / ECOG performance status 
♦ Adverse events 
♦ Concomitant medication  
♦ Hematology and serum chemistry see Section 6.2.3 
♦ Urinalysis see Section 6.2.2 
♦ Thyroid function see Section 6.2.2 
♦ HRQoL evaluation see Section 6.3.4.3 
♦ Imaging assessments 
Baseline imaging scan prior to first dose in Part 2 should be within 4 weeks (+/- 7 days) 
of planned EOT visit. If the recurrence scan falls outside of this window, a new scan is 
required as baseline. Baseline imaging includes CT with contrast or MRI of brain, chest, 
abdomen, pelvis and any specific body region based on the location of the primary 
melanoma (e.g. neck).  
Imaging work up during Part 2 of the study will be at 12 weeks after the first dose, then 
every 12 weeks until disease progression/ second recurrence or completion of treatment 
(up to 1 year (local recurrence) or 2 years treatment period unless occurrence of a 
withdrawal criterion).Imaging during Part 2 treatment includes full chest/abdomen/pelvis 
CT and/or MRI; Neck CT and/or MRI (for head and neck primaries); other CT and/or 
MRI (e.g. Brain, Deep Soft Tissue) when clinically indicated, including and not limited 
to: Brain CT or MRI in case of headache or neurologic symptoms; chest CT in case of 
cough, dyspnea, thoracic pain; abdominal US or CT in case of abdominal pain, occlusive 
syndrome 
Upon disease progression or second recurrence or after the completion of treatment 
period, please refer to Section 6.3.8.1 
6.3.7 
End of treatment (Part 2) 
6.3.7.1 
Discontinuation due to progression or 2nd recurrence 
The EOT visit should be performed at 30 days +/- 2 weeks after the last treatment 
administration and the following exams will be performed:  
♦ Pregnancy test in women of child bearing potential 
♦ Physical examination / ECOG performance status 
♦ Assessment of adverse events 
♦ If at the time of treatment discontinuation, the patient suffers from a severe (Grade 3 
or 4) adverse event, the event must be followed until resolution or determination by 
the investigator that the event has become stable or irreversible. Any treatment related 
death occurring during and beyond this time frame must be reported to EORTC. 
 
 
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♦ Concomitant medications  
♦ Hematology and serum chemistry see Section 6.2.3 
♦ Urinalysis see Section 6.2.2 
♦ Thyroid function see Section 6.2.2 
♦ HRQoL to assess if needed as per Section 6.3.4.3  
Please refer to Table 8. 
6.3.7.2 
Discontinuation in absence of recurrence 
The following exams will be performed at 30 days +/- 2 weeks after the last treatment 
administration:  
♦ Pregnancy test in women of child bearing potential 
♦ Physical examination / ECOG performance status 
♦ Assessment of adverse events 
♦ If at the time of treatment discontinuation, the patient suffers from a severe (Grade 3 
or 4) adverse event, the event must be followed until resolution or determination by 
the investigator that the event has become stable or irreversible. Any treatment related 
death occurring during and beyond this time frame must be reported to EORTC. 
♦ Concomitant medications 
♦ Hematology and serum chemistry see Section 6.2.3 
♦ Urinalysis see Section 6.2.2 
♦ Thyroid function see Section 6.2.2 
♦ HRQoL to assess if needed as per Section 6.3.4.3  
♦ Imaging work up:  
Please refer to Table 8. 
6.3.8 
Follow-up (after end of pembrolizumab in Part 2) 
The Sponsor may request survival status to be assessed at additional time points during the 
course of the study (not to exceed approximately 12 weeks). 
Participants in survival follow up should be contacted by telephone approximately every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.  
In addition, upon Sponsor request, participants may be contacted for survival status at any 
time points during the course of the study. For example, survival status may be requested 
prior to the eDMC safety review, efficacy interim analyses, and final analysis. All 
participants who are in the Survival Follow-Up Phase and not known to have died prior to the 
request for these additional survival status time points will be contacted at that time. 
 
 
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6.3.8.1 
For patients who discontinued Part 2 due to progression or recurrence or 
completion of treatment  
Follow-up assessments for patients who discontinued Part 2 will be performed every 12 
weeks (± 2 weeks) and the following information will be collected: 
♦ HRQoL to assess if needed as per Section 6.3.4.3  
♦ Record of further anti-cancer therapies on e-CRF and the outcomes 
♦ No imaging assessment is required for these patients during survival follow up 
♦ Survival 
Please refer to Table 9. 
6.3.8.2 
Treatment discontinuation due to adverse event or ECI 
A patient who discontinues treatment due to an AE/ECI will be followed up for safety and 
overall survival. 
6.3.8.3 
Treatment discontinuation due to patient’s decision 
A patient who discontinues treatment due to personal decision not described in the protocol, 
is considered permanently discontinued from treatment for the remainder of the study 
 
 
 
 
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6.4 
Summary Tables 
6.4.1 
Part 1: Evaluations during adjuvant treatment (Part 1) 
  
Prior to 
randomizatio
n 
Prior to 
treatment 
initiation 
Treatment 
period 
At end of 
adjuvant 
treatment 
  
Within 
8 
weeks 
Within 
6 
weeks 
Within 
14 
days 
Within 
72 
hours 
Q 6 wks 
Q 12 
wks 
Discontinuation due 
to recurrence or in 
absence of recurrence 
Window to 
perform 
investigations 
 
 
 
 
+/- 3 
days 
+/- 7 
days 
 
Informed consents 
 
 
  
  
Refer to Table 4 
Pregnancy test1 
 
# 
# 
Tumor sample for 
PD-L1 test2 
 
 
 
 
  
  
Eligibility 
 
 
 
 
  
  
BRAF status 
 
 
 
 
  
  
Medical history, 
height 
demographics 
 
 
 
 
  
  
Physical 
examination 
(weight, pulse, 
BP, T, ECOG 
PS)3 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
Concomitant 
medications 
 
 
 
 
 
 
Hematology 4 
 
 
 
 
 
 
Serum or plasma 
chemistry 4 
 
 
 
 
 
 
Coagulation 
parameters4 
 
 
 
 
 
 
Urine analysis5 
 
 
 
 
 
Thyroid function6 
 
 
 
 
 
 
12-lead ECG 
 
HRQoL7 
 
 
Imaging work up8 
 
8 
 
 
 
9 
 
 
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EORTC v7.0/MK-3475-054-03 
page 70 / 204 
February 28, 2018 
  
Prior to 
randomizatio
n 
Prior to 
treatment 
initiation 
Treatment 
period 
At end of 
adjuvant 
treatment 
  
Within 
8 
weeks 
Within 
6 
weeks 
Within 
14 
days 
Within 
72 
hours 
Q 6 wks 
Q 12 
wks 
Discontinuation due 
to recurrence or in 
absence of recurrence 
Window to 
perform 
investigations 
 
 
 
 
+/- 3 
days 
+/- 7 
days 
 
Survival 10 
Refer to Table 7 for cross-over or rechallenge 
Refer to Table 5 for patients that will not cross-
over or be re-challenged 
Refer to Table 6 for patients who discontinued in 
absence of recurrence 
 
Anticancer 
therapies 
Refer to Table 7 for cross-over or rechallenge 
Refer to Table 5 for patients that will not cross-
over or be re-challenged  
Refer to Table 6 for patients who discontinued in 
absence of recurrence 
 in all cases 
 
# as per national regulations/institutions guidelines 
1. Women of child bearing potential must have a negative serum (or urine) pregnancy test within 72 hours prior to the 
first dose of study treatment. Note: the pregnancy test is to be repeated if performed more than 72 hours prior to the 
first dose of study treatment. 
2. PD-L1 testing: tumor material will be collected from positive lymph nodes (LN) embedded in paraffin. If the 
resection samples from LNs are not adequate for PD-L1 testing, the primary melanoma must be collected. Patients 
whose samples are inadequate for PD-L1 determination will not be randomized. In addition to the resection samples 
from LNs, the primary melanoma may also be collected if available to evaluate the PD-L1 expression 
3. Physical examination includes ECOG performance status, blood pressure, weight, pulse rate, temperature 
4. Complete blood count: WBC, ANC, differential cell count, RBC, Hgb, Hct, Platelets and serum or plasma 
chemistry: creatinine, urea or BUN , bilirubin, AST, ALT, alkaline phosphatase, LDH, total protein, K, Na, HCO3 
(Japanese and German patients are excluded from HCO3 testing) and Ca, albumin, glucose, CRP. Coagulation 
parameters at baseline: INR or PT and aPTT. 
Note: hematology and serum chemistry are to be repeated if performed more than 14 days prior to the first dose of 
study treatment. 
5.Urine analysis: specific gravity, pH, proteins, glucose, blood using a dipstick; elements and microscopic 
examination if needed 
6.Thyroid function: TSH; in case of elevated TSH to add free T3 and T4 
7.HRQoL questionnaires (EORTC QLQ-C30 version 3 and EQ-5D-3L) are filled in at baseline within 6 weeks prior 
to randomization or at any point prior to treatment start, then every 12 weeks for the first 2 years and every 6 months 
up to the 4th year (included). HRQoL data must be collected regardless of the patient’s recurrence/progression status , 
unless patient withdraws from this part of the study. 
8. Imaging work up: Full chest/abdomen/pelvis CT and/or MRI; Neck CT and/or MRI (for head and neck primaries); 
other CT and/or MRI (e.g. Brain, Deep Soft Tissue) when clinically indicated, including and not limited to: Brain CT 
or MRI in case of headache or neurologic symptoms; chest CT in case of cough, dyspnea, thoracic pain; abdominal 
US or CT in case of abdominal pain, occlusive syndrome 
9. During adjuvant treatment imaging will be performed at baseline, then every 12 weeks after first dose until 
recurrence or end of adjuvant treatment phase.  
10. Upon Sponsor request, participants may be contacted for survival status at any time points during the course of the 
study. 
Table 3: Evaluations during adjuvant therapy 
 
 
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6.4.1.1 
Overview EOT for adjuvant treatment (Part 1) 
 
At end of adjuvant treatment  
 
Discontinuation due to 
recurrence 
Discontinuation in absence of 
recurrence2 
 
A 
B 
C 
D 
  
Discontinued 
before 
completion of 
adjuvant 
treatment and 
will not proceed 
to Part 2 
Discontinued 
before 
completion of 
adjuvant 
treatment and 
will proceed 
to Part 2 
 
If adjuvant 
therapy 
completed 
 
If discontinued 
before completion 
of adjuvant therapy 
(visit 30 days after 
last dose or before 
new therapy, 
whichever is sooner) 
(visit as soon as 
possible) 
(visit 30 days after 
last dose 
(visit 30 days after last 
dose) 
Window to 
perform 
investigations 
+/- 2 weeks  
as soon as 
possible 
+/- 2 weeks 
+/- 2 weeks 
Pregnancy test 
 
 
 
 
Physical 
examination 1 
(weight, pulse, 
BP, T, ECOG 
PS) 
 
 
 
 
Adverse events 
 
 
 
 
Concomitant 
medications 
 
 
 
 
Hematology 2 
 
 
 
 
Serum or 
plasma 
chemistry 2 
 
 
 
 
Urine analysis3 
 
 
 
 
Thyroid 
function4 
 
 
 
 
HRQoL5 
 
 
 
 
Imaging work 
up 
6 
7 
8 
8 
 
 
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February 28, 2018 
 
At end of adjuvant treatment  
 
Discontinuation due to 
recurrence 
Discontinuation in absence of 
recurrence2 
 
A 
B 
C 
D 
  
Discontinued 
before 
completion of 
adjuvant 
treatment and 
will not proceed 
to Part 2 
Discontinued 
before 
completion of 
adjuvant 
treatment and 
will proceed 
to Part 2 
 
If adjuvant 
therapy 
completed 
 
If discontinued 
before completion 
of adjuvant therapy 
(visit 30 days after 
last dose or before 
new therapy, 
whichever is sooner) 
(visit as soon as 
possible) 
(visit 30 days after 
last dose 
(visit 30 days after last 
dose) 
Window to 
perform 
investigations 
+/- 2 weeks  
as soon as 
possible 
+/- 2 weeks 
+/- 2 weeks 
 in all cases 
1. Physical examination includes ECOG performance status, blood pressure, weight, pulse rate, temperature 
2. Complete blood count: WBC, ANC, differential cell count, RBC, Hgb, Hct, Platelets and serum or plasma 
chemistry: creatinine, urea or BUN, bilirubin, AST, ALT, alkaline phosphatase, LDH, total protein, K, Na, HCO3 
(Japanese and German patients are excluded from HCO3 testing )and Ca, albumin, glucose, CRP 
3. Urine analysis: specific gravity, pH, proteins, glucose, blood using a dipstick; elements and microscopic 
examination if needed 
4. Thyroid function: TSH; in case of elevated TSH to add free T3 and T4 
5. HRQoL questionnaires (EORTC QLQ-C30 version 3 and EQ-5D-3L) that started during adjuvant treatment are 
filled in every 12 weeks for the first 2 years and every 6 months up to 4th year (included).  
Note: HRQoL data must be collected regardless of the patient’s recurrence/progression status/treatment completion, 
unless patient withdrawal from this part of the study, unless patient withdraws from this part of the study. 
6. Imaging scan for EOT visit is considered the scan taken at recurrence. Patients who discontinue due to recurrence 
before completion of adjuvant treatment and will not proceed to Part 2 will not require further imaging scans, and will 
continue to survival follow up per section 6.3.5.1 
7. Patients who did not complete the one year adjuvant treatment due to recurrence will be unblinded and will be 
offered to crossover if allowed per protocol qualifications in section 4.2. They should rapidly receive pembrolizumab 
after cross-over. And therefore the EOT visit should be done as soon as possible (site must not wait for 30 days) as per 
section 6.3.4.1.  
Note: the recurrence scan date should be used as the reference date for scheduling future imaging scans.Baseline 
imaging scan prior to first dose in Part 2 should be within 4 weeks (+/- 7 days) of planned EOT visit. If the recurrence 
scan falls outside of this window, a new scan is required as baseline. Imaging includes CT with contrast or MRI of 
brain, chest, abdomen, pelvis and any specific body region based on the location of the primary melanoma (e.g. neck).  
8. After completion of adjuvant treatment in absence of recurrence, follow-up imaging will be performed every 12 
weeks for the first two years, every 6 months for the next 3 years (from year 3 to 5), and then on a yearly basis 
thereafter.  
Patients who discontinue adjuvant treatment for other reason than recurrence should follow procedures per sections 
6.3.5.2. or 6.3.5.3 
Table 4: Evaluations for EOT 
 
 
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EORTC v7.0/MK-3475-054-03 
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February 28, 2018 
6.4.1.2 
Follow-up evaluation Part 1: for patients who discontinue due to 
recurrence but do not cross-over/re-challenge or due to patient’s decision 
Follow-up assessments 
Every 12 weeks (+/- 2 wks 
after EOT) after 
discontinuation or 
recurrence 
HRQoL 1 
 
Survival 2 
 
Record anticancer therapies and outcomes2 
 
Imaging work up3 
 
 in all cases 
1. HRQoL questionnaires (EORTC QLQ-C30 version 3 and EQ-5D-3L) are filled in every 12 weeks 
for the first 2 years and every 6 months up to 4th year (included). HRQoL data must be collected 
regardless of the patient’s recurrence/progression status/treatment completion, unless patient 
withdraws from this part of the study. 
2. Upon disease progression/second recurrence during Part 1 or after Part 1 treatment 
discontinuation, whichever is first. Upon Sponsor request, participants may be contacted for survival 
status at any time points during the course of the study. 
Note: Survival follow up and record of anticancer therapies and outcomes will be conducted via 
phone calls once there are no further HRQoL questionnaires scheduled for completion.2. After first 
recurrence during Part 1. Upon Sponsor request, participants may be contacted for survival status at 
any time points during the course of the study 
3. Patients without distant metastasis detected, will continue imaging assessments every 12 weeks 
for the first two years, every 6 months for the next 3 years (from year 3 to 5), and on a yearly basis 
thereafter until detection of distant metastasis or patient withdrawal of consent. 
Table 5: Follow up evaluations for patients who discontinue Part 1due recurrence (but no 
cross-over or rechallenge) or patient's decision 
 
 
 
 
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6.4.1.3 
Follow-up evaluation Part 1: for patients who discontinued in absence of 
recurrence 
Every 12 weeks (+/- 2 
wks) after EOT 
Pregnancy test 
 
Physical examination/ECOG PS 
 
Adverse events 
 
Concomitant medications 
 
Hematology and serum chemistry 
 
Urinalysis 
 
Thyroid function 
 
HRQoL¹ 
 
Imaging work up2 
 
 in all cases 
1. HRQoL questionnaires (EORTC QLQ-C30 version 3 and EQ-5D-3L) that started during adjuvant 
treatment are filled in every 12 weeks for the first 2 years and every 6 months up to 4th year 
(included).  
Note: HRQoL data must be collected regardless of the patient’s recurrence/progression 
status/treatment completion, unless patient withdrawal from this part of the study.  
2. Imaging work up will be performed every 12 weeks for the first two years, every 6 months for the 
next 3 years (from year 3 to 5), and on the yearly basis thereafter. 
NOTE: Upon first recurrence, the treatment arm should be unblinded per protocol procedures 
indicated in Section 14.7.2. If the patient qualifies for Part 2 of the study, the follow-up will be as 
per Section 6.3.6.2. Patients who do not proceed to Part 2 of the study will be followed for survival 
and other therapies, but no further imaging assessments as per Section 6.3.5.1 
Table 6: Follow-up evaluations for patients discontinued in absence of recurrence 
 
 
 
 
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EORTC v7.0/MK-3475-054-03 
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February 28, 2018 
6.4.2 
Part 2: Cross-over or rechallenge after the 1st recurrence 
6.4.2.1 
Evaluations during cross-over or re-challenge with pembrolizumab 
Evaluation every 12 weeks (± 2 
weeks) up to 1 year (local 
recurrence) or 2 years treatment 
period unless occurrence of a 
withdrawal criterion 
 
Imaging evaluation 
every 12 weeks until 
disease progression 
Informed consent 
 
 
Pregnancy test 1 
# 
 
Physical examination 
(weight, pulse, BP, T) ECOG PS 2 
 
 
Adverse events 
 
 
Concomitant medications 
 
 
Hematology 3 
 
 
Serum or plasma chemistry 3 
 
 
Urine analysis4 
 
 
Thyroid function 5 
 
 
HRQoL 6 
 
 
Imaging work up 7 
 
 
 in all cases 
 
# as per national regulations/institutions guidelines 
1. Women of child bearing potential must have a negative serum (or urine) pregnancy test within 72 hours prior to the first 
dose of study treatment in Part 2 of the study. 
2. Physical examination includes ECOG performance status, blood pressure, weight, pulse rate, temperature 
3. Complete blood count: WBC, ANC, differential cell count, RBC, Hgb, Hct, Platelets and serum or plasma chemistry: 
creatinine, urea or BUN, bilirubin, AST, ALT, alkaline phosphatase, LDH, total protein, K, Na, HCO3 (Japan and German 
patients are excluded from HCO3 testing ) and Ca, albumin, glucose, CRP 
4. Urine analysis: specific gravity, pH, proteins, glucose, blood using a dipstick; elements and microscopic examination if 
needed 
5. Thyroid function: TSH; in case of elevated TSH to add free T3 and T4 
6. HRQoL questionnaires (EORTC QLQ-C30 version 3 and EQ-5D) are filled in every 12 weeks for the first 2 years and 
every 6 months up to 4th year (included). HRQoL data must be collected regardless of the patient’s recurrence/progression 
statuts, unless patient withdraws from this part of the study. 
7. Baseline imaging scan prior to first dose in Part 2 should be within 4 weeks (+/- 7 days) of planned EOT visit. If the 
recurrence scan falls outside of this window, a new scan is required as baseline. Baseline imaging includes CT with 
contrast or MRI of brain, chest, abdomen, pelvis and any specific body region based on the location of the primary 
melanoma (e.g. neck). Imaging work up during Part 2 of the study will be at 12 weeks after the first dose, then every 12 
weeks until disease progression/ second recurrence/ or completion of treatment (up to 1 year (local recurrence) or 2 years 
treatment period unless occurrence of a withdrawal criterion). Imaging during Part 2 treatment includes full 
chest/abdomen/pelvis CT and/or MRI; Neck CT and/or MRI (for head and neck primaries); other CT and/or MRI (e.g. 
Brain, Deep Soft Tissue) when clinically indicated, including and not limited to: Brain CT or MRI in case of headache or 
neurologic symptoms; chest CT in case of cough, dyspnea, thoracic pain; abdominal US or CT in case of abdominal pain, 
occlusive syndrome 
Table 7: Evaluations during cross-over or re-challenge with pembrolizumab 
 
 
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EORTC v7.0/MK-3475-054-03 
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February 28, 2018 
6.4.2.2 
Overview EOT (Part 2) 
 
EOT visit  
 
Discontinuation due to 
progression or 2nd 
recurrence 
Discontinuation in 
absence of progression or 
2nd recurrence 
Window to perform 
investigations 
30 days +/- 2 weeks  
30 days +/- 2 weeks 
Pregnancy test 
 
 
Physical examination 1 (weight, 
pulse, BP, T, ECOG PS) 
 
 
Adverse events 
 
 
Concomitant medications 
 
 
Hematology 2 
 
 
Serum or plasma chemistry 2 
 
 
Urine analysis3 
 
 
Thyroid function4 
 
 
HRQoL5 
 
 
Imaging work up 
 
 
1. Physical examination includes ECOG performance status, blood pressure, weight, pulse rate, temperature 
2. Complete blood count: WBC, ANC, differential cell count, RBC, Hgb, Hct, Platelets and serum or plasma 
chemistry: creatinine, urea or BUN, bilirubin, AST, ALT, alkaline phosphatase, LDH, total protein, K, Na, HCO3 
(Japan and German patients are excluded from HCO3 testing ) and Ca, albumin, glucose, CRP 
3. Urine analysis: specific gravity, pH, proteins, glucose, blood using a dipstick; elements and microscopic 
examination if needed 
4. Thyroid function: TSH; in case of elevated TSH to add free T3 and T4 
5. HRQoL questionnaires (EORTC QLQ-C30 version 3 and EQ-5D) : to assess if needed as Section 6.3.4.3 
Table 8. Evaluation for EOT visit 
 
 
 
 
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EORTC v7.0/MK-3475-054-03 
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February 28, 2018 
6.4.2.3 
Follow-up evaluation for patients who discontinue Part 2 
Follow-up assessments 
Every 12 weeks (+/- 2 wks after EOT) 
HRQoL 1 
 
Survival 2 
 
Record anticancer therapies and outcomes2 
 
Imaging work up3 
 
 in all cases 
1. HRQoL questionnaires (EORTC QLQ-C30 version 3 and EQ-5D-3L): to assess if needed as Section 6.3.4.3 
2. Upon disease progression/second recurrence during Part 2 or after Part 2 treatment discontinuation, whichever is 
first. Upon Sponsor request, participants may be contacted for survival status at any time points during the course of 
the study 
Note: Survival follow up and record of anticancer therapies and outcomes will be conducted via phone calls once 
there are no further HRQoL questionnaires scheduled for completion. 
3. Patients without distant metastasis detected, will continue imaging assessments every 12 weeks (from last scan in 
Part 2) for the first two years, every 6 months for the next 3 years (from year 3 to 5), and on a yearly basis thereafter 
until detection of a distant metastasis (if not detected in Part 1) or patient withdrawal of consent. 
Table 9: Follow up evaluations for patients who discontinue Part 2  
 
 
 
 
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February 28, 2018 
6.4.3 
Blood, serum and tumor samples 
Samples 
Prior to 
random 
Within 
24 hrs 
prior 
to 
treat. 
start 
Treatment Period 
After end of 
adjuvant 
treatment 
(EOT)* 
 
Within 
8 wks  
Within 
6 wks 
Wk4 Wk 
10 
Wk 
13 
Wk 
22 
6 
mo 
12 
mo 
30 
days 
after 
last 
dose 
Years 
2-3-4-
5 Q12 
months  
TR 
FFPE  
 
 
 
 
 
 
 
 
 
 
 
TR 
whole 
blood 
samples1 
 
 
 
 
 
 
 
 
 
 
 
TR 
Serum 
and 
Plasma 
samples 
2  
 
 
 
 
 
 
 
 
 
 
 
PK 
samples3 
 
 
 
 
 
 
 
 
 
 
 
ADA 
samples 
3 
 
 
 
 
 
 
 
 
 
 
 
 in all cases 
* Samples are collected regardless of the patient’s recurrence/ progression status/treatment completion and for 
patients receiving pembrolizumab. 
1. Two tubes of 5 mL each. It is acceptable to collect the TR samples after randomization but before treatment start. 
2. Serial samples of serum and plasma (9 ml +/- 1mL each) will be collected during the first year: at baseline before 
treatment initiation (timepoint 0), week 4, week 13, then at 6 and 12 months. For the next years (2-3-4-5), every 12 
months. It is acceptable to collect the TR samples after randomization but before treatment start. 
3. All pre-dose blood samples should be drawn within 24 hours before infusion of pembrolizumab: prior to 
treatment start, week 4, week 10 , week 22 and at 12 months (before last infusion N°18).  
PK (3 mL each) and ADA (6 mL each) samples will also be collected 30 days after discontinuation of study drug 
(or until starts new anti-cancer therapy). 
As PK and ADA samples are collected within 24 hours before infusion: if treatment has to be postponed the 
collection of PK and ADA samples has to be adjusted accordingly. 
Table 10: Timeschedule for blood, serum and tumor samples collection 
 
 
 
 
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7 Criteria of evaluation 
7.1 
Evaluation of efficacy 
7.1.1 
Recurrence 
7.1.1.1 
Definition 
Recurrence is defined as appearance of one or more new melanoma lesions: local, regional or 
distant (Ref. 59).  
♦ Local cutaneous recurrence:  
♦ It is generally accepted that local recurrences occur within 2 cm of the tumor bed. Its 
neoplastic nature must be confirmed either by histology/cytology 
♦ Local recurrence after inadequate excision of the primary lesion occurs usually at 
the periphery of the previous surgical bed. In such instances, the risk of distant 
metastases and death may be similar to that of primary lesions with the same 
thickness, ulceration, and nodal status. 
♦ Local recurrence after adequate surgical excision of the primary melanoma is 
associated with aggressive tumor biologic features and is frequently a harbinger of 
metastases. 
♦ Regional lymphatic and nodal recurrences: The neoplastic nature of the regional 
recurrences should be attempted and confirmed by histology/cytology. 
♦ In Transit Metastases: 
♦ The American Joint Committee on Cancer (AJCC) defines in transit metastases as 
any skin or subcutaneous metastases that are more than 2 cm from the primary 
lesion but are not beyond the regional nodal basin. In transit metastases occur in 
10% to 15% of patients with stage III disease. When present, in transit metastases 
are usually multiple, evolve over time and are often the harbinger of subsequent 
systemic disease. 
♦ Regional Nodal Recurrences: Regional nodal failure in a previously dissected basin is 
usually found at the periphery of the prior surgical procedure. 
♦ Distant metastases:  
♦ Patterns of Metastases: Melanoma is well known for its ability to metastasize to 
virtually any organ or tissue. The most common initial sites of distant metastases are 
the non–visceral as the skin, subcutaneous tissue, and lymph nodes, which are 
recurrence sites for 42% to 59% of patients in various studies. Visceral locations are 
the lung, brain, liver, gastrointestinal tract, and bone which are the initial sites of 
relapse in approximately 25% of all melanoma patients who experienced recurrence. 
♦ Distant metastases may be measurable or non-measurable lesions:  
♦ Measurable disease - the presence of at least one measurable lesion.  
 
 
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o Single measurable lesions (visceral or nodal) should measure ≥ 10 mm in 
two dimensions. If the measurable disease is restricted to a solitary lesion 
(visceral or nodal), its neoplastic nature must be confirmed either by 
cytology/histology either by lesion progression certified on the next 
CT/MRI examination. 
o Multiple measurable lesions - lesions that can be accurately measured with 
spiral CT scan must be ≥ 10 mm in at least one dimension. 
♦ Non-measurable lesions - all other lesions, including small lesions (< 10 mm with 
spiral CT scan) and other non-measurable lesions. Other non measurable lesions 
include but are not limited to: bone lesions; leptomeningeal disease; ascites; 
pleural / pericardial effusion; inflammatory breast disease; lymphangitis cutis / 
pulmonis; abdominal masses that are not confirmed and followed by imaging 
techniques; and cystic lesions. 
Note: 
♦ Cutaneous relapses occurring beyond the periphery of the previous surgical bed (i.e. over 
2 cm) are considered distant metastases. 
♦ Node relapses occurred beyond the anatomical compartment of the dissected basins are 
considered distant metastases. 
♦ Node relapses in nodal basins situated in a different anatomical compartment or beyond 
the previously dissected basin or in two nodal basins (even if contiguous; i.e. 2 pelvic 
nodal basins, 2 mediastinal nodal basins) are considered distant metastases. 
7.1.1.2 
Methods of measurements 
♦ CT and MRI are mandatory to establish recurrence. Conventional CT with i.v. contrast 
and MRI gadolinium should be performed with contiguous cuts of 10 mm or less slice 
thickness. Spiral CT should be performed using a 3 or 5 mm contiguous reconstruction 
algorithm; this specification applies to the tumors of the chest, abdomen and pelvis while 
head & neck tumors and those of the extremities usually require specific protocols. In 
each institute the same technique for CT/MRI should be used to characterize each new 
lesion. 
♦ PET alone will not be considered for the disease assessment. Complementary CT/MRI or 
biopsy must be performed in such cases. 
♦ Cytology and/or histology are mandatory to confirm recurrence in solitary or in doubtful 
lesions, cutaneous, subcutaneous or lymph node lesions. Histological or cytological 
evidence of recurrence should be attempted in all cases except for brain metastases. 
♦ Clinically detected new lesions: 
♦ Superficial cutaneous lesions: the neoplastic nature must be confirmed by 
cytology/histology. 
♦ Deep subcutaneous lesions and lymphnode lesions should be documented by 
ultrasound and histological/cytological evidence should be attempted. In absence of 
 
 
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pathology report, lesion progression (recurrence) will be documented with a CT 
scan/MRI. 
7.1.1.3 
Date of recurrence 
The first date when recurrence was observed is taken into account regardless the method of 
assessment. Therefore recurrence will be declared for any lesion when: 
♦ Only imaging was performed and progression confirmed 
♦ Only pathology was done and malignancy confirmed (in solitary or in doubtful lesions, 
cutaneous, subcutaneous or lymph node lesions) 
♦ Both pathology and imaging were done and progression/malignancy confirmed. In this 
case, whatever examination came first, its date is considered to be the date of recurrence. 
7.1.2 
Progression During Part 2 (Cross-over/Re-challenge) 
Refer to Section 5.4.2.4 for reasons to discontinue treatment during the cross-over/re-
challenge treatment part. 
Treatment after Initial Radiologic Progression During Cross-over/Re-challenge Portion 
of Trial 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with 
cytotoxic agents, and can manifest as a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. 
If radiologic imaging shows progression of disease during cross-over/re-challenge treatment 
although patient appears to have a clinical benefit according to investigator’s judgment, 
tumor assessment may be repeated by the site 4 weeks later in order to confirm progression 
of disease with the option of continuing treatment per below while awaiting radiologic 
confirmation of progression. If repeat imaging shows a reduction in the tumor burden 
compared to the initial scan demonstrating progression of disease, treatment may be 
continued as per treatment calendar. If repeat imaging confirms progressive disease, patients 
will be discontinued from study therapy. In determining whether or not the tumor burden has 
increased or decreased, investigators should consider all target lesions as well as non-target 
lesions. 
The decision to continue study treatment after the first evidence of disease progression 
during cross-over/re-challenge treatment is at the Investigator’s discretion based on the 
clinical status of the patient. 
Patients may receive study treatment while waiting for confirmation of progression of disease 
if they are clinically stable as defined by the following criteria: 
♦ Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
♦ No decline in ECOG performance status 
♦ Absence of rapid progression of disease  
 
 
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♦ Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
Discontinuation of Study Therapy after Complete Response 
Discontinuation of cross-over/re-challenge treatment may be considered for patients who 
have attained a confirmed complete response that have been treated for at least 24 weeks 
with pembrolizumab and had at least 2 treatments with pembrolizumab beyond the date when 
the initial complete response was declared. 
7.1.3 
Time to event endpoints 
7.1.3.1 
Recurrence-free survival 
Recurrence-free survival (RFS) is defined as the time between the date of randomization and 
the date of first recurrence (local, regional, distant metastasis) or death (whatever the cause), 
whichever occurs first. For patients who remain alive and whose disease has not recurred, 
RFS will be censored on the date of last visit/contact with disease assessments. RFS will be 
based on the disease assessment or date of death provided by the local investigator. 
All imaging (radiologic) from a sample of patients will be reviewed in a blinded fashion by 
an Independent Review Committee to assess recurrence. The IRC review is defined in a 
separate IRC charter. 
7.1.3.2 
Distant metastasis-free survival 
Distant metastasis-free survival (DMFS) is defined as the time between the date of 
randomization and the date of 1st distant metastasis or date of death (whatever the cause), 
whichever occurs first. For patients who remain alive and distant metastasis-free, DMFS will 
be censored on the date of last visit/contact with disease assessments. DMFS will be based on 
the 1st date of distant metastasis assessment or date of death provided by the local 
investigator. 
7.1.3.3 
Duration of overall survival 
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death, whatever the cause. The follow-up of patients still alive will be censored at the 
moment of last visit/contact. 
7.1.3.4 
Duration of progression/recurrence-free survival 2 
Progression/recurrence-free survival 2 (PRFS2) is defined as the time between the date of 
randomization and the earliest of the following: 
♦ date of 1st disease progression per RECIST 1.1 (Appendix O) beyond the initial 
unresectable disease recurrence (e.g. unresectable distant metastases);  
♦ date of 2nd recurrence in patients without evidence of disease after surgery of a 
resectable 1st recurrence (e.g. local regional recurrences or resectable distant metastases);  
♦ death. 
 
 
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For patients who remain alive and whose disease has not recurred, or disease has recurred but 
subsequent disease progression or recurrence has not occurred, PRFS2 will be censored on 
the date of last visit/contact with disease assessments or date of last follow up.  
7.2 
Evaluation of safety 
7.2.1 
Adverse events 
All adverse events will be recorded; the investigator will assess whether those events are 
drug related (reasonable possibility, no reasonable possibility) and this assessment will be 
recorded in the database for all adverse events. 
All adverse events must be followed until resolution or stabilization. 
7.2.2 
General evaluation of adverse events 
This study will use the International Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.0, for adverse event reporting. A copy of the CTCAE can be accessed 
from the EORTC home page www.eortc.org\investigators-area\ctc. 
Hematological toxicity will be assessed on the basis of regular blood tests. The nadir count 
will be computed at each study medication administration and graded according to the 
CTCAE version 4.0.  
Non hematological acute side effects will be assessed and reported separately for each study 
medication administration, and graded according to the CTCAE version 4.0. 
Planned safety analysis and tabulations are described in the statistics Section 8. 
7.2.3 
Serious adverse events and Events of Clinical Interest 
Serious adverse events are defined by the Good Clinical Practice Guideline. 
Serious adverse events should be immediately reported according to the procedure detailed in 
this PROTOCOL (see chapter on Reporting Serious Adverse Events). 
For guidance regarding Events of Clinical Interest (ECI) for pembrolizumab please 
refer to Appendix H. 
7.2.4 
Toxic deaths 
Toxic death is defined as death due to toxicity (defined as adverse events that are not 
confirmed as unrelated). The cause of death must be reported as "toxicity". 
The evaluation of toxic deaths is independent of the evaluation of response (patients can die 
from toxicity after a complete assessment of the response to therapy). 
7.2.5 
Evaluability for safety 
All patients who have started the treatment will be included in overall safety analyses. 
Patients who have discontinued treatment because of toxicity will always be included in the 
safety analyses. 
 
 
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8 Statistical considerations 
8.1 
Statistical design 
This is a double-blind randomized phase III trial. 
8.1.1 
Sample size 
The primary objective of this study is to determine whether post-operative adjuvant therapy 
with Pembrolizumab improves recurrence-free survival (RFS) (definition: Section 7.1.3.1) as 
compared to placebo in patients with complete resection of stage IIIA (>1 mm metastasis), 
IIIB and IIIC (no past or current in-transit metastases or satellitosis) melanoma (AJCC 2010). 
Also, whether in PD-L1-positive expression subgroup, Pembrolizumab improves RFS. 
Secondary efficacy endpoints (DMFS and OS) will evaluate whether an immediate 
administration of Pembrolizumab improves the outcome as compared to those who initially 
received placebo, even if cross-over from placebo to Pembrolizumab after a 1st recurrence is 
performed. As for RFS endpoint, the impact of Pembrolizumab on these 2 secondary efficacy 
endpoints will be evaluated in the subgroup of PD-L1-positive expression subgroup as well. 
In the observation group of the EORTC 18991 study, stage IIIb/IIIc patients had a median 
RFS of 1.1 yr, the 1-yr RFS rate was 54% and the 3-yr RFS rate was 33%. On the other hand, 
stage IIIA patients had a 1-yr RFS of 90% and 3-yr RFS of 65%.  
In this new trial, one expects that patient population will be represented by a mixture of Stage 
IIIA (> 1 mm) (20%) and stage IIIb/IIIc (80%). In the EORTC 18071 study, the stage 
distribution was: Stage IIIA (> 1 mm) (20%), stage IIIb (45%) and stage IIIc (35%). In such 
a mixed population, based on the results of the 18071 study (Q12014), one may expect in the 
control group (placebo) a RFS hazard rate of 0.045 per month during the first year (so a 
cumulative hazard rate of 0.54 per year), a RFS hazard rate of 0.02 per month years 1 to 3 (so 
a cumulative hazard rate of 0.25 per year), and 0.005 per month thereafter (so a cumulative 
hazard rate of 0.06 per year). Therefore, in the placebo group the expected 1-yr RFS rate is 
58.3% and the 3-yr RFS rate is 35.3%. Based on piece-wise exponential assumption, the 
expected median RFS in the placebo arm is 1.64 years (19.7 months). Such estimates are 
quite reasonable, as in the 18071 trial, the 1-yr and 3-yr RFS rates based on the local 
investigator was 57.4% and 35.9% respectively, and the median estimation was 17.5 months.  
The study is powered for the primary endpoint, RFS. Assuming RFS hazard rates for placebo 
of 0.54 pre- 1 year and 0.25 post-1 year from randomization, a total of 409 events 
(local/regional/distant metastasis/death) for RFS are needed to provide 95% power to detect 
an Pembrolizumab:placebo hazard ratio (HR) of 0.70 (1-sided logrank test, alpha=2.5%) or 
an increase of the median RFS from 1.64 to 2.87 years (median ratio=1.75). This corresponds 
also to an increase of 10.2% (from 58.3% to 68.5%) in the 1-year RFS rate (see Table 11). 
The power could also be 92% according to the multiplicity strategy which allocates 
alpha=1.4% to RFS (discussed below).  
 
 
 
 
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Endpoint: RFS 
Hazard ratio (HR) = 0.70 , 1-sided alpha=1.4%, power=92% 
Hazard ratio (HR) = 0.70 , 1-sided alpha=2.5%, power=95% 
 
Expected RFS rate at 
Hazard rate 
(lambda) per year 
 
Total nb. 
of pts: 
900 
 
1-yr 
3-yr 
7-yr 
<=1 
yr 
1-<3 
yr 
3+ yrs 
Total 
nb. of 
RFS 
Events 
100 
pts/first 6 
months 
200 
pts/month 
7-12 
600 
pts/2nd 
year 
Placebo 
58.3% 35.3% 27.8% 0.54 0.25 
0.06 
 
409 
Accrual: 
2 yrs 
± 
additional 
follow-
up: 1 year 
± total 
follow-
up: 3 
years 
Pembrolizumab 68.5% 48.3% 40.8% 0.38 0.175 0.0042 
Difference/HR 
10.2% 13.0% 13.0% 0.7 
0.7 
0.7 
 
 
Table 11: Estimations of RFS events 
In this study it is planned to randomize a total of approximately 900 eligible patients 
(approximately 450 patients per arm) 
Up to 2.5% additional patients may be enrolled in order to compensate: 
♦ Ineligible patients 
♦ Early consent withdrawal 
In addition, if by the time the targeted enrollment is completed there are patients in 
consenting process, they will be authorized to be randomized in the study. 
Assuming that the entry rate will be, on average, 100 patients/first 6 months 200 
patients/month 7-12, and 600 patients/2nd year, the total accrual period will be 
approximately 2 years. If one assumes that the hazard of patient drop-out for RFS evaluation 
 
 
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will be 0.015 per year in the placebo vs 0.03 per year in the Pembrolizumab arm, during the 
first year, and it will be 0.015 subsequently, in both arms, and if alternative hypothesis H1 
(actual treatment HR=0.7) is true, the required 409 RFS events will be reached after a 
subsequent follow-up of approximately 12 months (i.e. approximately 3.0 years from the 
start of the trial). Approximately 6-9 months thereafter, once the data are complete and 
correct, the data-base will be locked, the final analysis for RFS will be performed.  
RFS for the PD-L1+ subgroup is the other main endpoint of this study. The power is 
presented for the PD-L1+ subgroup where the events in the subgroup range from 30%-60% 
of the 409 overall RFS events, the subgroup HR=0.55, 0.6, 0.65, or 0.7 and alpha is allocated 
or alpha=0.025 (see Table 12). Under these scenarios, the power for the subgroup ranges 
from 41% to 100%. Finally the power for rejecting the RFS hypothesis for either the PD-L1+ 
subgroup or overall is presented. Under these scenarios, the power for rejecting at least 1 
RFS hypothesis is at least 93%. 
Endpoint: RFS for the PD-L1+ Subgroup 
% Events PD-
L1+  
Allocated 
Alpha† 
HR 
% Power 
(alpha=allocated)† 
% Power 
(alpha=0.025) †† 
% Power reject at 
least 1 RFS 
Hypothesis 
30 (123/409) 
0.0134 
0.55 
86 
91 
96 
0.6 
73 
81 
95 
0.65 
57 
66 
93 
0.7 
41 
50 
93 
40 (164/409) 
0.0143 
0.55 
95 
97 
98 
0.6 
86 
90 
96 
0.65 
71 
79 
94 
0.7 
54 
63 
93 
50 (205/409) 
0.0154 
0.55 
98 
99 
99 
0.6 
93 
95 
97 
0.65 
82 
87 
94 
0.7 
65 
72 
93 
60 (245/409) 
0.0167 
0.55 
99 
100 
100 
0.6 
97 
98 
98 
0.65 
89 
92 
95 
0.7 
75 
80 
93 
 
 
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Endpoint: RFS for the PD-L1+ Subgroup 
% Events PD-
L1+  
Allocated 
Alpha† 
HR 
% Power 
(alpha=allocated)† 
% Power 
(alpha=0.025) †† 
% Power reject at 
least 1 RFS 
Hypothesis 
According to the multiplicity strategy (Bonferroni-Holm), the hypothesis for the overall population will 
first be tested at alpha=1.4%.  
† According to the multiplicity strategy, RFS for the PD-L1+ subgroup will be tested at the allocated 
alpha if the RFS hypothesis for the overall population is not rejected at alpha=0.014. 
†† According to the multiplicity strategy, RFS for the PD-L1+ subgroup will be tested at alpha=0.025 if 
the RFS hypothesis for the overall population is rejected at alpha=0.014. 
If the hypothesis for the PD-L1+ subgroup is rejected at the allocated alpha (alpha in parentheses), then 
the hypothesis for the overall population will be tested at alpha=2.5% 
Table 12: Estimations of RFS events in PD-L1+ Subgroup 
One interim analysis is planned for assessing whether pembrolizumab is superior to placebo 
with respect to the improvement of RFS in the overall population. The interim analysis will 
occur after approximately 330 RFS events have been reported, and will be based on the 
primary efficacy analysis on the primary efficacy population (ITT population). Additional 
details regarding the interim analysis can be found in Section 8.3 (Interim analyses) of the 
protocol. 
After the RFS final analysis, patients will continue to be followed for the efficacy endpoints: 
RFS (for those still alive and disease-recurrence free), DMFS (for those still alive and distant 
-metastasis free) and OS (for those still alive). 
DMFS is a secondary endpoint of this study. In case the treatment comparisons regarding 
RFS and RFS in the PD-L1+ subgroup are both significant, DMFS (and DMFS in the PD-
L1+ subgroup) will be tested (see Table 13). 
 
 
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Endpoint: DMFS 
Hazard ratio (HR) = 0.725, 1-sided alpha=1.4%, power=87% 
Hazard ratio (HR) = 0.725, 1-sided alpha=2.5%, power=91% 
 
Expected DMFS rate at 
Hazard rate (lambda) per 
year 
 
Total nb. 
of pts: 900 
 
1-yr  
4-yr  
7-yr  
<=1 yr 
1-<4 yr 
4+ yrs 
Total 
nb. of 
DMFS 
Events 
100 
pts/first 6 
months 
200 
pts/month 
7-12 
600 
pts/2nd 
year 
Placebo 
70.5% 
44.9% 
40.0% 
0.35 
0.15 
0.0385 
 
423 
Accrual: 2 
years 
± 
additional 
follow-up: 
3.1 years 
± total 
follow-up: 
5.1 years 
Pembrolizumab 
77.6% 
55.96% 
51.5% 
0.2538 
0.109 
0.0279 
Difference/HR 
7.1% 
11.06% 
11.5% 
0.725 
0.725 
0.725 
 
 
Table 13: Estimations of DMFS events 
DMFS for the PD-L1+ subgroup is another secondary endpoint of this study. The power is 
presented for the PD-L1+ subgroup where the events in the subgroup range from 30%-60% 
of the 423 overall DMFS events, the subgroup HR=0.55, 0.6, 0.65, or 0.725, and alpha is 
allocated or alpha=0.025 (see Table 14). Under these scenarios, the power for the subgroup 
ranges from 34% to 100%. Finally the power for rejecting the DMFS hypothesis for either 
the PD-L1+ subgroup or overall is presented. Under these scenarios, the power for rejecting 
at least 1 DMFS hypothesis is at least 88%. 
 
 
 
 
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Endpoint: DMFS for the PD-L1+ Subgroup 
% Events 
PD-L1+ 
Allocated 
Alpha† 
HR 
% Power 
(alpha=allocated)† 
% Power 
(alpha=0.025) 
†† 
% Power 
reject at least 1 
DMFS 
Hypothesis 
30 
(127/423) 
0.0134 
0.55 
88 
92 
95 
0.6 
75 
82 
92 
0.65 
58 
68 
90 
0.725 34 
44 
88 
40 
(169/423) 
0.0143 
0.55 
96 
97 
97 
0.6 
87 
91 
94 
0.65 
73 
80 
91 
0.725 46 
55 
88 
50 
(212/423) 
0.0154 
0.55 
99 
99 
99 
0.6 
94 
96 
96 
0.65 
83 
88 
92 
0.725 57 
65 
88 
60 
(254/423) 
0.0167 
0.55 
100 
100 
100 
0.6 
97 
98 
98 
0.65 
90 
93 
94 
0.725 67 
73 
88 
† According to the multiplicity strategy, DMFS for the PD-L1+ subgroup will be tested at the allocated 
alpha if the DMFS hypothesis for the overall population is not rejected at alpha=0.014. 
†† According to the multiplicity strategy, DMFS for the PD-L1+ subgroup will be tested at alpha=0.025 
if the DMFS hypothesis for the overall population is rejected at alpha=0.014. 
Table 14: Estimations of DMFS events in PD-L1+ Subgroup 
 
 
 
 
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After the DMFS final analysis, patients will continue to be followed for the efficacy 
endpoints: RFS (for those still alive and disease-recurrence free), DMFS (for those still alive 
and distant -metastasis free) and OS (for those still alive). 
OS is a secondary endpoint of this study. In case the treatment comparisons regarding DMFS 
and DMFS in the PD-L1+ subgroup are both significant, OS (and OS in the PD-L1+ 
subgroup) will be tested. 
Assuming that the median survival post a RFS event is 1.64, approximately 30% of patients 
will still be alive 3 years post a RFS event (see Table 15).  
In order to detect an OS HR=0.75 with 80% power a total of 380 deaths are required. After a 
2-year accrual period and based on the scenarios indicated above regarding RFS results, 
approximately 520 RFS events will be reported after 3 years of additional follow-up, and 540 
RFS events one year later. Therefore, given that 70% of patients with an RFS are expect to 
die within 3 years, a total of 380 deaths could be reached within 8-8.5 years from the start of 
the accrual. 
Assuming a piece wise exponential distribution in the placebo randomized arm, i.e. OS 
hazard rates of 0.026 pre-0.5 year, of 0.161 per year, post-0.5 year till year 3, of 0.0912 per 
year during year 3 till 5, and 0.026 per year thereafter, the OS comparison will be powered to 
detect a treatment HR of 0.75, corresponding to an increase of the 3-year OS rate from 66.0% 
to 73.2% and of the 5-year OS rate from 55% to 63.9%. The power could also be 73% 
according to the multiplicity strategy which allocates alpha=1.4% to OS (discussed below). 
 
 
 
 
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Endpoint: OS 
Hazard ratio (HR) = 0.75 , 1-sided alpha=1.4%, power=73% 
Hazard ratio (HR) = 0.75 , 1-sided alpha=2.5%, power=80% 
 
Expected OS rate at 
Hazard rate (lambda) 
per year 
 
 
Total 
nb. of 
pts: 
900 
 
0.5 yr  
3 yrs  
5 yrs  
<=0.5 
yr 
0.5 -
<3 
yrs 
3-<5 
yrs 
5+ yrs 
Total 
nb. of 
deaths  
100 
pts/first 
6 
months 
200 
pts/mo
nth 7-
12 
600 
pts/2nd 
year 
Placebo 
98.7% 
66.0% 
55.0% 
0.026 
0.161 
0.0912 
0.026 
 
380 
Accrual
: 2 yrs 
± 
additio
nal 
follow-
up: 6.5 
years 
± total 
follow-
up: 8.5 
years 
Pembrolizumab 
99.0% 
73.2% 
63.9% 
0.019 
0.121 
0.068 
0.0195 
Difference/HR 
1.3% 
7.2% 
8.9% 
0.75 
0.75 
0.75 
0.75 
 
 
Table 15: Estimations of OS events 
The analysis of OS will be performed once 380 deaths have been reported, i.e. approximately 
7.0 years from the trial inception, if H1 is true (actual treatment HR=0.75), and considering 
that the drop out hazard rate will be 0.015 per year in the placebo vs 0.03 per year in the 
Pembrolizumab arm, during the first year, and it will be 0.015 subsequently, in both arms. 
In case the HR=0.8 (i.e. lower randomized treatment difference regarding OS due to a larger 
impact of the crossover on OS post-recurrence), 380 deaths will provide a power for 
detecting a treatment difference of approximately 56% (1-sided alpha=2.5%). In case the HR 
is as high as 0.90, the power will be 16% (1-sided alpha=2.5%). 
OS for the PD-L1+ subgroup is another endpoint of this study. The power is presented for the 
PD-L1+ subgroup where the events in the subgroup range from 30%-60% of the 380 OS 
events, the subgroup HR=0.6, 0.65, 0.7, or 0.75, and alpha is allocated or 0.025 (see Table 
16). Under these scenarios, the power for the subgroup ranges from 70% to 97% (if HR=0.6) 
and from 25% to 58% (if HR=0.75). Finally the power for rejecting the OS hypothesis for 
 
 
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either the PD-L1+ subgroup or overall is presented. Under these scenarios, the power for 
rejecting at least 1 OS hypothesis is at least 74%. 
 
Endpoint: OS for the PD-L1+ Subgroup  
% Events 
PD-L1+  
Allocated 
Alpha† 
HR 
% Power 
(alpha=allocated)† 
% Power 
(alpha=0.025) 
†† 
% Power 
reject at least 
1 OS 
Hypothesis 
30 (114/380) 
0.0134 
0.6 
70 
78 
84 
0.65 53 
63 
80 
0.7 
38 
48 
76 
0.75 25 
34 
74 
40 (152/380) 
0.0143 
0.6 
83 
88 
89 
0.65 68 
76 
83 
0.7 
50 
59 
78 
0.75 34 
43 
75 
50 (190/380) 
0.0154 
0.6 
91 
94 
93 
0.65 79 
84 
86 
0.7 
62 
69 
79 
0.75 43 
51 
75 
60 (228/380) 
0.0167 
0.6 
96 
97 
96 
0.65 87 
90 
89 
0.7 
71 
77 
81 
0.75 52 
58 
76 
† According to the multiplicity strategy, OS for the PD-L1+ subgroup will be tested at the allocated 
alpha if the OS hypothesis for the overall population is not rejected at alpha=0.014. 
†† According to the multiplicity strategy, OS for the PD-L1+ subgroup will be tested at alpha=0.025 if 
the OS hypothesis for the overall population is rejected at alpha=0.014. 
Table 16: Estimations of OS events in PD-L1+ Subgroup 
 
 
 
 
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The "graphical approach" (see Figure 5) to testing the hypotheses that the Pembrolizumab 
and placebo groups differ with respect to RFS, DMFS, OS and these endpoints in the PD-
L1+ subgroup, will be adopted.  
The initial 1-sided alpha allocation to RFS, DMFS and OS, will be 0.025, 0 and 0, 
respectively. This indicates that RFS, DMFS and OS will be tested sequentially. Both 
hypotheses (for the overall population and for the PD-L1+ subgroup) must be rejected to 
proceed to the next endpoint as indicated by the downward arrows and the boxed “1” 
indicating 100% of the alpha moves to the next endpoint. 
For each endpoint, alpha allocation was determined as follows. For the overall population, 1-
sided alpha=0.014. For the PD-L1+ subgroup, the allocated alpha will be calculated as a 
function of the event ratio (number of observed events in the PD-L1+ subgroup: total number 
of observed events) using a method by Spiessen and Debois. Several scenarios are discussed 
in the sample size calculation (above). 
This "graphical approach" (see Figure 5) guarantees a 1-sided significance level of 0.025 for 
the study, as a whole. No multiplicity adjustment for other secondary analyses will be made. 
 
Figure 5: Graphical approach 
At the time of OS final analysis, an assessment of the long term treatment impact on RFS and 
DMFS will be evaluated as well. 
8.1.2 
Randomization and stratifications 
Patients will be centrally randomized (for practical details, see chapter on registration / 
randomization procedure). A minimization technique will be used for random treatment 
allocation stratifying by stage (IIIA (> 1 mm metastasis) vs. IIIB vs. IIIC 1-3 positive lymph 
 
 
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nodes vs. IIIC 4 positive lymph nodes) and region/country (North America, European 
countries, Australia and other countries as designated ). 
8.2 
Statistical analysis plan 
8.2.1 
Primary and secondary endpoints 
The main efficacy endpoints that will be used in the statistical analysis are listed in Section 2 
and defined in Section 7.1. 
8.2.2 
Analysis populations 
♦ Intention-to-treat (ITT) population: All randomized patients will be analyzed in the arm 
they were allocated by randomization. 
♦ Per protocol treatment (PPT) population: All patients who are eligible and have started 
their allocated treatment (at least one dose of the study drug) 
♦ Safety population: All patients who have started their allocated treatment (at least one 
dose of the study drug) 
A patient will be considered to be eligible if he/she did not have any clinically relevant 
major deviations impacting efficacy analysis. Potential eligibility problems will be 
assessed by the Clinical Research Physician and Medical Review Team at time of 
medical review. 
8.2.3 
Statistical methods 
8.2.3.1 
Analysis methods for efficacy endpoints 
All the main analyses of the efficacy endpoints (RFS, DMFS, OS) will be performed on the 
ITT population using the ITT principle: patients will be considered in the treatment group as 
indicated at randomization, regardless the “treatment” duration, cause of going off-protocol 
treatment, possible switch to another treatment before the 1st recurrence, etc. 
The Kaplan-Meier technique will be used to obtain estimates of the survival-type 
distributions (RFS, DMFS, OS), and the standard error of the estimates will be computed 
using the Greenwood formula. Medians - if reached - will be presented with a 95% 
confidence interval based on the non-parametric method of Brookmeyer and Crowley. 
The comparison of the time-to-event distributions (RFS, DMFS, OS) between the two 
treatment arms will be done using the log-rank test stratified by stage (IIIA (> 1 mm 
metastasis) vs. IIIB vs. IIIC 1-3 positive lymph nodes vs. IIIC 4 positive lymph nodes), as 
indicated at randomization. The HR, and its (1-2xα)*100% confidence interval, of 
Pembrolizumab:Placebo, will be estimated using a Cox proportional hazards (PH) model 
(using Efron’s tie-handling method), stratified by stage (IIIA (> 1 mm metastasis) vs. IIIB vs. 
IIIC 1-3 nodes vs. IIIC 4 nodes) as indicated at randomization, with treatment as the single 
covariate. 
 
 
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8.2.3.2 
Analysis methods for safety endpoints 
No formal toxicity treatment comparison with p-values will be carried out.  
8.2.4 
Pre-planned sensitivity or exploratory analyses 
8.2.4.1 
Sensitivity analyses for efficacy endpoints (RFS, DMFS, OS) 
For the efficacy endpoints, sensitivity analyses will be performed (see Table 17): 
♦ to ensure true randomization via minimization, a re-randomization test will be performed: 
♦ RFS for ITT population 
♦ RFS for PD-L1+ ITT population 
♦ DMFS for ITT population 
♦ DMFS for PD-L1+ ITT population 
♦ OS for ITT population  
♦ OS for PD-L1+ ITT population 
♦ using the ITT population, but considering the stratification factor (AJCC stage) 
information as indicated on the CRFs, based on pathology report(s) and applying the 
AJCC staging rules. 
♦ using the PPT population. 
♦ adjusting the treatment comparison by additional factors which appeared to be of 
prognostic importance (see below). 
♦ In order to evaluate the robustness of the RFS endpoint, we will perform two sensitivity 
analyses with a different set of censoring rules (refer to the table below).  
 
 
 
 
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Situation 
Primary Analysis 
Sensitivity  
Analysis 1 
Sensitivity  
Analysis 2 
No recurrence and 
no death; new 
anticancer 
treatment is not 
initiated 
Censored at last 
disease assessment  
Censored at last disease 
assessment  
Censored at last 
disease assessment  
No recurrence and 
no death; new 
anticancer 
treatment is 
initiated 
Censored at last 
disease assessment  
Censored at last disease 
assessment before new 
anticancer treatment 
Recurrence at date of 
new anticancer 
treatment 
Recurrence or 
death documented 
after ≤ 1 missed 
disease assessment 
Recurrence at date of 
documented 
recurrence or death 
Recurrence at date of 
documented recurrence 
or death 
Recurrence at date of 
documented 
recurrence or death 
Recurrence or 
death documented 
after ≥ 2 missed 
disease assessments 
Recurrence at date of 
documented 
recurrence or death 
Censored at last disease 
assessment prior to the ≥ 
2 missed disease 
assessment 
Recurrence at date of 
documented 
recurrence or death 
Table 17: Sensitivity analyses 
♦ In case there is an imbalance between the treatment groups on disease assessment 
schedules or censoring patterns, we will also perform the following two additional RFS 
sensitivity analyses: 1) a RFS analysis using time to scheduled tumor assessment visit 
from randomization as opposed to actual tumor assessment time; 2) Finkelstein (1986)’s 
likelihood-based score test for interval-censored data, which modifies the Cox 
proportional hazard model for interval censored data, will be used as a supportive 
analysis for the RFS endpoint. The interval will be constructed so that the left endpoint is 
the date of the last disease assessment without documented recurrence and the right 
endpoint is the date of documented recurrence or death, whichever occurs earlier. 
8.2.4.2 
Exploratory analyses for primary and secondary efficacy endpoints (RFS, 
DMFS, OS) 
Predictive importance of a factor (see list below), i.e. its impact on the treatment difference 
regarding the time to event end point (RFS, DMFS, OS) will be investigated for exploratory 
purposes. Consistency of treatment comparisons among subgroups of variables (see below) 
will be investigated using the Forest plot techniques. Subgroup analyses will be performed at 
2-sided alpha=0.01 and 0.05. One should acknowledge the fact that the statistical power for 
the treatment comparisons will be limited in each subgroup. When interpreting the results of 
subgroup analyses, emphasis should be placed on the relevant tests for heterogeneity between 
subgroups, and not on the p-values obtained within the subgroups of all variables analyzed. 
 
 
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All subgroup analyses should be interpreted with caution and should be considered 
hypothesis-generating.  
In addition, possible interactions between a factor and treatment effect will be assessed in a 
Cox model, in a bi-variate setting (i.e. treatment, variable, treatment x variable) and a 
multivariate one, i.e. adding in the model those factors which appear to be of independent 
prognostic importance (see below). 
The PD-L1 patient distribution and magnitude of the treatment difference in the 2 main 
subgroups (PD-L1 positive vs PD-L1 negative) is unknown. So assuming:  
♦ The prevalence of PD-L1 positive patients is 40%-60%,  
♦ The treatment HR is 0.7 in the overall population,  
♦ PD-L1 status has no prognostic importance in the placebo arm, i.e. 3-yr RFS (PD-L1+) = 
3-yr RFS (PD-L1-) = 35.3%, 
♦ PD-L1 status has prognostic importance in the Pembrolizumab arm: 3-yr RFS (PD-L1+) 
= 56.4%, 
♦ In PD-L1-positive expression, the treatment HR = log(.564)/log(.353) = 0.55, and  
♦ In PD-L1-negative expression, the treatment HR is 0.95-1.00.  
 
 
Prevalence PD-L1+/Prevalence PD-L1- in the entire cohort 
Pembrolizumab 
arm 
40%/60%  
50%/50%  
55%/45%  
60%/40%  
3-yr RFS (PD-L1-) 42.5% 
39.5% 
37.6% 
35.1% 
HR in PD-L1- 
0.82 
0.89 
0.94 
1.00 
Power for the 
treatment - PD-L1 
interaction 
48.9% 
66.9% 
76.3% 
83.9% 
Study number of 
events 
409 
410 
409 
409 
Number of events 
for an 80% power 
for the treatment - 
PD-L1 interaction 
825 
554 
447 
370 
Table 18: Prevalence PD-L1+/Prevalence PD-L1- in the entire cohort 
So assuming the prevalence of PD-L1 positive patients is 40%-60% and the treatment HR is 
0.55 in PD-L1 positive patients vs. 0.95-1.00 in PD-L1 negative patients, this large study is 
sufficiently powered to detect an interaction between PD-L1 expression and treatment 
difference regarding RFS, at the time of the final analysis, when 409 RFS events will be 
reported (see Table 18). 
 
 
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This PD-L1 expression interaction test is exploratory. These results will not supersede the 
PD-L1+ subgroup primary analysis for RFS and secondary analysis for DMFS and OS.  
8.2.4.3 
Exploratory analyses for exploratory efficacy endpoint (PRFS2) 
The main analysis of this endpoint (PRFS2) will be performed on the ITT population using 
the ITT principle: patients will be considered in the treatment group as indicated at 
randomization, regardless the “treatment” duration, cause of going off-protocol treatment, 
possible switch to another treatment before the 1st recurrence and/or before the progression 
or 2nd recurrence. 
The Kaplan-Meier technique will be used to obtain estimates of the survival-type 
distributions (PRFS2), and the standard error of the estimates will be computed using the 
Greenwood formula. Medians - if reached - will be presented with a 95% confidence interval 
based on the non-parametric method of Brookmeyer and Crowley. 
8.2.5 
Prognostic factor analyses 
The following variables will be considered for the efficacy endpoints (RFS, DMFS, OS): 
♦ PD-L1 expression (negative vs positive vs undetermined). 
♦ Variables considered in the AJCC Staging: 
♦ LN involvement: micro vs. macro- involvement 
♦ Ulceration: absent vs. present vs. unknown 
♦ Number of lymph-nodes positive: 1 vs. 2-3 vs. 4+ 
♦ Breslow thickness (< 2 mm vs 2-<4 mm vs 4 mm) 
♦ BRAF-mutation status (negative vs positive vs unknown) 
♦ Sex (Male vs. Female) 
♦ Age (at randomization <65 vs. 65 yrs) 
Other variables might also be assessed based on new information that may become available 
during the course of the study. 
In order to avoid a possible treatment influence on the prognostic importance of these factors, 
univariate analyses (Kaplan-Meier curves, logrank test, Cox model) will be done in each 
treatment group, separately. 
Thereafter a multivariate Cox model will be fitted using both treatment groups, including as 
covariates randomized treatment group and all factors which appeared of prognostic 
importance in univariate analyses. A step down and step-up procedure will be used for the 
multivariate model selection at the 2-sided 5% significance level, and forcing treatment arm 
to stay in the model. The model with the lowest Akaike information criterion (AIC) will be 
retained. Such analysis of the treatment comparison adjusted by prognostic factors will be 
considered as a sensitivity analysis of the main one (see Section 8.2.4). The assumption of 
proportional hazards will be checked using a procedure derived from cumulative sums of 
martingale-based residuals over follow-up time (method of Lin, Wei, and Ying). In case one 
 
 
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of the strong prognostic factors will violate the PH assumption, a Cox model stratified by this 
factor will be considered. 
8.2.6 
Data recoding and display 
Frequency tables will be tabulated (by treatment group or otherwise) for all categorical 
variables by the levels of the variables as they appear on the CRF (with %). Categories with a 
text field specification will be tabulated as categories and then supplemented by a listing with 
the following information for the patients fulfilling the condition for the specification (patient 
id, institution, treatment group, value of the item and text field contents). 
Dates relating to events prior to entry will be presented as the delay in days (or weeks, 
months, or years) between the past event and the date of entry (date of randomization – date 
of past event + 1) and presented using the median and range. For example, on the 
randomization checklist, the date of last administration of prior treatment (or the date of first 
diagnosis of the cancer) will be presented as the time elapsed (in days, weeks, months or 
years, as appropriate) since the day of the last administration and the date of entry on study 
(date of randomization – last administration/diagnosis +1). 
Other delays (e.g., re-treatment delays) are presented as continuous variables using the 
median and range. 
Continuous variables for which a coding system exists (such as for laboratory data) will be 
recoded into categories (for adverse events, the grading scale specified in the protocol will be 
used). Whenever no specific scale exists, lab data will be categorized based on the normal 
range: for example, below the lower normal limit (when appropriate), within the normal 
range, above the upper normal limit (ULN) and the degree to which it is above the ULN (for 
example > 2.5 x ULN, > 5 x ULN, > 10 x ULN). For laboratory data, the nadir is generally 
displayed. The nadir in a given cycle is the lowest laboratory value in that cycle; the overall 
nadir for a patient is the lowest laboratory value among all cycles. 
Other continuous variables (for example age, dose …) are presented using the median and 
range (minimum, maximum).  
If appropriate, continuous data may also be presented in categories (for example, age may 
also be grouped in decades). 
8.3 
Interim analyses 
One interim analysis is planned for assessing whether pembrolizumab is superior to placebo 
with respect to the improvement of RFS in the overall population. The interim analysis will 
occur after approximately 330 RFS events have been reported, and will be based on the 
primary efficacy analysis on the primary efficacy population (ITT population). An unblinded 
statistician not connected with the project will perform the interim analysis so that the project 
statistician can remain blinded until the time of the final RFS analysis. The final RFS 
analysis will either occur immediately after the interim analysis is performed (if superiority is 
concluded at the time of the interim analysis) or after 409 RFS events have been observed (if 
superiority is not concluded at the time of the interim analysis). The EORTC Independent 
Data Monitoring Committee (IDMC) will review the analysis results and recommend 
whether the study should continue as planned or if there is sufficient evidence to conclude 
 
 
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that pembrolizumab is superior to placebo with respect to the improvement of RFS in the 
overall population. The stopping boundaries for the interim analysis will be based on the 
O’Brien-Fleming spending function. 
The final RFS analysis will be performed with early rejection of the null hypothesis (i.e., 
pembrolizumab is superior to placebo with respect to the improvement of RFS in the overall 
population) if the test statistic crosses the pre-specified stopping boundaries (i.e., the value of 
the test statistic is greater than the value of the O’Brien-Fleming stopping boundary at the 
time of the interim analysis, suggesting that pembrolizumab is superior to placebo). 
Table 19 displays the operating characteristics of the interim analysis, in case 330 RFS 
events have been reported, superiority would be concluded if the observed RFS hazard ratio 
is ≤ 0.76. 
 
Power (%) to detect a HR=0.7 
(overall 1-sided alpha=0.014) 
91.4 
# of events (interim) 
330 
p-value to show superiority (interim) 
≤0.006 
p-value to show superiority (final) 
≤0.012 
Observed HR to show superiority (interim) 
≤0.76 
Observed HR to show superiority (final) 
≤0.8 
Probability (%) of superiority (interim) 
77.1 
Probability (%) of superiority (final, if 
superiority not detected at interim analysis) 
14.3 
Probability (%) no superiority (final) 
8.6 
Table 19: Operating Characteristics of the Interim Analysis 
The O’Brien-Fleming stopping boundary at the interim analysis using Lan-DeMets alpha 
spending function will be derived based on the exact number of reported RFS events. EAST 
6.4 program will be used. 
In terms of analysis, the statistical methods described in 8.2.3 will be used for the interim 
analysis. However, the (1-2xα)*100% confidence interval of the Pembrolizumab:Placebo HR 
will be computed using the 1-sided alpha error “adjusted” by the interim look (e.g. 0.006, in 
case 330 RFS events were reported at the time of interim analysis for the overall population). 
If, at the time of the interim analysis, pembrolizumab is shown to be superior to placebo with 
respect to the improvement of RFS in the overall population, then the multiplicity strategy 
will be carried out as described in Section 8.1.1 (i.e. using a 1-sided alpha=0.014). If 
pembrolizumab is not shown to be superior to placebo at the time of the interim analysis, 
then the multiplicity strategy will be carried out using a 1-sided alpha=0.012 (rather than 
0.014). 
See section 9 for interim safety monitoring. 
 
 
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8.4 
End of study 
End of study occurs when all of the following criteria have been satisfied: 
1. Thirty days after all patients have stopped protocol treatment 
2. The trial is mature (i.e. reached the required number of events) for the 3 final analyses of 
the efficacy endpoints as defined in the protocol: one for RFS (overall, and in PD-L1-positive 
expression), one for DMFS (overall, and in PD-L1-positive expression) and one for OS 
(overall, and in PD-L1-positive expression). 
3. The database has been fully cleaned and frozen for all of these 3 final analyses. 
4. As in other EORTC melanoma adjuvant trials, a very long term follow-up, when all 
patients have a 10-year follow-up is foreseen. 
9 Data Monitoring 
9.1 
Safety data monitoring 
The EORTC Independent Data Monitoring Committee (IDMC) will review safety 
information at six monthly intervals or when appropriate. 
The Study Steering Committee will not review safety information. For the Trial Steering 
Committee members and role refer to Steering Committee Charter. 
Unblinding for global safety reasons and unblinding at interim safety analyses will be 
performed according to EORTC SOP CM-011-SOP “Blind Studies”. The unblinded 
Statistician, an independent Statistician at the EORTC Headquarters not involved in the 
conduct of the trial and the Pharmacovigilance Physician will write the unblinded safety 
interim report and will present it to the IDMC. 
No efficacy results will be presented at EORTC Group meetings or elsewhere before the trial 
is closed to recruitment and the data are mature for the analysis of the primary endpoint, 
unless recommended otherwise by the EORTC IDMC. 
9.2 
Efficacy data monitoring 
In general, the EORTC IDMC is charged with the interim review (planned in the protocol or 
ad hoc) of randomized phase II and phase III studies. When interim analyses are carried out, 
the interim monitoring of efficacy and safety data is performed according to the Statistical 
Considerations chapter in this protocol and EORTC Policy 004 on “Independent Data 
Monitoring Committees and Interim Analyses”. 
In the present study, an interim analysis will be performed after approximately 330 RFS 
events have been documented. The IDMC will independently review the interim analysis 
following the EORTC POL004 (for more details see chapter 8.3).  
The results of the interim analyses are confidential and are discussed by the EORTC IDMC. 
The IDMC will subsequently recommend to the EORTC Group whether any changes should 
be made to the study (protocol).  
 
 
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No efficacy results will be presented at EORTC Group meetings or elsewhere, before the 
trial is closed to recruitment and the data are mature for the analysis of the primary endpoint, 
unless recommended otherwise by the EORTC IDMC. 
10 Quality of life assessment 
10.1 Rationale 
HRQoL is a multidimensional construct, which can be defined as a state of general wellbeing 
reflecting physical, psychological, and social wellbeing and the impact of the disease and/or 
treatment related symptoms on daily-life functioning. The patient’s subjective perspective is 
an inherent component of HRQoL and is therefore best assessed via self-administration. 
Reducing mortality and morbidity is still the most important factor in cancer clinical 
research. Nevertheless, issues such as reducing side effects, symptom relief and improving 
patients’ satisfaction have also become relevant parameters in the evaluation of medical 
strategies. Cancer treatments may produce adverse effects and diminish a patient’s quality of 
life even when survival is extended. Progress in the acceptance of new cancer therapies is 
sometimes critically dependent on their HRQoL consequences. 
Patients with resected stage III melanoma report good and stable overall HRQoL during the 
subsequent years after resection. Adjuvant treatment (such as interferon) can however 
interfere through side effects on the patients functioning. In this study, QoL is an exploratory 
endpoint. The main objective of HRQoL assessment within this clinical trial is to determine 
the impact of adjuvant immunotherapy versus placebo. The primary HRQoL endpoint will be 
overall health/QoL. Patients undergoing adjuvant immunotherapy may experience reduction 
in overall HRQoL due to side effects such as fatigue, nausea, pruritus, diarrhea and rash.  
The primary hypothesis is we expect no clinically relevant differences between the two 
treatment arms using the global QoL scale during the first two years. To meet this objective 
QoL questionnaires will also be administered after progression. Secondary objectives include 
evaluation of the effect of adjuvant immunotherapy specifically during the treatment period. 
10.2 Objective 
The primary hypothesis is we expect no clinically relevant differences between the two 
treatment arms using the global QoL scale during the first two years. To meet this objective, 
QoL questionnaires will also be administered after recurrence/progression. Secondary 
objectives include evaluation of the effect of adjuvant immunotherapy specifically during the 
treatment period. 
10.3 HRQoL instrument 
No validated immune-specific questionnaires for use in oncology trials exist. Quality of life 
will be assessed with the EORTC Quality of Life Questionnaire (QLQ-C30) version 3. This 
instrument is composed of multi-item and single-item scales. These include five functional 
scales (physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and 
vomiting and pain) and a global health status/QoL scale and six single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single 
 
 
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items meet the standards for reliability. The reliability and validity of the questionnaire is 
highly consistent across different language-cultural groups (Ref. 64). The average time to 
complete the questionnaire is approximately 10 minutes. 
The EORTC QLQ-C30 version 3 has been translated in over 50 languages according to a 
standardized translation procedure.  
The domains of interest as specified in the previous paragraph are covered by global 
health/QoL scale. The other scales will be considered secondary. 
10.4 Study design 
HRQoL questionnaires must be filled out at the hospital when patients come for a scheduled 
visit according to the EORTC “Guidelines for administration of questionnaires” (see 
Appendix D). The pre-treatment questionnaires must be filled at baseline (within 6 weeks 
before randomization). Subsequent questionnaires are filled in every 12 weeks after the first 
study drug treatment for the first two years. HRQoL data must be collected regardless of the 
patient’s recurrence/progression status, unless patient withdraws from this part of the study.  
Master copies of the HRQoL questionnaires will be sent to the institutions. Additional copies 
or translations can be provided upon request via the EORTC contact person. The clinical 
report forms will include a question whether the HRQoL forms have been filled in, and if 
not, the reason why. The questionnaire will be handed out to the patients by the investigator 
or a study nurse prior to seeing the doctor for clinical evaluations. The patient should 
complete the questionnaires by her/himself in her/his own language during the visit to the 
outpatient clinic as completely and accurately as possible. It is recommended that a key 
person (e.g. research nurse) at each center should be responsible for questionnaire data 
collection in order to optimize the compliance of the patient and to ensure the completeness 
of the data. 
During the study, compliance with completing questionnaires will be investigated at each 
time point. The compliance of the HRQoL assessments will also be reviewed twice a year 
and will be part of the descriptive report. 
10.4.1 
HRQoL schedule 
The time windows for eligible HRQoL (EORTC QLQ-C30 and EQ-5D-3L) assessments will 
be as follows (see Table 20): 
 
 
 
 
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Assessment 
Time window  
Baseline 
Can be completed before or on the day of randomization 
itself but no earlier than 6 weeks before. 
Every 12 weeks  
(during year 1 and 2 after 
randomization) 
At week 12, 24, 36, 48, 60, 72, 84, 96, 108. 
Can be completed up to 2 weeks before or after the 
intended visit date. 
Every 6 months 
(during year 3 and 4 after 
randomization) 
At month 30, 36, 42 and 48. 
Can be completed up to 6 weeks before or after the 
intended visit date. 
Table 20: HRQoL schedule 
Note: A maximum of 14 assessments per patient are required, namely: baseline, week 12, 24, 
36, 48, 60, 72, 84, 96, 108, month 30, 36, 42 and 48. At each scheduled visit, EQ-5D-3L will 
be collected prior to EORTC QLQ-C30. Refer to "Guidelines for administration of 
questionnaires". These data must be collected regardless of the patient’s 
recurrence/progression status, section 6.3.4.3 for this part of the study. 
10.5 Statistical considerations 
The primary HRQoL endpoint that is considered relevant for this study is the global 
health/QoL scale. The other available scales will only be analyzed on a descriptive basis. 
A difference of 10 points on the 100-point QLQ-C30 scale between the two arms will be 
considered as clinically relevant. The standard deviation of this scale is approximately 20 
points. With the 2-sided alpha set at 5% and a power of 80% to detect a difference of 10 
points (effect size of 0.5), a minimum of 128 patients (64 per treatment arm) is required. For 
an effect size of 0.75 (difference of 15 points), 56 patients (28 per treatment arm) are 
required. Therefore, this study is sufficiently powered to detect differences in HRQoL. 
Data will be scored according to the algorithm described in the EORTC scoring manual. All 
scales and single items are scored on categorical scales and linearly converted to 0-100 
scales. 
The QoL scores in the two arms will be compared by using summary statistics. Three 
summary statistics will be calculated per patient: 
♦ The average change from baseline reported during the first four years.  
♦ The average change from baseline reported during treatment (up to 21 days after last 
administration).  
♦ The average change from baseline reported after treatment (from 21 days after last 
administration until four years).  
Non-parametric rank-order tests will be performed using a two-sided significance level of 5% 
to test for significant differences between the treatment arms. Change from baseline per 
timepoint will be reported in a descriptive manner to provide support for the main results.  
 
 
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An overall effect of the treatment on the QoL scores will be determined primarily on the 
basis of the primary analysis. Because the study is overpowered, both statistical significance 
and the treatment effect size of clinical relevance on the QoL scores should be taken into 
consideration. Differences will only be considered as clinically relevant if they exceed the 
10-point threshold. The proportion of patients experiencing a clinical relevant change will be 
calculated as well per summary statistic. 
For all quality of life domains and items, cross-sectional descriptions of the average scores 
will be presented by treatment arm at each time point of assessment together with confidence 
intervals and a graphical display of the patterns of change over time will be provided. The 
proportion of patients experiencing a clinical relevant deterioration per scale will be provided 
as well. 
10.5.1 
Missing data 
Missing data is a potential major source of bias in HRQoL assessment. 
In order to check the potential impact in the study, the compliance mechanism will be 
investigated prior to initiating the HRQoL analysis. Compliance by instrument, visit and 
treatment arm will be described by absolute number and relative percentage. Compliance rate 
is defined as the proportion of valid forms received versus the number expected. 
Once the main analysis is completed, sensitivity analyses will be undertaken to verify the 
robustness of the results vis-à-vis the missing data. Missing values will be imputed via 
various linear regression models. These completed data will be analyzed similar to the main 
method as sensitivity analyses to assess the stability of the main results vis-à-vis the missing 
data. 
In case overall compliance is deemed too low (<50%), only an exploratory analysis will be 
performed in lieu of the main analysis. 
10.6 Health outcomes evaluation 
10.6.1 
EQ-5D-3L instrument 
The EQ-5D-3L is a general health status and health utility measure (Ref. 65). It measures 5 
dimensions of health state: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression each assessed by a single question on a three-point ordinal scale. It also 
includes a VAS scale to measure health state. The EQ-5D will be included in this study for 
the purpose of the computation of utilities that can be used in health economic studies. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability (Ref. 66). In addition, validated translations for this 
instrument are available for a number of countries and languages (Appendix M). 
The assessment schedule of the EQ-5D-3L is identical to the schedule of the QoL instrument 
(QLQ-C30) as described in 10.4.1. 
 
 
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11 Pharmacokinetic/Pharmacodynamic Evaluations 
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure in this 
indication, and also to evaluate exposure of the proposed dosing regimen, samples will be 
collected for analysis of anti-drug antibodies (ADA) and PK. 
Based on pharmacokinetic (PK) data obtained in this study as well as PK data obtained from 
other studies (if available), a population PK analysis will be performed to characterize 
pharmacokinetic parameters (Clearance (CL), Volume of distribution (V)) as endpoints and 
evaluate the effect of extrinsic and intrinsic factors to support proposed dosing regimen. 
Pharmacokinetic samples will also be used to explore the exposure-response relationships for 
pembrolizumab antitumor activity/efficacy as well as safety in the proposed patient 
population, if feasible. The results of these analyses, if performed, will be reported 
separately. 
If ongoing ADA and/or PK results continue to be consistent with existing ADA and/or 
PK data from other pembrolizumab clinical trials, it may be decided to discontinue 
further sample collection or analysis in this study. 
11.1 Timepoints 
Sample collection is currently planned as shown in Section 6.4.3. 
11.2 PK Blood Collection for Serum MK-3475 
Sample collection, storage and shipment instructions for serum PK samples will be provided 
in the Procedures Manual. 
11.3 Blood Collection for Anti-Pembrolizumab Antibodies 
Sample collection, storage and shipment instructions for anti-pembrolizumab antibody 
samples will be provided in the Procedures Manual. 
12 Translational research 
Overall Biobanking and Translational Research Study Coordinator: 
 
Institut de Cancérologie Gustave Roussy 
Villejuif, France 
12.1 Objectives 
In order to explore the biology of melanoma and in parallel assessing the prognostic and/or 
predictive value of potential biomarkers, this protocol includes a prospective biobanking for 
patients who have consented to take part in this research in view of translational research. 
The objectives of this prospective biobanking are to prospectively collect biological material 
(whole blood, plasma, serum and tissue) for translational research projects for patients who 
have consented to take part in this research. Projects may include but are not restricted to: 
 
 
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♦ Targeted mutation analysis  
♦ Targeted RNA expression analysis 
♦ Liquid biopsies to monitor therapy response 
♦ Immunohistochemistry 
To ensure confidentiality, all samples and the information associated with the samples will be 
coded to prevent the exposure of subject information and identity. These evaluations are not 
expected to benefit the subject directly or to alter their treatment course. The results will not 
be communicated or placed in their medical record and will not be made available to 
members of their family, treating physicians, or other third parties except as specified in the 
informed consent 
12.2 Patient selection criteria 
♦ Signed “Biobanking” informed consent. 
♦ Eligible for and enrolled in EORTC-1325-MG study.  
12.3 Biological material 
Tumor tissue will be collected from positive lymph nodes. Lymph nodes embedded in 
paraffin will be banked for studies of additional correlates of response. 
Primary melanoma may also be collected if available and used for additional correlative 
analyses. 
Samples collection (whole blood, plasma, serum and tissue) is currently planned as shown by 
the Trial Flowchart see Section 6.4.3. Sample collection, storage and shipment instructions 
for TR samples will be provided in the Procedures Manual. 
12.4 Data storage, transfer and development of technical 
appendices 
The translational projects will be the result of the work of collaborating institutions and 
EORTC HQ. Bioinformatics and statistical analysis plan will be jointly developed for each 
project. These documents will be developed and approved before starting any analysis. They 
will specify the analytical and methodological details. Clinical and patient-reported outcome 
data will be stored in the EORTC clinical database and biological investigational data will be 
stored in respective collaborating institutions. Transfer of data will be performed according 
to applicable policies in each organization (e.g. EORTC POL008) or according to jointly 
approved data transfer charters. 
12.5 General principles for human biological material (HBM) 
collection 
Human biological material (HBM) collection involves the collection and storage of 
biological material, residual biological material or derivatives in compliance with ethical and 
technical requirements.  
 
 
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Biobanking refers to the chain of procedures that encompass the life cycle of the biological 
material, e.g. from collection, shipping to long term storage and use, and may also be subject 
to local regulation and/or national/international legislation. 
In this study, biological material for translational research will be centralized and stored at 
Institut de Cancérologie Gustave Roussy, Paris, France. The biobank will perform the above 
research project as stated in the protocol. In addition the biobank will distribute HBM to the 
other research laboratories involved in the translational research (TR) projects that will be 
defined in the future.  
The following principles apply to storage of HBM: 
♦ The collected HBM should be documented, i.e. the amount remaining and its location. 
The study chairman (SC) and the study coordinator (SC) will be responsible for TR project 
review and prioritization, including the consideration of newly proposed TR projects not 
specified in the protocol. 
Access to HBM is defined by the EORTC Biobanking Policy POL020 and will follow the 
next steps:  
A short description of the new TR projects will be written and submitted to EORTC HQ for 
coordination with SCs. 
♦ The SCs will prioritize the TR projects. Access procedures defined by the SCs will build 
on the following key points:  
♦ Project prioritization  
♦ should be strongly based on scientific merit,  
♦ should consider the contribution of the different investigators to the trial and TR 
project,  
♦ will take into consideration if the applicant is an EORTC member or not (whilst 
maintaining the principle of access to the wider scientific community and 
commitments owed to study participants and ethical committees). 
♦ Protection of confidentiality must be respected. 
♦ An EORTC HQ feasibility check, including recommendations for regulatory and ethical 
matters and other restrictions on the use of the HBM, will take place. If in the event the 
HBM collections are still retained at individual clinical sites, the TR project leader and 
the involved EORTC Group are responsible for collecting and providing information on 
availability of HBM for the feasibility assessment. 
♦ Prioritized TR projects will then be reviewed by the Translational Research Advisory 
Committee (TRAC). 
♦ Once SCs prioritization, the EORTC HQ feasibility assessment, and TRAC review are 
complete and when all applicable competent Ethics Committees approvals are in place 
and ethical principles are met, the TR project can be activated and HBM release and 
analysis can commence. 
♦ The EORTC Board will mediate any disagreements of opinion between TRAC, the 
EORTC HQ feasibility assessment, the SCs and the TR project leader(s), as needed. 
 
 
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13 Investigator authorization procedure 
Investigators will be authorized to register and/or randomize patients in this trial only once 
the following documents have been provided: 
♦ The updated signed and dated curriculum vitae of the Principal Investigator in English 
with a GCP training proof. 
♦ The (updated) list of normal ranges for the investigator’s institution signed and dated by 
the head of the laboratory. Please make sure normal ranges are provided also for those 
tests required by the protocol but not routinely done at the investigator’s institution. 
♦ The Confirmation of interest, confirming that the investigator will fully comply with the 
protocol. This must include an estimate of yearly accrual and a statement on any conflict 
of interest that may arise due to trial participation. 
 
NB: A signed conflict of interest disclosure form will be required only if a possible 
conflict is declared.  
♦ The Study Agreement with investigator’s institution. 
♦ A copy of the favorable opinion of the local or national (whichever is applicable) ethics 
committee mentioning the documents that were reviewed (including the version numbers 
and version dates of all documents). A list of all members of the ethics committee is also 
requested. 
♦ A copy of the translated and adapted (according to all national requirements) Patient 
Information / Informed Consent sheet. Version numbers and dates must be clearly stated 
on each page.  
♦ The signature log-list of the staff members with a sample of each authorized signature 
and the indication of the level of delegations. In case patients receive treatment at a 
satellite institution, i.e. outside the authorized institution, details on the satellite 
institution, including the CV of the local investigator, normal lab ranges and the approval 
of an ethics committee will have to be provided. 
♦ The full name, address, phone numbers and e-mail address of the local pharmacist who 
will be responsible for the trial medication (for any trial where the drug will be provided). 
♦ An accreditation, a certification, an established quality control / external quality 
assessment or another validation should be provided for the own laboratory. 
The center specific list of required documents will be included in the protocol activation 
package, with proper instructions as required by this protocol, your group and / or the 
applicable national law. 
The new investigator will be added to the “authorization list”, and will be allowed to 
register/randomize patients in the trial as soon as 
♦ All the above mentioned documents are collected. 
♦ All applicable national legal and regulatory requirements are fulfilled. 
Patient registration/randomization from centers not (yet) included on the authorization list 
will not be accepted. 
 
 
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14 Patient registration and randomization 
procedure 
14.1 General procedure 
Investigator will register and enroll patients during screening through EORTC, following the 
standard EORTC procedure. Patient registration and randomization will only be accepted 
from authorized investigators (see Section 13 on “investigator authorization procedure"). 
Patients should be registered directly on the EORTC online system  
(ORTA = online randomized trials access), accessible 24 hours a day, 7 days a week, through 
the internet. To access the interactive randomization program, the investigator needs a 
username and a password (which can be requested at http://orta.eortc.be). 
In case of problems investigators can phone the EORTC Headquarters from 9.00 am to 5.00 
pm (Belgian local time) from Monday through Friday in order to register patients via the 
EORTC call center. Registration via the phone is not available on Belgian holidays. A list of 
these holidays is available on the EORTC web site (http://orta.eortc.be) and it is updated 
annually. 
Through Internet: 
http://orta.eortc.be 
In case of problems registration by phone:  
 
A patient can only be randomized after verification of eligibility. Both the eligibility 
check and randomization must be done before the start of the protocol treatment. 
The study is referred as EORTC-1325 and MK-3475-054. However, in order to ease the 
registration process, the protocol number will be entered as 1325 at each step of the 
process below. 
In order to protect patients’ privacy when required by local regulations, clinical sites 
will report the day/month of birth as 01-January. 
14.2 Registration - step 1 (ORTA Step-1) 
Patient registration will only be accepted from authorized investigators. 
A patient can only be registered after signature of the Patient Informed Consent for tumor 
testing and fulfillment of all criteria listed in protocol section 3.1. Patients who are not 
eligible for registration will not be assigned a patient identifier and no information will be 
recorded in the database. 
A short list of questions needs to be answered during the registration (step 1). Those 
questions are included in the Registration Form, which is part of the case report forms. 
STANDARD INFORMATION REQUESTED: 
♦ institution number 
♦ protocol number: 1325 
♦ step number: 1 
 
 
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♦ name of the responsible investigator 
♦ patient's code (maximum 4 alphanumerics, a unique code to help identify the patient 
within your institution) 
♦ patient's birth date (day/month/year) or year of birth (as allowed per applicable 
legislation) 
PROTOCOL SPECIFIC QUESTIONS: 
♦ date of written informed consent for tumor testing (day/month/year) 
A sequential patient identification number (“seqID”) will also be assigned at the end of 
the registration procedure.The seqID will allow the identification of the patients in the 
VISTA/Remote Data Capture system (VISTA/RDC) that will be used to complete the Case 
Report Forms. 
Note: A patient who is ineligible during initial screening assessments, may be re-screened by 
starting a new registration and a new sequential identification number will be assigned. 
14.3 Central confirmation of PD-L1 expression testing - step 2 
The outcome of the central confirmation will be provided to clinical site after patient has 
been registered (step 1). Clinical site must enter PD-L1 eligibility status in ORTA prior to 
proceeding to step 3. 
14.4 Enrollment and Randomization - step 3 (ORTA Step-2) 
After registration (step 1), the central laboratory will confirm the results of the PD-L1 status 
testing (step 2) 
A patient can only be enrolled after verification of eligibility.  
An exhaustive list of questions to be answered during the enrollment procedure.  
STANDARD INFORMATION REQUESTED: 
♦ institution number 
♦ protocol number: 1325 
♦ step number: 2 
♦ name of the responsible investigator 
♦ patient's code (maximum 4 alphanumerics, a unique code to help identify the patient 
within your institution) 
♦ patient's birth date (day/month/year) or year of birth (as allowed per applicable 
legislation) 
 
 
 
 
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PROTOCOL SPECIFIC QUESTIONS: 
♦ result of the PD-L1 expression test 
♦ all eligibility criteria will be checked one by one 
♦ actual values for the eligibility parameters will be requested when applicable 
♦ stratification factors 
♦ date of written informed consent to participate in the trial (day/month/year) 
♦ TNM stage 
At the end of the randomization procedure, the treatment will be randomly allocated to the 
patients (minimization technique) through the IVRS system. As this is a double blind trial, 
neither the treatment arm nor its description will be provided to the investigator, the Sponsor, 
EORTC staff, CRO, patients and site staff. 
The local pharmacists and limited CRO personnel will be unblinded.  
14.5 Description of the blind procedure 
The IVRS system will assign to each patient a treatment dynamically, based on the other 
patients randomized in the study and the stratification factors defined in the protocol. The 
treatment arm will be blinded for patients participating in Part 1 of the study until first 
recurrence. 
14.6 Stock management process 
The stock of pembrolizumab is maintained in each institution participating in the protocol 
with the help of the IVRS system for both ongoing and new patients. 
The institution needs to confirm to the IVRS system the reception of each shipment of 
pembrolizumab before it can be allocated to patients. 
14.7 Unblinding procedure 
The following are expected authorized unblinding events in the study: 
♦ Emergency unblinding 
♦ Unblinding by investigator after first disease recurrence 
♦ Unblinding at final analysis 
♦ Other unblinding during the course of the study  
14.7.1 
Emergency unblinding 
At any time during the trial, in case of a safety concern affecting an individual patient, the 
site investigator can request the unblinding of that patient.  
The unblinding requests should be made by the site investigator through the emergency 
unblinding call center. Alternatively, a health care provider can obtain information about the 
 
 
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trial medication in emergency situations where the investigator is not available, as per section 
6.1.1. 
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind patients and to unmask treatment identity. In the event that the emergency unblinding 
call center is not available for a given site in this trial, the central electronic randomization 
system (IVRS) should be used in order to unblind patients and to unmask treatment identity. 
The Sponsor will not provide random code/disclosure envelopes or lists with the clinical 
supplies. 
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the patient. Every effort should be made not to unblind the patient unless necessary.The 
system will ask the reason why the treatment needs to be unblinded. If the reason given 
justifies unblinding, an automatic email describing the unblinded treatment will be sent to the 
investigator. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible. The principal investigator or delegate and the respective patient will be 
unblinded. If other trial site personnel, EORTC HQ (except the statistician), Sponsor 
personnel or Covance study teams become unblinded to assist the case, it is acceptable and 
not considered an inadvertent unblinding incident due to the emergency unblinding.  
14.7.2 
Unblinding by investigator after first disease recurrence 
The investigator will request authorization for official unblinding upon disease recurrence 
and consideration to proceed to Part 2 of the study (Cross-over or Re-challenge treatment).  
The emergency unblinding methods described in Section 14.7.1 should not be used in this 
process.  
During the study, all data must be entered in the eCRF within 5 days of each patient’s visit. 
Upon first recurrence, every effort will be made to have all pending data entered into the 
eCRFs within 1 business day or before the site is unblinded to the patient’s treatment 
assignment. 
The site should ensure data for disease recurrence is entered in the database prior to 
unblinding. Additionally, any AEs and/or Serious AEs should be reported and causality 
attributed in the database prior to unblinding. Please refer to the CRF guidelines and contact 
the site monitor for operational details. The site will request a unique unblinding code to the 
EORTC Unblinding Mailbox 
 in order to proceed 
to unblinding via IXRS. 
After unblinding is complete, the site will assess patient eligibility for Cross-over/Re-
challenge by reviewing all qualifications per protocol Sections 4.2.1.1 and 4.2.2.1. If patient 
fulfills eligibility criteria, the site will access the recurrence phase module in IXRS and 
request treatment assignment in Part 2 of the study (Cross-over or Re-challenge treatment).  
After disease recurrence, the study subject, investigator, site personnel, Sponsor personnel, 
EORTC HQ study team (except the statistician), and Covance study teams associated with 
the conduct of the trial will become unblinded in order to continue monitoring each patient in 
the study.  
 
 
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14.7.3 
Unblinding at final analysis 
The patient, the investigator and the site team and the EORTC HQ study team will be 
unblinded after database lock for the final analysis of the primary endpoint. At unblinding for 
final analysis, the project manager will inform investigators that the allocated treatment of 
their patients is available upon request. 
Translational medicine studies will only be performed after unblinding for the primary 
endpoint 
14.7.4 
Other unblinding during the course of the study  
Unblinding for the analysis planned in Section 8.3 and unblinding for global safety reasons 
are described in chapter 9. 
Finally, unblinding may be required for the reporting of serious adverse events (SAEs) or 
pregnancies or submission of Development Safety Update Report (DSUR) to Competent 
Authorities, EudraVigilance Clinical Trial Module (EVCTM) and Ethics Committees. In this 
case, the patient, the investigator, the site team and the EORTC HQ study team remain 
blinded. The procedure is described in Section 16.7. 
15 Forms and procedures for collecting data 
15.1 Case report forms and schedule for completion 
Data will be reported on the forms specifically designed by the EORTC Headquarters for this 
study. Forms should be electronically sent to the EORTC Headquarters through the 
VISTA/RDC (Remote Data Capture) system, with the exception of the QLQ-C30 form, the 
EQ-5D-3L form, the SAE/ECI form and the Pregnancy notification form which are paper 
CRFs. 
Copies of the Quality of Life forms (QLQ-C30 and the EQ-5D-3L) should be sent directly to 
the EORTC Headquarters by one of the following means: 
♦ By fax, to the attention of Melanoma Data manager: 
 
♦ By scanning and e-mailing the forms (see CRF completion guidelines) 
♦ By post to the EORTC Headquarters: 
(Melanoma 1325 Data Manager) 
EORTC Headquarters 
Avenue E. Mounierlaan 83/11 
Brussel 1200 Bruxelles 
België - Belgique 
SERIOUS ADVERSE EVENTS (INCLUDING EVENTS OF CLINICAL INTEREST) 
AND PREGNANCY NOTIFICATION FORMS SHOULD BE IMMEDIATELY 
REPORTED ACCORDING TO THE PROCEDURE DETAILED IN THIS 
PROTOCOL (see Section on Reporting Serious Adverse Events). 
 
 
 
 
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A. Before the treatment starts: 
♦ The patient must be registered/randomized in the trial by INTERNET or in case of 
problems by phone. 
The electronic CRFs to be completed for a patient are available on the VISTA/RDC website 
one hour after the registration/randomization on http://rdc.eortc.be/ or on 
http://www.eortc.org in the Section “Research tools”. 
B. During/after treatment 
The list of forms to be completed for this study and their submission schedule are available 
on the VISTA/RDC website and are also described in the "guidelines for completion of case 
report forms" that are provided to each participating investigator.  
ALL Forms must be electronically approved and sent by the responsible investigator or 
one of his/her authorized staff members with the exception of the paper HRQoL forms (no 
signature needed) 
15.2 Data flow 
The forms must be completed electronically, with the exception of the paper forms (the 
Quality of Life form, SAE form, Pregnancy notification form and EQ-5D-3L form), 
according to the schedule defined in the guidelines for completion of Case Report Forms. 
The list of staff members authorized to enter data (with a sample of their signature) must be 
identified on the signature log and sent to the EORTC Headquarters by the responsible 
investigator before the start of the study. To enter the RDC system, the investigator or 
authorized staff member needs to use the same username and password that are used to 
access the interactive randomization program (ORTA). 
In all cases, it remains the responsibility of the principal investigator to check that data are 
entered in the database as soon as possible and that the electronic forms are filled out 
completely and correctly.  
The EORTC Headquarters will perform extensive consistency checks on the received data 
and will issue queries in case of inconsistent data. The queries for the electronic forms will 
appear in the VISTA/RDC system and must be answered there directly. 
A copy of the quality of life forms should be sent to EORTC Headquarters as soon as 
possible, while the original source document should be kept on site. If there are queries on 
the quality of life form, they will be raised electronically on a patient level in the 
VISTA/RDC system and they must be answered there directly. 
The EORTC data manager will subsequently apply the corrections into the database. 
When satellite institutions are involved, all contact is made exclusively with the primary 
institution, for purposes of data collection and all other study related issues. 
If an investigator (or an authorized staff member) needs to modify a CRF after the form has 
been electronically sent to the EORTC Headquarters, he/she should create a request for data 
correction in the VISTA/RDC system. 
 
 
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Quality of life forms: If an investigator (or an authorized staff member) needs to modify the 
paper quality of life form after the copy has been sent to the EORTC Headquarters, he/she 
should create a request for data correction on a patient level in the VISTA/RDC system. 
15.3 HBM* sample registration and tracking  
Once the patient is registered, this procedure might take up to one hour, the investigator or 
his/her authorized staff must log on "Samples" website at https://samples.eortc.be/ or by 
clicking on the link "Samples Website" at the bottom of the page http://rdc.eortc.be  
"Samples" is a web based tracking tool designed to register, manage and track Human 
Biological Materials collected in the frame of EORTC clinical trials.  
Details about access the "Samples" Website, register samples and tracking shipments are 
described on the guidelines of HBM* management.  
(*) Human Biological Material 
16 Reporting of Serious Adverse Events 
ICH GCP and the EU Directive 2001/20/EC require that both investigators and Sponsor 
follow specific procedures when notifying and reporting adverse events/reactions in clinical 
trials. These procedures are described in this Section of the protocol.  
16.1 Definitions 
These definitions reflect the minimal regulatory obligations; specific protocol requirements 
might apply in addition. 
AE: An Adverse Event is defined as “any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment”. An adverse event can 
therefore be any unfavorable and unintended signs (such as rash or enlarged liver), symptoms 
(such as nausea or chest pain), an abnormal laboratory finding (including results of blood 
tests, x-rays or scans) or a disease temporarily associated with the use of the protocol 
treatment, whether or not considered related to the investigational medicinal product. 
AR: An Adverse reaction of an investigational medicinal product is defined as “any 
noxious and unintended response to a medicinal product related to any dose administered”. 
All adverse events judged by either the reporting investigator or the Sponsor as having a 
reasonable causal relationship to a medicinal product qualify as adverse reactions. The 
expression reasonable causal relationship means to convey in general that there is evidence 
or argument to suggest a causal relationship. 
UAR: An Unexpected Adverse Reaction is “any adverse reaction, the nature, or severity of 
which is not consistent with the applicable product information" (e.g. investigator's brochure 
for an unapproved investigational product or summary of product characteristics (SmPC) for 
a marketed product). 
When the outcome of the adverse reaction is not consistent with the applicable product 
information this adverse reaction should be considered as unexpected. 
 
 
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Severity: The term “severe” is often used to describe the intensity (severity) of a specific 
event (as in mild, moderate or severe, or as described in CTC grades); the event itself, 
however, may be of relative minor medical significance (such as severe headache). This is 
not the same as “serious,” which is based on patient/event outcome or action criteria usually 
associated with events that pose a threat to patient’s life or functioning. Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations.  
SAE: A Serious Adverse Event is defined as any untoward medical occurrence or effect in a 
patient, whether or not considered related to the protocol treatment, that at any dose: 
♦ results in death 
♦ is life-threatening (i.e. an event in which the subject was at risk of death at the time of 
event; it does not refer to an event which hypothetically might have caused death if it was 
more severe) 
♦ requires inpatient hospitalization or prolongation of existing patient hospitalization 
♦ results in persistent or significant disability or incapacity 
♦ is a congenital anomaly or birth defect 
♦ is a medically important event or reaction. 
♦ Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious such as important medical events that might not be 
immediately life-threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are 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. 
ECI: The following Events of Clinical Interest should be reported as a SAE in an expedited 
way: 
♦ Drug Induced Liver Injury (DILI): AST or ALT elevations ≥ 3 x ULN with concurrent 
elevation of total bilirubin ≥ 2 x ULN and, at the same time, alkaline phosphatase < 2 x 
ULN 
♦ If grade ≥ Grade 2: Pneumonitis, Interstitial lung disease, Acute interstitial pneumonitis. 
♦ If grade ≥ Grade 2: Nephritis, Autoimmune nephritis, Renal Failure, Acute Renal Failure  
♦ If grade ≥ Grade 2 or any grade resulting in dose modification (please refer to protocol 
Appendix H) or use of systemic steroids to treat the AE: Intestinal Obstruction, Colitis, 
Colitis microscopic, Necrotizing colitis, Enterocolitis, Hemorrhagic enterocolitis, GI 
perforation, Diarrhea, Hepatitis, Autoimmune hepatitis, Transaminase elevations, Uveïtis, 
Iritis 
♦ If grade ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification (please refer to 
protocol Appendix H) or use of systemic steroids to treat the AE: Adrenal Insufficiency, 
Hyperthyroidism, Hypothyroidism, Thyroid Disorder, Thyroiditis, Hypophysitis, 
Hypopituitarism 
 
 
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♦ If grade ≥ Grade 3 or any grade resulting in dose modification (please refer to protocol 
Appendix H) or use of systemic steroids to treat the AE: Autoimmune hemolytic anemia, 
Aplastic anemia, Thrombotic Thrombocytopenic Purpura (TTP), Idiopathic (or immune) 
Thrombocytopenia Purpura (ITP), Disseminated Intravascular Coagulation (DIC), 
Haemolytic Uraemic Syndrome (HUS), Creatinine elevations 
♦ If grade ≥ Grade 3: Pruritus, Rash, Rash generalized, Rash maculo-papular, Any other 
Grade 3 (or higher) event which is considered immune-related by the physician 
♦ If grade ≥ Grade 4: Any Grade 4 anemia regardless of underlying mechanism 
♦ Regardless of grade: Dermatitis Exfoliative, Erythema Multiforme, Stevens-Johnson 
Syndrome, Toxic Epidermal Necrolysis, Allergic reaction, Anaphylaxis, Cytokine release 
syndrome, Serum sickness, Infusion reactions, Infusion-like reactions, Autoimmune 
Neuropathy, Demyelinating Polyneuropathy, Guillain-Barre syndrome, Myasthenic 
syndrome, Myocarditis, Pericarditis, Pancreatitis, Any rash considered clinically 
significant in the physician’s judgment 
SAR: A Serious Adverse Reaction is defined as any SAE which is considered related to the 
protocol treatment.  
SUSAR: Suspected Unexpected Serious Adverse Reaction.  
SUSARs occurring in clinical investigations qualify for expedited reporting to the 
appropriate Regulatory Authorities within the following timeframes: 
♦ Fatal or life-threatening SUSARs within 7 calendar days 
♦ Non-fatal or non-life-threatening SUSARs within 15 calendar days 
Inpatient hospitalization: a hospital stay equal to, or greater than, 24 hours. 
Second primary malignancy is one unrelated to the treatment of a previous malignancy 
(and is NOT a metastasis from the previous malignancy). 
Secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the previous malignancy. 
Overdose: For this trial, an overdose will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab. No specific information is available on the treatment of an overdose of 
pembrolizumab. In the event of overdose, the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
16.2 Exceptions 
The following situations do not need to be reported as SAEs:  
♦ Elective hospitalization for pre-existing conditions that have not been exacerbated by 
study treatment. 
♦ A hospitalization which was planned before the patient consented for study participation 
and where admission did not take longer than anticipated. 
 
 
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♦ A hospitalization planned for protocol related treatment or protocol related procedure as 
per institutional standard timelines. 
♦ Social and/or convenience admission to a hospital 
♦ Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that leads 
to the procedure is an (S)AE. 
♦ Situations where an untoward medical occurrence did not occur (palliative care, 
rehabilitation). 
♦ 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. 
By EORTC convention, clinical events related to the primary cancer being studied or to the 
primary cancer progression are not to be reported as SAEs, even if they meet any of the 
seriousness criteria from the standard SAE definition, unless the event is more severe than 
expected and therefore the investigator considers that their clinical significance deserves 
reporting.  
16.3 Severity assessment 
The severity of all AEs (serious and non-serious) in this trial should be graded using CTCAE 
v4.0 www.eortc.org\investigators-area\ctc. 
16.4 Causality assessment 
The investigator is obligated to assess the relationship between protocol treatment and the 
occurrence of each SAE following the definitions in Table 21: 
Relationship to the 
protocol treatment  
Description 
Reasonable 
possibility 
There is a reasonable possibility that the protocol treatment 
caused the event 
No reasonable 
possibility 
There is no reasonable possibility that the protocol treatment 
caused the event 
Table 21: Relationship to the protocol treatment 
The investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as natural history of the underlying diseases, medical history, concurrent conditions, 
concomitant therapy, other risk factors, and the temporal relationship of the event to the 
protocol treatment will be considered and investigated. 
The decision will be recorded on the SAE form and if necessary the reason for the decision 
will also be recorded. 
 
 
 
 
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16.5 Expectedness assessment 
The expectedness assessment is the responsibility of the Sponsor of the study. The 
expectedness assessment will be performed against the following reference documents: 
♦ For Pembrolizumab: Investigator's Brochure 
♦ For Placebo: Safety Data Sheet 
16.6 Reporting procedure for investigators 
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before 
randomization/treatment allocation must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.  
From the time of randomization/treatment allocation through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Please refer to Section 
16.2 for exceptions. 
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause, that occurs to any subject must be reported within 24 hours to the Sponsor 
if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
All Serious Adverse Events (SAEs)/Events of Clinical Interest (ECI) occurring from the time 
a subject is randomized until 90 days after last blinded treatment administration (or 30 days 
following cessation of study treatment if the subject initiates new anticancer therapy, 
whichever is earlier) and to patients who continue or crossover to receive Pembrolizumab 
after first recurrence (i.e. patients with recurrence occurring more than 6 months after 
completion of 1 year (blinded) Pembrolizumab treatment or patients crossing-over from 
placebo), must be reported within 24 hours.  
Any SAE/ECI that occurs outside of the SAE detection period and is considered to have a 
reasonable possibility to be related to the blinded treatment or study participation also needs 
to be reported to EORTC. SAEs/ECIs occurring to patients who continued or crossed-over to 
Pembrolizumab need to be sent until 90 days after last administration, thereafter only SARs 
need to be sent. 
All SAEs must be followed up for outcome. 
All SARs occurring to patients receiving investigator's choice of treatment (i.e. not 
Pembrolizumab) need to be reported to the Marketing Authorization Holder (MAH) of the 
administered drug(s). 
Reporting schedule is detailed in Table 22. 
 
 
 
 
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Adjuvant part 1 
Documents 
Signed Patient Registration Informed Consent till 
randomization: 
All SAEs* to EORTC 
Randomization till 90 days after last blinded 
treatment administration: 
All SAEs/ECIs to EORTC 
From day 91 after last blinded treatment 
administration: 
Only SARs/ECIs considered to 
have a reasonable possible 
relationship to blinded 
treatment/study participation to 
EORTC 
After first recurrence part 2: for patients that 
will cross-over or be re-challenged 
 
Patients receiving Pembrolizumab after first 
recurrence till 90 days after last Pembrolizumab 
administration: 
All SAEs/ECIs to EORTC 
From day 91 after last Pembrolizumab 
administration (for patients after first recurrence): 
Only SARs/ECIs considered to 
have a reasonable possible 
relationship to treatment/study 
participation to EORTC 
After first recurrence for patients that will not 
cross-over or not be re-challenged 
 
if the subject initiates new anticancer therapy 
reporting till 30 days after last Pembrolizumab 
administration  
All SAEs/ECIs to EORTC 
From day 31 after last dose, all patients who 
receive new anticancer therapy after unblinding: 
All SARs to MAH (NOT to 
EORTC)[for new anticancer 
therapy] 
All SARs/ECI considered to have 
a reasonable possible relationship 
to treatment/study participation to 
EORTC 
Table 22: Reporting schedule 
* if it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention  
Any secondary malignancy or second primary malignancy should also be reported in an 
expedited way on a SAE form with the appropriate seriousness criteria! 
All reporting must be done by the principal investigator or authorized staff member (i.e. on 
the signature list) to confirm the accuracy of the report. 
 
 
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All SAE data must be collected on the study-specific SAE form. 
All SAEs must be reported immediately and no later than 24 hours from the time the 
investigator or staff became aware of the event. 
All SAE-related information needs to be provided in English. 
All additional documents in local language must be accompanied by a translation in English, 
or the relevant information must be summarized in a follow-up SAE report form. 
All SAE-related information must be faxed or emailed to: 
 
EORTC Pharmacovigilance Unit: 
 
Fax No.
 
 
 
To enable the EORTC to comply with regulatory reporting requirements, all initial SAE 
reports should always include the following minimal information: an identifiable patient 
(SeqID), a suspect medicinal product if applicable, an identifiable reporting source, the 
description of the medical event and seriousness criteria, as well as the causality assessment 
by the investigator. Complete information requested on the SAE form of any reported serious 
adverse event must be returned within 7 calendar days of the initial report. If the completed 
form is not received within this deadline, the Pharmacovigilance Unit will make a written 
request to the investigator. 
Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 
calendar days. 
All forms need to be dated and signed by the principal investigator or any authorized staff 
member (i.e. on the signature list). 
16.7 Reporting responsibilities of the Sponsor 
The EORTC Pharmacovigilance Unit will forward all SAE reports to the appropriate persons 
within the EORTC Headquarters and to the pharmacovigilance contact at Merck as per 
Safety Data Exchange Agreement. 
After receipt of the initial report, all information will be reviewed and, if necessary, the 
Investigator will be contacted to obtain further information for assessment of the event. The 
Sponsor will evaluate the seriousness and the causal relationship of the event to study 
medication. In addition, the Sponsor will evaluate the expectedness according to the 
reference safety information (see above). Based on the Investigator and Sponsor’s assessment 
of the event, a decision will be made concerning the need for further action. 
Unblinding may be required for the reporting of serious adverse events (SAEs) or 
pregnancies or submission of Development Safety Update Report (DSUR) to Competent 
Authorities, EudraVigilance Clinical Trial Module (EVCTM) and Ethics Committees. In this 
case, the patient, the investigator, the site team and the EORTC HQ study team remain 
blinded. 
The EORTC Pharmacovigilance Unit and Merck have outlined the reporting of SUSARs in a 
Safety Data Exchange Agreement.  
 
 
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16.8 Pregnancy reporting 
Pregnancy occurring during a patient’s participation in this trial, although not considered an 
SAE, must be notified to the EORTC Pharmacovigilance Unit within the same timelines as 
an SAE (within 24 hours) on a Pregnancy Notification Form. The outcome of a pregnancy 
should be followed up carefully and any adverse outcome to the mother or the child should 
be reported. This also applies to pregnancies in female partners of a male patient 
participating in this trial. 
♦ Any pregnancy in a female subject or in a female partner of a male subject diagnosed 
during the treatment period or within 120 days after last protocol treatment 
administration, or within 30 days after last protocol treatment administration if new 
anticancer therapy is initiated (whichever is earlier), must be reported to the EORTC 
Pharmacovigilance Unit  
♦ This must be reported within 24 hours of first becoming aware of the event by fax, to the 
Pharmacovigilance Unit on a Pregnancy Notification Form  
♦ If an SAE occurs in conjunction with the pregnancy, please also complete an SAE form 
as explained in the SAE reporting chapter 
♦ 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. 
17 Quality assurance 
17.1 Control of data consistency 
Data forms will be entered in the EORTC Headquarters database by using the VISTA/RDC 
(Remote Data Capture) system. Computerized and manual consistency checks will be 
performed on newly entered forms; queries will be issued in case of inconsistencies. 
Consistent forms will be validated by the Data Manager. Inconsistent forms will be kept 
"pending" until resolution of the inconsistencies. 
17.2 On-site quality control 
Covance will periodically perform on-site quality control visits as as described in the 
Monitoring Plan: The first visit in a participating site will be performed within 2 months after 
the first patient's inclusion. Frequency of subsequent visits will depend on site's accrual and 
quality observed during the first visit. 
17.3 Audits 
The EORTC Quality Assurance and Control Unit (QA&C) regularly conducts audits of 
institutions participating in EORTC protocols. In addition, Merck, as the protocol Sponsor, 
routinely conducts audits of participating investigator sites in accordance with the sponsor's 
approved audit plan. These audits are performed to provide assurance that the rights, safety 
and wellbeing of patients are properly protected, to assess compliance with the protocol, 
 
 
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processes and agreements, ICH GCP standards and applicable regulatory requirements, and 
to assess the quality of data. 
The investigator, by accepting to participate in this protocol, agrees that EORTC, the 
Sponsor, any third party (e.g. a CRO) acting on behalf of the EORTC or the Sponsor, or any 
domestic or foreign regulatory agency, may come at any time to audit or inspect their site and 
all subsites, if applicable.  
This audit consists of interviews with the principal investigator and study team, review of 
documentation and practices, review of facilities, equipment and source data verification. 
The investigator will grant to the EORTC, the Sponsor, any third party (e.g. a CRO) acting 
on behalf of the EORTC or the Sponsor, direct access to paper and/or electronic 
documentation pertaining to the clinical study (e.g. CRFs, source documents such as hospital 
patient charts and investigator study files) to these authorized individuals. All site facilities 
related to the study conduct could be visited during an audit (e.g. pharmacy, laboratory, 
archives …). The investigator agrees to co-operate and provide assistance at reasonable times 
and places with respect to any auditing activity. 
If a regulatory authority inspection is announced, the investigator must inform the EORTC 
Headquarters QA&C Unit immediately (contact at: 
. 
In this way EORTC can provide support in preparing and/or facilitating the inspection. 
EORTC representatives/delegates may also attend the inspection. 
18 Ethical considerations 
18.1 Patient protection 
The responsible investigator will ensure that this study is conducted in agreement with either 
the Declaration of Helsinki (available on the World Medical Association web site 
(http://www.wma.net)) and/or the laws and regulations of the country, whichever provides 
the greatest protection of the patient. 
The protocol has been written, and the study will be conducted according to the ICH 
Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC
500002874.pdf). 
The protocol must be approved by the competent ethics committee(s) as required by the 
applicable national legislation. 
18.2 Subject identification 
The name of the patient will neither be asked for nor recorded at the EORTC Headquarters. 
A sequential identification number will be automatically allocated to each patient registered 
in the trial. This number will identify the patient and will be included on all case report 
forms. In order to avoid identification errors, the patient’s code (maximum of 4 
alphanumerics) and date of birth or year of birth (as allowed per applicable legislation) will 
 
 
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also be reported on the case report forms. Day and month will be reported as 01-January to 
protect individual privacy if required by country local regulations. 
18.3 Informed consent 
All patients will be informed about 
♦ the aims of the study 
♦ the possible adverse events 
♦ the procedures and possible hazards to which the patient will be exposed 
♦ the mechanism of treatment allocation 
♦ strict confidentiality of any patient data 
♦ medical records possibly being reviewed for trial purposes by authorized individuals 
other than their treating physician 
The template of the patient’s informed consent statement is given as a separate document 
dated and version controlled to this protocol. 
An adapted translation of the PIS/PIC will be provided by EORTC Headquarters and, in 
some countries, it is the responsibility of the Coordinating investigators for this trial 
(sometimes called National Coordinators) to adapt it to national/local requirements where 
necessary. 
The translated informed consent documents are to be submitted to ethics committees for 
approval. The competent ethics committee for each institution must approve the informed 
consent documents before the center can join the study. It is the responsibility of the 
competent ethics committee to ensure that the translated informed documents comply with 
ICH-GCP guidelines and all applicable national legislation. 
It is emphasized in the patient information sheet that participation is voluntary and that the 
patient is free to refuse further participation in the protocol whenever he/she wants to. This 
will not have any impact on the patient’s subsequent care. Documented informed consent 
must be obtained for all patients included in the study before they are registered and/or 
randomized at the EORTC Headquarters. The written informed consent form must be signed 
and personally dated by the patient or by the patient’s legally acceptable representative. 
All of the above must be done in accordance with the applicable national legislation and local 
regulatory requirements. 
19 Administrative responsibilities 
19.1 The study coordinator 
The Study Coordinator works closely with the study team to develop the outline and full 
protocol and discusses the contents of the reports with the study team. The Study coordinator 
is responsible for publishing the study results. He/she will assist the Clinical Research 
Physician for answering some clinical questions concerning eligibility, treatment, and 
contributes to the medical review of the patients. 
 
 
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Study coordinator: 
Institut de Cancérologie Gustave Roussy 
114 Rue Edouard Vaillant, 94800 Villejuif, Paris, France 
Phone: 
Fax: 
E-mail: 
Study chair 
 
Institut de Cancérologie Gustave Roussy 
114 Rue Edouard Vaillant, 94800 Villejuif, Paris, France 
Phone: 
Fax: 
E-mail: 
19.2 The EORTC Headquarters 
The EORTC Headquarters will be responsible for writing the protocol and PIS/IC, reviewing 
the protocol, setting up the trial, collecting case report forms, controlling the quality of the 
reported data, organizing the medical review and generating reports and analyses in 
cooperation with the Study Coordinator. All methodological questions should be addressed to 
the EORTC Headquarters. 
EORTC HEADQUARTERS 
 
Avenue E. Mounierlaan 83/11 
 
Brussel 1200 Bruxelles 
 
België - Belgique 
 
Fax: 
 
19.3 The EORTC group 
All questions concerning ongoing membership in the group should be addressed to the 
chairman and/or secretary of the group. 
For new membership contact Membership Committee at 
 
EORTC Melanoma group 
Chairman: 
 
 
 
Institut de Cancérologie Gustave Roussy 
 
114, rue Edouard Vaillant 
 
94805 Villejuif CEDEX 
 
France 
 
Phone: 
 
Fax: 
 
e-mail: 
 
 
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Secretary: 
 
 
 
Department of Surgical Oncology 
 
Netherlands Cancer Institute – 
 
 
Phone: 
 
Fax: 
 
e-mail: 
20 Trial sponsorship and financing 
The legal Sponsor of this trial is Merck Sharp & Dohme Corp., a Subsidiary of Merck & Co. 
Inc 
One Merck Drive 
P.O. Box 100 
Whitehouse Station, NJ, 08889-0100, U.S.A. 
21 Administrative and regulatory details 
21.1 Confidentiality 
21.1.1 
Confidentiality of Data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications Section 
of this protocol. 
21.1.2 
Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data. By signing the consent form, the subject 
agrees to this process. If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor. 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations. 
 
 
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21.1.3 
Confidentiality of Investigator Information 
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law. This information may include: 
1. name, address, telephone number and e-mail address; 
2. hospital or clinic address and telephone number; 
3. curriculum vitae or other summary of qualifications and credentials; and 
4. other professional documentation. 
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses and 
disclosures. 
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request. 
21.1.4 
Confidentiality of IRB/IEC Information 
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial. The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies. 
21.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data. 
 
 
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21.3 Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial. 
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Appendix L - 
Merck Code of Conduct for Clinical Trials. 
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents. 
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor. 
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms. 
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae. By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
 
 
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when documents may be destroyed. The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained. The Sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files. 
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed. 
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial. 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC. 
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational). When more than one trial site is 
open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations. For a single-center trial, the Protocol CI is the principal investigator. In addition, 
the Sponsor must designate a principal or coordinating investigator to review the trial report 
that summarizes the trial results and confirm that, to the best of his/her knowledge, the report 
accurately describes the conduct and results of the trial [Clinical Study Report (CSR) CI]. 
The Sponsor may consider one or more factors in the selection of the individual to serve as 
the Protocol CI and or CSR CI (e.g., availability of the CI during the anticipated review 
process, thorough understanding of clinical trial methods, appropriate enrollment of subject 
cohort, timely achievement of trial milestones). The Protocol CI must be a participating trial 
investigator. 
21.4 Compliance with Trial Registration and Results Posting 
Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements. Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
 
 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank. 
21.5 Quality Management System 
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial. 
21.6 Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature. By entering his/her 
electronic signature, the investigator confirms that all recorded data have been verified as 
accurate. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately. 
21.7 Calibration of Critical Equipment 
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible. Documentation of equipment calibration must be retained as source 
documentation at the trial site. 
Critical Equipment for this trial includes: 
Laboratory equipment – as required for inclusion labs and trial assessments 
Imaging equipment – as required for study objectives 
Drug administration equipment – as required for storing, preparing, and administering study 
treatment 
22 Trial insurance 
A clinical trial insurance has been taken out according to the laws of the countries where the 
study will be conducted. An insurance certificate will be made available to the participating 
sites at the time of study initiation.  
 
 
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Clinical trial insurance is only valid in centers authorized by the EORTC Headquarters. For 
details please refer to the chapter on investigator authorization. 
23 Publication policy 
The publication of the main trial results will be written by the Study Coordinator on the basis 
of the final analysis performed at the EORTC Headquarters and will be sent to a major 
scientific journal. Authors of the manuscript will include at least the Study Coordinator, 
Study Chair, the investigators who have included more than 2.5% of the eligible patients in 
the trial (by order of inclusion), a minimum of two Merck representatives and a minimum of 
two members of the EORTC Headquarters team who have contributed to the trial. 
The title of all manuscripts will include “EORTC”, and all manuscripts will include an 
appropriate acknowledgment Section, mentioning all investigators who have contributed to 
the trial, the EORTC Headquarters staff involved in the study, as well as the trial Sponsor 
(Merck). 
It is the EORTC’s policy not to release trial results before data maturity has been reached for 
the primary endpoint(s) of the trial unless the publication is authorized by the Data 
Monitoring Committee. If the group wishes to publish or present study data before the 
publication of the primary trial endpoint, this may be authorized under the conditions 
specified in the EORTC Policy 009 “Release of Results and Authorship Policy” available 
from http:\\www.eortc.be, or authorized by the Data Monitoring Committee. 
The Group Chairman, the Study Coordinator, the Merck responsible(s) and the EORTC 
Headquarters Team must approve all publications, abstracts and presentations of data 
pertaining to patients included in this study. 
The data collected during this study are confidential. Any publications or abstracts arising 
from this study require approval by the Sponsor prior to publication or presentation and must 
adhere to the Sponsor’s publication requirements as set forth in the approved clinical trial 
agreement (CTA). All draft publications, including abstracts or detailed summaries of any 
proposed presentations, must be submitted to the Sponsor at the earliest practicable time for 
review, not less than 30 days before submission or presentation unless otherwise set forth in 
the CTA. 
Sponsor shall have the right to delete any confidential information contained in any proposed 
presentation or abstract and may delay publication for up to 60 days for purposes of filing a 
patent application.  
 
 
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Appendix A: References 
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1;383(9919):816-27.  
Ref. 2 
Balch CM, Gershenwald JE, Soong S-J, et al. Final version of 2009 AJCC 
melanoma staging and classification. J Clin Oncol 2009; 27: 6199–206. 
Ref. 3 
Balch CM, Gershenwald JE, Soong S-J, et al. Multivariate analysis of prognostic 
factors among 2,313 patients with stage III melanoma: comparison of nodal 
micrometastases versus macrometastases. J Clin Oncol 2010; 28: 2452–9. 
Ref. 4 
Van Akkooi ACJ, Nowecki ZI, Voit C, et al. Sentinel node tumor burden according 
to the Rotterdam criteria is the most important prognostic factor for survival in 
melanoma patients: a multicenter study in 388 patients with positive sentinel nodes. 
Ann Surg 2008; 248: 949–55. 
Ref. 5 
Van der Ploeg APT, Van Akkooi ACJ, Rutkowski P, et al. Prognosis in patients 
with sentinel node-positive melanoma is accurately defined by the combined 
Rotterdam tumor load and Dewar topography criteria. J Clin Oncol 2011; 29: 2206–
14. 
Ref. 6 
van der Ploeg AP, van Akkooi AC, Haydu LE, Scolyer RA, Murali R, Verhoef C, 
Thompson JF, Eggermont AM. The prognostic significance of sentinel node tumour 
burden in melanoma patients: An international, multicenter study of 1539 sentinel 
node-positive melanoma patients. Eur J Cancer. 2014 Jan;50(1):111-20. 
Ref. 7 
Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Elashoff R, Essner R, Nieweg 
OE, Roses DF, Hoekstra HJ, Karakousis CP, Reintgen DS, Coventry BJ, Glass EC, 
Wang HJ; MSLT Group. Sentinel-node biopsy or nodal observation in melanoma. N 
Engl J Med. 2006 Sep 28;355(13):1307-17. 
Ref. 8 
Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Spatz A, Grob JJ, Malvehy J, 
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treatment of melanoma. European consensus-based interdisciplinary guideline--
Update 2012. Eur J Cancer. 2012 Oct;48(15):2375-90.  
Ref. 9 
van der Ploeg AP, van Akkooi AC, Verhoef C, Eggermont AM. Completion lymph 
node dissection after a positive sentinel node: no longer a must? Curr Opin Oncol. 
2013 Mar;25(2):152-9.  
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therapy in melanoma. Semin Oncol. 2010 Oct;37(5):455-9.  
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interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-
analysis of the randomised trials. Cancer Treat Rev 2003; 29: 241–52. 
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melanoma: An individual patient data meta-analysis of randomised trials. J Clin 
Oncol. 2007; 25:Suppl.8526.abstract. 
 
 
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Ref. 13 Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in 
patients with high-risk melanoma: a systematic review and meta-analysis. J Natl 
Cancer Inst 2010; 102: 493–501. 
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interferon alfa-2b versus observation alone in resected stage III melanoma: final 
results of EORTC 18991, a randomised phase III trial. Lancet 2008; 372: 117–26. 
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intermediate doses of interferon alfa 2b versus observation in patients with stage 
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1189–96. 
Ref. 16 Eggermont AMM, Suciu S, Testori A, et al. Ulceration and stage are predictive of 
interferon efficacy in melanoma: Results of the phase III adjuvant trials EORTC 
18952 and EORTC 18991. Eur J Cancer 2012; 48: 218–25. 
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Salès F, Dummer R, Robert C, Schadendorf D, Patel PM, de Schaetzen G, Spatz A, 
Keilholz U. Long term results of the randomized phase III trial EORTC 18991 of 
adjuvant therapy with pegylated interferon alfa-2b versus observation in resected 
stage III melanoma. J Clin Oncol. 2012 Nov 1;30(31):3810-8.  
Ref. 18 Flaherty LE, Moon J, Atkins MB et al. Phase III trial of high-dose interferon alpha-
2b versus cisplatin, vinblastin, DTIC, plus IL-2 and interferon in patients with high-
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SWOG. J Clin Oncol 2012;30 Suppl: abstract 8504 
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complete resection of stage III melanoma: Initial efficacy and safety results from the 
EORTC 18071 phase III trial. J Clin Oncol 2014;(suppl):LBA9008 
Ref. 20 Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med 2010; 363: 711–23. 
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previously untreated metastatic melanoma. N Engl J Med 2011; 364: 2517–26 
Ref. 22 Attia P, Phan GQ, Maker AV, et al. Autoimmunity correlates with tumor regression 
in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte 
antigen-4. J Clin Oncol 2005; 23: 6043–53. 
Ref. 23 Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in 
melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507–16. 
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melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 
2012; 380: 358–65. 
Ref. 25 Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in 
BRAF-mutated melanoma. N Engl J Med 2012; 367: 107–14. 
 
 
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Ref. 26 Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in 
melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov;367(18):1694-
703. 
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melanoma who received ipilimumab in four phase II trials. J Clin Oncol 2013; 31 
suppl; abstr 9053 
Ref. 28 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–54. 
Ref. 29 Sznol M, Kluger HM, Hodi FS, et al. Survival and long-term follow-up of safety 
and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of 
nivolumab (anti-PD-1; BMS-936558; ONO-4538). J Clin Oncol 2013 ;31(suppl); 
abstr CRA9006) 
Ref. 30 Hamid O, Robert C, Daud A, et al. Safety and Tumor Responses with 
Lambrolizumab (Anti-PD-1) in Melanoma. N Engl J Med. 2013 Jun 2.  
Ref. 31 F. Stephen Hodi, Mario Sznol, Harriet M. Kluger, et al. Long-term survival of 
ipilimumab-naive patients (pts) with advanced melanoma (MEL) treated with 
nivolumab (anti-PD-1, BMS-936558, ONO-4538) in a phase I trial. J Clin Oncol 
2014;(suppl): A9002 
Ref. 32 Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, 
Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, 
Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, 
Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor 
responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 
11;369(2):134-44 
Ref. 33 Ribas A, F. Hodi S, Kefford K, Hamid O, Daud A, Wolchok JD, Hwu WJ, 
Gangadhar TC, Patnaik A,. Joshua AM, Hersey P, Weber JS, Dronca RS,. Zarour 
HM, Gergich K, Li XN, Iannone R, Kang SP, Ebbinghaus S, Robert C; Efficacy and 
safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with 
melanoma (MEL). J Clin Oncol 2014 (suppl): abstract LBA9000 
Ref. 34 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus Ipilimumab in 
Advanced Melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33.  
Ref. 35 Sznol M, Kluger HM, Callahanet MK, et al. Survival, response duration, and 
activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-
936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced 
melanoma (MEL). J Clin Oncol 32:5s, 2014 (suppl; abstr LBA9003) 
Ref. 36 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48. 
Ref. 37 Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-
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Ref. 38 Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Lorenz M, et al. Structural and 
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associate with immunoreceptor tyrosine-based switch motif of programmed death 1 
upon primary human T cell stimulation, but only receptor ligation prevents T cell 
activation. J Immunol 2004;173:945-54. 
Ref. 40 Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J et al. PD-1 
inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to PKCtheta. FEBS Lett 2004;574:37-41. 
Ref. 41 Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25. 
Ref. 42 Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi 
SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 2005;25:9543-53. 
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autoimmunity. Immunol Rev 2010;236:219-42. 
Ref. 44 Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, et al. 
Expression of the PD-1 antigen on the surface of stimulated mouse T and B 
lymphocytes. Int Immunol 1996;8(5):765-72. 
Ref. 45 Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger LR. Activation induced 
expression of human programmed death-1 gene in T-lymphocytes. Exp Cell Res 
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Ref. 46 Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191:891-8. 
Ref. 47 Disis ML. Immune Regulation of Cancer. J Clin Oncol 2010;28:4531-8. 
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of programmed death-1 ligands on dendritic cells enhances T cell activation and 
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Ref. 67 Dummer R, Daud A, Puzanov I, Hamid O, Schadendorf D, Robert C, Schachter J, 
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Mateus, C., Shapira-Frommer, R., Kosh, M., Zhou, H., Ibrahim, N., Ebbinghaus, S., 
Ribas, A. Pembrolizumab versus Ipilimumab in Advanced Melanoma N Engl J 
Med. 2015  
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RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47 
 
 
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Appendix B: Abbreviations 
ADA 
Anti-Drug Antibodies 
AE 
Adverse Event 
ASCO 
American Society of Clinical Oncology 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BMG 
Board of Melanoma Group 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Counts 
CI 
Confidence Interval 
CLIND 
Complete Lymph Node Dissection 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DMFS 
Distant Metastases-Free Survival 
ECI 
Events of Clinical Interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
FFPE 
Formalin Fixed Paraffin Embedded 
G-CSF 
Granulocyte Colony-Stimulating Factor 
HBM 
Human Biological Material 
HCO3 
Bicarbonate 
HCT 
Hematocrit 
HGB 
Hemoglobin 
 
 
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HLA 
Human Lymphocyte Antigen 
HQ 
Headquarters 
HR 
Hazard Ratio 
HRQoL 
Health Related Quality of Life 
IB 
Investigator brochure 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IHC 
Immunohistochemistry 
IL-2 
interleukin-2 
ITP 
immune thrombocytopenia  
IPI 
Ipilimumab 
IrAE 
Immune-related Adverse Event 
IrRC 
Immune-related Response Criteria 
ITIM 
Immunoreceptor Tyrosine-based Inhibition Motif 
ITSM 
Immunoreceptor Tyrosine-based Switch Motif 
ITT 
intent-to-treat 
IV 
Intravenous 
K: 
Potassium 
LDH 
Lactate dehydrogenase (enzyme) 
LFT 
Liver Function Test 
Na 
Sodium 
NCI 
National Cancer Institute 
NK 
Natural Killer 
NOEL 
No Observable Effect Level 
NSCLC 
Non-Small Cell Lung Carcinoma 
OTC 
over-the-counter 
ORR 
Overall Response Rate 
 
 
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OS 
Overall Survival 
PD 
Pharmacodynamics 
PD-L1 
Programmed death-ligand 1 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PPT 
Per-protocol treatment 
PRFS2 
Progression/Recurrence-Free Survival 2 
Q2W 
Every-2-weeks 
Q3W 
Every-3-weeks 
RBC 
Red Blood Cells 
RCT 
Randomized Controlled Trial 
RFS 
Recurrence Free Survival 
SAE 
Serious Adverse Event 
SN 
Sentinel node 
TB 
Bacillus Tuberculosis 
TNF 
Tumor Necrosis Factor 
TR 
Translational Research 
TRAC 
Translational Research Advisory Committee 
ULN 
Upper Limit of Normal 
V-Type 
Variable- Type 
 
 
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Appendix C: ECOG performance status scale 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. 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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Appendix D: EORTC Quality of Life evaluation: 
guidelines for administration of questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
EORTC Quality of Life evaluation: guidelines for administration of questionnaires 
The instructions given below are intended to provide some general guidelines for collecting 
quality of life (QOL) data in EORTC studies. These instructions apply for all types of 
questionnaires. 
1. Who is the responsible person (RP) for QOL data collection? 
In each institution, the principal investigator is the responsible for the local organization of 
QoL data collection. This can be delegated to a physician, data manager, (research) nurse or a 
psychologist. Such a person should have the full protocol at his/her disposal as well as the 
questionnaire(s). This person would also be the intermediate contact point in case of any 
necessary clarification asked by the EORTC Headquarters. 
2. Who should fill out the questionnaire? 
In principle it is the patient who has to complete the QOL forms and preferably without help 
from others. In the case where a patient is too sick to fill out the questionnaire by him/herself 
or if the patient is not able to complete the questionnaire for such reasons as forgetting 
his/her glasses, another person could read the questions without making any suggestions and 
report the answers on the forms. It is not allowed for another person to fill in the 
questionnaire as if (s)he was the patient (proxy assessment) unless specifically allowed by 
the protocol. 
3. What instructions should be given to the patient? 
At entry in a study, the RP should give the patient an explanation of the objective of the 
study and instructions for completing the questionnaires. 
The patient should be informed that participation in the QOL protocol is voluntary and that 
the information provided is confidential (identification is only for administrative purposes 
and includes date of birth and today’s date (completion date)). 
The following issues should be explained to the patient: 
♦ The schedule of assessments. 
♦ The questionnaire is a self administered questionnaire that should be completed by the 
patient him(her)self. The patient can ask for aid in reading or writing but should not let 
another person provide the answers. 
♦ The patient should   circle   the choice that best corresponds to his/her situation. 
♦ There is no right or wrong answer to any of these questions. The answers will not 
influence any medical decision making. 
 
 
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♦ All questions should be answered.  
♦ The patient will be given a questionnaire in the default language(s) of the hospital. If 
desired, the patient may request another language. The RP will then contact the EORTC 
Headquarters for the appropriate translation. 
The RP should make sure that the patient understands the instructions. 
At each subsequent assessment as defined by the protocol, the patient should receive the 
questionnaire from the RP or from other appropriate staff if the RP is unavailable. 
4. Where should the patient complete the questionnaire? 
The patient should complete the questionnaire at the clinic, and, ideally in a quiet, private 
room. If this is not possible, the waiting room is an acceptable alternative. In general it does 
not take long to complete the questionnaire, but patients should be given the time they need 
to answer all questions. 
5. When should they complete the questionnaire? 
The timing of the planned QoL assessments is detailed in the protocol. When a QOL 
assessment is planned, the questionnaire should be given to the patient preferably before the 
meeting with the physician, ensuring that the patient has enough time to complete the 
questionnaire. If the patient is to receive a therapy, the questionnaire should be filled out 
before administration of the treatment (unless indicated otherwise in the protocol). The 
questionnaire should not be taken home and/or mailed (unless indicated otherwise in the 
protocol). 
6. Review of the completed questionnaire 
After the patient has completed the questionnaire, the person handling the questionnaire 
should: 
♦ Complete the “Hospital Staff” specific data box. 
♦ Check that the completion date is correctly filled in by the patient. 
♦ Screen the questionnaire for omissions. 
If this is the case: 
♦ Please ask the patient the reason for omissions. It may be that patient forgot to flip a page 
or did not understand a question. The patient should not be forced to provide an answer if 
(s)he does not wish to do so. 
♦ Additional explanation may be provided, but the questions should not be rephrased. 
7. Missing forms 
If for some reason the patient is unable or does not wish to complete a quality of life 
questionnaire the reason and the date of visit should be documented on the corresponding 
CRF (case report form).  
 
 
 
 
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8. Mailing to EORTC Headquarters 
A copy of the questionnaires should be sent to EORTC Headquarters as soon as possible, 
while the original source document should be kept on site. As it is impossible to 
retrospectively collect missing quality of life data, please make sure the patient completes the 
questionnaire at the time-point when he/she is supposed to complete it. 
Thank you very much for your cooperation. If you have any remarks about this leaflet or if 
you need further information, please contact: 
 - EORTC Headquarters: 
Phone: 
 
Fax: 
 
E-mail: 
 
 
 
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PPD
PPD
PPD
PPD
 
 
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Appendix E: AJCC 2010 for Melanoma 
The American Joint Committee on Cancer (AJCC) has designated staging by TNM 
classification to define melanoma (Ref. 60, Ref. 61). 
TNM 2010 Definitions 
Primary tumor (T) 
TX: Primary tumor cannot be assessed (e.g., shave biopsy or regressed melanoma)  
T0: No evidence of primary tumor  
Tis: Melanoma in situ  
T1: Tumor 1.0 mm or less in thickness with or without ulceration  
♦ T1a: Tumor 1.0 mm or less in thickness without ulceration and with mitotic index < 
1/mm2 
♦ T1b: Tumor 1.0 mm or less in thickness with ulceration or with mitotic index ≥ 
1/mm2 
T2: Tumor more than 1.0 mm but 2.0 mm or less in thickness with or without ulceration  
♦ T2a: Tumor more than 1.0 mm but 2.0 mm or less in thickness with no ulceration  
♦ T2b: Tumor more than 1.0 mm but 2.0 mm or less in thickness with ulceration  
T3: Tumor more than 2.0 mm but 4.0 mm or less in thickness with or without ulceration  
♦ T3a: Tumor more than 2.0 mm but 4.0 mm or less in thickness without ulceration  
♦ T3b: Tumor more than 2.0 mm but 4.0 mm or less in thickness with ulceration  
T4: Tumor more than 4.0 mm in thickness with or without ulceration  
♦ T4a: Tumor more than 4.0 mm in thickness without ulceration  
♦ T4b: Tumor more than 4.0 mm in thickness with ulceration  
Regional lymph nodes (N) 
NX: Regional lymph nodes cannot be assessed  
N0: No regional lymph node metastasis  
N1: Metastasis to one lymph node  
♦ N1a: Clinically occult (microscopic) metastasis  
♦ N1b: Clinically apparent (macroscopic) metastasis  
N2: Metastasis to two or three regional nodes or intralymphatic regional metastasis without 
nodal metastases  
♦ N2a: Clinically occult (microscopic) metastasis  
♦ N2b: Clinically apparent (macroscopic) metastasis  
♦ N2c: In-transit metastasis /satellites or without nodal metastasis  
 
 
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N3: Metastasis in four or more regional nodes, or matted lymph nodes, or in-transit 
metastasis or satellite(s) with metastatic regional node(s)  
[Note: Micrometastases are diagnosed after sentinel lymphnode biopsy. Macrometastases are 
defined as clinically detectable lymph nodes metastases confirmed pathologically, or when 
any lymph node metastasis exhibits gross extracapsular extension.] 
Distant Metastasis (M) 
MX: Distant metastasis cannot be assessed  
M0: No distant metastasis  
M1: Distant metastasis  
♦ M1a: Metastasis to skin, subcutaneous tissues, or distant lymph nodes  
♦ M1b: Metastasis to lung  
♦ M1c: Metastasis to all other visceral sites or distant metastasis at any site associated 
with an elevated serum lactic dehydrogenase  
Clinical Staging - AJCC 2010 stage groupings 
Clinical staging includes microstaging of the primary melanoma and clinical and/or 
radiologic evaluation for metastases. By convention, it should be assigned after complete 
excision of the primary melanoma with clinical assessment for regional and distant 
metastases (Ref. 60) 
Stage 0  
Tis, N0, M0 
Stage IA 
T1a, N0, M0 
Stage IB 
T1b, N0, M0 
 
T2a, N0, M0 
Stage IIA 
T2b, N0, M0 
 
T3a, N0, M0 
Stage IIB 
T3b, N0, M0 
 
T4a, N0, M0 
Stage IIC 
T4b, N0, M0 
Stage III 
Any T, N1, M0 
 
Any T, N2, M0 
 
Any T, N3, M0 
Stage IV 
Any T, any N, M1 
 
 
 
 
 
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Pathologic Staging 
With the exception of clinical stage 0 or stage IA patients (who have a low risk of lymphatic 
involvement and do not require pathologic evaluation of their lymph nodes), pathologic 
staging includes microstaging of the primary melanoma and pathologic information about the 
regional lymph nodes after sentinel node biopsy and, complete lymphadenectomy (Ref. 60) 
 
Stage 0 
Tis, N0, M0 
Stage IA 
T1a, N0, M0 
Stage IB 
T1b, N0, M0 
 
T2a, N0, M0 
Stage IIA 
T2b, N0, M0 
 
T3a, N0, M0 
Stage IIB 
T3b, N0, M0 
 
T4a, N0, M0 
Stage IIC 
T4b, N0, M0 
Stage IIIA 
T1-4a, N1a, M0 
 
T1-4a, N2a, M0 
 
Tx, N1a, M0 
 
Tx, N2a, M0 
Stage IIIB 
T1-4b, N1a, M0 
 
T1-4b, N2a, M0 
 
T1-4a, N1b, M0 
 
T1-4a, N2b, M0 
 
T1-4a, N2c, M0 
 
Tx, N1b-2b, M0 
 
Tx, N2c, M0 
Stage IIIC 
T1-4b, N1b, M0 
 
T1-4b, N2b, M0 
 
T1-4b, N2c, M0 
 
Any T, N3, M0 
Stage IV 
Any T, any N, M1 
 
 
 
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Agreement between pathologists in the histologic diagnosis of melanomas and benign 
pigmented lesions has been studied and found to be considerably variable. One such study 
found that there was discordance on the diagnosis of melanoma versus benign lesions in 37 
of 140 cases examined by a panel of experienced dermatopathologists (Ref. 62).For the 
histologic classification of cutaneous melanoma, the highest concordance was attained for 
Breslow thickness and presence of ulceration, while the agreement was poor for other 
histologic features such as Clark’s level of invasion, presence of regression, and lymphocytic 
infiltration. In another study, 38% of cases examined by a panel of expert pathologists had 
two or more discordant interpretations. These studies convincingly show that distinguishing 
between benign pigmented lesions and early melanoma can be difficult, and even 
experienced dermatopathologists can have differing opinions. To reduce the possibility of 
misdiagnosis for an individual patient, a second review by an independent qualified 
pathologist should be considered (Ref. 63). 
The microstage of melanoma is determined on histologic examination by the vertical 
thickness of the lesion in millimeters (Breslow’s classification) and/or the anatomic level of 
local invasion (Clark’s classification). The Breslow thickness is more reproducible and more 
accurately predicts subsequent behavior of melanoma in lesions larger than 1.5 mm in 
thickness and should always be reported. Accurate microstaging of the primary tumor 
requires careful histologic evaluation of the entire specimen by an experienced pathologist. 
Estimates of prognosis should be modified by sex and anatomic site as well as by clinical and 
histologic evaluation. 
Clark’s Classification (Level of Invasion)  
Level I: Lesions involving only the epidermis (in situ melanoma); not an invasive lesion.  
Level II: Invasion of the papillary dermis but does not reach the papillary-reticular dermal 
interface.  
Level III: Invasion fills and expands the papillary dermis but does not penetrate the reticular 
dermis.  
Level IV: Invasion into the reticular dermis but not into the subcutaneous tissue.  
Level V: Invasion through the reticular dermis into the subcutaneous tissue. 
 
 
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Appendix F: Surgical and pathological 
considerations for melanoma 
Surgical considerations 
1. Recommendation for management of the primary: 
Wide excision with a minimum 1 cm margin surrounding the primary lesion or biopsy scar is 
recommended for entry onto this protocol. As long as the primary melanoma is completely 
resected within the margin the resection is acceptable. For lesions whose Breslow’s thickness 
is >2 mm, a 2 cm minimum margin is preferred when anatomically feasible (i.e., for lesions 
of the trunk and proximal extremities). On other sites narrower margin is preferred to avoid 
mutilation. For sub-ungual melanoma, a distal interphalangeal amputation with histologically 
negative margins constitutes an adequate wide excision. The specimen shall be excised to 
include skin and all subcutaneous tissue down to the muscular fascia. Fascia may be included 
at the discretion of the operating surgeon. The pathology report should state the surgical 
margins and adequacy of the resection. 
Closure of the defect may be via primary closure, split thickness skin graft, or rotation-flap at 
the discretion of the surgeon. 
2. Sentinel Node Procedure: See guidelines for pathological considerations below. It is 
mandatory that these guidelines are fully respected in order for the patient to be eligible. 
3. Axillary Lymphadenectomy: 
For this study a complete axillary lymph node dissection will be performed including nodes 
at levels I, II and III (level III in case of overt nodal involvement). Axillary node dissection 
must include at least 10 nodes taken from Levels I and II and the level III nodes dissected for 
palpable axillary nodes. Minimum of 10 nodes must be pathologically investigated. The 
boundaries of the dissection should include the axillary vein superiorly beginning at the 
thoracic outlet and coursing to the latissimus dorsi tendon. The lateral border of the 
dissection is the anterior edge of the lattisimus dorsi muscle. The posterior boundary is the 
subscapular muscle. The anterior border of the resection is the pectoralis major group. The 
inferior boundary of the dissection should be the juncture of the latissimus dorsi and the 
serratus anterior muscles. 
The contents within these boundaries should be completely removed with the exception of 
the long thoracic nerve and the thorocodorsal nerve which should be identified during the 
dissection and preserved throughout. As stated, the pectoralis minor muscle may be divided 
or sacrificed with the specimen at the discretion of the surgeon. Care should be exercised that 
in the superior part of the dissection, the anterior pectoral nerve is not injured. The preferable 
approach to the axilla is through a horizontal incision in the line of the skin crease, 3 or 4 cm 
below the apex of the skin fold of the axilla. 
4. Inguinal Lymphadenectomy: 
A superficial femoral node dissection should be performed by excising all of the nodes 
inferior to the inguinal ligament and bounded by the medical border of the sartorius muscle 
in the lateral border of the adductor magnus muscle. The fatty and lymphatic tissues should 
be dissected carefully off of the femoral vessels and nerves all the way up to the inguinal 
 
 
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canal and for 3 cm superior to the inguinal ligament. The saphenous vein is resected to 
ensure complete excision of the lymphnodes. Transposition of the sartorius muscle should be 
considered (but is not mandatory) to cover the femoral vessels after complete lymphatic 
excision. Ideally, this area should be entered through a curvilinear incision staring laterally 
over the inguinal ligament and curving medially and inferiorly ending over the mid-point of 
the adductor magnus muscle. A superficial femoral node dissection suffices for clinically 
node negative, but sentinel node positive patients. Minimum of 5 nodes must be 
pathologically investigated. 
5. Deep Inguinal and External Iliac Node Dissection: 
Deep Inguinal and External Iliac Node Dissection can be most easily approached by incising 
the abdominal wall musculature 3 or 4 cm superior to the inquinal ligament. This incision is 
taken down through the external oblique, internal oblique and transversus muscles and the 
surgeon at that point stays extraperitoneally as in the approach to the iliac vessels for renal 
transplantation. With this approach, the external, internal and common iliac arteries are 
exposed and the lymphatics coursing among the iliac vessels are excised. A full ilio- inguinal 
(deep) inguinal node dissection is advised in case of overt inguinal node- metastasis and 
when Cloquet’s node is positive. 
6. (Modified) Radical Neck Dissection: 
Classic or modified radical neck dissection may be performed for patients with melanoma of 
the head and neck. Minimum of 15 nodes must be pathologically investigated. As noted 
above, patients with melanoma located on the ear and anterior scalp and face will require 
superficial parotidectomy along with a radical neck procedure. The boundaries of the radical 
neck dissection are inferiorly the clavicle; the mandible, the mastoid and the tail of the 
parotid gland superiorly; the anterior border of the trapezius muscle posteriorly and the strap 
muscle of the larynx anteriorly. The sternocleidomastoid muscle may be sacrificed or 
preserved at the surgeon's discretion. For posterior lesions the radical neck incision must be 
extended posteriorly or a second incision must be made so that the sub-occipital nodal group 
can be sampled. For posterior neck dissection, surgical and pathol-ogical exploration of 5 
nodes are sufficient to consider the procedure is adequate. 
Note: the number of nodes pathologically investigated takes into account nodes removed 
from the sentinel node dissection and the CLND.  
Pathological considerations for Sentinel Lymph Nodes (SLN) 
1. Parameters to include in the SLN pathology report are: 
♦ number of sentinel nodes 
♦ number of micro-metastatic sentinel nodes 
♦ for each micro-metastatic sentinel node: 
♦ topography of the micro-metastasis: capsular, sub-capsular, parenchymatous or 
sinusal 
♦ the largest diameter of the tumor cluster 
 
 
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Handling of SLN for melanoma involves bivalving  
and sectioning the cut surface of both halves 
 
 
 
 
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2. Sequence of sectioning and staining in SLN protocol for melanoma  
Section 1 (first full section) 
H&E 
Section 2 
S100 
Section 3 
spare 
Section 4 
spare 
50µ gap (+50µ) 
 
Section 5 
H&E 
Section 6 
S100 
Section 7 
spare 
Section 8 
spare 
50µ gap (+100 µ) 
 
Section 9 
H&E 
Section 10 
S100 
Section 11 
spare 
Section 12 
spare 
50µ gap (+150µ) 
 
Section 13 
H&E 
Section 14 
S100 
Section 15 
spare 
Section 16 
spare 
50µ gap (+200 µ) 
 
Section 17 
H&E 
Section 18 
S100 
Section 19 
spare 
Section 20 
spare 
 
When S100 section reveals micro-metastasis, isolated tumors cells or is doubtful, 
immunostaining with MELAN-A or HMB45 is performed on the subsequent spared slide. 
 
 
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Appendix G: Guidelines for management of toxicity 
The guidelines are based on the guidance provided by Merck. 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 23 below. See Events 
of Clinical Interest Guidance (Appendix H) Document for supportive care guidelines 
(below), including use of corticosteroids. 
Toxicity 
Hold Treatment For 
Grade 
Timing for 
Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity 
resolves to 
Grade 0-1. 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
4 
Permanently 
discontinue 
Permanently discontinue 
AST, ALT 
elevation or 
Increased 
Bilirubin 
2 
Toxicity 
resolves to 
Grade 0-1 
Toxicity does not resolve 
within 12 weeks of last 
dose. 
3-4 
Permanently 
discontinue 
 
Permanently discontinue 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
Newly onset T1DM 
or  
Grade 3-4 
Hold 
pembrolizumab 
for new onset 
Type 1 
diabetes 
mellitus or 
Grade 3-4 
hyperglycemia 
associated with 
evidence of 
beta cell 
failure. 
Resume pembrolizumab 
when patients are 
clinically and 
metabolically stable. 
 
 
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Toxicity 
Hold Treatment For 
Grade 
Timing for 
Restarting 
Treatment 
Treatment Discontinuation 
Hypophysitis 
2 
Toxicity 
resolves to 
Grade 0-1. 
Therapy with 
pembrolizumab 
can be 
continued 
while 
endocrine 
replacement 
therapy is 
instituted 
Toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
 
3-4 
Withhold or 
permanently 
discontinue 
pembrolizumab 
at the 
discretion of 
the investigator 
or treating 
physician. 
If withhold, 
restart 
treatment if 
toxicity 
resolves to 
Grade 0-1 
Withhold or permanently 
discontinue 
pembrolizumab at the 
discretion of the 
investigator or treating 
physician 
Permanent discontinuation 
if toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
Hyperthyroidism  3-4 
Withhold or 
permanently 
discontinue 
pembrolizumab 
at the 
discretion of 
the investigator 
or treating 
physician. 
If withhold, 
restart 
treatment if 
toxicity 
Withhold or permanently 
discontinue 
pembrolizumab at the 
discretion of the 
investigator or treating 
physician. 
Permanent discontinuation 
if toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
 
 
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Toxicity 
Hold Treatment For 
Grade 
Timing for 
Restarting 
Treatment 
Treatment Discontinuation 
resolves to 
Grade 0-1 
12 weeks. 
Hypothyroidism 
 
Therapy with 
pembrolizumab 
can be 
continued 
while thyroid 
replacement 
therapy is 
instituted for 
Grades 2-4 
Therapy with 
pembrolizumab can be 
continued for Grades 2-4 
while thyroid replacement 
therapy is instituted. 
Infusion 
Reaction (a) 
2a 
Toxicity 
resolves to 
Grade 0-1  
Permanently discontinue if 
toxicity develops despite 
adequate premedication  
3-4 
Permanently 
discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity 
resolves to 
Grade 0-1 
Permanent discontinuation 
if toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
3-4 or recurrent 
grade 2 
Permanently 
discontinue 
Permanently discontinue 
Nephritis and 
renal dysfunction 
2 
Toxicity 
resolves to 
Grade 0-1 
Permanent discontinuation 
if toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
3-4 
Permanently 
discontinue 
Permanently discontinue 
 
 
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Toxicity 
Hold Treatment For 
Grade 
Timing for 
Restarting 
Treatment 
Treatment Discontinuation 
Myocarditis 
1-2 
Toxicity 
resolves to 
Grade 0-1 
Permanent discontinuation 
if toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
3-4 
Permanently 
discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity 
Intolerable/Persistent 
Grade 2 
Toxicity 
resolves to 
Grade 0-1 
Permanent discontinuation 
if toxicity does not resolve 
within 12 weeks of last 
dose or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 
12 weeks. 
3 
 
Withhold or 
discontinue 
based on the 
type of event. 
Events that 
require 
discontinuation 
include and not 
limited to: 
GBS,SOTR, 
encephalitis 
If withhold, 
restart 
treatment if 
toxicity 
resolves to 
Grade 0-1 
 
Permanently discontinue 
based on the type of event. 
Events that require 
discontinuation include 
and not limited to: 
GBS,SOTR, encephalitis 
 
If on hold, proceed to 
permanent discontinuation 
when toxicity does not 
resolve within 12 weeks of 
last dose or inability to 
reduce corticosteroid to 10 
mg or less of prednisone or 
equivalent per day within 
12 weeks. 
 
4 or recurrent grade 
3 
Permanently 
discontinue 
Permanently discontinue 
 
 
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Toxicity 
Hold Treatment For 
Grade 
Timing for 
Restarting 
Treatment 
Treatment Discontinuation 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or 
any life-threatening event. For participants with Grade 3 or 4 immune-related 
endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be 
resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement 
therapy or achieved metabolic control (in case of T1DM). 
 (a) For patients with infusion reaction Grade 2, if symptoms resolve within one hour of 
stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until symptoms 
resolve and the subject should be pre-medicated for the next scheduled dose; Refer to 
Table 24– Infusion Reaction Treatment Guidelines for further management details. 
Table 23: Dose Modification Guidelines for Drug-Related Adverse Events 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Patients should be placed back on study therapy within 3 weeks of 
the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
1) Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids. Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
 
 
 
 
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2) Pneumonitis  
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. 
For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed. 
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
3) Diarrhea/Colitis  
Patients should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
All patients who experience diarrhea/colitis should be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral corticosteroids.  
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
4) Hyperglycemia 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
For T1DM or Grade 3-4 Hyperglycemia 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria.  
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
5) Hypophysitis 
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
 
 
 
 
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February 28, 2018 
6) Hyperthyroidism or Hypothyroidism 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism): 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial 
therapy. 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
Grade 3-4 hyperthyroidism  
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose 
is tapered. 
7) Hepatic 
For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
Treat with IV or oral corticosteroids 
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued 
over no less than 4 weeks. 
8) Renal Failure or Nephritis 
For Grade 2 events, treat with corticosteroids. 
For Grade 3-4 events, treat with systemic corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  
9) Infusion reaction 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion.  
below shows treatment guidelines for patients who experience an infusion reaction associated 
with administration of pembrolizumab (MK-3475). 
 
 
 
 
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February 28, 2018 
 
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 patient 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 subject is deemed medically 
stable in the opinion of the 
investigator. 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 
mL/hr). Otherwise dosing will 
be held until symptoms resolve 
and the subject should be 
premedicated for the next 
scheduled dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
patient may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 
 
 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; 
pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine** 
 
Increase monitoring of vital 
signs as medically indicated until 
the patient is deemed medically 
stable in the opinion of the 
investigator. 
Hospitalization may be 
indicated. 
**In cases of anaphylaxis, 
epinephrine should be used 
immediately. 
Patient is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
The severity of all AEs (serious and non-serious) in this trial should be graded using 
CTCAE v4.0 www.eortc.org\investigators-area\ctc 
Table 24: Infusion Reaction Treatment Guidelines 
 
 
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Appendix H: Guidelines for Management of 
Adverse Events (AE) and Events of clinical interest 
(ECI) 
The purpose of this document is to provide study sites with guidance on the identification 
and management of Events of Clinical Interest for pembrolizumab program. 
Based on the literature review (Ref. 1 – Ref. 11), and consideration of mechanism of action 
of pembrolizumab, potential immune-related adverse events (irAEs) are the primary Event of 
Clinical Interest (ECI). Immune-related AEs are adverse events associated with the treatment 
of patients with immunotherapy treatments that appear to be associated with the immune 
therapy’s mechanism of action. Based on these potential irAEs, the sponsor has defined a list 
of specific adverse event terms (ECIs) that are selected adverse experiences that must be 
reported to EORTC within 24 hours (refer Section 16) from the time the 
Investigator/physician is aware of such an occurrence, regardless of whether or not the 
investigator/physician considers the event to be related to study drug(s). In addition, these 
ECIs require additional detailed information to be collected and entered in the study 
database. ECIs may be identified through spontaneous patient report and / or upon review of 
patient data. Table 25 provides the list of terms and reporting requirements for AEs that must 
be reported as ECIs for pembrolizumab protocols. Of note, the requirement for reporting of 
ECIs applies to all arms of pembrolizumab clinical trials  
Given that our current list of events of clinical interest is not comprehensive for all potential 
immune-related events, it is possible that AEs other than those listed in this document may be 
observed in patients receiving pembrolizumab.  
Therefore any Grade 3 or higher event that the investigator/physician considers to be 
immune-related should be reported as an ECI regardless of whether the specific event 
term is in Table 25 and reported to EORTC within 24 hours from the time the 
Investigator/physician is aware of such an occurrence. 
Adverse events that are both an SAE and an ECI should be reported one time as an SAE 
only, however the event must be appropriately identified as an ECI as well in in the database. 
 
 
 
 
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Pneumonitis (reported as ECI if ≥ Grade 2) 
Acute interstitial 
pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use 
of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal 
perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification 
or use of systemic steroids to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
 
 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification 
or use of systemic steroids to treat the AE) 
Autoimmune hemolytic 
anemia  
Aplastic anemia  
Thrombotic 
Thrombocytopenic 
Purpura (TTP) 
Idiopathic (or immune) 
Thrombocytopenia Purpura 
(ITP) 
Disseminated Intravascular 
Coagulation (DIC) 
Haemolytic Uraemic 
Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use 
of systemic steroids to treat the AE) 
Hepatitis  
Autoimmune hepatitis  
Transaminase 
elevations 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release 
syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
 
 
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Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating 
polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if ≥ Grade 2)  
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any 
grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson 
syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment  
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
Table 25: Events of Clinical Interest 
In addition, the guidelines include recommendations on the management of these ECIs. 
These guidelines are intended to be applied when the physician determines the events to be 
related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the physician is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (below). Therefore, these recommendations should be seen as guidelines and the 
treating physician should exercise individual clinical judgment based on the patient. 
For any question of dose modification or other treatment options, the specific language in the 
protocol should be followed. Any questions pertaining to the collection of this information or 
management of ECIs should be directed to the Sponsor.  
 
 
 
 
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Dose Modification/Discontinuation 
The treatment guidance provides specific direction when to hold and/or discontinue 
pembrolizumab for each immune related adverse event. 
Of note, when the guidance states to “discontinue” pembrolizumab this is the permanent 
discontinuation of treatment with pembrolizumab. “Hold” means to stop treating with 
pembrolizumab but resumption of treatment may be considered assuming the patient meets 
the criteria for resumption of treatment. 
ECI reporting guidelines and patient management 
ECIs are selected non-serious and serious adverse experiences that must be reported to 
EORTC within 24 hours regardless of attribution to study treatment. The AEs listed in this 
chapter and any event that meets the ECI criteria (as noted) in Table 25 or in the respective 
protocol (event term and Grade) must be reported regardless of physician-determined 
causality with study medication and whether or not considered immune-related by the 
physician (unless otherwise specified).  
♦ PNEUMONITIS 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be 
reported to EORTC within 24 hours of the event: 
♦ Pneumonitis 
♦ Interstitial lung disease 
♦ Acute interstitial pneumonitis  
If symptoms indicate possible new or worsening cardiac abnormalities additional testing 
and/or a cardiology consultation should be considered.  
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
viral infection. It is important that patients with a suspected diagnosis of pneumonitis be 
managed as per the guidance below until treatment-related pneumonitis is excluded. 
Treatment of both a potential infectious etiology and pneumonitis in parallel may be 
warranted. Management of the treatment of suspected pneumonitis with steroid treatment 
should not be delayed for a therapeutic trial of antibiotics. If an alternative diagnosis is 
established, the patient does not require management as below; however the AE should be 
reported regardless of etiology. 
CTCAE Grade 
Course of Action 
Grade 2 
Report as ECI 
Hold pembrolizumab. 
Consider pulmonary consultation with bronchoscopy and 
biopsy/BAL. 
Consider ID consult 
Conduct an in person evaluation approximately twice per week 
Consider frequent Chest X-ray as part of monitoring 
 
 
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CTCAE Grade 
Course of Action 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day 
prednisone or equivalent. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 
weeks. 
Add prophylactic antibiotics for opportunistic infections. 
Permanently discontinue for inability to reduce corticosteroid dose to 
10 mg or less of prednisone or equivalent per day within 12 weeks. 
Second episode of pneumonitis – discontinue pembrolizumab if upon 
re-challenge the patient develops a second episode of Grade 2 or 
higher pneumonitis. 
Grade 3 and 4  
Report as ECI 
Discontinue pembrolizumab. 
Hospitalize patient 
Bronchoscopy with biopsy and/or BAL is recommended. 
Immediately treat with intravenous steroids (methylprednisolone 125 
mg IV). When symptoms improve to Grade 1 or less, a high dose 
oral steroid (prednisone 1 to 2 mg/kg once per day or dexamethasone 
4 mg every 4 hours) taper should be started and continued over no 
less than 4 weeks. 
If IV steroids followed by high dose oral steroids does not reduce 
initial symptoms within 48 to 72 hours, treat with additional anti-
inflammatory measures. Discontinue additional anti-inflammatory 
measures upon symptom relief and initiate a prolonged steroid taper 
over 45 to 60 days. If symptoms worsen during steroid reduction, 
initiate a retapering of steroids starting at a higher dose of 80 or 100 
mg followed by a more prolonged taper and administer additional 
anti-inflammatory measures, as needed 
Add prophylactic antibiotics for opportunistic infections. 
Table 26: Pneumonitis 
♦ COLITIS 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of 
systemic steroids to treat the AE, are considered ECIs and should be reported to EORTC 
within 24 hours of the event:  
♦ Colitis  
♦ Colitis microscopic 
♦ Enterocolitis 
♦ Enterocolitis hemorrhagic  
 
 
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♦ Gastrointestinal perforation 
♦ Intestinal obstruction  
♦ Necrotizing colitis 
♦ Diarrhea 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or 
parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel 
disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and 
endoscopy. However the AE should be reported regardless of etiology. 
 
CTCAE Grade 
Course of Action 
Grade 2  
Diarrhea/Colitis (4-6 stools/day 
over baseline, dehydration 
requiring IV fluids < 24 hours, 
abdominal pain, mucus or 
blood in stool) 
Report as ECI 
Hold pembrolizumab.  
Symptomatic Treatment 
For Grade 2 diarrhea that persists >1 week, and for 
diarrhea with blood and/or mucus,  
Consider GI consultation and endoscopy to confirm or 
rule out colitis  
Administer oral corticosteroids (prednisone 1-2 mg/kg 
QD or equivalent) 
When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 
4 weeks. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
If symptoms worsen or persist > 3 days treat as Grade 
3 
 
 
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CTCAE Grade 
Course of Action 
Grade 3  
Diarrhea/Colitis (or Grade 2 
diarrhea that persist for greater 
than 3 days) 
Report as ECI 
Hold pembrolizumab.  
Rule out bowel perforation. Imaging with plain films 
or CT can be useful. 
Recommend consultation with Gastroenterologist and 
confirmation biopsy with endoscopy. 
Treat with intravenous steroids (methylprednisolone 
125 mg) followed by high dose oral steroids 
(prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours). When symptoms 
improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Taper 
over 6 to 8 weeks in patients with diffuse and severe 
ulceration and/or bleeding. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
If IV steroids followed by high dose oral steroids does 
not reduce initial symptoms within 48 to 72 hours, 
consider treatment with additional anti-inflammatory 
measures as described in the literature [5]. Discontinue 
additional anti-inflammatory measures upon symptom 
relief and initiate a prolonged steroid taper over 45 to 
60 days. If symptoms worsen during steroid reduction, 
initiate a retapering of steroids starting at a higher dose 
of 80 or 100 mg followed by a more prolonged taper 
and administer additional anti-inflammatory measures 
as needed.  
Grade 4 
Report as ECI 
Permanently discontinue pembrolizumab. 
Manage as per Grade 3. 
Table 27: Colitis 
♦ ENDOCRINE 
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require 
holding/discontinuation/ modification of pembrolizumab dosing, are considered ECIs and 
should be reported to EORTC within 24 hours of the event: 
♦ Adrenal insufficiency 
♦ Hyperthyroidism 
 
 
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♦ Hypophysitis 
♦ Hypopituitarism  
♦ Hypothyroidism 
♦ Thyroid disorder  
♦ Thyroiditis  
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection. However the AE should be reported regardless of etiology. 
 
CTCAE Grade 
Course of Action 
Grade 2-4 
Report as ECI if appropriate 
Hold pembrolizumab  
Rule out infection and sepsis with appropriate cultures 
and imaging 
Monitor thyroid function or other hormonal level tests 
and serum chemistries more frequently until returned to 
baseline values. 
Pituitary gland imaging should be considered (MRIs 
with gadolinium and selective cuts of the pituitary can 
show enlargement or heterogeneity and confirm the 
diagnosis). 
Treat with prednisone 40 mg p.o. or equivalent per day. 
When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered.  
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks.  
Hypophysitis with clinically significant adrenal 
insufficiency and hypotension, dehydration, and 
electrolyte abnormalities (such as hyponatremia and 
hyperkalemia) constitutes adrenal crisis 
Consultation with an endocrinologist may be 
considered. 
Table 28: Hypophysitis or other symptomatic endocrinopathy other than hypo- or 
hyperthyroidism 
 
 
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Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
 
 
 
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CTCAE Grade 
Course of Action 
Grade 2 event hyperthyroidism 
Grade 3-4 hypothyroidism 
Report as ECI if appropriate (see Table 25) 
Monitor thyroid function or other hormonal level tests 
and serum chemistries more frequently until returned 
to baseline values. 
Thyroid hormone and/or steroid replacement therapy 
to manage adrenal insufficiency. 
Therapy with pembrolizumab can be continued while 
treatment for the thyroid disorder is instituted.  
In hyperthyroidism, non-selective beta-blockers (e.g. 
propranolol) are suggested as initial therapy.  
In hypothyroidism, thyroid hormone replacement 
therapy, with levothyroxine or liothyroinine, is 
indicated per standard of care.  
Consultation with an endocrinologist may be 
considered. 
Grade 3 hyperthyroidism  
Report as ECI 
Hold pembrolizumab.  
Rule out infection and sepsis with appropriate cultures 
and imaging. 
Treat with an initial dose of methylprednisolone 1 to 2 
mg/kg intravenously followed by oral prednisone 1 to 
2 mg/kg per day. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is 
tapered.  
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 4  
Report as ECI 
Discontinue pembrolizumab.  
Manage as per Grade 3 
Table 29: Hyperthyroidism and Hypothyroidism 
 
 
 
 
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♦ HEMATOLOGIC 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of 
systemic steroids to treat the AE, are considered an ECI and should be reported to EORTC 
within 24 hours of the event: 
♦ Autoimmune hemolytic anemia 
♦ Aplastic anemia 
♦ Disseminated Intravascular Coagulation (DIC) 
♦ Haemolytic Uraemic Syndrome (HUS) 
♦ Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
♦ Thrombotic Thrombocytopenic Purpura (TTP) 
♦ Any Grade 4 anemia regardless of underlying mechanism 
All attempts should be made to rule out other causes such as metastases, sepsis and/or 
infection. Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, 
LDH, haptoglobin, bone marrow biopsy or Coomb’s test, etc., should be considered to 
confirm the diagnosis. However the AE should be reported regardless of etiology. 
CTCAE Grade 
Course of Action 
Grade 2 
Report as ECI 
Hold pembrolizumab 
Prednisone 1-2 mg/kg daily may be indicated 
Consider Hematology consultation. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 3 
Report as ECI 
Hematology consultation.  
Hold pembrolizumab Discontinuation should be 
considered as per specific protocol guidance. 
Treat with methylprednisolone 125 mg iv or prednisone 
1-2 mg/kg p.o. (or equivalent) as appropriate 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
 
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CTCAE Grade 
Course of Action 
Grade 4 
Report as ECI 
Hematology consultation 
Discontinue pembrolizumab for all solid tumor 
indications; refer to protocol for hematologic 
malignancies. 
Treat with methylprednisolone 125 mg iv or prednisone 
1-2 mg/kg p.o. (or equivalent) as appropriate 
Table 30: Hematologic ECIs 
♦ HEPATIC 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose 
modification or use of systemic steroids to treat the AE), are considered ECIs and should be 
reported to EORTC within 24 hours of the event: 
♦ Autoimmune hepatitis  
♦ Hepatitis  
♦ Transaminase elevations 
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other hepatic diseases. However the AE should be reported regardless of etiology. 
Drug Induced Liver Injury (DILI) 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the 
patient meets the laboratory criteria for potential DILI defined as:  
♦ An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab 
value that is greater than or equal to three times (3X) the upper limit of normal 
(ULN) and  
♦ An elevated total bilirubin lab value that is greater than or equal to two times 
(2X) ULN and 
♦ At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X 
ULN,  
♦ As a result of within-protocol-specific testing or unscheduled testing. 
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as 
a DILI event. 
 
 
 
 
 
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CTCAE Grade 
Course of Action 
Grade 2 
Report as ECI 
Hold pembrolizumab when AST or ALT >3.0 to 5.0 
times ULN and/or total bilirubin >1.5 to 3.0 times 
ULN. 
Monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
Treat with 0.5-1 mg/kg/day methylprednisolone or oral 
equivalent and when LFT returns to grade 1 or baseline, 
taper steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic infections, 
and resume pembrolizumab per protocol  
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Permanently discontinue pembrolizumab for patients 
with liver metastasis who begin treatment with Grade 2 
elevation of AST or ALT, and AST or ALT increases 
≥50% relative to baseline and lasts ≥1 week. 
 
 
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CTCAE Grade 
Course of Action 
Grade 3 
Report as ECI 
Discontinue pembrolizumab when AST or ALT >5.0 
times ULN and/or total bilirubin >3.0 times ULN. 
Consider appropriate consultation and liver biopsy to 
establish etiology of hepatic injury, if necessary 
Treat with high-dose intravenous glucocorticosteroids 
for 24 to 48 hours. When symptoms improve to Grade 
1 or less, a steroid taper with dexamethasone 4 mg 
every 4 hours or prednisone at 1 to 2 mg/kg should be 
started and continued over no less than 4 weeks.  
If serum transaminase levels do not decrease 48 hours 
after initiation of systemic steroids, oral mycophenolate 
mofetil 500 mg every 12 hours may be given. 
Infliximab is not recommended due to its potential for 
hepatotoxicity. 
Several courses of steroid tapering may be necessary as 
symptoms may worsen when the steroid dose is 
decreased. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 4 
Report as ECI 
Permanently discontinue pembrolizumab 
Manage patient as per Grade 3 above 
Table 31: Hepatic adverse ECIs 
 
 
 
 
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♦ NEUROLOGIC 
The following AE terms, regardless of grade, are considered ECIs and should be reported to 
EORTC within 24 hours of the event: 
♦ Autoimmune neuropathy 
♦ Demyelinating polyneuropathy 
♦ Guillain-Barre syndrome 
♦ Myasthenic syndrome 
All attempts should be made to rule out other causes such as metastatic disease, other 
medications or infectious causes. However the AE should be reported regardless of etiology. 
 
CTCAE Grade 
Course of Action 
Grade 2 
Report as ECI 
Moderate (Grade 2) – consider withholding 
pembrolizumab.  
Consider treatment with prednisone 1-2 mg/kg p.o. 
daily as appropriate 
Consider Neurology consultation. Consider biopsy for 
confirmation of diagnosis. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 3 and 4 
Report as ECI 
Discontinue pembrolizumab 
Obtain neurology consultation. Consider biopsy for 
confirmation of diagnosis 
Treat with systemic corticosteroids at a dose of 1 to 2 
mg/kg prednisone or equivalent once per day. If 
condition worsens consider IVIG or other 
immunosuppressive therapies as per local guidelines 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
Table 32: Neurologic ECIs 
♦ OCULAR 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of 
systemic steroids to treat the AE, is considered an ECI and should be reported to EORTC 
within 24 hours of the event: 
 
 
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♦ Uveitis 
♦ Iritis  
All attempts should be made to rule out other causes such as metastatic disease, infection or 
other ocular disease (e.g. glaucoma or cataracts). However the AE should be reported 
regardless of etiology. 
 
CTCAE Grade 
Course of Action 
Grade 2 
Evaluation by an ophthalmologist is strongly 
recommended. 
Treat with topical steroids such as 1% prednisolone 
acetate suspension and iridocyclitics. 
Discontinue pembrolizumab as per protocol if 
symptoms persist despite treatment with topical 
immunosuppressive therapy. 
Grade 3 
Evaluation by an ophthalmologist is strongly 
recommended  
Hold pembrolizumab and consider permanent 
discontinuation as per specific protocol guidance. 
Treat with systemic corticosteroids such as prednisone 
at a dose of 1 to 2 mg/kg per day. When symptoms 
improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 4 
Evaluation by an ophthalmologist is strongly 
recommended  
Permanently discontinue pembrolizumab. 
Treat with corticosteroids as per Grade 3 above 
Table 33: Ocular ECIs 
♦ RENAL 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
♦ Nephritis 
♦ Nephritis autoimmune 
♦ Renal failure 
 
 
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♦ Renal failure acute 
♦ Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of 
systemic steroids to treat the AE. 
All attempts should be made to rule out other causes such as obstructive uropathy, 
progression of disease, or injury due to other chemotherapy agents. A renal consultation is 
recommended. However the AE should be reported regardless of etiology. 
 
CTCAE Grade 
Course of Action 
Grade 2 
Hold pembrolizumab 
Treatment with prednisone 1-2 mg/kg p.o. daily. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 3-4 
Discontinue pembrolizumab 
Renal consultation with consideration of ultrasound 
and/or biopsy as appropriate 
Treat with systemic corticosteroids at a dose of 1 to 2 
mg/kg prednisone IV or equivalent once per day. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
Table 34: Renal ECIs 
♦ SKIN 
Rash and Pruritus 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the 
Sponsor within 24 hours of the event:  
♦ Pruritus 
♦ Rash 
♦ Rash generalized 
♦ Rash maculo-papular 
♦ In addition to CTCAE Grade 3 rash, any rash that is considered clinically 
significant, in the physician's judgment, should be treated as an ECI. Clinical 
significance is left to the physician to determine, and could possibly include 
rashes such as the following:  
o rash with a duration >2 weeks; OR  
o rash that is >10% body surface area; OR  
 
 
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o rash that causes significant discomfort not relieved by topical medication 
or temporary cessation of study drug. 
Other Skin ECIs 
The following AEs should always be reported as ECIs, regardless of grade, and should be 
reported to the Sponsor within 24 hours of the event:  
♦ Dermatitis exfoliative 
♦ Erythema multiforme 
♦ Steven’s Johnson syndrome 
♦ Toxic epidermal necrolysis 
Please note, the AE should be reported regardless of etiology. 
CTCAE Grade 
Course of Action 
Grade 2 
Symptomatic treatment should be given such as topical 
glucocorticosteroids (e.g., betamethasone 0.1% cream 
or hydrocortisone 1%) or urea-containing creams in 
combination with oral anti-pruritics (e.g., 
diphenhydramine HCl or hydroxyzine HCl).  
Treatment with oral steroids is at physician’s discretion 
for Grade 2 events. 
Grade 3 
Hold pembrolizumab. 
Consider Dermatology Consultation and biopsy for 
confirmation of diagnosis. 
Treatment with oral steroids is recommended, starting 
with 1 mg/kg prednisone or equivalent once per day or 
dexamethasone 4 mg four times orally daily. When 
symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 
weeks. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
Grade 4 
Permanently discontinue pembrolizumab. 
Dermatology consultation and consideration of biopsy 
and clinical dermatology photograph. 
Initiate steroids at 1 to 2 mg/kg prednisone or 
equivalent. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over 
no less than 4 weeks. 
Table 35: Skin ECIs 
 
 
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♦ IMMEDIATE EVALUATION FOR POTENTIAL SKIN ECIs 
A. Photographs:  
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as 
soon as possible. Obtain appropriate consent for patient photographs if a consent form 
addendum is required by your IRB/ERC.  
♦ Take digital photographs of:  
♦ the head (to assess mucosal or eye involvement),  
♦ the trunk and extremities, and  
♦ a close-up of the skin lesion/rash.  
♦ If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance.  
♦ The time/date stamp should be set in the 'ON' position for documentation purposes.  
♦ Photographs should be stored with the patient’s study records.  
♦ The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will 
provide guidance to the site, if needed.  
B. Past Medical History:  
Collect past medical history relevant to the event, using the questions in sub Appendix I (Past 
Medical History Related to Dermatologic Event) as a guide. Any preexisting conditions not 
previously reported (e.g., drug allergy) should be entered into the eCRF.  
C. Presentation of the Event:  
Collect information on clinical presentation and potential contributing factors using the 
questions in Appendix J (Presentation of the Dermatologic Event) as a guide. This 
information should be summarized and entered in narrative format in the AE eCRF. Note 
pertinent negatives where applicable to reflect that the information was collected. Any 
treatments administered should be entered on the Concomitant Medication eCRF.  
D. Vitals Signs and Standard Laboratory Tests:  
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on 
the Vital Signs eCRF. Perform standard laboratory tests (CBC with manual differential and 
serum chemistry panel, including LFTs).  
E. Focused Skin Examination:  
Perform a focused skin examination using the questions in Appendix K (Focused Skin 
Examination) as a guide. Information should be summarized and entered on the eCRF.  
F. Dermatology Consult  
Refer the patient to a dermatologist as soon as possible.  
♦ For a “severe rash”, the patient must be seen within 1-2 days of reporting the 
event.  
♦ For clinically significant rash, the patient should be seen within 3-5 days.  
 
 
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The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory 
or to a pathologist experienced in reviewing skin specimens.  
The site should provide the dermatologist with all relevant case history, including copies of 
clinical photographs and laboratory test results.  
♦ OTHER 
The following AEs, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
♦ Myocarditis 
♦ Pericarditis 
♦ Pancreatitis 
♦ Any additional Grade 3 or higher event which the physician considers to be 
immune related 
All attempts should be made to rule out other causes. Therapeutic specialists should be 
consulted as appropriate. However the AE should be reported regardless of etiology. 
CTCAE Grade 
Course of Action 
Grade 2 or Grade 1 that do not 
improve with symptomatic 
treatment 
Withhold pembrolizumab. 
Systemic corticosteroids may be indicated.  
Consider biopsy for confirmation of diagnosis. 
If pembrolizumab held and corticosteroid required, 
manage as per grade 3 below. 
Grade 3 
Hold pembrolizumab 
Treat with systemic corticosteroids at a dose of 1 to 2 
mg/kg prednisone or equivalent once per day. 
When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 
4 weeks. 
Permanently discontinue for inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. Otherwise, 
pembrolizumab treatment may be restarted and the 
dose modified as specified in the protocol. 
Grade 4 
Treat with systemic corticosteroids at a dose of 1 to 2 
mg/kg prednisone or equivalent once per day. 
Discontinue pembrolizumab  
Table 36: Other ECIs 
 
 
 
 
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♦ INFUSION REACTIONS 
The following AE terms, regardless of grade, are considered ECIs and should be reported to 
the Sponsor within 24 hours of the event: 
♦ Allergic reaction 
♦ Anaphylaxis 
♦ Cytokine release syndrome 
♦ Serum sickness 
♦ Infusion reactions 
♦ Infusion-like reactions 
Please note, the AE should be reported regardless of etiology. 
 
 
 
 
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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 patient is 
deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Requires infusion 
interruption but 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for < 
=24 hrs 
Stop Infusion. 
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 patient is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held 
until symptoms resolve and the patient 
should be premedicated for the next 
scheduled dose. 
patients who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study treatment administration. 
Patient may be 
premedicated 1.5h (± 30 
minutes) prior to 
infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 mg 
p.o. (or equivalent dose 
of antihistamine). 
 
Acetaminophen 500-
1000 mg p.o. (or 
equivalent dose of 
antipyretic). 
 
 
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NCI CTCAE 
Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., 
not rapidly 
responsive to 
symptomatic 
medication and/or 
brief interruption 
of infusion); 
recurrence of 
symptoms 
following initial 
improvement; 
hospitalization 
indicated for 
other clinical 
sequelae (e.g., 
renal impairment, 
pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; 
pressor or 
ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as 
medically indicated until the patient is 
deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
Patient is permanently discontinued from 
further study treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
For Further information, please refer to the Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE) at http://ctep.cancer.gov 
Table 37: Infusion reactions ECIs 
♦ FOLLOW UP TO RESOLUTION 
Patients should be followed to resolution. The eCRF should be updated with information 
regarding duration and clinical course of the event. Information obtained from the consulting 
specialist, including diagnosis, should be recorded.  
Narrative information requested:  
♦ Clinical course of the event  
♦ Course of treatment  
♦ Evidence supporting recovery  
 
 
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♦ Follow-up to the clinical course  
Any treatments administered for the event should also be entered in the Concomitant 
Medication eCRF.  
 
REFERENCES 
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature 
Reviews Cancer 2012; 12:252-264. 
2. Weber JS Practical Management of Immune-Related Adverse Events from Immune 
Checkpoint Protein Antibodies for the Oncologist. American Society of Clinical Oncology 
2012; 1092-9118/10/1-10. 
3. Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse 
Events and Kinetics of Response With Ipilimumab. J Clin Oncol 30. 2012. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750. 
4. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival 
with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010. 
5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 
2012; 366:2443-2454. 
6. Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 
Antibody in Patients with Advanced Cancer. N Engl J Med 2012; 366:2455-2465. 
7. Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, 
phase II study comparing the tolerability and efficacy of ipilimumab administered with or 
without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin 
Cancer Res 15:5591-5598, 2009. 
8. Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and 
the Management of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–
66. 
9. Phan GQ, Weber JS, and Sondak VK. CTLA-4 Blockade with Monoclonal Antibodies in 
Patients with Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–
3021. 
10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated 
adverse reactions—YERVOY Risk Evaluation and Mitigation Strategy (REMS). 
http://www.yervoy.com/hcp/rems.aspx 
11. Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised March 
2011. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf 
 
 
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Appendix I: Past Medical History Related to 
Dermatologic Event 
Past Medical History:  
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into 
the Medical History eCRF.  
1. Does the subject have any allergies? □ Yes □ No  
 
If yes, please obtain the following information:  
 
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No  
 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc): 
______________________________________________  
_____________________________________________________________  
 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.? 
□ Yes □ No  
 
Describe the agent and type of allergic response: _____________________  
_____________________________________________________________  
 
c. Any allergy to food? □ Yes □ No  
 
Describe the food and type of allergic response: _____________________  
____________________________________________________________  
 
d. Any allergy to animals, insects? □ Yes □ No  
 
Describe the allergen and type of allergic response: ___________________  
____________________________________________________________  
 
e. Any other allergy? □ Yes □ No  
 
 
 
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Describe the allergen and type of allergic response: _________________  
___________________________________________________________  
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes 
□ No  
 
If so what kind? ______________________________________________  
 
3. Has the subject ever been treated for a skin condition? □ Yes □ No  
 
If so what kind? ______________________________________________  
 
4. Is the current finding similar to a past experience? □ Yes □ No  
 
 
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Appendix J: Presentation of the Dermatologic Event 
Presentation of the event:  
Collect information on clinical presentation and potential contributing factors. Key 
information should be summarized and entered on the Adverse Experience eCRF. Any 
treatments administered should be entered on the Concomitant Medication eCRF.  
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study 
drug? ___________________________________________  
 
2. Has the subject contacted any known allergens? □ Yes □ No  
 
If so what kind? ______________________________________________  
 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry 
detergents, soap, personal care product, poison ivy, etc.)? □ Yes □ No  
 
If so what kind? _________________________________________________  
 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and 
supplement)? □ Yes □ No  
 
If so what kind? _________________________________________________  
 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No  
 
If so what kind? _________________________________________________  
 
6. Does the subject have or had in the last few days any illness? □ Yes □ No  
 
If so what kind? __________________________________________________  
 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ 
No  
 
If so who and what? _____________________________________________  
 
 
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February 28, 2018 
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash 
(e.g. Molluscum Contagiosum)? □ Yes □ No  
 
9. Has the subject had recent sun exposure? □ Yes □ No  
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No  
 
If so what kind? ________________________________________________  
 
i. Anaphylaxis? □ Yes □ No  
ii. Signs of hypotension? □ Yes □ No  
iii. Signs of dyspnea? □ Yes □ No  
iv. Fever, night sweats, chills? □ Yes □ No  
 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic 
catecholamine therapy? □ Yes □ No  
 
If so what kind? ________________________________________________  
 
12. For the current rash, has the subject used any other medication, such as inhaled 
bronchodilators, antihistaminic medication, topical corticosteroid, and/or systemic 
corticosteroid? □ Yes □ No  
 
List medication(s) and dose(s): _________________________________________  
___________________________________________________________________ 
 
13. Is the rash pruritic (itchy)? □ Yes □ No  
 
 
 
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Appendix K: Focused Skin Examination 
 
Focused Skin Examination:  
Key information should be summarized and entered on the Adverse Experience eCRF.  
 
Primary Skin Lesions Description  
Color: _______________________________________________________  
 
General description:  
______________________________________________________________  
______________________________________________________________  
 
Describe the distribution of skin reaction, skin eruption, or rash on the body:  
______________________________________________________________  
______________________________________________________________  
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
______________________________________________________________  
______________________________________________________________  
 
Any associated signs on physical examination? 
______________________________________________________________ 
 
 
 
 
 
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Appendix L: Merck Code of Conduct for Clinical 
Trials 
Merck* 
Code of Conduct for Clinical Trials 
I. Introduction 
A. Purpose 
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and 
effectiveness of our products. As such, we are committed to designing, implementing, 
conducting, analyzing and reporting these trials in compliance with the highest ethical and 
scientific standards. Protection of subject safety is the overriding concern in the design of 
clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local 
and/or national regulations and in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki.  
B. Scope 
Such standards shall be endorsed for all clinical interventional investigations sponsored by 
Merck irrespective of the party (parties) employed for their execution (e.g., contract research 
organizations, collaborative research efforts). This Code is not intended to apply to trials 
which are observational in nature, or which are retrospective. Further, this Code does not 
apply to investigator-initiated trials which are not under the control of Merck. 
II. Scientific Issues 
A. Trial Conduct 
1. Trial Design 
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess 
safety, efficacy and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator 
products. Alternatively, Merck may conduct outcomes research trials, trials to assess or 
validate various endpoint measures, or trials to determine subject preferences, etc. 
The design (i.e., subject population, duration, statistical power) must be adequate to address 
the specific purpose of the trial. Research subjects must meet protocol entry criteria to be 
enrolled in the trial.  
2. Site Selection 
Merck selects investigative sites based on medical expertise, access to appropriate subjects, 
adequacy of facilities and staff, previous performance in Merck trials, as well as budgetary 
considerations. Prior to trial initiation, sites are evaluated by Merck personnel to assess the 
ability to successfully conduct the trial. 
3. Site Monitoring/Scientific Integrity 
Trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice. Merck reviews clinical data for accuracy, completeness and 
consistency. Data are verified versus source documentation according to standard operating 
 
 
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procedures. Per Merck policies and procedures, if fraud, misconduct or serious GCP-non-
Compliance are suspected, the issues are promptly investigated. When necessary, the clinical 
site will be closed, the responsible regulatory authorities and ethics review committees 
notified and data disclosed accordingly.  
B. Publication and Authorship 
To the extent scientifically appropriate, Merck seeks to publish the results of trials it 
conducts. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing. In such cases, publication of results may not be appropriate since the 
trial may be underpowered and the analyses complicated by statistical issues of multiplicity. 
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good 
Clinical Practice guidelines. In summary, authorship should reflect significant contribution to 
the design and conduct of the trial, performance or interpretation of the analysis, and/or 
writing of the manuscript. All named authors must be able to defend the trial results and 
conclusions. Merck funding of a trial will be acknowledged in publications.  
III. Subject Protection 
A. IRB/ERC review 
All clinical trials will be reviewed and approved by an independent IRB/ERC before being 
initiated at each site. Significant changes or revisions to the protocol will be approved by the 
IRB/ERC prior to implementation, except that changes required urgently to protect subject 
safety and well-being may be enacted in anticipation of IRB/ERC approval. For each site, the 
IRB/ERC and Merck will approve the subject informed consent form.  
B. Safety 
The guiding principle in decision-making in clinical trials is that subject welfare is of primary 
importance. Potential subjects will be informed of the risks and benefits of, as well as 
alternatives to, trial participation. At a minimum, trial designs will take into account the local 
standard of care. Subjects are never denied access to appropriate medical care based on 
participation in a Merck clinical trial.  
All participation in Merck clinical trials is voluntary. Subjects are enrolled only after 
providing informed consent for participation. Subjects may withdraw from a Merck trial at 
any time, without any influence on their access to, or receipt of, medical care that may 
otherwise be available to them. 
C. Confidentiality 
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. 
Unless required by law, only the investigator, Sponsor (or representative) and/or regulatory 
authorities will have access to confidential medical records that might identify the research 
subject by name. 
D. Genomic Research 
Genomic Research will only be conducted in accordance with informed consent and/or as 
specifically authorized by an Ethics Committee. 
 
 
 
 
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IV. Financial Considerations 
A. Payments to Investigators 
Clinical trials are time- and labor-intensive. It is Merck’s policy to compensate investigators 
(or the sponsoring institution) in a fair manner for the work performed in support of Merck 
trials. Merck does not pay incentives to enroll subjects in its trials. However, when 
enrollment is particularly challenging, additional payments may be made to compensate for 
the time spent in extra recruiting efforts. 
Merck does not pay for subject referrals. However, Merck may compensate referring 
physicians for time spent on chart review to identify potentially eligible subjects. 
B. Clinical Research Funding  
Informed consent forms will disclose that the trial is sponsored by Merck, and that the 
investigator or sponsoring institution is being paid or provided a grant for performing the 
trial. However, the local IRB/ERC may wish to alter the wording of the disclosure statement 
to be consistent with financial practices at that institution. As noted above, publications 
resulting from Merck trials will indicate Merck as a source of funding. 
C. Funding for Travel and Other Requests 
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator 
meetings, etc.) will be consistent with local guidelines and practices including, in the U.S., 
those established by the American Medical Association (AMA).  
V. Investigator Commitment 
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial 
protocol, and in signing the protocol, agree to support these ethical and scientific standards. 
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering 
Corporation, each of which is a subsidiary of Merck & Co., Inc. Merck is known as MSD 
outside of the United States and Canada. As warranted by context, Merck also includes 
affiliates and subsidiaries of Merck & Co., Inc." 
VI. Letter to Patients  
At the close of the trial after unblinding, a letter is to be sent by the investigator to those 
subjects who received placebos to provide the following advice: 
“You have participated in a trial conducted by the Sponsor. This is to advise you that you 
were among those who received placebo. You may also have received the active drug 
Pembrolizumab.” 
 
 
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Appendix M: EQ-5D-3L – Health Questionnaire 
 
 
 
 
 
 
Health Questionnaire 
 
(English version for the UK) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© EuroQoL Group 1990 
 
 
 
 
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February 28, 2018 
 
By placing a tick in one box in each group below, please indicate which statements best 
describe your own health state today. 
 
Mobility 
I have no problems in walking about  
 
 
 
 
 
 
I have some problems in walking about 
 
 
 
 
 
 
I am confined to bed  
 
 
 
 
 
 
 
 
 
Self-Care 
I have no problems with self-care 
 
 
 
 
 
 
 
I have some problems washing or dressing myself  
 
 
 
 
I am unable to wash or dress myself  
 
 
 
 
 
 
 
Usual Activities (e.g. work, study, housework, family or leisure activities) 
I have no problems with performing my usual activities 
 
 
 
 
I have some problems with performing my usual activities  
 
 
 
I am unable to perform my usual activities  
 
 
 
 
 
 
Pain/Discomfort 
I have no pain or discomfort  
 
 
 
 
 
 
 
I have moderate pain or discomfort  
 
 
 
 
 
 
I have extreme pain or discomfort 
 
 
 
 
 
 
 
 
Anxiety/Depression 
I am not anxious or depressed 
 
 
 
 
 
 
 
I am moderately anxious or depressed 
 
 
 
 
 
 
I am extremely anxious or depressed  
 
 
 
 
 
 
 
 
 
© EuroQoL Group 1990 
 
 
 
 
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To help people say how good or bad a health state is, we have drawn a 
scale (rather like a thermometer) on which the best state you can imagine 
is marked 100 and the worst state you can imagine is marked 0. 
We would like you to indicate on this scale how good or bad your own 
health is today, in your opinion. Please do this by drawing a line from the 
box below to whichever point on the scale indicates how good or bad 
your health state is today. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© EuroQoL Group 1990 
 
Your own 
health state 
today 
9 0 
8 0 
7 0 
6 0 
5 0 
4 0 
3 0 
2 0 
1 0 
100 
Worst 
imaginable 
health state 
0 
Best  
imaginable 
health state 
 
 
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February 28, 2018 
Appendix N: Recommendations for Contraception 
in United Kingdom, Portugal, Scandinavian 
countries and Other Applicable Countries 
It is unknown whether pembrolizumab has adverse effects on a fetus in utero or on the 
composition of sperm. Therefore, non-pregnant, non-breast-feeding women may only be 
enrolled if they are willing to follow the Clinical Trial Facilitation Group (CTFG) guidance 
(Final Version 2014-09-15, Sections 4.1 and 4.2) for highly effective birth control as outlined 
below, or are considered to be highly unlikely to conceive. Highly unlikely to conceive is 
defined as 1) surgically sterilized, or 2) postmenopausal1 (a woman who is ≥45 years of age 
and has not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active2 for the duration of the study. 
(1) and (2) Refer to Portugal section below 
Subjects should use birth control methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly and are considered as highly effective birth control 
methods. Such methods include:  
♦ Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: 
♦ Oral 
♦ Intravaginal 
♦ Transdermal 
♦ Progestogen-only hormonal contraception associated with inhibition of ovulation: 
♦ Oral 
♦ Injectable 
♦ Implantable 
♦ Intrauterine device (IUD) 
♦ Intrauterine hormone-releasing system (IUS) 
♦ Bilateral tubal occlusion 
♦ Vasectomised partner 
♦ Sexual abstinence3 
 (3) Refer to Portugal section below 
Subjects should start using birth control from study Visit 1 throughout the study period up to 
120 days after the last dose of study therapy. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study they must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 16.8 Reporting of 
 
 
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Pregnancy. If there is any question that a subject will not reliably comply with the 
requirements for contraception, that subject should not be entered into the study. 
Monthly4 pregnancy testing is recommended per local standards if applicable. 
(4) Refer to Portugal section below 
 
Specific guidelines for Portugal 
 
1. For Portugal 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 post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. However in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
2. For Portugal the absence of heterosexual activity refers to sexual abstinence. 
3. For Portugal, sexual abstinence (relative to heterosexual activity) can be used as the sole 
method of contraception only when it is consistently employed as the subject’s preferred and 
usual lifestyle, and if considered acceptable by local regulatory agencies and ethical 
committees. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
4. For Portugal, pregnancy testing should be performed at monthly intervals. 
 
 
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Appendix O: Guidelines for RECIST 1.1 
1. Criteria of evaluation 
Response criteria are essentially based on a set of measurable lesions identified at baseline as 
target lesions, and – together with other lesions that are denoted as non-target lesions – 
followed until disease progression. 
The following paragraphs are a quick reference to the RECIST criteria (version 1.1). The 
complete criteria are included in the published RECIST (Ref. 69) document also available at 
http://www.eortc.be/RECIST. 
1.1 Measurability of tumor lesions at baseline 
1.1.1 Definitions 
♦ Measurable disease - the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.  
♦ Measurable lesions - tumor lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray, and as ≥ 10 
mm with CT scan or clinical examination [using calipers]. Bone lesions are considered 
measurable only if assessed by CT scan and have an identifiable soft tissue component 
that meets these requirements (soft tissue component > 10 mm by CT scan). Malignant 
lymph nodes must be ≥ 15 mm in the short axis to be considered measurable; only the 
short axis will be measured and followed. All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters) by use of a ruler or calipers. Tumor 
lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been 
demonstrated progression in the lesion. 
♦ Non-measurable lesions - All other lesions (or sites of disease), including small lesions 
are considered non-measurable disease. Bone lesions without a measurable soft tissue 
component, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonis, inflammatory breast disease, lymphangitic involvement of lung or skin 
and abdominal masses followed by clinical examination are all non-measurable. Nodes 
that have a short axis <10 mm at baseline are considered non-pathological and should not 
be recorded or followed. 
♦ Target Lesions. When more than one measurable tumor lesion or malignant lymph node 
is present at baseline all lesions up to a maximum of 3 lesions total (and a maximum of 2 
lesions per organ) representative of all involved organs should be identified as target 
lesions and will be recorded and measured at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible 
repeated measurements. Note that pathological nodes must meet the criterion of a short 
axis of ≥ 15 mm by CT scan and only the short axis of these nodes will contribute to the 
baseline sum. At baseline, the sum of the target lesions (longest diameter of tumor lesions 
plus short axis of lymph nodes: overall maximum of 3 is to be calculated and recorded.  
 
 
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♦ Non-target Lesions. All non-measurable lesions (or sites of disease) including 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm), plus any measurable 
lesions over and above those listed as target lesions are considered non-target lesions. 
Measurements are not required but these lesions should be noted at baseline and should 
be followed as “present” or “absent”. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 4 weeks before the beginning of the treatment. 
1.1.2 Methods of measurements 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be 
identified on a calendar schedule and should not be affected by delays in therapy, which may 
be treatment arm dependent. While on study, all target lesions recorded at baseline should 
have their actual measurements recorded on the CRF at each subsequent evaluation, even 
when very small (e.g. 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned. For lesions which fragment/split add together the longest diameters of the 
fragmented portions; for lesions which coalesce, measure the maximal longest diameter for 
the “merged lesion”. 
♦ Clinical Lesions. Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10 mm as assessed using calipers (e.g. skin nodules). For the case of 
skin lesions, documentation by color photography including a ruler to estimate the size of 
the lesion is recommended. If feasible, imaging is preferred. 
♦ Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions > 20 mm on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung. 
♦ CT, MRI. CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans 
have slice thickness greater than 5 mm, the minimum size for a measurable lesion should 
be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body 
scans). While PET scans are not considered adequate to measure lesions, PET-CT scans 
may be used providing that the measures are obtained from the CT scan and the CT scan 
is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast). 
♦ Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT should be obtained. 
♦ Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor 
evaluation is not advised. However, they can be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response or surgical resection is an endpoint. 
 
 
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♦ Tumor Markers. Tumor markers alone cannot be used to assess objective tumor 
response. If markers are initially above the upper normal limit, however, they must 
normalize for a patient to be considered in complete response. 
Cytology, Histology. These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol (for example, residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain). When effusions are known to 
be a potential adverse effect of treatment (e.g. with certain taxane compounds or 
angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion 
that appears or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is advised to differentiate between response or stable disease and 
progressive disease. 
1.1.3 Tumor response evaluation 
All patients will have their BEST RESPONSE from the start of study treatment until the end 
of treatment classified as outlined below: 
Complete Response (CR): disappearance of all target and non-target lesions and 
normalization of tumor markers. Pathological lymph nodes must have short axis measures < 
10mm (Note: continue to record the measurement even if < 10 mm and considered CR). 
Tumor markers must have normalized. Residual lesions (other than nodes < 10 mm) thought 
to be non-malignant should be further investigated (by cytology or PET scans) before CR can 
be accepted.  
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for 
tumor lesions and short axis measure for nodes) of target lesions, taking as reference the 
baseline sum of diameters. Non target lesions must be non-PD.  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study. 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured 
lesions taking as references the smallest sum of diameters recorded on study (including 
baseline) AND an absolute increase of ≥ 5 mm. Appearance of new lesions will also 
constitute PD (including lesions in previously unassessed areas). In exceptional 
circumstances, unequivocal progression of non-target disease may be accepted as evidence of 
disease progression, where the overall tumor burden has increased sufficiently to merit 
discontinuation of treatment, for example where the tumor burden appears to have increased 
by at least 73% in volume (which is the increase in volume when all dimensions of a single 
lesion increase by 20%). Modest increases in the size of one or more non-target lesions are 
NOT considered unequivocal progression. If the evidence of PD is equivocal (target or non-
target), treatment may continue until the next assessment. If on further documentation PD is 
confirmed, the earlier date must be used. If this is not the case, so the subsequent disease 
evaluation does not confirm the PD (i.e. the first PD rather corresponds to a tumor flare 
reaction), patient should not be considered as having PD, and treatment should be 
continued. 
 
 
 
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Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this 
category also requires 
Patients with Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of tumor 
markers, tumor nodes < 
10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
documented at least 
once ≥ 12 wks. from 
previous assessment 
Not all 
evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any  
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Patients with Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of tumor 
markers, all tumor 
nodes < 10 mm 
No Target 
Non-CR/non-PD 
No 
Non-CR/ 
non-PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression [or evidence of 
unequivocal disease progression] at that time should be reported as “symptomatic 
deterioration”. This is a reason for stopping therapy, but is NOT objective PD. Every 
effort should be made to document the objective progression even after discontinuation 
of treatment. 
Table 38: Integration of Target, non-Target and New lesions into response assessment: 
 
 
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1.1.3.1 Frequency of tumor re-evaluation 
See Chapter 6.3.6. 
1.1.3.2 Date of progression 
This is defined as the first day when the RECIST (version 1.1) criteria for PD are met, unless 
this corresponds to a tumor flare reaction. 
1.1.4 Reporting of tumor response 
All patients included in the study must be assessed for response to treatment, even if there is 
a major protocol treatment deviation or if they are ineligible, or not followed/re-evaluated. 
Each patient will be assigned one of the following categories: complete response, partial 
response, stable disease, progressive disease, early death or not evaluable. 
Early death is defined as any death occurring before the first per protocol time point of tumor 
re-evaluation. 
Patients’ response will be classified as "not evaluable" if insufficient data were collected to 
allow evaluation per these criteria. 
1.1.5 Response duration 
Response duration will be measured from the time measurement criteria for CR/PR 
(whichever is first recorded) are first met until the first date that recurrent or progressive 
disease is objectively documented. 
1.1.6 Stable disease duration 
Stable disease duration will be measured from the time of start of treatment until the criteria 
for progression are met. 
 
 
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SUMMARY OF CHANGES  
AMENDMENT MK3475-054-03                                                                                                                                                                                                                                          EORTC 
 
EORTC protocol 1325-MG -  Adjuvant immunotherapy with anti-PD-1 monoclonal antibody Pembrolizumab (MK-3475) versus placebo after complete 
resection of high-risk Stage III melanoma: A randomized, double- blind Phase 3 trial of the EORTC Melanoma Group   
Amendment MK3475-054-03 
 
 
The changes in this new amendment are:  
- 
To allow radiotherapy as adjuvant therapy treatment after 1st recurrence and prior to entry in Part 2. This has been introduced as, in some 
participating countries, radiotherapy is part of standard of care after recurrence. It has been implemented in the following sections :  
o 4.2 Part 2 : after the first recurrence : changes to allow radiotherapy before entering Part 2 “Surgery, biopsy and/or radiotherapy (palliative or 
adjuvant) are allowed prior to Part 2. Radiotherapy has to be completed prior to first dose and complete wound healing is required prior to 
first dose“ 
o 4.3 Unblinding data : changes in Figure 3 Trial design to reflect changes in treatment duration and radiotherapy allowed before Part 2 
o 5.4.2 Part 2 After the first recurrence : changes to allow radiotherapy before Part 2 
o 5.6.1 Prohibited medications, therapies and procedures : changes to allow radiotherapy 
 
- 
Duration of treatment in Part 2 will be flexible for patients with local recurrence and treatment may stop after 1 year (left to investigator’s 
discretion). It has been implemented in the following sections: 
o Summary : Modification of the treatment duration : Treatment in Part 2 will be administered up to 1 year (local recurrence) or 2 years 
treatment period unless occurrence of a withdrawal criterion (see Section 5.4.2.4). For patients with local recurrence, the treatment may stop 
at 1 year at the discretion of the investigator. 
o 4.3 Unblinding data : changes in Figure 3 Trial design to reflect changes in treatment duration and radiotherapy allowed before Part 2 
o 5.4 Treatment schedule : changes in Figure 4 Treatment schedule : to reflect changes in treatment duration 
o 5.4.2.3 Treatment duration for pembrolizumab : changes of treatment duration 
o 5.4.2.4 Withdrawal criteria for Part 2 treatment : changes of treatment duration 
o 6.3.6.2 Evaluations for patients receiving pembrolizumab: changes of treatment duration 
o 6.3.8.1 For patients who discontinued Part 2 due to progression or recurrence or completion of treatment 
o 6.4.2.1 Evaluations during cross over or rechallenge with pembrolizumab : changes of treatment duration 
 
- 
Frequency of imaging work up in Part 2 will be every 12 weeks instead of 6 weeks 
o 6.3.6.2 Evaluations for patients receiving pembrolizumab 
o 6.4.2.1 Evaluations during cross over or re-challenge with pembrolizumab 
 
 
EORTC v7.0/ MK-3475-054-03                                                                                                                                                                                                                   February 28, 2018                                  
 
 
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SUMMARY OF CHANGES  
AMENDMENT MK3475-054-03                                                                                                                                                                                                                                          EORTC 
 
- 
Clarification that patients in follow up will continue imaging assessments as indicated: 
o 6.4.1.2 Follow up evaluation for Part 1 – footnote 3  
o 6.4.2.3 Follow up evaluation for patients who discontinue Part 2 – footnote 3 
 
- 
Other minor clarifications: 
o Updated CRO representative’s contact information 
o Summary, Section 3.3 Enrollment and Randomization chapter and Section 4.2 Part 2 : after the first recurrence (cross-over or re-challenge 
treatment): Clarification about the creatinine levels allowed for entering Part 2 
o 6.3.1 Part 1 : adjuvant therapy : changes of allowed window for tests to be performed every 12 weeks 
o 6.3.2. Translational research : clarification that baseline TR samples can be collected after randomization but before treatment start 
 
 
 
EORTC v7.0/ MK-3475-054-03                                                                                                                                                                                                                   February 28, 2018                                  
 
 
04WNSF
 
 
052Q4X