A Phase 1/2 Clinical Trial to Study the Safety and Tolerability of MK-3475 + Pegylated Interferon Alfa-2b (PEG-IFN) and MK-3475 + Ipilimumab (IPI) in Subjects With Advanced Melanoma (MEL) and Renal Cell Carcinoma (RCC) (KEYNOTE 029)
Phase: PHASE1
Conditions: Renal Cell Carcinoma, Melanoma
Sponsor: Merck Sharp & Dohme LLC

Product:  MK-3475 
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Protocol/Amendment No.: 029-05
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase 1/2 Clinical Trial to Study the Safety and Tolerability of MK-3475 + Pegylated 
Interferon alfa-2b (PEG-IFN) and MK-3475 + Ipilimumab (IPI) in Subjects With Advanced 
Melanoma (MEL) and Renal Cell Carcinoma (RCC)  (KEYNOTE 029)
IND NUMBER:  110080
EudraCT NUMBER:  2013-004072-36
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
2.1
Trial Diagram........................................................................................................ 21
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 23
Primary Objective(s) & Hypothesis(es) .............................................................. 23
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 24
3.2
Exploratory Objectives......................................................................................... 24
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 25
Background ........................................................................................................... 25
4.1
Pharmaceutical and Therapeutic Background .................................................... 25
4.1.1
Pembrolizumab ............................................................................................ 25
4.1.1.1
Pegylated Interferon Alfa-2b (PEG-IFN) .................................................... 27
4.1.1.2
Ipilimumab (IPI) .......................................................................................... 28
4.1.1.3
Pre-clinical Trial with Pembrolizumab............................................................... 29
4.1.2
Ongoing Clinical Trials....................................................................................... 29
4.1.3
Rationale................................................................................................................ 29
4.2
Rationale for the Trial and Selected Subject Population .................................... 29
4.2.1
Rationale for Evaluating anti-PD-1 Therapy in Advanced Melanoma 
4.2.1.1
and Renal Cell Carcinoma ........................................................................... 31
Rationale for Pembrolizumab ............................................................... 31
4.2.1.1.1
Rationale for PEG-IFN ......................................................................... 31
4.2.1.1.2
Hypothesis for Pembrolizumab + PEG-IFN Combination 
4.2.1.1.2.1
Therapies................................................................................................. 31
Rationale for IPI.................................................................................... 32
4.2.1.1.3
Hypothesis for Pembrolizumab + IPI Combination Therapies ...... 32
4.2.1.1.3.1
Rationale for Dose Selection/Regimen/Modification ......................................... 33
4.2.2
Rationale for Endpoints ...................................................................................... 36
4.2.3
Safety Endpoints .......................................................................................... 36
4.2.3.1
Efficacy Endpoints....................................................................................... 36
4.2.3.2
 
 
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Planned Exploratory Biomarker Research................................................... 38
4.2.3.3
Future Biomedical Research........................................................................ 39
4.2.3.4
5.0
METHODOLOGY ................................................................................................... 40
Entry Criteria........................................................................................................ 40
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 40
5.1.1
Subject Inclusion Criteria.................................................................................... 40
5.1.2
Subject Exclusion Criteria .................................................................................. 43
5.1.3
Trial Treatment(s) ................................................................................................ 45
5.2
Dose Selection/Modification .............................................................................. 45
5.2.1
Dose Selection (Preparation) ....................................................................... 45
5.2.1.1
Rules for Dose Finding (Part 1A) ................................................................ 46
5.2.1.2
Definition of Dose-Limiting Toxicities ................................................ 48
5.2.1.2.1
Replacement of Subjects in DLT Period (Part 1A) .............................. 49
5.2.1.2.2
Dose Modification (Escalation/Titration/Other).......................................... 50
5.2.1.3
Dose Modification Guidelines for pembrolizumab + PEG-IFN or 
5.2.1.3.1
pembrolizumab + IPI Combination Therapy ........................................ 52
Dose Modification Guidelines for Treatment Group A (Part 1A 
5.2.1.3.1.1
Only): pembrolizumab + PEG-IFN ........................................................ 52
Dose Modification Guidelines for PEG-IFN ................................. 54
5.2.1.3.1.2
5.2.1.3.1.2.1
Dose Modification for Management of Depression................ 54
5.2.1.3.1.2.2
Interruption or Discontinuation of PEG-IFN .......................... 55
Dose 
Modification 
Guidelines 
for 
Treatment 
Group 
B: 
5.2.1.3.2
pembrolizumab + IPI ............................................................................ 56
Dose Modification Guidelines for IPI............................................ 58
5.2.1.3.2.1
5.2.1.3.2.1.1
Interruption or Discontinuation of IPI..................................... 58
Dose Modification and Supportive Care Guidelines for DRAEs for 
5.2.1.3.3
Pembrolizumab Monotherapy and Part 1C........................................... 58
Timing of Dose Administration .......................................................................... 64
5.2.2
Treatment after Initial Evidence of Radiologic Disease Progression ................. 65
5.2.3
Trial Blinding/Masking....................................................................................... 66
5.2.4
Randomization or Treatment Allocation............................................................ 66
5.3
Stratification.......................................................................................................... 67
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 67
5.5
Acceptable Concomitant Medications ................................................................ 67
5.5.1
 
 
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Prohibited Concomitant Medications.................................................................. 67
5.5.2
Rescue Medications & Supportive Care............................................................. 68
5.6
Supportive Care Guidelines ................................................................................ 68
5.6.1
Guidelines for Pembrolizumab/PEG-IFN Combination Therapy....................... 69
5.6.2
PEG-IFN Dosing Considerations................................................................. 69
5.6.2.1
Diet/Activity/Other Considerations..................................................................... 69
5.7
Diet...................................................................................................................... 69
5.7.1
Contraception...................................................................................................... 69
5.7.2
Use in Pregnancy ................................................................................................ 71
5.7.3
Use in Nursing Women....................................................................................... 71
5.7.4
Subject Withdrawal/Discontinuation Criteria................................................... 71
5.8
Discontinuation of Study Treatment after CR .................................................... 72
5.8.1
Subject Replacement Strategy............................................................................. 72
5.9
Beginning and End of the Trial ........................................................................... 73
5.10
Clinical Criteria for Early Trial Termination ................................................... 73
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 74
Treatment Phase ................................................................................................... 74
6.1
Treatment Phase: Part 1A (MEL and RCC) and Part 1B and 1C (MEL only) ... 74
6.1.1
Treatment Group A: pembrolizumab + PEG-IFN Combination Therapy 
6.1.1.1
(Part 1A only) .............................................................................................. 74
6.1.1.2 Treatment Group B: pembrolizumab + IPI Combination Therapy (Part 
1A, Part 1B and Part 1C) ............................................................................. 78
Second Course Phase: All Parts - All Treatment Groups (MEL and RCC) ... 85
6.2
7.0
TRIAL PROCEDURES ........................................................................................... 89
Trial Procedures ................................................................................................... 89
7.1
Administrative Procedures.................................................................................. 89
7.1.1
Informed Consent......................................................................................... 89
7.1.1.1
General Informed Consent.................................................................... 89
7.1.1.1.1
Consent and Collection of Specimens for Future Biomedical 
7.1.1.1.2
Research................................................................................................ 90
Inclusion/Exclusion Criteria ........................................................................ 90
7.1.1.2
Subject Identification Card .......................................................................... 90
7.1.1.3
Medical History ........................................................................................... 90
7.1.1.4
 
 
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Prior and Concomitant Medications Review ............................................... 90
7.1.1.5
Prior Medications.................................................................................. 90
7.1.1.5.1
Concomitant Medications..................................................................... 90
7.1.1.5.2
Disease Details...................................................................................... 91
7.1.1.5.3
Prior Treatment Details......................................................................... 91
7.1.1.5.4
Subsequent Anti-Cancer Therapy Status .............................................. 91
7.1.1.5.5
Assignment of Screening Number............................................................... 91
7.1.1.6
Assignment of Randomization Number....................................................... 91
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other) ................................... 91
7.1.1.8
Clinical Procedures/Assessments........................................................................ 92
7.1.2
Adverse Event (AE) Monitoring.................................................................. 92
7.1.2.1
Physical Exam.............................................................................................. 92
7.1.2.2
Full Physical Exam ............................................................................... 92
7.1.2.2.1
Directed Physical Exam........................................................................ 92
7.1.2.2.2
Vital Signs.................................................................................................... 93
7.1.2.3
Electrocardiogram (ECG) ............................................................................ 93
7.1.2.4
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 93
7.1.2.5
Tumor Tissue Collection.............................................................................. 93
7.1.2.6
Tumor Imaging and Assessment of Disease................................................ 94
7.1.2.7
Assessment of Disease................................................................................. 94
7.1.2.8
Ophthalmologic Examination ...................................................................... 95
7.1.2.9
Laboratory Procedures/Assessments .................................................................. 95
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 95
7.1.3.1
Serum/Urine β-hCG.............................................................................. 97
7.1.3.1.1
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 97
7.1.3.2
Blood Collection for Serum MK-3475 ............................................... 100
7.1.3.2.1
Blood Collection for Anti-MK-3475 Antibodies (ADA) ................... 100
7.1.3.2.2
Blood Collection for total IgG ............................................................ 100
7.1.3.2.3
Future Biomedical Research...................................................................... 100
7.1.3.3
Other Procedures............................................................................................... 100
7.1.4
Withdrawal/Discontinuation...................................................................... 100
7.1.4.1
Withdrawal From Future Biomedical Research ................................. 101
7.1.4.1.1
Blinding/Unblinding .................................................................................. 101
7.1.4.2
 
 
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Calibration of Critical Equipment.............................................................. 101
7.1.4.3
Visit Requirements............................................................................................ 102
7.1.5
Screening.................................................................................................... 102
7.1.5.1
Treatment Period........................................................................................ 102
7.1.5.2
Second Course Phase.......................................................................... 103
7.1.5.2.1
Post-Treatment Visits................................................................................. 104
7.1.5.3
Safety Follow-up Visit........................................................................ 104
7.1.5.3.1
Follow-up Visits ................................................................................. 105
7.1.5.3.2
Survival Follow-up (SFU) .................................................................. 105
7.1.5.3.3
Survival Status ........................................................................................... 105
7.1.5.4
Assessing and Recording Adverse Events ........................................................ 106
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor........................................................................................................ 106
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 107
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................. 108
7.2.3
Serious Adverse Events ............................................................................. 108
7.2.3.1
Events of Clinical Interest.......................................................................... 109
7.2.3.2
Protocol-Specific Exceptions to Serious Adverse Event Reporting .......... 110
7.2.3.3
Evaluating Adverse Events ............................................................................... 110
7.2.4
Sponsor Responsibility for Reporting Adverse Events .................................... 113
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 113
Statistical Analysis Plan Summary ................................................................... 113
8.1
Part 1 ................................................................................................................. 113
8.1.1
Statistical Analysis Plan ..................................................................................... 114
8.2
Responsibility for Analyses/In-House Blinding ............................................... 114
8.2.1
Hypotheses/Estimation ..................................................................................... 114
8.2.2
Analysis Endpoints ........................................................................................... 114
8.2.3
Safety Endpoints ........................................................................................ 114
8.2.3.1
Efficacy Endpoints..................................................................................... 115
8.2.3.2
Analysis Populations......................................................................................... 115
8.2.4
Efficacy Analysis Populations ................................................................... 115
8.2.4.1
Safety Analysis Populations ...................................................................... 115
8.2.4.2
Statistical Methods............................................................................................ 116
8.2.5
 
 
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Statistical Methods for Efficacy Analyses ................................................. 116
8.2.5.1
Progression-free Survival (PFS) ......................................................... 116
8.2.5.1.1
Overall Survival (OS) ......................................................................... 116
8.2.5.1.2
Objective Response Rate (ORR) ........................................................ 116
8.2.5.1.3
Ordinal Response Score...................................................................... 116
8.2.5.1.4
Duration of Response (DOR) ............................................................. 116
8.2.5.1.5
Pharmacokinetic Parameters............................................................... 116
8.2.5.1.6
Statistical Methods for Safety Analyses .................................................... 117
8.2.5.2
Summaries of Baseline Characteristics, Demographics, and Other 
8.2.5.3
Analyses..................................................................................................... 118
Multiplicity ....................................................................................................... 119
8.2.6
Sample Size and Power Calculations................................................................ 119
8.2.7
Part 1.......................................................................................................... 119
8.2.7.1
Interim Analyses ............................................................................................... 120
8.2.8
Compliance (Medication Adherence) ............................................................... 120
8.2.9
Extent of Exposure............................................................................................ 121
8.2.10
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 121
Investigational Product ...................................................................................... 121
9.1
Packaging and Labeling Information ............................................................... 122
9.2
Clinical Supplies Disclosure............................................................................... 122
9.3
Storage and Handling Requirements................................................................ 122
9.4
Returns and Reconciliation................................................................................ 122
9.5
Standard Policies................................................................................................. 123
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 123
Confidentiality..................................................................................................... 123
10.1
Confidentiality of Data ..................................................................................... 123
10.1.1
Confidentiality of Subject Records ................................................................... 123
10.1.2
Confidentiality of Investigator Information...................................................... 123
10.1.3
Confidentiality of IRB/IEC Information........................................................... 124
10.1.4
Compliance with Financial Disclosure Requirements..................................... 124
10.2
Compliance with Law, Audit and Debarment ................................................. 124
10.3
Compliance with Trial Registration and Results Posting Requirements ...... 126
10.4
 
 
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Quality Management System............................................................................. 127
10.5
Data Management............................................................................................... 127
10.6
Publications ......................................................................................................... 127
10.7
11.0
LIST OF REFERENCES....................................................................................... 128
12.0
APPENDICES......................................................................................................... 137
Merck Code of Conduct for Clinical Trials...................................................... 137
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 139
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 145
ECOG Performance Status................................................................................ 156
12.4
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 157
12.5
Response Evaluation Criteria in Solid Tumors (RECIST 1.1)....................... 158
12.6
List of Abbreviations .......................................................................................... 159
12.7
13.0
SIGNATURES......................................................................................................... 163
Sponsor's Representative ................................................................................... 163
13.1
Investigator.......................................................................................................... 163
13.2
 
 
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LIST OF TABLES
Table 1
Dose Finding Scheme for Treatment Group A: pembrolizumab + PEG-
IFN (Part 1A only)................................................................................................ 17
Table 2
Dose for Treatment Group B: pembrolizumab + IPI (Part 1A and 1B)................ 17
Table 3
Adequate Organ Function Laboratory Values ...................................................... 42
Table 4
Trial Treatments.................................................................................................... 45
Table 5
Dose Finding Rules............................................................................................... 47
Table 6
Dose Modification Guidelines for DRAEs for pembrolizumab + PEG-
IFN........................................................................................................................ 52
Table 7
Recommended Dose Reduction for PEG-IFN...................................................... 54
Table 8
Dose Modification Guidelines for DRAEs for pembrolizumab + IPI 
(Part 1A and 1B)................................................................................................... 56
Table 9
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs for Pembrolizumab Monotherapy and Part 1C................................ 59
Table 10
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ............................................................................................................. 63
Table 11
Imaging and Treatment after 1st Radiologic Evidence of PD.............................. 66
Table 12
Laboratory Tests ................................................................................................... 96
Table 13
Pharmacokinetic, Total IgG, and ADA Assessments........................................... 97
Table 14
Timing of PK and ADA Assessments, Parts 1A and 1B...................................... 98
Table 15
Timing of PK and ADA Assessments, Part 1C .................................................... 99
Table 16
Evaluating Adverse Events................................................................................. 111
Table 17
Summary of Analysis Strategy for Key Efficacy Endpoints .............................. 117
Table 18
Analysis Strategy for Safety Parameters............................................................. 118
Table 19
Product Descriptions........................................................................................... 121
 
 
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LIST OF FIGURES
Figure 1
Pembrolizumab + PEG-IFN Dose finding: Part 1A ............................................. 22
Figure 2
Pembrolizumab + IPI dose finding: Part 1A Safety run-in and Part 1B 
Expansion cohort in MEL subjects....................................................................... 22
Figure 3
Part 1C – Phase I/II portion of the trial................................................................. 23
Figure 4
Effect of IFNα and Anti-PD-1 in MC38 models .................................................. 32
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.3.3 
Dose Modification and 
Supportive Care 
Guidelines for DRAEs for 
Pembrolizumab 
Monotherapy and Part 1C
Insertion of subheading “Dose modification 
and toxicity management for immune-related 
AEs associated with pembrolizumab” and 
associated program language.
Revised dose modification table to include
myocarditis-specific guidelines and actions in 
the event of myocarditis; revised action for 
all other immune-related Grade 3 AEs; and 
other clarifications.
Consistency and alignment 
with program-wide safety 
update to dose modification 
guidance
6.0 
Trial Flow Chart
To all flow charts: amended survival status 
rows to allow assessment throughout the trial.
Clarification of existing footnotes for survival 
status follow-up.
Clarification and alignment 
with program standards
7.1.5.3.2
Follow-up Visits
Addition of text: 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).  
7.1.5.3.3
Survival Follow-up (SFU)
Clarification that subjects should be 
contacted approximately every 12 weeks.
Deletion of redundant text.
7.1.5.4
New Section: Survival 
Status
Addition of text to enable survival follow-up 
activities throughout the study.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.1
Background
Insertion of latest program-aligned 
background information for pembrolizumab.
Alignment with program 
language
4.1.1
Pharmaceutical and 
Therapeutic Background
Deletion of redundant text now inserted in 
Section 4.1.
Deletion of repetition
4.2.3.2
Efficacy Endpoints
Clarification of clinical stability to include:
• Absence of signs and symptoms (including 
worsening of laboratory values) indicating 
clinically significant disease progression.
Improved clarity and 
consistency with program 
language
5.2.3
Treatment after Initial 
Evidence of Radiologic 
Disease Progression
For the definition of clinical stability –
insertion of text  “clinically significant” to 
the bullet: 
• Absence of signs and symptoms (including 
worsening of laboratory values) indicating 
clinically significant disease progression
Improved clarity and 
consistency with program 
language
Clarification of clinical stability to include  
…clinically significant disease progression
Table 11 – insertion of abbreviations to 
footnote.
Clarification
5.8
Subject 
Withdrawal/Discontinuation 
Criteria
Cross-reference to Section 7.1.5 amended to 
Section 5.2.3
Correction
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.0 
Trial Flow Chart
“also” replaced with “not” in Section 6.1.1.1 
footnote #21, Section 6.1.1.2 footnote #22, 
and Section 6.2 footnote #19:
“Copies of digital photographs should also 
not be submitted to the central imaging 
vendor unless otherwise noted by the 
Sponsor”
Correction
7.1.2.8
Assessment of Disease
Insertion of program language.
Amended the definition of clinical stability: 
Absence of signs and symptoms indicating 
clinically significant disease progression, 
including worsening of laboratory values
Consistency with program 
language
Alignment with Section 5.2.3 
and programe language
7.1.3.1
Laboratory Safety 
Evaluations (Hematology, 
Chemistry and Urinalysis)
To Table 12:

Footnote c deleted and moved into a table 
note.

Additional information added to footnote 
e regarding hepatitis B/C testing.

Addition of footnote e to LDH.

Deletion of Anti-HDV.
Clarification/correction
7.2.3.1
Serious Adverse Events 
Cross-reference to Table 14 amended to 
Table 16
Correction
Throughout
Minor typographical corrections.
Improved 
consistency/readability
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase
1/2
Study
of
Pembrolizumab (MK-3475)
+
PEG-IFN
& 
Pembrolizumab + IPI in Subjects with Advanced MEL & RCC
(KEYNOTE 029)
Trial Phase
Phase 1/2
Clinical Indication
Advanced or Metastatic Melanoma and Renal Cell Carcinoma
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous (pembrolizumab and IPI) and subcutaneous (PEG-IFN)
Trial Blinding
Unblinded Open-label
Treatment Groups
Part 1A:
Treatment Group A:
Pembrolizumab 2 mg/kg (or 200 mg)* IV every 3 weeks (q3w) + PEG-
IFN 0.5μg/kg weekly Pembrolizumab 2 mg/kg (or 200 mg)* IV q3w +
PEG-IFN 1μg/kg weekly Pembrolizumab 2 mg/kg (or 200 mg)* IV q3w +
PEG-IFN 2μg/kg weekly; Pembrolizumab 2 mg/kg (or 200 mg)* IV q3w
+ PEG-IFN 3μg/kg weekly
Treatment Group B:
Pembrolizumab 2 mg/kg (or 200 mg)* IV q3w + IPI 1 mg/kg q3w
Part 1B:
Treatment Group B:
Pembrolizumab 2 mg/kg (or 200 mg)* IV q3w + IPI 1mg/kg q3w
*With the approval of Amendment 03, subjects continuing pembrolizumab
treatment in Parts 1A and 1B will switch to a fixed dose of 200 mg q3w
(not weight-based).
Prior to the approval of Amendment 03, the Sponsor notified sites and 
IRBs that Part 2 would not be initiated.  Part 2 is deleted in Amendment 
03.
Part 1C:
Treatment Group B:
Arm 1:
Pembrolizumab 200 mg q3w + IPI 50 mg every 6 weeks (q6w)
Arm 2:
Pembrolizumab 200 mg q3w + IPI 100 mg every 12 weeks (q12w)
Number of trial subjects
Approximately 233 up to a maximum of approximately 293 (up to 43 in 
Part 1A, 90 to 150 in Part 1B and up to 100 in Part 1C) subjects will be 
enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 32 months
for Parts 1A and 1B, from the time the first subject signs the informed 
consent until the last subject’s last visit. For Part 1C, the Sponsor also 
estimates that the trial will require approximately 32 months from the time 
the first subject signs the informed consent until the last subject’s last 
visit.
 
 
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Duration of Participation
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through the final contact.  
After a screening phase of up to 28 days, eligible subjects will receive
assigned treatment on Day 1 of each dosing cycle and thereafter following 
a weekly (PEG-IFN) or q3w (IPI) schedule in Part 1A and 1B, and q6w or 
q12w schedule (IPI) in Part 1C. Pembrolizumab will be given q3w. A 
cycle is 6 weeks.
In Part 1A, RCC and MEL subjects will be randomly assigned to receive 
pembrolizumab + PEG-IFN or pembrolizumab + IPI. 
Treatment with pembrolizumab + PEG-IFN doublet (Treatment Group A) 
will continue until up to two years of therapy have been administered, 
documented disease progression, unacceptable adverse events (AEs), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons. 
Treatment with pembrolizumab + IPI doublet (Treatment Group B) will 
continue for 2 cycles
(12 weeks), followed by treatment with 
pembrolizumab single agent until up to 24 months of therapy have been 
administered, documented disease progression, unacceptable AEs, 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons.
In Part 1B, MEL subjects will receive pembrolizumab + IPI (Treatment 
Group B). Treatment duration will follow the same schema as described 
in Part 1A. Subjects in Part 1B who attain an investigator-determined
complete response (CR) may consider stopping trial treatment with 
pembrolizumab, after all 4 doses of IPI and at least 24 weeks of
pembrolizumab have been administered. In addition, if a confirmed CR 
per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
is attained, at least 2 additional doses of pembrolizumab must be received 
after CR is first documented.
In Part 1C, MEL subjects will be randomly assigned to pembrolizumab +
2 dose regimens of IPI (Treatment Group
B).
Treatment with 
pembrolizumab + IPI will continue for a maximum of 4 cycles (24 weeks)
in Arm 1 or 8 cycles (48 weeks) in Arm 2, followed by treatment with 
pembrolizumab single agent until up to 24 months of pembrolizumab
have been administered, documented disease progression, unacceptable 
AEs, intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons. Subjects in Part 1C 
who attain an investigator-determined CR may consider stopping trial 
treatment with pembrolizumab, after at least 24 weeks of pembrolizumab
have been administered. In addition, if a confirmed CR per modified 
RECIST 1.1 is attained, at least 2 additional doses of pembrolizumab must 
be received after CR is first documented. In addition, and only in Part 1C,
upon Sponsor consultation, subjects who attain an investigator-determined
CR or a very good partial response [VGPR: partial response per RECIST 
1.1 with Percent Change from Baseline (maximum reduction in tumor line 
length) >60%] may consider stopping treatment with IPI, after a minimum 
of one dose of IPI on either treatment arm.
 
 
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In Part 1A, 1B and 1C, upon Sponsor consultation, subjects who stop 
pembrolizumab with SD or better per modified RECIST 1.1 may be 
eligible for retreatment with pembrolizumab + IPI or pembrolizumab
monotherapy if they progress after stopping pembrolizumab at the 
discretion of the Investigator if they meet the criteria for retreatment, as 
long as the Part to which the subject was initially enrolled remains open; 
this will be designated the Second Course Phase. Subjects in Part 1A who 
received PEG-IFN will not be allowed to restart Second Course Phase 
with pembrolizumab + PEG-IFN; these subjects can only receive 
pembrolizumab monotherapy in Second Course. The Second Course 
Phase will be administered for a maximum of 17 doses of pembrolizumab 
and 4 doses of IPI. After the end of treatment, each subject will be 
followed for a minimum of 30 days for AE monitoring [serious adverse 
events (SAEs) will be collected for up to 90 days after the end of 
treatment]. Subjects will go into survival follow-up (SFU) for disease 
status, including initiating a non-study cancer treatment and experiencing 
disease progression, until death, withdrawal of consent, or lost to follow-
up.
Randomization Ratio
Part 1A (MEL and RCC):  1:1. 
Part 1B (MEL):  Single Arm Expansion.
Part 1C (MEL):  1:1
A list of abbreviations used in this document can be found in Section 12.7.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a multi-center, open-label, 3-part Phase 1/2 trial of intravenous (IV) pembrolizumab
in combination with subcutaneous (SC) Pegylated Interferon Alfa-2b (PEG-IFN) or IV 
ipilimumab (IPI) in subjects with advanced or metastatic melanoma (MEL) or renal cell 
carcinoma (RCC).
The trial consists of three parts: 
Part 1A is the phase I portion of the trial to define the preliminary maximum-tolerated dose 
(MTD) or maximum administered dose (MAD) for the combination doublets listed below 
and confirm the tolerability of the dose combination.
Treatment Group A: pembrolizumab + PEG-IFN
Treatment Group B: pembrolizumab + IPI
Subjects will be treated with doublets administered as detailed in Table 1 and Table 2.
If dose levels are open in Part 1A in both PEG-IFN and IPI dose finding Arms, subjects will
be randomly assigned between the two combinations. Intermediate dose levels may be 
pursued, depending on emerging data from the current and other pembrolizumab studies.
 
 
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Table 1
Dose Finding Scheme for Treatment Group A: pembrolizumab + PEG-IFN
(Part 1A only)
Dose Level
(DL)
Pembrolizumab Dose 
(mg/kg) IV 
PEG-IFN Dose (μg/kg) 
SC Weekly
-1
2 mg/kg (or 200 mg)** q3w
0.5
1*
2 mg/kg (or 200 mg)** q3w
1
2
2 mg/kg (or 200 mg)** q3w
2
3
2 mg/kg (or 200 mg)** q3w
3
*Starting Dose
**With the approval of Amendment 03, subjects continuing pembrolizumab 
treatment will switch to a fixed dose of 200 mg (not weight-based).
Table 2
Dose for Treatment Group B: pembrolizumab + IPI (Part 1A and 1B)
Dose Level
(DL)
Pembrolizumab Dose 
(mg/kg)  IV
IPI Dose 
(mg/kg) q3w x 
4 doses
1
2 mg/kg (or 200 mg)* 
q3w
1
*With the approval of Amendment 03, subjects continuing 
pembrolizumab treatment will switch to a fixed dose of 200 mg 
(not weight-based).
Dose-limiting toxicities (DLTs) observed in Cycle 1 will be used to determine tolerability of 
the doublet and possible escalation to the next dose level (when applicable). A cycle is 
6 weeks. The guidelines used for dose escalation and dose confirmation are shown in Table 
5.
The rules applied for the dose finding algorithm are as follows:
In the pembrolizumab + PEG-IFN combination, an initial cohort of 3 subjects is enrolled.  
Subsequent dosing decisions within a dose combination will be based on the rules in Table 5.  
The dose confirmation part will continue until ≤4 of 14 subjects experience a DLT.  As 
subjects become evaluable for DLT assessment, the number of subjects who are evaluable for 
DLT versus the number of subjects who developed a DLT will be continuously assessed and 
de-escalation and re-escalation to eligible doses will occur as shown in Table 5. In the 
pembrolizumab + IPI combination, an open-label run-in period (Part 1A), will be used to 
assess the safety and tolerability of the doublet therapy during the first cycle of treatment. A 
total of up to 18 subjects will be enrolled at dose level 1 (DL1) of pembrolizumab
administered at a dose of 2 mg/kg q3w in combination with IPI administered at dose of 1 
mg/kg q3w (for a total of 4 doses).  
If ≤6 DLTs are observed in the 18 subjects enrolled, this dose level will be considered 
tolerable, and Part 1B will be initiated. Should this dose level (DL1) not be proven tolerable 
(>6 DLTs), the combination with IPI will not be further developed. 
Part 1B is a single arm expansion cohort, designed to better characterize the safety and 
tolerability, as well as to evaluate preliminary efficacy of the combination pembrolizumab +
IPI in MEL subjects. Pembrolizumab will be administered at a dose of 2 mg/kg q3w (or 
 
 
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200mg q3w) in combination with IPI administered at a dose of 1 mg/kg (for 4 doses). At 
least 90 and up to an additional 150 subjects with advanced or metastatic MEL will be 
enrolled in the expansion cohort at this dose level.
With the approval of Amendment 03, subjects continuing pembrolizumab treatment on Parts 
1A and 1B will switch to a fixed dose of 200 mg q3w (not weight-based). The rationale for 
fixed dose regimen is outlined in Section 4.2.2.
Prior to the approval of Amendment 03, the Sponsor notified sites and IRBs that Part 2 
would not be initiated. Part 2 is removed from the protocol in Amendment 03.
Part 1C is the phase I/II randomized portion of the trial and is to further evaluate safety and 
tolerability of pembrolizumab + IPI in advanced MEL subjects, as well as preliminary 
clinical efficacy of the combination. Part 1C will evaluate the below listed treatments.
Treatment Group B: pembrolizumab + IPI
Arm 1: pembrolizumab 200 mg q3w for a maximum of 24 months + IPI 50 mg q6w for a 
maximum of 4 doses.
Arm 2: pembrolizumab 200 mg q3w for a maximum of 24 months + IPI 100 mg q12w for a 
maximum of 4 doses. Part 1C subjects will be randomized to the treatment groups in a 1:1 
ratio. There will be no stratification prior to the randomization of subjects.
Approximately 233 to a maximum of approximately 293 subjects (up to 43 in Part 1A, at 
least 90 and up to 150 in Part 1B, and up to approximately 100 in Part 1C) will be enrolled in 
this trial to examine the safety and efficacy of the combinations pembrolizumab + PEG-IFN
and pembrolizumab + IPI. The Part 1B sample size is driven by the expected number of 
PD-L1 negative subjects. Assuming that the prevalence of PD-L1 negative subjects is ~25%, 
then 90 subjects would be expected to provide ~22 subjects with PD-L1 negative MEL. If 
less than 22 PD-L1 negative MEL were enrolled in the pembrolizumab + IPI Arm in Part 1A 
and 1B combined, enrollment will continue until at least 22 PD-L1 negative subjects are 
enrolled, up to a maximum of 150 subjects in Part 1B. 
Parts 1A and 1B:
Subjects will undergo first imaging evaluation at week 12 (± 3 days). Subsequently, subjects 
will be evaluated every 6 weeks (42 days ± 3 days), independently of any treatment delays, 
with radiographic imaging to assess response to treatment, until week 30. Subjects will then 
undergo imaging evaluation every 12 weeks (84 ± 7 days). RECIST 1.1 will be used as the 
primary response rate efficacy endpoint. RECIST 1.1 will be adapted as described in 
Section 4.2.3.2 to adjust for the tumor response patterns seen with pembrolizumab treatment 
(e.g., tumor flare), and this adapted/modified RECIST 1.1 will be used by the sites for 
treatment decisions. The primary response rate efficacy endpoint will be based on 
independent central review using RECIST 1.1 [1]. Modified RECIST 1.1 will also be used by
the local site to determine eligibility and make treatment decisions. 
 
 
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AEs will be monitored throughout the trial and graded in severity according to the guidelines 
outlined in the National Cancer Institute (NCI) Common Terminology Criteria for AEs 
(CTCAE) Version 4.0.
Treatment will continue as outlined in Table 1 and Table 2 until documented disease 
progression, unacceptable AEs, intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, subject withdraws consent, 
pregnancy of the subject, noncompliance with trial treatment or procedure requirements, 
completion of 24 months of treatment with pembrolizumab, or administrative reasons.
Subjects in the pembrolizumab + IPI Arm who initially attain clinical benefit (defined as 
modified RECIST 1.1 confirmed PR or SD >6 months), and experience disease progression 
while receiving single agent pembrolizumab will be eligible for reinduction with a maximum 
of 4 doses of IPI q3w as long as Part 1A or 1B remains open.
Subjects who attain an investigator-determined confirmed CR may consider stopping trial 
treatment after receiving at least 6 weeks of PEG-IFN treatment/all 4 doses of IPI and at least 
24 weeks of pembrolizumab. In addition, if a confirmed CR per modified RECIST 1.1 is 
attained, at least 2 additional treatments of pembrolizumab must be received prior to 
treatment discontinuation. Upon consultation with the Sponsor, subjects who stop 
pembrolizumab with SD or better per modified RECIST 1.1 may be eligible for retreatment 
with a maximum of 17 doses of pembrolizumab and 4 doses of IPI if they progress after 
stopping pembrolizumab at the discretion of the investigator according to the criteria in 
Section 7.1.5.2.1, as long as the trial part to which the subject was initially enrolled remains 
open; this retreatment will be the Second Course Phase. Subjects enrolled in Part 1A who 
received PEG-IFN who are eligible for Second Course Phase will only be allowed to receive 
pembrolizumab monotherapy in Second Course. Response or progression in the Second 
Course Phase will not count towards the overall response rate (ORR) and progression-free 
survival (PFS) of the primary endpoint in this trial. The decision to retreat will be at the 
discretion of the investigator only if no cancer treatment was administered since the last dose 
of pembrolizumab, the subject still meets the safety parameters listed in the 
Inclusion/Exclusion criteria and the trial remains open (refer to Section 7.1.5.2.1 for further 
details).
After the end of treatment, each subject will be followed for 30 days for AE monitoring 
(SAEs will be collected for 90 days after the end of treatment). Subjects who discontinue 
treatment for reasons other than disease progression will have SFU for disease status until 
disease progression, initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All subjects will be followed by telephone contact for overall 
survival (OS) until death, withdrawal of consent or the end of the trial, whichever comes 
first.
All subjects will be required to submit a tumor tissue sample for biomarker analyses and 
PD-L1 expression evaluation. In Part 1B, PD-L1 status must be assessed during screening, 
and if the tumor biopsy submitted is inadequate for determination of PD-L1 status by 
immunohistochemistry (IHC) at a central pathology laboratory, the subject will not be 
randomized. Subjects with an inadequate archival sample may obtain a new biopsy and 
 
 
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subjects with an inadequate newly obtained biopsy may undergo re-biopsy at the discretion 
of the investigator. 
The primary safety objectives of the trial (Part 1A and Part 1B) are to determine the safety 
and tolerability of pembrolizumab in combination with PEG-IFN or IPI in subjects with 
advanced MEL and RCC. The primary efficacy objective of Part 1B of the trial is to evaluate 
the anti-tumor activity in PD-L1 negative MEL subjects treated with pembrolizumab in 
combination with IPI at DL1.
Part 1C: Part 1C of the trial will enroll approximately 100 subjects with advanced MEL. 
The primary objectives for Part 1C are rate of drug-related adverse events (DRAEs) and 
ORR. Secondary objectives include PFS, OS and duration of response (DOR). The 
pharmacokinetic (PK) properties for pembrolizumab + IPI in each doublet setting will be 
investigated as an exploratory objective.
In Part 1C, subjects will undergo imaging evaluation every 6 weeks (± 3 days), independent 
of any treatment delays, with radiographic imaging to assess response to treatment, until 
week 24. Subjects will then undergo imaging evaluation every 12 weeks (84 ± 7 days).
RECIST 1.1 will be used as the primary response rate efficacy endpoint and 
adapted/modified RECIST 1.1 will be used by the investigative sites for treatment decisions.
The primary response rate efficacy endpoint will be based on independent central review 
using RECIST 1.1 [1]. Modified RECIST 1.1 will also be used by the treating investigator
local site to determine eligibility. 
AEs will be monitored throughout the trial and in severity according to the guidelines 
outlined in the NCI CTCAE Version 4.0.
Treatment with pembrolizumab + IPI doublets (Treatment Group B) will continue for a 
maximum of 4 cycles (24 weeks) in Arm 1 and 8 cycles (48 weeks) in Arm 2, followed by 
treatment with pembrolizumab single agent for up to 24 months of therapy, documented 
disease progression, unacceptable AEs, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons.
Subjects in Part 1C who attain an investigator-determined confirmed CR may consider 
stopping trial treatment with pembrolizumab after receiving at least 24 weeks of 
pembrolizumab. In addition, if a confirmed CR per modified RECIST 1.1 is attained, at least 
two additional doses of pembrolizumab must be received prior to treatment discontinuation. 
Upon Sponsor consultation, subjects who attain an investigator-determined confirmed CR or 
a VGPR [partial response per RECIST 1.1 with Percent Change from Baseline (maximum 
reduction in tumor line length) >60%] may consider stopping treatment with IPI after a 
minimum of one dose of IPI on either Arm of treatment.
Upon Sponsor consultation, subjects who stop pembrolizumab with SD or better per 
modified RECIST 1.1 may be eligible for retreatment with pembrolizumab + IPI or 
pembrolizumab monotherapy if they progress after stopping pembrolizumab at the discretion 
 
 
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of the investigator according to the criteria in Section 7.1.5.2.1 as long as Part 1C remains 
open. Second Course Phase will be administered for a maximum of 17 doses of 
pembrolizumab and 4 doses of IPI.
After the end of treatment, each subject will be followed for 30 days for AE monitoring 
(SAEs will be collected for 90 days after the end of treatment). Subjects who discontinue 
treatment for reasons other than disease progression will have SFU for disease status until 
disease progression, initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up. All subjects will be followed by telephone contact for OS until 
death, withdrawal of consent or the end of the trial, whichever comes first.
All subjects will be required to submit a tumor tissue sample for biomarker analyses and 
PD-L1 expression evaluation. Confirmation of the tumor tissue sample adequacy for 
determination of PD-L1 status by IHC at a central pathology laboratory is not required prior 
to enrollment in Part 1C.
The trial will be conducted in conformance with Good Clinical Practices.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Based on the data from Part 1A, pembrolizumab + PEG-IFN combination will not be pursued 
any further due to lack of added efficacy with the combination compared with
pembrolizumab monotherapy, as well as the added toxicities. Part 1B further supported the 
early efficacy of pembrolizumab + IPI seen in Part 1A and confirmed a DRAE rate of 42% 
(data cutoff date March 17, 2016). Based on the goal to further minimize the AE profile of 
pembrolizumab + IPI, Part 1C has been designed to investigate two different dosing regimens
of pembrolizumab + IPI. The previously described Part 2 in this protocol has been deleted as 
it is no longer applicable based on now available data from Parts 1A and 1B.
Upon consultation with the Sponsor, subjects in Part 1A, 1B and 1C may be eligible for
Second Course Phase if they progress after stopping pembrolizumab as long as the trial Part 
to which the subject was initially enrolled remains open as per Section 7.1.5.2.1. Subjects 
enrolled in Part 1A who received PEG-IFN who are eligible for Second Course Phase will 
only be allowed to receive pembrolizumab monotherapy.
Subjects may have the opportunity to transition to a pembrolizumab extension trial if 
available in the future after closure of this trial.
Trial Diagram
2.2
The trial design is depicted in Figure 1, Figure 2, and Figure 3 below.
 
 
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*DL1 starting dose
**With the approval of Amendment 03, subjects continuing pembrolizumab treatment will switch 
to a fixed dose of 200 mg (not weight-based).
Figure 1
Pembrolizumab + PEG-IFN Dose finding: Part 1A 
Note that if dose levels are opened in both PEG-IFN and IPI Arms, subjects will be randomly 
assigned to the two combinations. 
*With the approval of Amendment 03, subjects continuing pembrolizumab treatment will switch 
to a fixed dose of 200 mg (not weight-based).
Figure 2
Pembrolizumab + IPI dose finding: Part 1A Safety run-in and Part 1B
Expansion cohort in MEL subjects. 
Expansion in MEL subjects will proceed once DL1 is declared safe on safety run-in
(Part 1A).
 
 
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With the approval of Amendment 03, subjects continuing pembrolizumab treatment on Parts 
1A and 1B will switch to a fixed dose of 200mg q3w (not weight-based).
Figure 3
Part 1C – Phase I/II portion of the trial.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1. Objective (Part 1A): To establish a maximum tolerated dose (MTD) or a maximum 
administered dose (MAD) of pembrolizumab when given in combination with PEG-
IFN to subjects with advanced MEL or RCC.
Hypothesis: The DLTs observed in subjects with advanced MEL or RCC after IV
administration of pembrolizumab in each combination will allow for definition of an 
MTD or a MAD.
2. Objective (Part 1A, 1B): To establish the tolerability of pembrolizumab when given 
in combination with IPI at the DL1 (pembrolizumab 2 mg/kg or 200 mg IV q3w + IPI 
1 mg/kg q3w) in subjects with advanced MEL or RCC.
3. Objective (Part 1A, 1B): To determine the safety and tolerability of pembrolizumab
in combination with PEG-IFN or IPI in subjects with advanced MEL or RCC.
Hypothesis: IV administration of pembrolizumab in combination with PEG-IFN or 
IPI to subjects with advanced MEL or RCC is sufficiently well-tolerated to permit 
continued clinical investigation.
4. Objective (Part 1C): To establish the safety and tolerability of pembrolizumab in 
combination with either IPI 50 mg q6w or IPI 100 mg q12w in subjects with 
advanced MEL.
Hypothesis:  IV administration of pembrolizumab in combination with IPI to 
subjects with advanced MEL is sufficiently well-tolerated to permit continued clinical 
investigation.
5. Objective (Part 1C): To determine the rate of Grade 3-5 DRAEs.
Hypothesis: IV administration of pembrolizumab in combination with either IPI 
50 mg q6w or IPI 100 mg q12w will produce Grade 3-5 DRAEs that are <40-55% as 
 
 
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observed with the combination of pembrolizumab + IPI 1 mg/kg in Part 1A and 1B.
The criteria are described in section 8 – SAP.
6. Objective (Part 1C): To evaluate efficacy of pembrolizumab + IPI in subjects with 
advanced unresectable/metastatic MEL in Part 1C.  
Hypothesis: IV administration of pembrolizumab in combination with either IPI 
50 mg q6w or IPI 100 mg q12w will produce ORR rates similar to the 48% or higher 
observed with combinations of pembrolizumab + IPI 1 mg/kg in Part 1B.
Secondary Objective(s) & Hypothesis(es)
3.2
1. Objective (Part 1B): To evaluate efficacy of pembrolizumab in combination with IPI 
in subjects with advanced unresectable/metastatic MEL.
Hypothesis: IV administration of pembrolizumab in combination with IPI to subjects 
with PD-L1 negative advanced MEL results in a clinically meaningful ORR through 
24 weeks based on RECIST 1.1 by central independent review.  
2. Objective (Part 1B, 1C):  To evaluate the efficacy of pembrolizumab administered 
intravenously in combination with IPI with respect to ordinal response score [derived 
from RECIST 1.1 definitions, with PR being divided into Moderate Partial Response 
(MPR) and VGPR based on the degree of tumor shrinkage] in subjects with advanced 
MEL (more details in Section 8.2.5.1.4).
3. Objective (Part 1B, 1C):  To evaluate the DOR in subjects with advanced MEL 
receiving pembrolizumab in combination with IPI.
4. Objective (Part 1B, 1C): To evaluate efficacy with respect to PFS of pembrolizumab
in  combination with IPI in subjects with advanced MEL.  
5. Objective (Part 1B, 1C):  To evaluate OS in subjects with advanced MEL receiving 
pembrolizumab in combination with IPI.
6. Objective (Part 1A, 1B): To compare the rates of Grade ≥3 toxicities across all
subjects treated with each doublet (pembrolizumab + PEG-IFN and pembrolizumab + 
IPI).
Hypothesis: Administration of pembrolizumab + PEG-IFN results in different rate of 
Grade 3-4 toxicity than pembrolizumab + IPI.
7. Objective (Part 1B and 1C): To evaluate the relationship between PD-L1 expression 
on IHC to clinical outcomes (ORR, PFS and OS) in MEL subjects treated with 
pembrolizumab + IPI.
Exploratory Objectives
3.3
1. Objective (Part 1A): To evaluate efficacy with respect to PFS and ORR based on 
modified RECIST 1.1 by site investigator, ordinal response score, DOR and OS of 
pembrolizumab in combination with PEG-IFN or IPI in subjects with RCC.
 
 
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2. Objective (Part 1A):  To evaluate the relationship between PD-L1 expression on 
IHC to clinical outcomes (ORR, PFS and OS) in Part 1A RCC subjects treated with 
pembrolizumab + IPI or pembrolizumab + PEG-IFN.
3. Objective (Part 1A, 1B, 1C): To investigate the relationship between candidate 
efficacy biomarkers and anti-tumor activity of pembrolizumab utilizing pre- and post-
treatment biopsies and blood sampling using in vitro assays.  
4. Objective (Part 1A, 1B, 1C): To evaluate ORR as determined by RECIST 1.1 
criteria using line length compared to RECIST 1.1 criteria using tumor volumetric 
changes of subjects with MEL and RCC treated with pembrolizumab + IPI and 
pembrolizumab + PEG-IFN.
5. Objective (Part 1A, 1B, 1C): To evaluate the rate of pembrolizumab anti-drug 
antibodies (ADA) and impact on PK when pembrolizumab is given in monotherapy 
and in combination with PEG-IFN or IPI.
6. Objective (Part 1B): To evaluate the best objective response rate (ORR) by RECIST 
1.1 in subjects on pembrolizumab + IPI after re-induction with IPI.
7. Objective (Part 1A, 1B, 1C): To evaluate the ORR by RECIST 1.1 in subjects 
treated with pembrolizumab + IPI or pembrolizumab monotherapy as part of Second 
Course Phase. 
8. Objective (Part 1A, 1B, 1C): To evaluate the use of time to growth (TTG) modeling 
and simulation and correlate with clinical outcomes in MEL and RCC subjects treated 
with pembrolizumab + PEG-IFN and pembrolizumab + IPI.
4.0 BACKGROUND & RATIONALE
Background
4.1
Pembrolizumab (previously known as SCH 900475 and MK-3475) is a potent humanized 
immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to 
the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with programmed 
cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).  Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications.  Refer to the Investigator’s Brochure (IB)/approved labeling for detailed 
background information on PEG-IFN, IPI, and MK-3475.
Pharmaceutical and Therapeutic Background
4.1.1
Pembrolizumab
4.1.1.1
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [2]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [3] [4] [5] [6] [7]. In particular, the presence of CD8+ T-cells and the 
 
 
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ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in solid malignancies such as ovarian, colorectal and 
pancreatic cancer, hepatocellular carcinoma, malignant MEL and RCC. TILs can be 
expanded ex vivo and re-infused, inducing durable objective tumor responses in cancers such 
as MEL [8] [9]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[10] [11]. The structure of murine PD-1 has been resolved [12]. PD-1 and family members 
are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain 
responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade [10] [13] [14] [15]. 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 [16] [17]. PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, 
regulatory T cells (T regs) and Natural Killer cells [18] [19]. Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells [20]. The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including 
non-hematopoietic tissues as well as in various tumors [1] [16] [21] [22] [23]. Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues [16]. 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 RCC [24], pancreatic carcinoma [25], hepatocellular 
carcinoma [26], and ovarian carcinoma [27]. Furthermore, PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with MEL [28]. This suggests that the 
PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention.
 
 
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Based on the preliminary clinical data, PD-1 inhibitors such as pembrolizumab appear to be 
attractive candidates for pursuing the above goal. Nivolumab has an observed ORR of 28% 
in MEL subjects; pembrolizumab has shown a promising response rate of 25% in MEL 
subjects who have received prior IPI treatment in KEYNOTE 002 [29]. Specifically, a 
response rate of 36% was observed with pembrolizumab in MEL subjects who have not 
received prior IPI treatment in KEYNOTE 006 [30]. This response rate is much higher than 
the 11-15% response rate observed with IPI in IPI registration trials.
On September 4, 2014, the Food and Drug Administration (FDA) granted accelerated 
approval for pembrolizumab 2mg/kg q3w in advanced MEL following disease progression 
with IPI and, if BRAF V600 mutation positive, a BRAF inhibitor [31]. The approval was 
based on a strong efficacy and safety profile demonstrated in 4 MEL expansion parts of the 
Phase I trial (KEYNOTE 001) [32]; the B2 IPI-refractory population was the subject 
population for the approval. On December 18, 2015, the FDA granted full approval of 
pembrolizumab for the treatment of subjects with unresectable or metastatic MEL with 
pembrolizumab based on KEYNOTE 002 and 006 [30] [33].
Pegylated Interferon Alfa-2b (PEG-IFN)
4.1.1.2
PEG-IFN is a pleiotropic cytokine with anti-viral, anti-proliferative, anti-angiogenic and 
immunomodulatory properties. PEG-IFN is a modified form of IFN α-2b comprising a single 
molecule of polyethylene glycol (PEG) covalently linked to the IFN α-2b protein. PEG-IFN
has shown good tolerability and similar efficacy to conventional interferon and dacarbazine 
single agent chemotherapy in stage IV MEL [34]. Based on the European Organization for 
Research and Treatment of Cancer (EORTC) 18991 trial, the United States (US) Food and 
Drug Administration (FDA) approved PEG-IFN for the adjuvant treatment of MEL subjects 
following definitive surgical resection, including complete lymphadenectomy [35] [36].
PEG-IFN α-2b was administered at 6 μg/kg/week subcutaneously for 8 weeks (induction 
phase) then at 3 μg/kg/week subcutaneously (maintenance phase) for an intended treatment 
duration of 5 years. There was an 18% reduction in the risk of relapse and death. PEG-IFN 
was safe and relatively well tolerated. The median length of therapy with PEG-IFN α-2b was 
>12 months. The most commonly observed side-effects were fatigue, alanine and aspartate 
aminotransferase elevations and fever, myalgia, anorexia and nausea. A total of 525 deaths 
were reported during the trial (262 in the PEG-IFN group and 263 in the observation group). 
The most frequent causes of death were infection, malignant disease and cardiovascular 
disease. 31% of the 608 subjects who were treated with PEG IFNα-2b discontinued therapy 
due to Grade 3-4 AEs: fatigue (25%), anorexia (15%), depression (16%), liver function tests 
(13%), headache (12%), nausea (12%), and pyrexia (11%).  
IFN-α used to be the mainstay of therapy for advanced RCC. ORRs ranged from 15-25%, 
with 5-10% of these subjects having durable responses. Targeted therapies with VEGF and 
mTOR inhibitors have largely replaced IFN-based regimens due to the ease of use and the 
higher efficacy, notably in term of PFS. Nevertheless, IFN-α remains an option in metastatic 
RCC. Furthermore, some front-line trials with an IFN-α comparator vs. a targeted therapy 
(sorafenib) did not show a PFS advantage [37], and the majority of trials did not show an OS
advantage. The pegylated form of IFN-α is easier to use, may have less side effects [38] and 
 
 
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it is not an unreasonable choice especially in subjects who failed prior standard targeted 
therapies.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on PEG-IFN.
Ipilimumab (IPI)
4.1.1.3
Ipilimumab (Yervoy®) is an immunoregulatory agent that blocks CTLA-4 to promote 
anti-tumor immunity. In a Phase III study of 676 subjects with unresectable or metastatic 
MEL whose disease had progressed while receiving prior therapy for metastatic disease, IPI 
administered at 3 mg/kg q3w for up to 4 doses with or without a gp100 peptide vaccine was 
compared with gp100 alone [39]. The median OS was 10.1 months and 10.0 months for the 
IPI alone and IPI plus gp100 Arms respectively, while the median OS was 6.4 months for the 
gp100 alone Arm (p<0.001). An ORR of 10.9% was observed in IPI alone Arm, while the 
IPI plus gp100 Arm and gp100 alone Arm had lower response rates, 5.7% and 1.5%, 
respectively. The median duration of response was 11.5 months in the IPI plus gp100 Arm, 
and not reached in the IPI alone Arm with a median follow-up period of 27.8 months. The 
median time to progression was 2.86 months for the IPI alone Arm and 2.76 months for the 
other two Arms. In the IPI alone Arm, 97% of the subjects experienced an AE and Grade 3-4
AEs occurred in 46% of the subjects. The most common AEs related to IPI were 
immune-related events, which occurred in approximately 60% of the subjects treated with IPI 
and 32% of the subjects treated with gp100. The frequency of Grade 3-4 immune-related 
AEs was 15%. The immune-related AEs most often affected the skin and gastrointestinal 
tract, including pruritus, rash, vitiligo, diarrhea, and colitis. 
Based on the above Phase III trial, IPI was approved by the FDA for treatment of subjects 
with unresectable or metastatic MEL and by the European Commission for treatment of 
subjects with previously-treated advanced MEL. The recommended regimen is 3 mg/kg 
administered q3w for a total of four doses.
A reduction of the risk of death (28%; p<0.001) was also demonstrated for IPI in the first-
line setting when combined with dacarbazine in comparison with dacarbazine alone, and the
ORRs were 15% and 10% (Investigator assessment per RECIST 1.1) in the IPI/dacarbazine
Arm and dacarbazine alone Arm, respectively [40]. The IPI/dacarbazine Arm did show a
statistically significant PFS improvement [hazard ratio (HR) 0.76; p=0.006] over the 
dacarbazine alone Arm. Median OS in the IPI/dacarbazine and dacarbazine Arms was 
11.2 months and 9.1 months, respectively. The one-year OS rate for the IPI/dacarbazine Arm
was 47.3%; the rate for the dacarbazine Arm was 36.3%.
In RCC, a Phase I/II trial by Yang revealed an ORR 9.8% [41], across different dose levels,
in subject’s treatment naïve and previously treated with interleukin-2. Given the greater 
response rates seen with tyrosine kinase inhibitors, IPI was not further developed as 
monotherapy in RCC. 
Refer to the approved labeling for detailed background information on IPI.
 
 
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Pre-clinical Trial with Pembrolizumab
4.1.2
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
treatment modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a monotherapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma. Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [28] [42] [43] [44] [25] [45]. Experiments have confirmed the
in vivo efficacy of PD-1 blockade as a monotherapy as well as in combination with 
chemotherapy in syngeneic mouse tumor models (see the Investigator’s Brochure [IB]).
Ongoing Clinical Trials
4.1.3
Ongoing clinical trials are being conducted in advanced MEL, non-small cell lung cancer
(NSCLC), head and neck cancer, triple negative breast cancer, gastric cancer, bladder cancer 
and hematologic malignancies. For trial details please refer to the IB.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
MEL is the sixth most common malignancy in men and the seventh most common 
malignancy in women. The incidence of MEL is increasing worldwide, with a growing 
fraction of subjects with advanced disease for which prognosis remains poor. The median 
survival for subjects with metastatic MEL has been under 1 year. The 5-year survival rate of 
subjects with visceral involvement is under 10%. Treatment options for metastatic MEL have 
been limited to chemotherapeutic agents such as dacarbazine and high-dose interleukin-2 
immunotherapy in a small percentage of subjects. In the past few years there has been steady 
progress in the development of targeted therapy and immunotherapy for metastatic MEL. 
Since 2011, three new agents were approved for the treatment of BRAF mutant MEL: 
vemurafenib, dabrafenib and trametinib, which produce response rates of 22-57% and have 
demonstrated a survival advantage relative to chemotherapy [46] [47] [48]. It is important to 
note these agents are not indicated for up to 60% of MEL subjects whose tumors do not 
contain a BRAF mutation [47] [46] [49] [50]. In addition, a major limitation with kinase 
inhibitors in the treatment of BRAF mutant MEL is a nearly universal development of
resistance to these agents leading to the lack of response durability. Although high RRs offer 
benefits to the majority of subjects with BRAF mutant MEL, most subjects develop 
resistance rather quickly and experience progressive disease (PD). 
IPI, an anti-CTLA4 monoclonal antibody, was also approved in 2011 for the treatment of 
subjects with unresectable or metastatic MEL based on the data described in Section 4.1.1.3. 
More recently, IPI has demonstrated increased efficacy in combination with nivolumab in 
2 randomized phase III clinical trials. In CheckMate 069 [51], 142 patients with previously 
untreated metastatic MEL were randomly assigned to receive IPI 3 mg/kg combined with
 
 
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either nivolumab, 1 mg/kg, or placebo once q3w for 4 doses, followed by nivolumab 3 mg/kg
every 2 weeks until disease progression or unacceptable toxic effects. ORR was 61% in the 
group that received both IPI and nivolumab versus 11% in the group that received IPI 
monotherapy (p<0.001). After a minimum follow-up of 18 months, median PFS was not 
reported with the combination therapy and was 4.3 months with IPI monotherapy [HR 0.34; 
95% confidence interval (CI): 0.2, 0.57; p<0.0001] [52]. The 12- and 18-month PFS rates
were 55.1% and 53.4%, respectively, for the combination, and 16.2% and 8.1%, respectively, 
for IPI alone. At 18 months of follow-up, OS rates in BRAF wild-type patients were 73% for 
the combination versus 56% for IPI alone, and median OS had not been reached in either 
group (HR 0.56; 95% CI: 0.29, 1.10; p=0.089). Grade 3–4 DRAEs were reported more 
frequently with the combination than with IPI alone (55% vs. 22%) and led to
discontinuation in 30% and 9% of patients, respectively [52]. In CheckMate 067, 945 
subjects with unresectable stage III or IV MEL were randomly assigned in a 1:1:1 ratio to 
receive nivolumab 3 mg/kg every 2 weeks, nivolumab 1 mg/kg q3w plus IPI 3 mg/kg q3w
for 4 doses followed by nivolumab 3 mg/kg every 2 weeks for Cycle 3 and beyond, or IPI 3
mg/kg q3w for 4 doses [53]. The median PFS was 11.5 months (95% CI: 8.9, 16.7) with 
nivolumab plus IPI, 2.9 months (95% CI: 2.8, 3.4) with IPI (HR 0.42; 99.5% CI: 0.31, 0.57;
p < 0.001), and 6.9 months (95% CI: 4.3, 9.5) with nivolumab (HR for the comparison with 
IPI, 0.57; 99.5% CI: 0.43, 0.76; p<0.001). DRAEs of Grade ≥3 were reported in 16.3% of 
the subjects treated with nivolumab, 55.0% of the subjects treated with the combination, and 
27.3% of those treated with IPI alone. On September 30, 2015, the FDA granted accelerated 
approval to nivolumab in combination with IPI for the treatment of subjects with BRAF 
V600 wild-type, unresectable or metastatic MEL. Approval was based on demonstration of 
an increase in the ORR, prolonged response durations, and improvement in PFS observed in 
CheckMate 069 trial.
RCC is the seventh most common cancer among US men and ninth among US women. 
Twenty percent of people present with advanced disease, and an additional 30% of those who 
present with localized disease will eventually develop distant metastases and become largely 
incurable. The targeted drugs, pazopanib, sunitinib, sorafenib, axitinib, bevacizumab, 
everolimus, and temsirolimus transformed the management of metastatic RCC after 
demonstration of superiority to cytokine therapy and placebo in pivotal phase III trials [54] 
[55] [56] [57]. Cytokine-based treatment with interleukin-2 (IL-2) or interferon-α (IFN-α) 
used to be the mainstay of therapy for RCC and can still benefit a small proportion of
subjects.
More recently, nivolumab has been shown to improve OS in the second-line setting for
subjects with previously treated advanced clear-cell RCC compared with everolimus; 
25 months (95% CI: 21.8, not estimable) with nivolumab and 19.6 months (95% CI: 17.6, 
23.1) with everolimus) [58]. The HR for death with nivolumab versus everolimus was 0.73 
(98.5% CI: 0.57, 0.93; P=0.002). ORR was greater with nivolumab than with everolimus 
(25% vs. 5%; odds ratio, 5.98 (95% CI: 3.68, 9.72); P<0.001). The median PFS was 4.6 
months (95% CI: 3.7, 5.4) with nivolumab and 4.4 months (95% CI: 3.7, 5.5) with 
everolimus (HR 0.88; 95% CI: 0.75, 1.03; P=0.11). 
This is a multi-center, open-label, 3-part Phase I/II trial of pembrolizumab in combination 
with PEG-IFN or IPI in subjects with advanced or metastatic MEL and RCC. Subjects with 
 
 
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advanced or metastatic MEL with any prior lines of therapy (Part 1A and 1B) and subjects 
with advanced or metastatic RCC with ≥1 line of therapy (Part 1A only) as well as subjects 
with advanced or metastatic MEL with no prior lines of therapy (Part 1C) will be enrolled in 
this trial.
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and Informed Consent documents.
Rationale for Evaluating anti-PD-1 Therapy in Advanced Melanoma and 
4.2.1.1
Renal Cell Carcinoma
Rationale for Pembrolizumab
4.2.1.1.1
Pembrolizumab is a highly specific humanized anti-PD-1 antibody, which has shown to be 
very well-tolerated and lead to ORRs in MEL subjects of 36% [59]. KEYNOTE 006, a phase 
III trial, has demonstrated superior efficacy of pembrolizumab compared to IPI in PFS, OS 
and ORR, with an estimated 46.4% 6-month PFS rate versus 26.5% for IPI. The ORR was 
32.9% for pembrolizumab versus 11.9% for IPI. Responses were ongoing in 96.7% of 
subjects after a median follow-up of 7.9 months. One-year estimates of survival for subjects
receiving pembrolizumab q3w were 68.4% compared with IPI 58.2% (HR for death as 
compared with IPI 0.69; 95% CI: 0.52, 0.90; p=0.0036). Because the OS results were 
superior to IPI, the external Data Monitoring Committee (DMC) recommended stopping the 
study early to allow patients on IPI who progressed the option of receiving pembrolizumab
[30].
Blockage of the PD-1/PD-L1 pathway also appears to be effective in a heavily pre-treated 
population with metastatic RCC [60] [61], leading to ORRs of up to approximately 29%. 
Rationale for PEG-IFN
4.2.1.1.2
IFNα, the active component of PEG-IFN, is a pleiotropic cytokine, with anti-angiogenic and 
immunomodulatory properties. In MEL, IFNα is approved in the adjuvant setting. While IFN 
treatment as monotherapy has shown some clinical activity in metastatic MEL [62], IFN in 
metastatic MEL is only used as part of bio-chemotherapy combination regimens, albeit rarely
[63] [64].
In RCC, IFNα has shown similar clinical activity as sorafenib, a tyrosine kinase inhibitor, in 
the first line setting [38]. Currently in metastatic RCC, IFNα is used in combination with 
bevacizumab [54], an anti-angiogenesis antibody targeting VEGF-A (vascular endothelial 
growth factor-A).
Hypothesis for Pembrolizumab + PEG-IFN Combination Therapies
4.2.1.1.2.1
Internal pre-clinical studies have shown that IFNα increases the expression of PD-L1 in RCC 
and MEL cell lines, as well as in breast cancer histoculture (data not published). In a 
pre-clinical study by Terawaki and others, IFNα increased PD-1 expression in tumor 
infiltrating lymphocytes (TILs) in MC38 (mouse colorectal) model [65].
 
 
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This study also evaluated the potential additive anti-tumor effect of the combination IFNα 
and anti-PD-1. In their experiment, mice received SC tumor implants in the flank, then 
received IFNα daily from Days 1–13. Anti-PD-1 (4H2) antibody was given at doses of 6 or 
20 mg/kg on Days 0 and 3, or of 10 mg/kg three times with a 6-day interval. Figure 4A 
illustrates the mean tumor volumes in mice treated with IFNα, anti-PD-1 or the combination, 
showing a greater tumor control when both agents were given in combination. Figure 4B 
illustrates the individual tumor volumes in these mice. The median size of tumors was 
smaller in the animals treated with the combination IFNα+Anti-PD-1 and a greater number of 
mice had profound responses (tumors smaller than 100mm3, dashed line). None of the 
15 animals treated with IFNα had profound responses, whereas a total of 9 out of 30 animals 
treated with 4H2 (at 3 and 10 mg/kg), and 12 out of 30 animals treated with IFNα+4H2 (at 3 
and 10 mg/kg) were nearly disease free. 
Figure 4
Effect of IFNα and Anti-PD-1 in MC38 models
Rationale for IPI
4.2.1.1.3
IPI (Yervoy®) is approved for treatment of metastatic MEL, as it has shown OS advantage 
compared with peptide vaccine [66]. IPI monotherapy has shown modest activity in RCC
[41]; however, it is not being further developed as a single agent.
Hypothesis for Pembrolizumab + IPI Combination Therapies
4.2.1.1.3.1
Pre-clinical studies have shown that concomitant CTLA-4 and PD-1 blockage elicited greater 
response rates than either single agent in MC38 mouse models [67]. Notably, while no mice 
treated with anti-CTLA-4 or anti-PD-1 were free of disease at the end of the experiment, 7-
60% of mice treated with the combination at various dose levels were tumor free. This served 
as the foundation to explore anti-CTLA-4 in combination with anti-PD-1 in the clinical 
setting.
In a Phase 1 trial in subjects with MEL, IPI (anti-CTLA-4) combined with nivolumab (anti-
PD-1) led to response rates ranging from 21-53%. These may represent greater responses 
than nivolumab monotherapy [68] [69] and historical responses to IPI in monotherapy
(approximately 20-31% and 10%, respectively) [66]. As mentioned above, both anti-PD-1 
antibodies nivolumab and pembrolizumab demonstrated superiority over single-agent IPI in 
 
 
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previously untreated subjects (pembrolizumab), and over chemotherapy both in untreated 
subjects and after failure of IPI (nivolumab, pembrolizumab). The addition of IPI to 
nivolumab is associated with a higher response rate and a better PFS; however, it is 
associated with a high rate of Grade 3-4 DRAEs.
Rationale for Dose Selection/Regimen/Modification
4.2.2
An open-label Phase I trial (KEYNOTE 001) was conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(q2w) in subjects with advanced solid tumors. All three dose levels were well-tolerated and 
no dose-limiting toxicities were observed. This first in human trial of pembrolizumab showed 
evidence of target engagement and objective evidence of tumor size reduction at all dose 
levels (1 mg/kg, 3 mg/kg and 10 mg/kg q2w). No MTD has been identified to date.
PK data analysis of pembrolizumab administered q3w showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days). This early 
PK and pharmacodynamic data provides scientific rationale for starting the dose escalation 
with a q3w dosing schedule for pembrolizumab.
The dose of pembrolizumab with Amendment 03 is 200 mg q3w. The dose recently approved 
in the United States and several other countries for treatment of MEL and NSCLC subjects is 
2 mg/kg q3w. Information on the rationale for selecting 200 mg q3w is summarized below.
An integrated body of evidence suggests that 200 mg q3w is expected to provide similar 
response to 2 mg/kg q3w, 10 mg/kg q3w and 10 mg/kg q2w. A flat pembrolizumab 
exposure-response relationship for efficacy and safety has been found in subjects with MEL
as well as NSCLC in the range of doses between 2 mg/kg and 10 mg/kg. Exposures for 200 
mg q3w are expected to lie within this range and will be close to those obtained with 2 mg/kg 
q3w dose. 
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed. The PK profile of pembrolizumab is consistent 
with that of other humanized monoclonal antibodies, which typically have a low clearance 
and a limited volume of distribution. The distribution of exposures from the 200 mg fixed 
dose are predicted to (1) considerably overlap with those obtained from the 2 mg/kg dose and 
(2) maintain the individual patient exposures within the exposure range established in MEL
to be associated with maximal clinical response. PK properties of pembrolizumab, and 
specifically the weight-dependency in clearance and volume of distribution are consistent 
with no meaningful advantage to weight-based dosing relative to fixed dosing.   
In translating to other tumor types, similarly flat exposure-response relationships for efficacy 
and safety as observed in subjects with MEL can be expected, as the anti-tumor effect of 
pembrolizumab is driven through immune system activation rather than through a direct 
interaction with tumor cells, rendering it independent of the specific tumor type. In addition, 
available PK results in subjects with MEL, NSCLC, and other tumor types support a lack of 
 
 
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meaningful difference in PK exposures obtained at tested doses among tumor types. Thus, 
the 200 mg q3w fixed dose regimen is considered an appropriate fixed dose for other tumor 
types as well.  
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 the existing data,
200 mg q3w is the appropriate dose for pembrolizumab.
In the pembrolizumab + PEG-IFN treatment Arms, the dose finding portion of this trial will 
evaluate up to four doses of PEG-IFN, 0.5 μg/kg, 1 μg/kg, 2μg/kg, and 3 μg/kg, administered 
SC weekly. A lower dose of PEG-IFN, 0.5 μg/kg/week, will be evaluated as DL-1, if needed.
As single agent, PEG-IFN is tolerated at doses higher than 3 μg/kg weekly dose; the MTD 
was defined at 7.5-9 μg/kg and 6 μg/kg weekly, respectively, in subjects with CML and solid 
tumors [70] [71]. These studies showed a trend toward a dose-related increase of AEs. Lower
rates of AEs were also seen when single agent non-pegylated IFNα was given at lower (5MU 
total/week) versus higher doses (25 MU total/week) in a randomized trial in RCC subjects
[72]).
In combination with other immune-modulators, PEG-IFN 3 μg/kg/week was found to be 
tolerable when given with IL-2 three times per week in subjects with RCC [73]. More 
recently, PEG-IFN was tolerated at 2 μg/kg/week in combination with standard dose IPI, in 
subjects with MEL [74].
In addition to the greater tolerability, lower PEG-IFN doses (3µg/kg/week and below, or the 
equivalent of non-pegylated IFN) have shown biological activity as single agent and in 
combinations. In RCC, a Phase I trial using PEG-IFN doses of 0.5-2µg/kg revealed an ORR 
of 14% [75]. A previously mentioned RCC trial used low dose non-pegylated IFNα, 0.5 MU 
twice/day (5 MU total/week), versus higher doses of IFNα, 5 MU/day (25 MU total/week) 
showing the same ORR 6.7%, including a CR, and yielded a trend to better OS in the low 
dose IFN group, 25.5 months and 17.5 months, respectively [72]. These doses correspond to 
less than 0.25µg/kg to approximately 1µg/kg weekly doses of PEG-IFN [70] In addition, 
larger trials used non-pegylated IFNα at 9 MIU/kg three times/week (27 MU/week 
corresponding approximately to PEG-IFN 1µg/kg weekly), yielded an ORR of 13% [76] 
[77]. In MEL, low dose PEG-IFNα2a (with same active principle, but a different PEG
moiety) yielded an ORR of 6% in 48 subjects [36], including a CR. 
In the combination setting, low dose IFNα (9 MU/week) with bevacizumab [78] appeared to 
have similar efficacy and a favorable side effect profile compared with historical data on 
standard dose IFNα (27 MU/week) plus bevacizumab [79]. Despite small numbers (3 PR/10 
evaluable subjects), results of low dose PEG-IFN in combination with IPI also appear 
promising [74].
Given the toxicities associated with higher doses of IFN, this trial will investigate doses of up 
to 3 μg/kg/week of PEG-IFN. These are biologically active doses, aiming at priming the 
immune system and increasing responses to anti-PD-1 therapy. The overall dosing strategy is 
 
 
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intended to emphasize dose intensity with pembrolizumab rather than PEG-IFN, due to the 
known safety and efficacy of both agents. 
In the pembrolizumab + IPI treatment Arms of Part 1A and 1B, pembrolizumab will be 
evaluated in combination with IPI 1 mg/kg. The schedule of IPI will follow the approved 
drug label of q3w. In a Phase I study by Sznol at ESMO 2013, efficacy of nivolumab
3 mg/kg + IPI 1 mg/kg (ORR 40% (95% CI 16-68%) and Aggregate Clinical Activity Rate 
(ACAR; defined as CR + PR + unconfirmed CR+ unconfirmed PR+ immune-related PR+ SD 
>24 week + irSD >24 week) 73%] appeared to have similar efficacy as nivolumab 1mg/kg + 
IPI 3 mg/kg (ORR 53% (95% CI 28-77%) and ACAR 65%) [68]. In addition, the 
combination of nivolumab 3 mg/kg + IPI 1 mg/kg showed lower rate of Grade 3-4 DRAEs 
compared with nivolumab 1 mg/kg + IPI 3 mg/kg (44% versus 65%, respectively). A total of 
6/28 (21%) of patients experienced Grade 3-4 toxicities that were found to be dose-limiting.
The overall dosing strategy is intended to emphasize dose intensity with pembrolizumab
rather than IPI; in addition, the dosing paradigm of anti-PD-1+ anti-CTLA4 combination will 
explore the lowest therapeutic dose of anti-PD-1 (pembrolizumab at 2 mg/kg q3w) and a 
lower dose than recommended monotherapy dose of anti-CTLA4 (IPI at 1 mg/kg q3w x
4 doses) in Part 1A as a safety run-in, due to known safety and efficacy profile of both 
agents. Up to 18 subjects will receive pembrolizumab 2 mg/kg q3w + IPI 1 mg/kg q3w x
4 doses. Once DL1 (pembrolizumab 2mg q3w + IPI 1mg/kg q3w x4 injections) is declared 
safe, dose expansion at DL1 in MEL subjects (Part 1B) will proceed.
In the pembrolizumab + IPI treatment Arms of Part 1C, the dose of pembrolizumab will be
200 mg q3w based on the rationale provided above. The dose of IPI will be 50 mg fixed dose
q6w (Arm 1) and 100 mg IPI fixed dose q12w (Arm 2). The dose of IPI approved in the US 
and several other countries for treatment of MEL is 3 mg/kg q3w. Information on the 
rationale for selecting IPI 50 mg q6w and 100 mg q12 w is summarized below. 
Results of 153 MEL patients in Part 1B show that lower doses of IPI (1 mg/kg q3w) in 
combination with pembrolizumab 2mg/kg q3w have a confirmed ORR of 57% by 
independent central review and a comparable rate of Grade 3-4 DRAEs to nivolumab
3 mg/kg + IPI 1 mg/kg (42 vs 44%) [53] or nivolumab 3 mg/kg + IPI 3mg/kg (55% and 54% 
for CheckMate 067 and CheckMate 069, respectively) [53] [80]. In Part 1B, 72% of the
subjects were able to complete all 4 planned doses of IPI, however, DRAEs were present in
42% of the subjects. To improve the safety and tolerability of the combination, 
pembrolizumab + IPI, lower doses as well as increased dosing interval of IPI will be explored
in Part 1C.
An integrated body of evidence suggests that in combination with a PD-1 inhibitor, IPI 
50 mg q6w and 100 mg q12w is expected to provide a similar response to IPI 1 mg/kg q6w 
and IPI 1 mg/kg q12w, respectively. Both IPI 1 mg/kg q6w and 1 mg/kg q12w have been 
shown to be effective when combined with nivolumab 3 mg/kg in subjects with NSCLC [81]. 
Simulations of PK profiles suggest that the systemic exposure and trough concentrations 
(Ctrough=pre-dose serum concentration of drug) for IPI 50 mg q6w are between those for IPI 
1 mg/kg q12w and IPI 1 mg/kg q6w, and those for IPI 100 mg q12w overlap with IPI 1mg/kg 
q12w. The increased dosing interval (q6w or q12w) compared to the approved dosing 
 
 
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interval for IPI monotherapy (q3w) may potentially increase the duration of time with IPI 
coverage and maintain IPI exposure for a longer time interval, while the lower Cmax
(Cmax=maximum serum concentration of drug) may improve tolerability. The existing data 
suggest IPI 50 mg q6w and IPI 100 mg q12w are appropriate doses for IPI in combination 
with pembrolizumab 200 mg q3w. 
The proposal to use fixed dose for IPI compared to weight-based dosing is supported by the 
published population PK analysis for IPI [82]. An allometric relationship is reported between 
IPI clearance and body weight, with estimated allometric coefficient of 0.642, which is 
consistent with no advantage for weight-based dosing compared to a fixed dose with respect 
to controlling exposure variability [83]. 
A fixed dose regimen is expected to simplify the dosing regimen (potentially reducing dosing 
errors), as well as be more convenient for physicians.
A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities, as well as reducing waste.
Rationale for Endpoints
4.2.3
Safety Endpoints
4.2.3.1
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in combination with PEG-IFN or IPI in subjects with advanced MEL and 
RCC. The primary safety analysis will be based on subjects who experienced toxicities as 
defined by CTCAE criteria. Safety will be assessed by quantifying the toxicities and grades 
experienced by subjects who have received pembrolizumab, including SAEs and events of 
clinical interest (ECIs).
Safety will be assessed by reported adverse experiences using CTCAE Version 4.0. The
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, potential immune-related 
adverse events (irAEs) will be collected and designated as immune-related ECIs as described 
in Section 7.2.3.2.
Efficacy Endpoints
4.2.3.2
The primary efficacy objective of this trial is to evaluate the anti-tumor activity of 
pembrolizumab in subjects with advanced MEL treated with pembrolizumab in combination 
with PEG-IFN or IPI. Response rates per RECIST 1.1 and volumetric analysis will be 
evaluated.
The primary response rate efficacy endpoint will be based on independent central review 
using RECIST 1.1 (see Appendix 12.6) [1]. RECIST 1.1 will also be used by the local site to 
determine eligibility and make treatment decisions. For this later purpose, RECIST 1.1 will 
be adapted to account for the unique tumor response profile seen with treatment of 
pembrolizumab and this adapted/modified RECIST 1.1 will be used by the sites for treatment 
decisions. Modified RECIST 1.1 will also be used by the local site to determine eligibility.
The primary efficacy endpoint is ORR, based on RECIST 1.1. Secondary endpoints are listed 
 
 
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in section 3.2. As data permits, same efficacy endpoints will also be evaluated in Part 1A
RCC subjects. 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses which may be functionally 
anergic. The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions. Standard 
RECIST criteria may not provide an accurate assessment of immunotherapeutic agents such 
as pembrolizumab. Therefore, RECIST 1.1 will be used with the following adaptation:
If radiologic imaging shows PD, tumor assessment should be repeated ≥4 weeks later in 
order to confirm PD 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 PD, treatment may be continued as per 
treatment calendar. If repeat imaging confirms PD, subjects will be discontinued from trial
therapy (exception noted in Section 7.1.2.8). In determining whether or not the tumor burden 
has increased or decreased, investigators should consider all target lesions as well as 
non-target lesions (please refer to the Site Imaging Manual).
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment until repeat imaging is obtained a 
minimum of 4 weeks later. This decision should be based on the clinical judgment of the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. Subjects may receive treatment while waiting for confirmation of PD if they 
are clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
clinically significant disease progression

No decline in Eastern Cooperative Oncology Group (ECOG) performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, but with subsequent disease response. Subjects that are deemed 
clinically unstable or who have biopsy proven new metastatic lesions are not required to have 
repeat imaging for confirmation of PD.
Note: Treatment may be continued despite modified RECIST 1.1 defined progression if the 
subject is clinically stable and is considered to be deriving clinical benefit by the 
investigator. In these cases, subjects should continue to undergo imaging as outlined in the 
footnote in Table 11.
 
 
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Retrospective central review of all imaging time points may be performed for this study 
using volumetric analysis. Additional information is included in the Site Imaging Manual.  
Planned Exploratory Biomarker Research
4.2.3.3
Tumor tissue for biomarker analysis from formalin fixed paraffin embedded tumor tissue 
sample or newly obtained formalin fixed biopsy of a tumor lesion not previously irradiated 
must be provided in the form of a tissue block or at least ten unstained slides and received by 
the central vendor before randomization. 
Subjects must submit the tumor sample during screening. Subjects will be eligible to 
participate regardless of the level of PD-L1 expression. Subjects who do not submit a sample 
adequate for PD-L1 determination will not be enrolled in Part 1A or 1B. Subjects with an 
archival sample considered not acceptable may obtain a new biopsy. Subjects with a newly 
obtained biopsy considered not acceptable may undergo re-biopsy at the discretion of the 
investigator. Note for Part 1C: adequacy of the tumor sample for determination of PD-L1 
status by IHC at the central pathology laboratory prior to enrollment is not required.
Additional biopsy sample submission is encouraged but not mandatory for Part 1C when the 
sample is inadequate for PD-L1 testing.
Note: A fine needle aspirate, frozen sample, plastic embedded sample, bone, bone marrow, 
cell block, clot, or cytologic specimen will not be acceptable.
If new scientific data emerge that indicate that an existing biopsy or surgical specimen is 
suboptimal for identification of subjects, then only new biopsies will be acceptable for 
determination of PD-L1 status.
Biomarker research to identify factors important for pembrolizumab monotherapy or 
treatment doublets may also be pursued. For example, pre- and post-dose tumor (post-
treatment tumor biopsies are optional at 12 weeks and upon progression) and blood samples 
from this study may undergo proteomic, genomic and transcriptional analyses. Additional 
research may evaluate factors important for predicting responsiveness or resistance to 
pembrolizumab monotherapy or doublets therapy and other immunologic targets.
Assays may include but are not be limited to:
Multiparametric (Two-Color) IHC
Spatial association of PD-1+ tumor infiltrating lymphocytes (TILs) and PD-L1+ cells (tumor 
and myeloid cells) suggests “induction” of PD-L1. Interferon-gamma production by 
antigen-specific PD-1+ CD8+ T cells is hypothesized to drive local intratumoral upregulation 
of PD-L1 on adjacent tumor and myeloid cells, leading to a “stalled Cytotoxic T Lymphocyte 
(CTL)” response which may be predictive of response to pembrolizumab therapy. By 
assessing both of the required elements, i.e. PD-L1 positive cells and PD-1+ T cells, a 
two-color IHC assay may be a better predictor of response than PD-L1 positivity alone.
 
 
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Transcriptional Analyses
Messenger RNA (mRNA) expression profiling will be completed to assess expression of 
approximately 600 genes and attempt to define a gene set critical for clinical response to 
pembrolizumab. The hypothesis to be tested is that pembrolizumab responders will exhibit a 
“stalled CTL” response within the tumor reflected in the physical proximity between PD-1 
and PD-L1 expression and the presence of an aborted (e.g., weak but discernible) interferon-
gamma transcriptional program will be detectable by profiling analyses. Global profiling will 
also be pursued. 
Expression of individual genes related to the immune system may also be evaluated such as 
immune signatures and critical cytokines (e.g., IL-10).
Genetic Analysis
New data are emerging that suggest we can define certain tumor types as being 
‘hypermutated’. There is a potential that this hypermutated state may correlate with response 
to pembrolizumab therapy, and/or that the converse, ‘hypomutated’ state may correlate with 
non-response.  
DNA isolated from blood or tumor tissue will be analyzed in order to identify genetic 
alterations and to evaluate specific genetic alterations that may correlate with clinical 
response to pembrolizumab. These and other additional biomarker or genomic research to 
identify factors important for pembrolizumab therapy (for example, HLA genotype) may also 
be pursued.
Future Biomedical Research
4.2.3.4
The Sponsor will conduct Future Biomedical Research on blood and tumor tissue specimens 
collected during this clinical trial. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
 
 
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material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with advanced MEL (Part 1A, Part 1B and Part 1C) or RCC (Part 1A
only) of at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial. The 
subject may also provide consent/assent for Future Biomedical Research. However, 
the subject may participate in the main trial without participating in Future 
Biomedical Research.
2. Be ≥18 years of age on day of signing informed consent.
3. Have histologically or cytologically confirmed diagnosis of cancer that is recurrent, 
metastatic, or persistent and meet the following corresponding requirements for the 
cohort of the study they will enroll into.  
a.
MEL: histologically confirmed diagnosis of unresectable stage III or
metastatic MEL not amenable to local therapy (Part 1A, Part 1B, and Part 1C).
i. Subject may not have a diagnosis of uveal or ocular MEL.
b. RCC: histologically confirmed diagnosis of advanced/unresectable or 
metastatic RCC with predominantly clear cell elements (Part 1A only).
4. MEL subjects may have received any number of prior lines of therapy for metastatic 
disease for Part 1A and 1B. RCC subjects must have received ≥1 prior line of therapy 
for metastatic disease.
Note for Part 1C: Subjects must have previously untreated stage III-IV 
advanced or metastatic MEL. 
Note for Part 1C: Prior adjuvant or neoadjuvant therapy is allowed as long as 
that therapy did not include compounds targeting PD-1, PD-L1, BRAF or 
MEK. Also, subjects who received prior adjuvant or neoadjuvant therapy may 
only participate in Part 1C if they did not discontinue therapy due to a DRAE 
and all related AEs have either returned to baseline or stabilized (e.g., 
endocrinopathies). Prior adjuvant or neoadjuvant therapy with anti-CTLA-4 
will only be permitted if relapse did not occur during treatment or within 6 
months of treatment discontinuation.
 
 
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5. Have measurable disease based on RECIST 1.1. Cutaneous lesions and other 
superficial lesions that are detectable only by physical examination are not considered 
measurable lesions for the purposes of this protocol, but may be considered as non-
target lesions. Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.
6. Must provide a tumor sample (archival or newly obtained biopsy) that is adequate for 
determination of PD-L1 status by IHC at a central pathology laboratory prior to 
enrollment. Subjects must submit the tumor sample during screening. Subjects will be 
eligible to participate regardless of the level of PD-L1 expression. Subjects who do 
not submit a sample adequate for PD-L1 determination will not be enrolled. 
Note for Part 1C: Adequacy of the tumor sample for determination of PD-L1 
status by IHC at a central pathology laboratory prior to enrollment is not 
required.
Note: A fine needle aspirate, frozen sample, plastic embedded sample, bone, bone 
marrow, cell block, clot, or cytologic specimen will not be acceptable.
Subjects with an inadequate archival sample may obtain a new biopsy and subjects 
with non-acceptable newly obtained biopsy may undergo re-biopsy at the discretion of 
the investigator. Additional biopsy sample submission is encouraged but not 
mandatory for Part 1C when the sample is inadequate for PD-L1 testing.
7. Have a performance status of 0 or 1 on the ECOG Performance Scale.
8. Demonstrate adequate organ function as defined in Table 3. All screening labs should 
be performed within 10 days of treatment initiation.  
 
 
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Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for subject with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
subjects with total bilirubin levels 
>1.5 × ULN (or < 3x ULN in subjects with 
Gilbert’s syndrome)
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for subjects with 
liver metastases)
Albumin
≥3.0 g/dL
Coagulation
International normalized ratio (INR) OR
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as PT or aPTT 
is within therapeutic range of intended use of 
anticoagulants
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular filtration rate; ULN = upper limit of 
normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 
last 2 weeks.
b Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
9. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or 
less (except alopecia) for Part 1 A and B (Note: This sentence does not apply to Part 
1C subjects as they are not permitted to have had prior chemotherapy). If subject 
received major surgery or radiation therapy of > 30 Gy, they must have recovered 
from the toxicity and/or complications from the intervention. 
10. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of trial medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  
11. Female subjects of childbearing potential must be willing to use an adequate method 
of contraception as outlined in Section 5.7.2 - Contraception, for the course of the 
trial through 120 days after the last dose of trial drug.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
 
 
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12. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2 - Contraception, starting with the first dose 
of trial therapy through 120 days after the last dose of trial therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another co-inhibitory T-cell receptor (ie, CTLA-4, OX-40, 
CD137) or has previously participated in a pembrolizumab clinical trial.
2. Has received prior anti-cancer therapy, monoclonal antibody, chemotherapy, or an 
investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) 
before first dose of trial drug or not recovered (≤ Grade 1 or at baseline) from AEs 
due to previously administered agents. Exception to this rule would be use of 
denosumab, which is not excluded.
Note: Subjects with ≤ Grade 2 neuropathy are an exception and may qualify 
for the trial.
Note: If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
trial treatment.
Note for Part 1C: Prior chemotherapy or targeted small molecule therapy 
(including BRAF and MEK inhibitors) for the treatment of Stage III 
unresectable/Stage IV melanoma are not allowed prior to study treatment.
3. Has received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or 
recombinant erythropoietin) within 4 weeks prior to study Day 1. 
4. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial drug.
5. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include early stage cancers (carcinoma in situ or Stage 1) treated with 
curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
in situ cervical cancer, or in situ breast cancer that has undergone potentially curative 
therapy.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment.
Note for Part 1C: Baseline MRI brain scan will be conducted for all subjects.
 
 
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7. Has severe hypersensitivity (≥Grade 3) to any pembrolizumab excipients (excipients 
are listed in the pembrolizumab IB).  
8. Has an active autoimmune disease that has required systemic treatment in the past 
2 years (i.e., with use of disease modifying agents, corticosteroids
or 
immunosuppressive drugs).
Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) 
is not considered a form of systemic treatment and is allowed.
9. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has a known history of human immunodeficiency virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
12. Has a known history of or is positive for hepatitis B (hepatitis B surface antigen 
[HBsAg] reactive) or hepatitis C (hepatitis C virus [HCV] RNA [qualitative] is 
detected).  Note: Without known history, testing needs to be performed to determine 
eligibility.  Hepatitis C antibody (Ab) testing is allowed for screening purposes in 
countries where HCV RNA is not part of standard of care.
13. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
14. Has received any prior therapy with IFN-α (in neoadjuvant, adjuvant or metastatic 
settings). Note: This criterion only applies to Part 1A.  
15. Has severe cardiovascular disease, i.e. arrhythmias, requiring chronic treatment, 
congestive heart failure (NYHA Class III or IV) or symptomatic ischemic heart 
disease.
16. Has hepatic decompensation (Child-Pugh score > 6 [class B and C]).
17. Has uncontrolled thyroid dysfunction.
18. Has uncontrolled diabetes mellitus.
19. Has received a live vaccine within 30 days prior to the first dose of trial drug.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject's participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
21. Has known psychiatric or substance abuse disorders that would interfere with 
cooperating with the requirements of the trial.
 
 
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
Is or has an immediate family member (spouse or children) 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.
Trial Treatment(s)
5.2
The treatment(s) to be used in this trial are outlined below in Table 4. The dosing schedules 
for each doublet combinations are outlined in Section 6 - Trial Flow Chart.
Table 4
Trial Treatments
Drug
Dose/Potency
Dose Frequency
Route of 
Administration
Use
pembrolizumab
200 mg
q3w
IV infusion
Experimental
pembrolizumab
2 mg/kg
q3w
IV infusion
Experimental
PEG-IFN  
0.5 μg/kg
Weekly
SC
Experimental
PEG-IFN  
1 μg/kg
Weekly
SC
Experimental
PEG-IFN  
2 μg/kg
Weekly
SC
Experimental
PEG-IFN  
3 μg/kg
Weekly
SC
Experimental
IPI
1 mg/kg
q3w
IV infusion
Experimental
IPI
50 mg
q6w
IV infusion
Experimental
IPI
100 mg
q12w
IV infusion
Experimental
Trial treatment for Cycle 1 should begin within 7 days of randomization.
All supplies indicated in Table 4 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0. 
The dose amount required to prepare study treatments (pembrolizumab, PEG-IFN, and IPI)
will be based on the subject’s weight in kilograms (kg). Details on the dose calculation, 
preparation and administration are provided in the Pharmacy Manual.
 
 
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With the approval of Amendment 03, subjects continuing pembrolizumab treatment on Parts 
1A and 1B will switch to a fixed dose of 200mg q3w (not weight-based). The rationale for
the fixed dose regimen is outlined in Section 4.2.2.
In Part 1C, subjects will receive a fixed dose of pembrolizumab 200 mg q3w. IPI will be 
administered as a fixed dose of 50 mg q6w (Arm 1) or 100 mg q12w (Arm 2). The rationale 
for fixed dose regimen is outlined in Section 4.2.2.
Rules for Dose Finding (Part 1A)
5.2.1.2
Dose limiting toxicities (DLTs) observed in Cycle 1 will be used to determine escalation to 
the next dose level. A cycle is 6 weeks. The study is using a design based on the modified 
TPI method [84]. 
The rules applied for the dose finding algorithm are as follows:
Subjects will be initially assigned between combinations (pembrolizumab + PEG-IFN or 
pembrolizumab + IPI). For the pembrolizumab + PEG-IFN combination, an initial cohort of 
3 subjects will be enrolled. Subsequent dosing decisions will be based on the rules in Table 5. 
For the pembrolizumab + IPI combination, a run-in cohort of up to 18 subjects will be 
enrolled. If both combinations are open for enrollment, eligible subjects will be randomly 
assigned to a combination; otherwise, subjects will be enrolled to the combination that is 
open for enrollment.
Dose Finding Rules for pembrolizumab + PEG-IFN Combination (Part 1A)
Dose finding will continue until ≤4 of 14 subjects experience a DLT at a given dose 
combination level. As subjects become evaluable for DLT assessment, the number of 
subjects who are evaluable for DLT versus the number of subjects who developed a DLT 
will be continuously assessed and de-escalation and re-escalation to eligible doses will occur 
as shown in Table 5. The decisions are generated from Ji et al. (2010) [84] using the 
parameters in the table with a conservative adjustment by treating 5 or more DLTs observed 
in any dose combinations as unacceptably toxic (denoted as DU in Table 5).
 
 
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Table 5
Dose Finding Rules
Number of subjects treated at current dose
3
4
5
6
7
8
9
10
11
12
13
14
Number of toxicities
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
DU
DU
DU
DU
DU
6
DU
DU
DU
DU
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target DLT rate = 30%
Epsilon1=Epsilon2=0.05
Source:  Ji et al. (2010) [84]
It is conceptually acceptable to de-escalate to an intermediate, not pre-defined and not 
previously-studied dose, if evaluation of toxicity at such a dose is desired in lieu of de-
escalating to a lower dose. If this approach is taken, 3 new subjects should be enrolled at the 
new intermediate dose, and the aforementioned rules should be used to determine further 
enrollment at this dose level.
The maximum number of subjects who are enrolled at a certain dose but are not yet fully 
evaluable for DLT assessment may not exceed the number of remaining subjects who are at 
risk of developing a DLT before the dose would be considered unacceptably toxic (denoted 
as DU in Table 5). For example, if 0/3 subjects have experienced a DLT at a given dose 
level, no more than an additional 5 subjects should be enrolled at this dose level until 
additional DLT data are available. This is because this dose level would be considered 
unacceptably toxic if all 5 of the additional subjects experience a DLT (i.e., 5/8 subjects with 
DLT in Table 5). An exception to the rule above is that a minimum of 3 subjects must be 
enrolled upon each dose decision.
If enrollment expands to 14 subjects for a dose level and ≤4 of the 14 subjects develop a 
DLT, then the dose finding is expected to stop. However, additional dose expansion to 
14 subjects at a lower dose combination may be considered at the discretion of the Sponsor in 
consultation with the study investigators even if enrollment has expanded at a higher dose 
combination with ≤4 of the 14 subjects experiencing a DLT. If enrollment expands to 
14 subjects for a dose level and >4/14 subjects develop a DLT, then the next lower dose may 
be expanded to further explore the dose-response relationship. Note that while 30% has been 
the target toxicity rate used to generate the guidelines in Table 5, the observed rate of 
 
 
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subjects with DLT at the MTD will always be below 30% (i.e., ≤4/14) due to the 
conservative adjustment by treating 5 or more DLTs observed in any dose combinations as 
unacceptably toxic.
Safety Run-in/Dose Finding Rules for pembrolizumab + IPI Combination (Part 1A)
If ≤6 DLTs are observed in the 18 subjects enrolled in DL1 (Part 1A), this dose will be 
considered tolerable. If > 6 DLTs are observed in the 18 subjects enrolled, this dose level 
(DL1) will be proven not tolerable, and the combination with IPI will not be further 
developed.
If DL1 is considered tolerable, at least 90 and up to additional 150 MEL subjects will be 
enrolled in the expansion cohort (Part 1B) at DL1 for further evaluation of safety and 
tolerability. 
Definition of Dose-Limiting Toxicities
5.2.1.2.1
All toxicities will be graded using NCI CTCAE Version 4.0 (Appendix 12.5). Dose-limiting 
hematologic and non-hematologic toxicities will be defined differently. Dose-limiting 
toxicities (DLT) assessment will be based on events occurring during DLT assessment 
period, which is defined as the Cycle 1. The DLT portion of the study applies to Part 1A 
only. Dose-limiting toxicities include all adverse experiences that are clearly not related to 
disease progression or intercurrent illness if judged by the investigator to be possibly, 
probably or definitely related to study treatments. 
Hematological DLTs
1. Any Grade 3 or higher hematologic toxicity with the exception of 

Grade 3 neutropenia

Grade 3 anemia
Non-Hematological DLTs
1. Grade 4 non-hematologic toxicity (not laboratory).
2. Grade 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal 
supportive care with the exception of:

Hypersensitivity/infusion reactions lasting ≤2 days.  
3. Any Grade 3 or higher non-hematologic laboratory value if: 

Medical intervention is required to treat the subject, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week
 
 
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4. Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than one hour

Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than one hour, with life-threatening consequences 
and urgent intervention indicated
5. Thrombocytopenia <25,000/mm3 if associated with:

A bleeding event which does not result in hemodynamic instability but 
requires an elective platelet transfusion, or

A life-threatening bleeding event which results in urgent intervention and 
admission to an Intensive Care Unit
6. Grade 5 toxicity (i.e., death)
7. Delay in the scheduled administration of any component of therapy (IPI, PEG-IFN, 
pembrolizumab) of >14 days
8. A delay of >14 days due to drug-related toxicity in initiating Cycle 2
9. Unable to complete at least 80% of any of the three treatments during the first course 
of therapy due to treatment-related toxicity (even if not meeting above DLT criteria)
Replacement of Subjects in DLT Period (Part 1A)
5.2.1.2.2
Replacement of subjects in DLT Period applies to Part 1A only. In order to determine safety, 
all subjects selected must meet the criteria for evaluability for Cycle 1. Subjects are 
considered non-evaluable and will be replaced if:

they are randomized but not treated,

they discontinue from the trial prior to completing all safety evaluations due to 
reasons other than DRAEs,

they received <90% of the total pembrolizumab infusion in Cycle 1 (e.g., because the 
infusion had to be discontinued due to an infusion reaction) and did not experience a 
drug-related event, 

they received <80% of PEG-IFN or IPI intended for the trial during first Cycle 1 and 
did not experience a drug-related event.
Non-evaluable subjects will not be counted toward the cohort total for DLT evaluation.
Subjects who experience a DLT in Cycle 1 should be discontinued from the trial. However, if 
it has been determined that the subject is deriving clinical benefit from the study therapy, the 
subject may be allowed to continue at a lower dose.   
 
 
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Dose Modification (Escalation/Titration/Other)
5.2.1.3
AE Management Guidelines, including dose modification algorithms, are provided in this 
section for subjects treated with:

Treatment Group A: pembrolizumab + PEG-IFN (Part 1A)

Treatment Group B: pembrolizumab + IPI (Part 1A, 1B and 1C)
Toxicities common to PEG-IFN, IPI, and pembrolizumab include, but are not limited to rash,
endocrinopathy, hepatotoxicity, diarrhea, and pneumonitis. Therefore, it is possible that these 
and/or other toxicities may be exacerbated when pembrolizumab is given in combination 
with either PEG-IFN or IPI.
The dose levels for the doublets for this trial are provided in Table 1 and Table 2.
All AEs are to be graded according to NCI CTCAE v4 (http://ctep.cancer.gov). All dose 
modifications and the reason for the dose modification must be documented in the eCRF.
If possible, the investigator may attribute each toxicity event to pembrolizumab, PEG-IFN, or 
IPI alone such that a stepwise dose reduction or increase in dosing schedule, upon resolution 
of the event to baseline, can be made according to Table 6, Table 8, Table 9, and Table 10.
Subjects requiring an increase in dosing schedule due to toxicity may resume pembrolizumab
upon resolution of toxicity to Grade 0-1 or baseline. This dose would be considered Day 1 of 
the next cycle and should be in alignment with the new schedule.
For example: A subject is CURRENTLY on Cycle 3 of a pembrolizumab q3w schedule.
Subject has an AE on D22 resulting in increase of dosing schedule of pembrolizumab and 
resolution of AE is on C3D36, drug administration should resume on D37 (now called 
C4D1). 
Permanent discontinuation of PEG-IFN but not pembrolizumab is appropriate if in the 
opinion of the investigator and the Sponsor, the toxicity is clearly related to PEG-IFN.
Pembrolizumab treatment may resume upon resolution of toxicity to Grade 0-1 or baseline. If 
in the opinion of the Investigator and the Sponsor the toxicity is related to the combination of 
2 agents, both drugs should be modified according to the recommended dose modifications. 
Subjects who experience an unacceptable toxicity that is attributed to IPI in the opinion of 
the investigator and the Sponsor, may permanently discontinue IPI, but may continue with 
pembrolizumab, upon resolution of toxicity to Grade 0-1 or baseline, until unacceptable 
toxicity or progression. Subjects who discontinue pembrolizumab due to untoward toxicities 
may not continue on the trial receiving only PEG-IFN or IPI.
Study treatments will be withheld for drug-related ≥Grade 3 hematologic toxicities
(excluding Grade 3 neutropenia and anemia), ≥ Grade 3 non-hematologic toxicity, including 
laboratory abnormalities; and severe or life-threatening AEs as per Table 6 and Table 8. This 
will also apply to subjects included in Part 1C receiving IPI + pembrolizumab combination.
 
 
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In Part 1C, isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 within 7 days 
±3 days of onset will not require treatment discontinuation. If not resolved to < Grade 4 
within this window, trial treatment may continue with Sponsor consultation. Exceptions for 
restarting treatment according to the Dose Modification and Supportive Care Guidelines per 
Table 9 and Table 10 should be followed.
For subjects who experience a recurrence of the same AE(s) at the same grade or greater with
rechallenge of study treatment(s), a consultation between the Sponsor and the investigator 
should occur to determine whether the subject should continue on the trial. However, for a 
subject who experiences a recurrence of the same SAE at the same grade or greater with 
rechallenge, the subject must discontinue trial treatment.
Investigators should refer to the appropriate IB/label for PEG-IFN, pembrolizumab, and IPI
for additional information regarding the background of each drug and the management of 
other AEs or potential safety-related issues. Dosing interruptions are permitted in the case of 
medical/surgical events or logistical reasons not related to trial therapy (e.g., elective surgery, 
unrelated medical events, subject vacation, and/or holidays).  Subjects should be placed back 
on trial therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with 
the Sponsor. The reason for interruption should be documented in the subject's trial record.
 
 
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Dose Modification Guidelines for pembrolizumab + PEG-IFN or pembrolizumab + IPI Combination Therapy 
5.2.1.3.1
Dose Modification Guidelines for Treatment Group A (Part 1A Only): pembrolizumab + PEG-IFN
5.2.1.3.1.1
Table 6
Dose Modification Guidelines for DRAEs for pembrolizumab + PEG-IFN
Toxicity
Grade
Cycle 
Number
Hold 
Treatment 
(Y/N)
Timing for 
restarting 
treatment
Dose/Schedule for restarting treatment
Discontinue Subject (after 
consultation with 
Sponsor)
Hematological Toxicity
Any
C1
Please refer to Section 5.2.1.2.1
1, 2
C2 and 
Beyond
No
N/A
N/A
N/A
3
Excludes Grade 
3 neutropenia, 
and anemia
Yes
Toxicity
resolves to
Grade 0-1 or
baseline
Subject is dosed at DL1-DL3: May decrease 
PEG-IFN dose to next dose level below for each 
occurrence
Subject is dosed at DL(-1): May discontinue 
PEG-IFN and increase dosing interval of 
pembrolizumab by 1 week° for each occurrence
Toxicity does not resolve 
within 12 weeks of last 
infusion
Permanent discontinuation 
should be considered for 
any severe or life-
threatening event
4 
Yes
Toxicity 
resolves to 
Grade 0-1 or 
baseline and 
after
Sponsor 
consultation
Subject is dosed at DL1-DL3: May decrease 
PEG-IFN dose to next dose level below
Subject is dosed at DL(-1): May discontinue 
PEG-IFN and increase dosing interval of 
pembrolizumab by 1 week°
 
 
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Toxicity
Grade
Cycle 
Number
Hold 
Treatment 
(Y/N)
Timing for 
restarting 
treatment
Dose/Schedule for restarting treatment
Discontinue Subject (after 
consultation with 
Sponsor)
Non-hematological 
Toxicity
Note:  Exception to be 
treated similar to Grade 1 
toxicity

Grade 2 alopecia

Grade 2 fatigue
PEG-IFN should be 
permanently discontinued 
if subject experiences 
Grade 3 liver toxicity.
For additional information 
regarding irAEs, reference 
Section 5.6.1.
Any
C1
Please refer to Section 5.2.1.2.1.
1
C2 and 
Beyond
No
N/A
N/A
N/A
2
Consider 
withholding 
for persistent 
symptoms.
For Grade 2 
Ocular, Liver 
and GI 
toxicity, hold 
both
Toxicity 
resolves to 
Grade 0-1 or 
baseline
Clinical AE resolves within 4 weeks: Same dose 
and schedule (reference Section 5.6.1
for 
recommendations regarding pneumonitis)
Clinical AE does not resolve within 4 weeks
Subject is dosed at DL1-DL3: May decrease 
PEG-IFN dose to next lower dose level for each 
occurrence
Subject is dosed at DL(-1): May discontinue 
PEG-IFN and increase dosing interval of 
pembrolizumab by 1 week°
Toxicity does not resolve 
within 12 weeks of last 
infusion
3
Yes
Toxicity 
resolves to 
Grade 0-1 or 
baseline
Subject is dosed at DL1-DL3:May decrease
PEG-IFN dose to next dose level below
Subject is dosed at DL(-1): May discontinue 
PEG-IFN and increase dosing interval of 
pembrolizumab by 1 week°
Toxicity does not resolve 
within 12 weeks of last 
infusion
Permanent discontinuation 
should be considered for 
any severe or life-
threatening event
4
NA
NA
NA
Permanently discontinued
° Subject may resume pembrolizumab upon resolution of toxicity to baseline. This dose would be considered Day 1 of the next cycle and should be in alignment with the 
new schedule. For example: A subject is CURRENLTY on Cycle 3 of a pembrolizumab q3w schedule. Subject has an AE on D22 resulting in increase of dosing schedule of 
pembrolizumab and resolution of AE is on C3D36, drug administration should resume on D37 (now called C4D1).
 
 
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For Part 1A, in an individual subject, following a reduction in the dose of pembrolizumab
and PEG-IFN a subsequent increase in the dose will not be permitted.
Dose Modification Guidelines for PEG-IFN 
5.2.1.3.1.2
Follow criteria listed in Table 6 for withholding study drug and dose modification for 
pembrolizumab + PEG-IFN. In addition,

withhold PEG-IFN dose for the following:
Grade 3 or higher thrombocytopenia 
Grade 3 or higher flu-like symptoms (including fever, associated tachycardia,
myalgia, fatigue or chills)
Depressed mood/Neuropsychiatric disorder

reduce dose of PEG-IFN to lower dose level if CrCl decreases below 50 mL/min.
Please refer to criteria for PEG-IFN dose modification, as shown in Table 7.
Table 7
Recommended Dose Reduction for PEG-IFN 
Dose Level
Dosage and Schedule
PEG-IFN Treatment at DL3 
SC 3 μg/kg/weekly
Dose Modification #1 
SC 2 μg/kg/weekly
Dose Modification #2
SC 1 μg/kg/weekly
Dose Modification #3
SC 0.5 μg/kg/weekly
Permanently discontinue if unable to tolerate 
0.5 μg/kg/weekly
5.2.1.3.1.2.1 Dose Modification for Management of Depression
Subjects who develop mild depression during the trial may continue their study medication 
and should be monitored weekly (by visit or by phone) for 4 to 8 weeks. If the subject's status 
is stable at that time, the subject may resume the normal visit schedule with instructions to 
call the study center immediately if the subject feels that the depression has worsened. If the 
subject's condition worsens, see instructions for moderate and/or severe depression below.
Subjects who develop moderate depression during the trial should have their dose of 
PEG-IFN reduced (Table 7) at the discretion of the investigator. Subjects should be 
monitored weekly (by visit or phone for 4 to 8 weeks, depending on the subjects' status) to 
assure that their status is stable. These subjects may remain on reduced PEG-IFN dosing if 
the condition is considered stable and does not interfere with the subject's normal activities. 
Other clinical management intervention may be instituted as necessary. Subjects will be 
instructed to call the study center immediately if they feel their depression has worsened. 
If the subject's condition worsens, the subject should immediately discontinue PEG-IFN, and 
a physician should make a priority assessment of the severity of the subject's condition.
Appropriate therapeutic measures should be instituted, and the subject should be followed 
 
 
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weekly or biweekly (depending on the physician's clinical judgment) by visit or by phone 
until the subject's status has returned to baseline conditions.
5.2.1.3.1.2.2 Interruption or Discontinuation of PEG-IFN
Follow criteria for subject discontinuation listed in Table 6.
In addition, treatment with PEG-IFN should be permanently discontinued for any of the 
following reasons:

The subject experiences new onset of ventricular arrhythmia or cardiovascular 
decompensation.

The subject develops severe depression (≥ Grade 3).

The subject experiences a persistent or worsening severe (≥ Grade 3) 
neuropsychiatric disorder.

The subject experiences new or worsening retinopathy.

The subject experiences >Grade 3 liver toxicity (AST, ALT or bilirubin) or hepatic 
decompensation (Child-Pugh score > 6 [class B and C]).

The subject develops hypothyroidism, hyperthyroidism or diabetes mellitus that 
cannot be effectively managed.

The subject experiences drug-related ≥ Grade 3 fever, flu-like symptoms, fatigue, or 
chills.

The subject experiences drug-related ≥ Grade 3 injection reactions at site of SC 
administration.

The subject is unable to tolerate PEG-IFN at 0.5 μg/kg/weekly dose.
All subjects enrolled in the pembrolizumab + PEG-IFN treatment group should have a 
baseline ophthalmologic exam including visual acuity, visual field and color discrimination 
by an ophthalmologist.
Any subject complaining of ocular symptoms, including loss of visual acuity or visual field 
must have a prompt and complete ophthalmologic examination. In addition, because these 
ocular events may occur in conjunction with other disease states, periodic visual 
examinations during the trial are recommended, per standard of care, in subjects with 
disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. 
If a subject’s study treatment has been interrupted for more than 4 weeks for PEG-IFN and/or 
pembrolizumab have been withheld, the investigator must contact the Sponsor to review the 
subject’s condition in order to resume the treatment.
Subjects being treated on combination therapy with pembrolizumab + PEG-IFN who require 
discontinuation of PEG-IFN for toxicity may continue treatment with pembrolizumab. The 
reason for discontinuation must be recorded. For subsequent management of toxicities on 
pembrolizumab, see Section 5.2.1.3.3.
 
 
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Dose Modification Guidelines for Treatment Group B: pembrolizumab + IPI
5.2.1.3.2
Table 8
Dose Modification Guidelines for DRAEs for pembrolizumab + IPI (Part 1A and 1B)
Toxicity
Grade
Cycle 
Number
Hold Treatment 
(Y/N)
Timing for 
restarting 
treatment
Dose/Schedule for restarting treatment
Discontinue Subject (after 
consultation with Sponsor)
Any
Any
C1
Please refer to Section 5.2.1.2.1.
Hematological 
Toxicity
1, 2
C2 and 
Beyond
No
N/A
N/A
N/A
3
Excludes 
Grade 3 
neutropenia,
and anemia
C2 
Yes
Toxicity 
resolves to 
Grade 0-1 or 
baseline
Clinical AE resolves within 4§ weeks:  May 
decrease dose of IPI to 0.3 mg/kg for first 
occurrence.
Any 
subsequent 
occurrences, 
discontinue IPI
Clinical AE does not resolve within 4§ weeks: 
Discontinue IPI
Toxicity does not resolve 
within 12 weeks of last 
infusion
Permanent discontinuation 
should be considered for any 
severe or life-threatening 
event
C3° and 
beyond
Please refer to Table 9 and Table 10 Dose Modification and Supportive Care Guidelines for DRAEs for pembrolizumab 
monotherapy and Part 1C
4
C2
Yes
Toxicity 
resolves to 
Grade 0-1 or 
baseline and 
after
Sponsor 
consultation
Clinical AE resolves within 4§
weeks:
May 
decrease dose of IPI to 0.3 mg/kg for first 
occurrence.
Any 
subsequent 
occurrences, 
discontinue IPI
Clinical AE does not resolve within 4§ weeks: 
Discontinue IPI
Toxicity does not resolve 
within 12 weeks of last 
infusion
Permanent discontinuation 
should be considered for any 
severe or life-threatening 
event
4
C3° and 
beyond
Please refer to Table 9 and Table 10 Dose Modification and Supportive Care Guidelines for DRAEs for pembrolizumab 
monotherapy and Part 1C
 
 
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Toxicity
Grade
Cycle 
Number
Hold Treatment 
(Y/N)
Timing for 
restarting 
treatment
Dose/Schedule for restarting treatment
Discontinue Subject (after 
consultation with Sponsor)
Non-hematological 
Toxicity
Note:  Exception to 
be treated similar 
to Grade 1 toxicity:

Grade 
2 
alopecia

Grade 
2 
fatigue
For additional 
information 
regarding irAEs,
reference Section 
5.6.1.
1
C 2 and 
beyond
No
N/A
N/A
N/A
2
C2
Consider 
withholding for 
persistent symptoms.
For Grade 2 Ocular, 
Liver and GI 
toxicity, hold both 
drugs
Toxicity 
resolves to 
Grade 0-1 or 
baseline
Clinical AE resolves within 4§ weeks: May resume 
treatment at same schedule (reference Section 5.6.1
for recommendations regarding pneumonitis)
Clinical AE does not resolve within 4§ weeks: May 
decrease dose of IPI to 0.3 mg/kg for first 
occurrence.
Any 
subsequent 
occurrences, 
discontinue IPI
Toxicity does not resolve 
within 12 weeks of last 
infusion
2
C3° and 
beyond
Please refer to Table 9 and Table 10 Dose Modification and Supportive Care Guidelines for DRAEs for pembrolizumab 
monotherapy and Part 1C
3
C2
Yes
Toxicity 
resolves to 
Grade 0-1 or 
baseline
Permanently discontinue IPI for Grade 3 Immune-
related AE.
Clinical AE resolves within 4§
weeks:
May 
decrease dose of IPI to 0.3 mg/kg for first 
occurrence.
Any 
subsequent 
occurrences, 
discontinue IPI
Clinical AE does not resolve within 4§ weeks: 
Discontinue IPI
Toxicity does not resolve 
within 12 weeks of last 
infusion
Permanent discontinuation 
should be considered for any 
severe or life-threatening 
event
3
C3° and 
beyond
Please refer to and Table 10 Dose Modification and Supportive Care Guidelines for DRAEs for pembrolizumab 
monotherapy and Part 1C
4
C2 and 
beyond
NA
NA
NA
Permanently discontinued
°Scheduled treatment with pembrolizumab + IPI doublet is administrated for 2 cycles (12 weeks), followed by treatment with pembrolizumab single agent.
§ IPI should be permanently discontinued for subject’s failure to complete full treatment course of IPI within 16 weeks from administration of first dose.
Note:  Subject may resume pembrolizumab upon resolution of toxicity to baseline. This dose would be considered Day 1 of the next cycle and should be in alignment with the new 
schedule. For example: A subject is CURRENTLY on Cycle 3 of a pembrolizumab q3w schedule. Subject has an AE on D22 resulting in increase of dosing schedule of 
pembrolizumab and resolution of AE is on C3D36, drug administration should resume on D37 (now called C4D1).
 
 
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Dose Modification Guidelines for IPI
5.2.1.3.2.1
Please refer to criteria for IPI dose modification included in the approved label and described 
above in Table 8 for Part 1A and 1B and in Table 9 and Table 10 for pembrolizumab 
monotherapy and Part 1C.
5.2.1.3.2.1.1 Interruption or Discontinuation of IPI
In Part 1B, IPI should be permanently discontinued for subjects who fail to complete the full 
treatment course of IPI within 16 weeks from administration of first dose.
In Part 1C, IPI should be permanently discontinued for subjects who fail to complete the full 
treatment course of IPI within 30 weeks from administration of first dose for the IPI 50 mg 
q6w dose regimen and within 60 weeks for the IPI 100 mg q12w dose regimen.
If a subject’s study treatment has been interrupted for more than 2 doses of IPI (with or 
without pembrolizumab being withheld), the investigator must contact the Sponsor to review 
the subject’s condition in order to resume the treatment.
Subjects being treated on combination therapy with pembrolizumab + IPI who require 
discontinuation of IPI due to toxicity may continue treatment with pembrolizumab. The 
reason for discontinuation must be recorded.
Dose Modification and Supportive Care Guidelines for
DRAEs
for
5.2.1.3.3
Pembrolizumab Monotherapy and Part 1C
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to 
reduce complications.  Based on existing clinical trial data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, or skin biopsy may be included as part of the evaluation. Based on the severity 
of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated 
with pembrolizumab are provided in Table 9.
 
 
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Table 9
Dose Modification and Toxicity Management Guidelines for Immune-Related AEs for Pembrolizumab Monotherapy
and Part 1C
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus)

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
AST / ALT 
elevation or 
Increased 
bilirubin a
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable
Grade 3 or 4 
Permanently 
discontinue a

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemiab
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement 
therapy for subjects with T1DM 

Administer anti-hyperglycemic in 
subjects with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 b
Withhold or 
permanently 
discontinue c
Hyperthyroidismb
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4 b
Withhold or 
permanently 
discontinue c
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade 
or conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs d
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
AE=adverse event; ALT=alanine aminotransferase; AST= aspartate aminotransferase; CTCAE= Common Toxicity Criteria for Adverse Events; 
GI=gastrointestinal; irAE=immune related adverse event; IV=intravenous; T1DM=Type 1 diabetes mellitus. 
NOTES: 
a  For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to 
baseline and lasts for at least 1 week then subject should be discontinued. 
b  For subjects 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).  
c  Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
d In Part 1C, isolated Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis and decrease 
to < Grade 4 within 7 days ±3 days of onset will not require treatment discontinuation. If not resolved to < Grade 4 within this window, trial treatment 
may continue with Sponsor consultation.
 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 10.
 
 
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Table 10
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, 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 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, 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 study drug treatment.
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine);
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, 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:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of
drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
 
 
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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion of 
pembrolizumab, trial treatments should be discontinued after consultation with the Sponsor.
With investigator and Sponsor agreement, subjects with a laboratory AE still at Grade 2 after 
12 weeks may continue treatment in the trial only if asymptomatic and controlled. Refer to 
Table 9 for exception with regard to amylase and lipase abnormalities. For information on 
the management of AEs, see Section 5.6.1.
Timing of Dose Administration
5.2.2
Trial treatment should be administered following the schedule on Section 6 and after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 6).
Unless otherwise specified, trial treatment may be administered up to 3 days, before or after 
the scheduled day of each cycle due to administrative reasons.
The specific time of treatment administration (e.g., time of the week for first administration; 
time of the day for each administration) should take into consideration PK sampling time 
points and study visit procedures.
All trial treatments will be administered on an outpatient basis.
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. The local product labels 
and institutional standards for PEG-IFN and IPI should be referenced.
Pembrolizumab
Pembrolizumab will be administered as a 30 minute IV infusion q3w. Sites should make 
every effort to target infusion timing to be as close to 30 minutes as possible. However, given 
the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). Pembrolizumab should always 
be administered first when in combination with either PEG-IFN or IPI.
PEG-IFN 
PEG-IFN is a once-weekly SC injection that may be self-injected. Subjects should be 
premedicated with acetaminophen 500 to 1000 mg orally 30 minutes prior to the first dose of 
PEG-IFN and as needed for subsequent doses.  
The first dose of trial treatment will be administered at the trial site on Day 1. 
Acetaminophen [500-1000 mg orally (po)] will be given in the clinic 30 minutes prior to the 
first dose of PEG-IFN. Subjects should be monitored for 1-2 hours after the first dose. 
Acetaminophen (500-650 mg po every 4-6 hours) should be continued as needed, and should 
not exceed 3000 mg/day. 
Subsequent dosing will be performed once weekly by the subject (i.e., unsupervised at 
his/her home) at approximately the same time of day. Subjects may choose to take PEG-IFN 
with acetaminophen at bedtime to minimize common “flu-like” symptoms (including chills, 
fever, muscle aches, joint pain, headaches, and tiredness).
 
 
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IPI
In Part 1B, IPI will be administered once q3w for a total of 4 doses.
In Part 1C, IPI will be administered once q6w for a maximum of 4 doses (Arm 1) and once 
q12w for a maximum of 4 doses (Arm 2). 
IPI will be administered as a 90 minute IV infusion. Sites should make every effort to target 
infusion timing to be as close to 90 minutes as possible. For additional instructions regarding 
dosing please refer to the IPI label.  
The pharmacists will prepare IPI per the instructions in the label.
Treatment after Initial Evidence of Radiologic Disease Progression
5.2.3
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.  
In Part 1A and 1B, tumor imaging will be assessed first at week 12 (± 3 days), then every 
6 weeks (42 ± 3 days) until week 30. Subsequently, tumor imaging will be performed every 
12 weeks (84 ± 7 days). In Part 1C, tumor imaging will be assessed every 6 weeks (± 3 days)
until week 24. Subsequently, tumor imaging will be performed every 12 weeks (84 ± 7 days).
If radiologic imaging shows PD, tumor assessment should be repeated ≥4 weeks later in 
order to confirm PD 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 PD, treatment may be continued as per 
treatment calendar. If repeat imaging confirms PD, subjects will be discontinued from study 
therapy (exception noted in Section 7.1.2.8). In determining whether or not the tumor burden 
has increased or decreased, investigators should consider all target lesions as well as 
non-target lesions (please refer to the Site Imaging Manual).  
When feasible, subjects should not be discontinued until progression is confirmed; however, 
the decision to continue study treatment after the first evidence of disease progression is at 
the investigator’s discretion based on the clinical status of the subject as described in Table 
11 below. Subjects that are deemed clinically unstable or who have biopsy proven new 
metastatic lesions are not required to have repeat imaging for confirmation of PD.  
Note: Treatment may be continued despite modified RECIST 1.1 defined progression if the 
subject is clinically stable and is considered to be deriving clinical benefit by the 
investigator. In these cases, subjects should continue to undergo imaging as outlined in the 
footnote in Table 11.
 
 
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Clinical Stability is defined as:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
clinically significant disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
Table 11
Imaging and Treatment after 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
Repeat imaging at 
≥4 weeks to 
confirm PD
May continue 
study treatment at 
the investigator’s 
discretion while 
awaiting 
confirmatory scan 
Repeat imaging 
at ≥4 weeks to 
confirm PD if 
possible
Discontinue 
treatment
Repeat scan 
confirms PD
No additional 
imaging required
Discontinue 
treatment 
(exception noted 
in Section 7.1.2.8)
No additional 
imaging 
required
N/A
Repeat scan 
shows SD, PR or 
CR
Continue 
regularly 
scheduled 
imaging 
assessments, as 
per the schedule 
noted at the 
bottom of this 
table.  
Continue study 
treatment at the 
investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments, as 
per the 
schedule noted 
at the bottom 
of this table.  
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
investigator’s 
discretion
CR = complete response; irRECIST = immune-related Response Evaluation Criteria in Solid Tumors; PD = progressive 
disease; PFS = progression-free survival; PR = partial response; SD = stable disease.
In Parts 1A and 1B, tumor imaging will be assessed first at week 12 (± 3 days), then every 6 weeks (42 ± 3 days) until 
week 30. Subsequently, tumor imaging will be performed every 12 weeks (84 ± 7 days).
In Part 1C, tumor imaging will be assessed first at week 6 (± 3 days), then every 6 weeks (42 ± 3 days) until Week 24. 
Subsequently, tumor imaging will be performed every 12 weeks (84 ± 7 days).
Trial Blinding/Masking
5.2.4
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are two Part 1A treatment arms.  Subjects will be 
 
 
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assigned randomly in a 1:1 ratio to pembrolizumab + PEG-IFN and pembrolizumab + IPI, 
respectively, when both dose combination treatment groups are open for enrollment.  
In Part 1B, subjects with advanced MEL will be enrolled in the pembrolizumab + IPI
treatment group.
In Part 1C, subjects with advanced MEL will be randomized 1:1 to the following treatment 
groups:

Arm 1: pembrolizumab 200 mg q3w + IPI 50 mg q6w

Arm 2: pembrolizumab 200 mg q3w +IPI 100 mg q12w
Stratification
5.4
In Part 1A and 1C, there will be no stratification prior to randomization.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
5.5.1
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the screening visit and up to 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
5.5.2
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including Second Course Phase) of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol
 
 
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
Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab, PEG-IFN, or IPI

Radiation therapy 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are 
live attenuated vaccines and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from a 
drug-related AE of suspected immunologic etiology. Please note that inhaled or 
topical steroids are allowed, and systemic steroids at doses ≤10 mg/day prednisone or 
equivalent are allowed, as described in Section 5.6.

Local surgery resulting from disease progression is prohibited. However, if indicated 
for palliative measure and after Sponsor approval, local surgery may be permitted 
beyond Week 12 tumor assessment.  
Subjects who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment follow-up Phase.
Rescue Medications & Supportive Care
5.6
Supportive Care Guidelines
5.6.1
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification and supportive 
care guidelines in Section 5.2.1.3.3 Table 9 and Table 10 (pembrolizumab monotherapy and 
Part 1C). Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids.  Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased.  For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to trial 
treatment. 
 
 
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Note: If after the evaluation of the event, it is determined not to be related to trial treatment, 
the investigator does not need to follow the treatment guidance. Refer to Table 6 and Table 8
in Section 5.2.1.3.1 and Section 5.2.1.3.2, respectively for guidelines regarding dose 
modification for DRAEs (Part 1A and 1B).
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Guidelines for Pembrolizumab/PEG-IFN Combination Therapy
5.6.2
PEG-IFN Dosing Considerations 
5.6.2.1
Subjects can expect to get “flu-like” symptoms when taking PEG-IFN. Subjects may choose 
to take PEG-IFN with acetaminophen at bedtime to minimize common “flu-like” symptoms 
(including chills, fever, muscle aches, joint pain, headaches, and tiredness). Subjects should 
maintain hydration if experiencing “flu-like” symptoms.
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
5.7.2
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they meet 1 of the 
following criteria: 

She is postmenopausal, defined as at least 12 months with no menses without an 
alternative medical cause. In women < 45 years of age who are not using hormonal 
contraception or hormonal replacement therapy, a high follicle stimulating hormone 
(FSH) level in the postmenopausal range may be used to confirm a post-menopausal 
state. In the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.

She had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening.

She has a congenital or an acquired condition that prevents childbearing.
 
 
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Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving trial drug and for 120 days after the 
last dose of trial drug by complying with 1 of the following: 

Practice abstinence from heterosexual activity.
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and European 
Research Councils (ERCs)/Institutional Review Boards (IRBs). Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 

Use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:

Single method (1 of the following is acceptable):
o
Intrauterine device (IUD)
o
Vasectomy of a female subject’s male partner 
o
Contraceptive rod implanted into the skin

Combination method (requires use of 2 of the following):
o
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
o
Cervical cap with spermicide (nulliparous women only)  
o
Contraceptive sponge (nulliparous women only) 
o
Male condom or female condom (cannot be used together)
o
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Subjects should be informed that taking the trial medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the trial. In order to participate in 
the trial, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of trial medication initiation (or 14 days prior to the initiation 
of trial medication for oral contraception) throughout the trial period up to 120 days after the 
last dose of trial medication. If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the trial.
 
 
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Use in Pregnancy 
5.7.3
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will be immediately discontinued from trial treatment. The site will contact the
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The trial investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male subject impregnates his female partner, the trial personnel at the site must 
be informed immediately and the pregnancy must be reported to the Sponsor and followed as 
described in Section 7.2.
Use in Nursing Women
5.7.4
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breastfeeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

Confirmed radiographic disease progression outlined in Section 5.2.3 (exception
if the Sponsor approves treatment continuation).

Unacceptable adverse experiences as described in Section 7.2

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires systemic treatment

Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment

Recurrent Grade 2 pneumonitis
 
 
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
A confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

Investigator’s decision to withdraw the subject

Completed a maximum of 24 month of treatment with pembrolizumab
Note: 24 months of pembrolizumab is calculated from the date of first dose. 
Subjects who stop pembrolizumab after 24 months may be eligible for a 
maximum of 17 doses of pembrolizumab and 4 doses of IPI if they progress 
after stopping study treatment provided they meet the requirements detailed in 
Section 7.1.5.2.1 and the study remains open.

Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Trial Flow 
Chart) and Section 7.1.5 (Visit Requirements). After the end of treatment, each subject will 
be followed for 30 days for AE monitoring (SAEs will be collected for 90 days after the end 
of treatment as described in Section 7.2.3.1). Subjects who discontinue for reasons other than 
PD will have post-treatment follow-up for disease status until disease progression, initiating a 
non-study cancer treatment, withdrawing consent or becoming lost to follow-up. After 
documented disease progression, each subject will be followed by telephone for OS until 
death, withdrawal of consent, or the end of the study, whichever occurs first.
Discontinuation of Study Treatment after CR
5.8.1
Discontinuation of treatment with pembrolizumab may be considered for subjects who have 
attained an investigator-determined confirmed CR that have been treated for at least 24 
weeks with pembrolizumab and had at least two additional doses of pembrolizumab beyond 
the date when the initial CR was declared. Upon Sponsor consultation, subjects who stop 
pembrolizumab with SD or better per modified RECIST 1.1 may be eligible for retreatment
with pembrolizumab + IPI or pembrolizumab monotherapy for a maximum of 17 doses of 
pembrolizumab and 4 doses of IPI if they progress after stopping pembrolizumab at the 
discretion of the investigator according to the criteria in Section 7.1.5.2.1 as long as the trial 
Part to which the subject was initially enrolled remains open.
In Part 1C and upon Sponsor consultation, subjects who attain an investigator-determined CR
or a VGPR per modified RECIST 1.1 may consider stopping treatment with IPI after a 
minimum of one dose of IPI on either Arm of treatment. Subjects who then experience 
radiographic disease progression may be eligible for Second Course Phase. Additional details 
are provided in Section 7.1.5.2.1.
Subject Replacement Strategy
5.9
Additional subjects may be enrolled in a given treatment group to ensure that the required 
number of evaluable subjects in each treatment group is achieved. A subject that discontinues 
the trial for PD or a DRAE will not be replaced and will be counted in the evaluable 
population of subjects for the respective treatment group. Further details are provided in 
Section 8.0.
 
 
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Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  Part 1A and 
1B will be considered complete when all enrolled subjects are a minimum of 24 weeks post 
initial trial treatment administration.  At this point, a database lock may occur to allow 
analysis of the data. Part 1C will be considered complete for publication purposes when all 
enrolled subjects are a minimum of 72 weeks post initial treatment administration. At this 
point, database lock may occur to allow analysis of the data. Any remaining subjects may 
continue to receive trial treatment and be seen by the investigator per usual standard of care 
for this subject population. In addition, the investigator will be expected to monitor for and 
report any SAEs, events of clinical interest, and pregnancies as detailed in Section 7.2.3.1 
(SAEs). The subject is considered on study until such time that he/she meets any of the 
discontinuation criteria and written notification is given to the Sponsor.
Clinical Criteria for Early Trial Termination
5.11
Early trial termination will be the result of the criteria specified below:
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems, 
or the number of discontinuations for administrative reasons is too high.
 
 
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1.
Treatment cycles are 6 weeks. Imaging should always be performed as scheduled and follow calendar days, regardless of any treatment delays.  
2.
Subjects who discontinue trial treatment due to a reason other than disease progression should continue follow-up and assessment by radiologic imaging (and digital 
photography if applicable) every 12 weeks (± 1 week) for the first year after discontinuation, then every 6 months (± 2 weeks) for years two through five, and every 12
months (± 4 weeks) after year five. Imaging follow-up should continue until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) 
the end of the trial, whichever occurs first.
3.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks after the last 
contact date to assess for survival status. In certain situations, survival data may be requested more frequently than every 12 weeks as per Section 7.1.5.3.3.  Updated survival 
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or 
study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
4.
In general, the window for each visit is ± 3 days unless otherwise noted. 
5.
Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment).
Screening number will be assigned when the study informed consent is signed.  
6.
Informed consent for future biomedical research samples must be obtained before the DNA sample. DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained.
7.
Prior medications – All concomitant medications received within 28 days prior to the screening visit and up to 30 days after the last dose of trial treatment should be 
recorded.
8.
All subjects should have a baseline ophthalmologic exam including visual acuity, visual field and color discrimination by an ophthalmologist. Fundus photography should be 
performed in subjects with history of clinically significant retinal disease (defined as macular degeneration, retinal detachment and moderate/severe non-proliferative diabetic 
retinopathy and any proliferative diabetic retinopathy). Enrollment of subjects with clinically significant retinal disease will require consultation with the sponsor on risk-
benefit associated to treatment with pembrolizumab + PEG-IFN. Any subject complaining of ocular symptoms, including loss of visual acuity or visual field must have a 
prompt and complete ophthalmologic examination. In addition, because these ocular events may occur in conjunction with other disease states, periodic visual examinations 
during the trial are recommended in subjects with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of PEG-IFN 
should be considered in subjects who develop new or worsening ophthalmological disorders.
9.
ECG should be performed at screening and as clinically indicated thereafter. ECGs are performed locally.
10. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.
11. Record all AEs occurring within 30 days after the last dose of trial treatment and all SAEs (related and unrelated to trial treatment) / ECIs occurring up until 90 days 
following cessation of treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. Afterwards, report only 
SAEs and ECIs that are related to trial treatment.
12. Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests.
13. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 
7.1.3 for details regarding laboratory tests. After Cycle 8, lab samples should be collected every two cycles on D1 (i.e.; C8 D1, C10 D1, C12 D1, etc.)
14. Unresolved abnormal labs that are DRAEs should be followed until resolution.    
15. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
16. Pembrolizumab will be administered as a 30 minute IV infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Pembrolizumab should always be administered first when given in combination.
17. The first dose of PEG-IFN will be administered at the trial site at C1D1. Subsequent dosing will be performed once weekly (±1 day) by the subject (i.e., unsupervised at 
his/her home) at approximately the same time of day. Directions for the self-administration of SC injections of PEG-IFN can be found in the Pharmacy Manual.
 
 
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18. PK samples should be collected during: C1D1: pre- and post-dose, at C1D8 (post-dose), C1D22 (pre-dose), C2D22 (pre-dose), C4D1 (pre-dose), C7D1 (pre-dose) and every 
3 cycles thereafter and at 30 days after discontinuation of pembrolizumab treatment. Total IgG should be collected simultaneous with pre-dose pembrolizumab PK sampling. 
ADA (simultaneous with pre-dose PK sampling, except for the C2D22): C1D1 (pre-dose), C1D22 (pre-dose), C4D1 (pre-dose), C7D1 (pre-dose) and every 3 cycles 
thereafter and at 30 days after discontinuation of pembrolizumab treatment Pre-dose: within 60 minutes before infusion of pembrolizumab. Post-dose: within 30 minutes 
after the end of infusion of pembrolizumab C1D1 and at C1D8. A detailed PK/ADA scheme is described in Section 7.1.3.2.
19. A scan must be performed within 28 days prior to starting treatment with pembrolizumab. Scans performed as part of routine clinical management are acceptable for use as 
the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment. Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies. The first imaging assessment should be performed 12 weeks (± 3 days) 
after the first dose of trial treatment, and continue to be performed every 6 weeks (42 ± 3 days) until week 30, regardless of any treatment delays. Following week 30, tumor 
imaging will be performed approximately every 12 weeks (84 ± 7 days) (or as clinically indicated) while the patient remains on trial therapy. Subjects who discontinue trial 
treatment for a reason other than disease progression should continue to be assessed in Follow-up Phase with the first scan occurring 12 weeks (84 +/- 7 days) from the date 
of the last scan on study. The same imaging technique should be used in a subject throughout the trial. Local reading (investigator assessment with site radiology reading) 
will be used to determine eligibility and for subject management. The Sponsor will collect radiological assessments for retrospective analysis by a central vendor unless 
otherwise noted by the Sponsor. The processes for image collection and transmission to the central vendor are in the Site Imaging Manual.   
20. Per the modified RECIST 1.1 used in this protocol, if imaging shows PD, the imaging assessment should be performed no sooner than 4 weeks later in order to confirm PD 
as described in Section 4.2.3.2.
21. For subject with MEL only: Qualitative digital photography should be performed at baseline and at time of scheduled tumor assessments for cutaneous lesions. Cutaneous 
lesions are not considered measurable for the purposes of this protocol, but may be considered to be non-target lesions for tumor assessments by investigators. Copies of 
digital photographs should not be submitted to the central imaging vendor unless otherwise noted by the Sponsor.
22. Collection of archival tumor tissue for purpose of biomarker analysis. Written subject consent is required for collection of archival tumor tissue. Tumor sample should be 
adequate for biomarker analyses assessment. Subjects with an inadequate archival sample may obtain a new biopsy and subjects with an inadequate newly obtained biopsy 
may undergo re-biopsy at the discretion of the investigator. Specific instructions for tissue collection and shipment are provided in the Laboratory Manual.
23. A newly obtained biopsy of a tumor lesion is desirable but not mandatory. Written subject consent is required for newly obtained biopsies. Newly obtained biopsies should 
be limited to readily accessible tumor lesions (e.g., skin; peripheral lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed using 
computed tomography (CT) guidance). If performed, a tissue cylinder should be obtained that has proper size for histological examination and biomarker analysis. Specific 
instructions for tissue collection and shipment are provided in the Laboratory Manual. 
24. Blood samples should be obtained prior to Cycle 1, Cycle 3, and at discontinuation.
25. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if there 
is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. 
26. If the subject signs the Future Biomedical Research consent, any leftover samples may be stored for future biomedical research.
 
 
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1. Treatment cycles are 6 weeks.  Imaging should always be performed as scheduled and follow calendar days, regardless of any treatment delays.  
2. Subjects who discontinue trial treatment due to a reason other than disease progression should continue follow-up and assessment by radiologic imaging (and digital 
photography if applicable) every 12 weeks (± 1 week) for the first year after discontinuation, then every 6 months (± 2 weeks) for years two through five, and every 12 months 
(± 4 weeks) after year five. Imaging follow-up should continue until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of 
the study, whichever occurs first.
3. After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks after the last 
contact date to assess for survival status. In certain situations, survival data may be requested more frequently than every 12 weeks as per Section 7.1.5.3.3. Updated survival 
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or 
study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
4. In general, the window for each visit is ± 3 days unless otherwise noted. 
5. Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment). Screening 
number will be assigned when the study informed consent is signed.  
6. Informed consent for future biomedical research samples must be obtained before the DNA sample. DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained.
7. Prior medications – All concomitant medications received within 28 days prior to the screening visit and up to 30 days after the last dose of trial treatment should be recorded.
8. ECG should be performed at screening and as clinically indicated thereafter. ECGs are performed locally.
9. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.
10. Record all AEs occurring within 30 days after the last dose of trial treatment and all SAEs (related and unrelated to trial treatment)/ECIs occurring up until 90 days following 
cessation of treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. Afterwards, report only SAEs and ECIs 
that are related to trial treatment.
11. Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment. See Section 7.1.3 for details regarding laboratory tests.  
12. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 
for details regarding laboratory tests. After Cycle 8, lab samples should be collected every two cycles on D1 (i.e.; C8 D1, C10 D1, C12 D1, etc.)
13. Unresolved abnormal labs that are DRAEs should be followed until resolution.    
14. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
15. Pembrolizumab will be administered as a 30 minute IV infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Pembrolizumab should always be administered first when given in combination. 
16.In Part 1A and B, IPI will be administered for a total of 4 doses. In Part 1C, IPI will be administered for a maximum of 4 doses. Subjects will be administered IPI as a 90 
minute IV infusion. Sites should make every effort to target infusion timing to be as close to 90 minutes as possible. For additional instructions regarding dosing please refer to 
the IPI label. Subjects who initially attain clinical benefit (defined as modified RECIST 1.1 confirmed PR or SD>6 mo), and experience disease progression while receiving 
single agent pembrolizumab will be eligible for reinduction with 4 doses of IPI q3w as long as Part 1A or 1B remains open. Those subjects should follow the assessments 
detailed in Cycle 2 and beyond.
 
 
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17. IPI will be administered only on Cycle 3 and not on Cycle 4.
18. For PK samples, predose: within 60 minutes before infusion of pembrolizumab. Post-dose: within 30 minutes after the end of infusion of pembrolizumab. A detailed PK/ADA 
scheme is described in Section 7.1.3.2.
a. Parts 1A and 1B:  PK samples should be collected during C1D1 (pre- and post-dose), C1D8 (post-dose), C1D22 (pre-dose), C2D22 (pre-dose), C4D1 (pre-dose), C7D1 (pre-
dose) and every 3 cycles thereafter and at 30 days after discontinuation of pembrolizumab treatment Total IgG should be collected simultaneous with pre-dose 
pembrolizumab PK sampling. ADA (simultaneous with pre-dose PK sampling, except for C2D22): C1D1 (pre-dose), C1D22 (pre-dose), C4D1 (pre-dose), C7D1 (pre-dose) 
and every 3 cycles thereafter and at 30 days after discontinuation of pembrolizumab treatment. 
b. Part 1C:  PK samples will be collected during C1D1, C2D1, C3D1, C5D1, C7D1, C9D1, and every 2 cycles thereafter until treatment discontinuation. A PK sample at 30 
days after discontinuation of pembrolizumab treatment is not required for Part 1C. 
19. A scan must be performed within 28 days prior to starting treatment with pembrolizumab. Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment. Imaging timing should follow calendar days and should 
not be adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies. The same imaging technique should be used in a subject throughout the trial. Local 
reading (investigator assessment with site radiology reading) will be used to determine eligibility and for subject management. The Sponsor will collect radiological 
assessments for retrospective analysis by a central vendor unless otherwise noted by the Sponsor. The processes for image collection and transmission to the central vendor are 
in the Site Imaging Manual. Per the modified RECIST 1.1 used in this protocol, if imaging shows PD, the imaging assessment should be performed no sooner than 4 weeks 
later in order to confirm PD as described in Section 4.2.3.2. 
20. In Part 1A and B, the first imaging assessment should be performed 12 weeks (± 3 days) after the first dose of trial treatment, and continue to be performed every 6 weeks (42 ± 
3 days) until week 30, regardless of any treatment delays. Following week 30, tumor imaging will be performed approximately every 12 weeks (84 ± 7 days or as clinically 
indicated) while the subject remains on trial therapy.
21. In Part 1C, the first imaging assessment should be performed 6 weeks (± 3 days) after the first dose of trial treatment, and continue to be performed every 6 weeks (42 ± 3 days) 
until week 24, regardless of any treatment delays. Following week 24, tumor imaging will be performed approximately every 12 weeks (84 ± 7 days or as clinically indicated) 
while the subject remains on trial therapy. Subjects who discontinue trial treatment for a reason other than disease progression should continue to be assessed in Follow-up 
Phase with the first scan occurring 12 weeks (84 ± 7 days) from the date of the last scan on study. In Part 1C, a baseline brain MRI will be performed to rule out brain 
metastasis. 
22. For subject with MEL only: Qualitative digital photography should be performed at baseline and at time of scheduled tumor assessments for cutaneous lesions. Cutaneous 
lesions are not considered measurable for the purposes of this protocol, but may be considered to be non-target lesions for tumor assessments by investigators. Copies of digital 
photographs should not be submitted to the central imaging vendor unless otherwise noted by the Sponsor.
23. A newly obtained biopsy sample of at least one tumor lesion is preferred in all subjects and is mandatory for subjects who do not have an acceptable archival tumor tissue 
sample for PD-L1 evaluation. PD-L1 status must be assessed during screening, and if the tumor biopsy submitted is inadequate for determination of PD-L1 status by IHC at a 
central pathology laboratory, the subject will not be randomized. Subjects with an inadequate archival sample may obtain a new biopsy and subjects with an inadequate newly 
obtained biopsy may undergo re-biopsy at the discretion of the investigator. Confirmation of the tumor tissue sample adequacy for determination of PD-L1 status by IHC at a 
central pathology laboratory will not be required prior to enrollment in Part 1C. Additional biopsy sample submission is encouraged but not mandatory for Part 1C when the 
sample is inadequate for PD-L1 testing. Additional biopsy sample approximately at C3D1 and at disease progression are highly desirable when it is feasible. Newly obtained 
biopsies should be limited to readily accessible tumor lesions (e.g., skin; peripheral lymph nodes; lung, liver or internal lymph node metastases which can be readily accessed 
using CT guidance). If performed, a tissue cylinder should be obtained that has proper size for histological examination and biomarker analysis. Study sites should use the same 
biopsy techniques in this study as they routinely use for a given tumor lesion/location. Written subject consent is required for collection of tumor tissue. Specific instructions 
for tissue collection and shipment are provided in the Laboratory Manual.
 
 
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24. In Part 1A and 1B blood samples should be obtained prior to Cycle 1, Cycle 3, and at discontinuation. In Part 1C blood samples should be obtained prior to Cycle 1 Day 1, at 
Cycle 3 Day 1, at Cycle 4 Day 1 and then every 12 weeks (cycles 6 and beyond), and at Time of Discontinuation.
25. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if there is 
either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. 
26. If the subject signs the Future Biomedical Research consent, any leftover samples may be stored for future biomedical research. 
27. In Part 1C, blood for PBMC, serum and plasma biomarker analyses, TCR DNA and circulating tumor DNA should be collected at Cycle 1 Day 1, Cycle 1 Day 22, Cycle 2 Day 
1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 6 Day 1 and at Time of Discontinuation.
 
 
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1.
Treatment cycles are 6 weeks. Imaging should always be performed as scheduled and follow calendar days, regardless of any treatment delays. Subjects may receive 
Second Course Phase for a maximum of 17 doses of pembrolizumab and 4 doses of IPI. Subjects enrolled in Part 1A who received PEG-IFN who are eligible for Second 
Course Phase will only be allowed to receive pembrolizumab monotherapy.
2.
Subjects who discontinue Second Course Phase due to reasons other than disease progression should continue follow-up and assessment by radiologic imaging (and digital 
photography if applicable) every 12 weeks (± 1 week) for the first year after discontinuation, then every 6 months (± 2 weeks) for year two through five, and every 
12 months (± 4 weeks) after year five. Imaging follow-up should continue until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or 
(4) the end of the study, whichever occurs first.
3.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks after last 
contact to assess for survival status. In certain situations, survival data may be requested more frequently than every 12 weeks as per Section 7.1.5.3.3.  Updated survival 
status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit 
or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects that have a death event previously recorded).
4.
In general, the window for each visit is ± 3 days unless otherwise noted. 
5.
Subjects who either a) stopped initial treatment with pembrolizumab after attaining an investigator-determined confirmed CR according to modified RECIST 1.1 (subjects
treated with at least 24 weeks of pembrolizumab before discontinuing therapy and received at least two treatments with pembrolizumab beyond the date when the initial CR 
was declared or b) had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study therapy for reasons other than disease progression or intolerability 
may restart treatment if they meet the criteria specified in Section 7.1.5.2.1. 
6.
Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.
7.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.
8.
Record all AEs occurring within 30 days after the last dose of trial treatment and all SAEs (related and unrelated to trial treatment) / ECIs occurring up until 90 days 
following cessation of treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. Afterwards, report only 
SAEs and ECIs that are related to trial treatment.
9.
Laboratory tests for determining eligibility for retreatment are to be performed within 10 days prior to the first retreatment dose. See Section 7.1.3 for details regarding 
laboratory tests.
10. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. After Cycle 8, lab procedures should be collected every two cycles on D1 (i.e.; 
C8 D1, C10 D1, C12 D1, etc.). Laboratory results must be known and acceptable prior to dosing. See Section 7.1.3 for details regarding laboratory tests.
11. Unresolved abnormal labs that are DRAEs should be followed until resolution. 
12. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required. Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
13. Pembrolizumab will be administered as a 30 minute IV infusion. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
Pembrolizumab should always be administered first when given in combination.
14. IPI will be administered for a total of 4 doses for subjects that were previously included in Part 1B and for up to 4 doses for subjects that were previously included in Part 
1C. Subjects will be administered IPI as a 90 minute IV infusion. Sites should make every effort to target infusion timing to be as close to 90 minutes as possible. For 
additional instructions regarding dosing please refer to the IPI label. Subjects who initially attain clinical benefit (defined as modified RECIST 1.1 confirmed PR or SD>6 
mo), and experience disease progression while receiving single agent pembrolizumab will be eligible for reinduction with up to 4 doses of IPI q3w as long as Part 1A or 1B 
remain open. Those subjects should follow the assessments detailed in Cycle 2 and beyond.
 
 
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15. A scan must be performed within 28 days prior to starting treatment with pembrolizumab. Scans performed as part of routine clinical management are acceptable for use as 
the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment. Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies.  
16. For subjects that were previously included in Part 1A and Part 1B, the first imaging assessment should be performed 12 weeks (± 3 days) after the first dose of trial 
treatment, and continue to be performed every 6 weeks (42 ± 3 days) until week 30, regardless of any treatment delays. Following week 30, tumor imaging will be 
performed approximately every 12 weeks (84 ± 7 days) (or as clinically indicated) while the subject remains on trial therapy. For subjects that were previously included in 
Part 1A and 1B, a baseline brain MRI will be performed to rule out brain metastasis.
17. Subjects who discontinue trial treatment for a reason other than disease progression should continue to be assessed in Follow-up Phase with the first scan occurring 12 
weeks (84 + 7 days) from the date of the last scan on study. The same imaging technique should be used in a subject throughout the trial. Local reading (investigator 
assessment with site radiology reading) will be used to determine eligibility and for subject management. The Sponsor will collect radiological assessments for 
retrospective analysis by a central vendor unless otherwise noted by the Sponsor. The processes for image collection and transmission to the central vendor are in the Site 
Imaging Manual. Per the modified RECIST 1.1 used in this protocol, if imaging shows PD, the imaging assessment should be performed no sooner than 4 weeks later in 
order to confirm PD as described in Section 4.2.3.2.
18. For subjects that were previously included in Part 1C, the first imaging assessment should be performed 6 weeks (± 3 days) after the first dose of trial treatment, and 
continue to be performed every 6 weeks (42 ± 3 days) until week 24, regardless of any treatment delays. Following week 24, tumor imaging will be performed 
approximately every 12 weeks (84 ± 7 days or as clinically indicated) while the subject remains on trial therapy. For subjects that were previously included in Part 1C, a 
baseline brain MRI will be performed to rule out brain metastasis.
19. For subject with MEL only: Qualitative digital photography should be performed at baseline and at time of scheduled tumor assessments for cutaneous lesions. Cutaneous 
lesions are not considered measurable for the purposes of this protocol, but may be considered to be non-target lesions for tumor assessments by investigators. Copies of 
digital photographs should not be submitted to the central imaging vendor unless otherwise noted by the Sponsor.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
General Informed Consent
7.1.1.1.1
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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Consent and Collection of Specimens for Future Biomedical Research
7.1.1.1.2
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects 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 subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee. The medical
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically significant. Details regarding the 
disease for which the subject has enrolled in this trial will be recorded separately and not 
listed as medical history.
Prior and Concomitant Medications Review
7.1.1.5
Prior Medications
7.1.1.5.1
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this trial will be recorded separately and not listed as a prior medication.
Concomitant Medications
7.1.1.5.2
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the Safety Follow-up visit. In addition, new medications started 
during the Second Course Phase through the Second Course Safety Follow-up visit should be 
recorded.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2.
 
 
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Disease Details
7.1.1.5.3
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
Prior Treatment Details
7.1.1.5.4
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.
Subsequent Anti-Cancer Therapy Status
7.1.1.5.5
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject will 
move into SFU. 
Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.  
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
Assignment of Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
Drug administration should start within 7 days from assignment of a randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
7.1.1.8
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
 
 
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Administration of first dose of PEG-IFN will be witnessed by the investigator and/or trial
staff on Day 1. Drug accountability will be collected during the study. Compliance with
PEG-IFN administration will be measured by subjects: 1) receiving unscheduled study agent
injections; 2) missing an injection. Numbers and percentages of subjects and injection visits
with any deviation in these measures will be reported.
The instructions for preparing and administering trial treatments will be provided in the 
Study Manuals.
Clinical Procedures/Assessments
7.1.2
Adverse Event (AE) Monitoring
7.1.2.1
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart (Section 6) and more frequently if 
clinically indicated. Adverse events will be graded and recorded throughout the trial and 
during the follow-up period according to NCI CTCAE Version 4.0 (see [Section 12.5).  
Toxicities will be characterized in terms including seriousness, causality, toxicity grading, 
and action taken with regard to trial treatment.
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irAE). See Section 5.6.1 and the separate guidance document in the administrative 
binder regarding the identification, evaluation, and management of AEs of a potential 
immunological etiology.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Physical Exam
7.1.2.2
Full Physical Exam
7.1.2.2.1
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 6. After the first 
dose of trial treatment, new clinically significant abnormal findings should be recorded as
AEs.
Directed Physical Exam
7.1.2.2.2
For cycles that do not require a full physical exam as defined in Section 6, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the trial treatment. New clinically significant abnormal findings should be 
recorded as AEs.
 
 
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Vital Signs
7.1.2.3
Vital signs include temperature, pulse, respiratory rate, weight and blood pressure. The 
investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment and during the follow-up period as specified in the Trial Flow 
Chart (Section 6). Height will be measured at Screening.
Electrocardiogram (ECG)
7.1.2.4
A standard 12-lead ECG will be performed using local standard procedures at Screening.  
Clinically significant abnormal findings should be recorded as medical history. Additional
time points for standard 12-lead ECGs must be performed as per Section 6 – Trial Flow
Charts. Clinically significant abnormal findings seen on the follow-up ECGs should be
recorded as adverse events.
Eastern Cooperative Oncology Group (ECOG) Performance Scale
7.1.2.5
The investigator or qualified designee will assess ECOG status (see Appendix 12.4) at 
screening, additional time points for assessment of ECOG must be performed as per Section 
6 – Trial Flow Charts.
Tumor Tissue Collection
7.1.2.6
Tumor tissue for biomarker analysis from formalin fixed paraffin embedded tumor tissue 
sample or newly obtained formalin fixed biopsy of a tumor lesion not previously irradiated 
must be provided in the form of a tissue block or at least ten unstained slides and received by 
the central vendor and tested for PD-L1 status by IHC before randomization. Subjects will 
be enrolled in the trial regardless of the expression. Subjects who do not submit a sample 
adequate for PD-L1 determination will not be enrolled. Subjects with an archival sample 
considered not adequate may obtain a new biopsy. Subjects with a newly obtained biopsy
considered not adequate may undergo re-biopsy at the discretion of the investigator. Note for
Part 1C: adequacy of the tumor sample for determination of PD-L1 status by IHC at a central 
pathology laboratory prior to enrollment is not required.
Additional biopsy sample 
submission is encouraged but not mandatory for Part 1C when the sample is inadequate for 
PD-L1 testing.
Note: A fine needle aspirate or cytologic specimen will not be acceptable. Core needle or 
excisional biopsies, or resected tissue is required. Newly obtained formalin fixed specimens 
are encouraged.
If new scientific data emerge that indicate that an existing biopsy or surgical specimen is 
suboptimal for identification of subjects, then only new biopsies will be acceptable for 
determination of PD-L1 status. 
If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue 
biopsies that would ordinarily be discarded at the end of the main study will be retained for 
FBR, again providing the subject has signed the FBR consent.
 
 
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Detailed instructions for tissue collection, processing and shipment are provided in the 
Laboratory Manual.
Tumor Imaging and Assessment of Disease
7.1.2.7
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM). Tumor imaging is strongly preferred to be acquired 
by computed tomography (CT). Magnetic resonance imaging (MRI) should be used only 
when CT is contraindicated or for imaging of the brain. The same imaging technique 
regarding modality and the use of contrast should be used in a subject throughout the trial to 
optimize the visualization of existing and new tumor burden. 
At least 1 year after the last subject has enrolled in Parts 1A, 1B and 1C, the Sponsor may 
elect to halt central vendor imaging collection and continue with investigator assessment 
only. If this switch will occur, the decision will be announced through an administrative 
memo from the Sponsor.
Assessment of Disease
7.1.2.8
The primary measure for assessment of tumor response will be based on independent central 
review using RECIST 1.1 [1]. RECIST 1.1 will be used by independent central review as the 
primary measure for assessment of tumor response, date of disease progression, and as a 
basis for all protocol guidelines related to disease status (eg, discontinuation of trial therapy). 
Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, the 
Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant 
to enable a broader sampling of tumor burden.
Modified RECIST 1.1 will be applied by the site as the basis for all protocol guidelines 
related to disease status (e.g., discontinuation of study therapy).
RECIST 1.1 will be adapted as follows to account for the unique tumor response seen in this 
class of therapeutics.
If RECIST 1.1 defined progression has been assessed then the subject will be discontinued 
from trial treatment unless, in the opinion of the investigator, the subject is deriving clinical 
benefit from the therapy and the subject does not have any signs or symptoms of clinical
instability as discussed in Table 11 Imaging and Treatment after 1st Radiologic Evidence of 
PD in Section 5.2.3.
Clinically stable is defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
clinically significant disease progression

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
 
 
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Note: Treatment may be continued despite modified RECIST 1.1 defined progression if the 
subject is clinically stable and is considered to be deriving clinical benefit by the 
investigator. In these cases, subjects should continue to undergo imaging as outlined in the 
footnote in Table 11.
Ophthalmologic Examination
7.1.2.9
All subjects receiving pembrolizumab + PEG-IFN should have a baseline ophthalmologic 
exam including visual acuity, visual field and color discrimination by an ophthalmologist. 
Fundus photography should be performed in subjects with history of clinically significant 
retinal disease (defined as macular degeneration, retinal detachment and moderate/severe 
non-proliferative diabetic retinopathy and any proliferative diabetic retinopathy). Enrollment 
of subjects with clinically significant retinal disease will require consultation with the 
sponsor on risk-benefit associated to treatment. Any subject randomized in the 
pembrolizumab + PEG-IFN treatment group complaining of ocular symptoms, including loss 
of visual acuity or visual field must have a prompt and complete ophthalmologic 
examination. In addition, because these ocular events may occur in conjunction with other 
disease states, periodic visual examinations during the trial are recommended in subjects with 
disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. 
Discontinuation of PEG-IFN should be considered in subjects who develop new or 
worsening ophthalmological disorders.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Trial Laboratory
Manual. Refer to the Trial Flow Chart (Section 6) for the timing of laboratory assessments.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 12.
 
 
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Table 12
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum 
or urine)a
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
Alanine aminotransferase
Protein
aPTT
WBC (total
and 
differential)d
Amylase
Specific gravity 
Total T3 or free T3, 
FT4, and TSHb
RBC
Aspartate aminotransferase
Microscopic exam, if 
abnormal 
results 
are 
noted
Anti-HCVe
Absolute 
lymphocyte countd
Bicarbonatec
HCV viral loade
Absolute 
neutrophil countd
Calcium
HCV genotypee
Chloride
anti-HBse
Creatinine
HBsAge
Glucose
Anti-HBc 
(total 
and 
IgM)e
LDHe
HBeAge
Lipase
anti-HBee
Magnesium
HBV viral loade
Phosphorus
Potassium
AFPe
Sodium
CRPe
Total bilirubin  
GGTe
Direct bilirubin
Total protein
Blood urea nitrogen
a  Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1. Pregnancy tests must be repeated 
prior to every cycle if required or as specified per local regulatory guidance.
b  T3 is preferred; if not available, free T3 may be tested. 
c  If this test is not done as part of local standard of care, this test does not need to be performed.  
d  Report % or absolute results per standard of practice. Report the results in the same manner throughout the trial.
e These tests should be performed at screening, and then as clinically indicated, except for AFP and GGT, which should 
only be performed as clinically indicated. For the purpose of determining eligibility, perform HBsAg and HCV viral load. 
Anti-HCV is allowed for screening purposes in countries where HCV viral load is not part of standard of care. All other 
hepatitis tests should be performed per standard of care.
Note: If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for 
testing. Details are provided in the Laboratory Manual.
AFP=alpha-fetoprotein; aPTT=activated partial thrombin time; CRP=C-reactive protein; FT4=free thyroxine; 
GGT=gamma-glutamyl transferase; HBc=hepatitis B core; HBeAg=hepatitis B e antigen; HBe=hemoglobin E; 
HBs=hepatitis B surface; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; IgM=gamma 
M immunoglobulin; INR=insulin receptor; LDH=lactate dehydrogenase; PT=prothrombin time; RBC=red blood cells; 
T3=triothyronine; TSH=thyroid stimulating hormone (thyrotropin); WBC=white blood cells.
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of trial treatment. An exception is hepatitis and thyroid 
serologies, which may be performed within 28 days prior to first dose. After Cycle 1, 
pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. After Cycle 
 
 
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Table 14
Timing of PK and ADA Assessments, Parts 1A and 1B
Drug
Study Part
Pembrolizumab Dose 
Number
Time of PK and ADA Blood Sample Collection
IPI
(PK and ADA)
Treatment Phase
Dose  1 and 4
Predose IPI: within 60 min before the infusion of IPI
Postdose IPI: within 30 min after end of infusions of IPI (only PK)
Dose 5 (q3w) 
Predose pembrolizumab: within 60 min before the infusion of pembrolizumab
pembrolizumab 
(total IgGa, PK 
and ADA)
Treatment Phase
Dose 1
Predose pembrolizumab: within 60 min before the start of the infusion and prior to a
potential IPI or PEG-IFN dosing on the same dayd
Only for pembrolizumab (not for total IgG and ADA): Postdose pembrolizumab: 
within 30 min after the end of the infusion
Only for pembrolizumab (not for total IgG and ADA): Postdose pembrolizumab: at 
Day 8 (and prior to a potential IPI or PEG-IFN dosing on that same day)
Dose 2, 4, 7, 13, etc.b
Predose pembrolizumab: within 60 min before the start of the infusiond
For ADA: Predose pembrolizumab within 60 min before start of the infusion 
EXCEPT for the 4th dose of pembrolizumab
30 
day 
post 
pembrolizumab
treatmentc
Obtain a PK blood sample at 30 days (±7 days) after the last dose of pembrolizumab
and at the same time that the blood sample is obtained for anti-pembrolizumab 
antibody testing
a. Total IgG should be collected simultaneous with every pre-dose pembrolizumab PK sampling.
b. After Dose #7 of pembrolizumab, obtain PK and total IgG blood samples before dosing of every 6th dose for the duration of the study (i.e., pembrolizumab dose 13, 19, 25, 
31, 37, 43, and 49).
c. Post-treatment samples may not be collected if the subject has started treatment with a new anti-cancer therapy.
d. Predose pembrolizumab samples should be obtained at the same time that blood samples are drawn for total IgG and anti-pembrolizumab antibody testing (ADA).
 
 
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Table 15
Timing of PK and ADA Assessments, Part 1C
Drug
Study Part
Pembrolizumab Dose Number
Time of PK and ADA Blood Sample Collection
IPIa
(PK and ADA)
Treatment Phase 
Arm 1 (50 mg q6w):  dose 1, 3, 5, 7, 9
Predose IPI: within 60 min before the infusion of IPI
Postdose IPI: within 30 min after end of infusions of IPI (only PK)
Arm 2 (100 mg q12w):  dose 1, 5, 9, 
13, 17
Pembrolizumaba
(total IgGb,  PK, 
and ADA)
Treatment Phase 
Dose 1, 3, 5, 9, then every 4th dose 
thereafter
Predose pembrolizumab: within 60 min before the start of the 
infusionc
NOTE:  Only three samples will be collected at visits which require IPI and pembrolizumab PK. The predose sample will be the baseline for both pembrolizumab and IPI PK 
assessments.
NOTE:  All PK and ADA samples should be taken at the same time.
a  At time points with both pembrolizumab and IPI samples, predose IPI and predose pembrolizumab samples can be obtained from the same extraction.
b  Total IgG should be collected simultaneous with every pre-dose pembrolizumab PK sampling.
c  Predose pembrolizumab samples should be obtained at the same time that blood samples are drawn for total IgG and anti-pembrolizumab antibody testing (ADA).
 
 
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Blood Collection for Serum MK-3475
7.1.3.2.1
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Laboratory Manual.
Blood Collection for Anti-MK-3475 Antibodies (ADA)
7.1.3.2.2
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Laboratory Manual.
Every effort should be taken to collect samples at 30 days after end of pembrolizumab
treatment for ADA. 
Simultaneous PK sampling is required for interpretation of ADA analysis.
Blood Collection for total IgG
7.1.3.2.3
Endogenous IgG levels were found in internal unpublished studies to be a factor significantly 
affecting the exposure of pembrolizumab. Additional information about individual IgG levels 
is required to confirm this effect, in particular when patients do receive immune modulatory 
co-medications such as PEG-IFN and IPI.
Total IgG should be collected simultaneous with every pre-dose pembrolizumab PK 
sampling.
Future Biomedical Research
7.1.3.3
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Leftover correlative blood samples

Leftover blood for genetics sample

Leftover archival tumor tissue or leftover newly obtained biopsy samples taken 
throughout the study
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. In Part 1A and 1B and upon Sponsor consultation, subjects who 
 
 
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either a) stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to modified RECIST 1.1 (subjects treated with at least 
24 weeks of pembrolizumab before discontinuing therapy and received at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared) or b) had 
SD, PR or CR and stopped pembrolizumab treatment after 24 months of study therapy for 
reasons other than disease progression or intolerability may restart trial Second Course Phase
if they meet the criteria specified in Section 7.1.5.2.1. Additionally in Part 1C and upon 
Sponsor consultation, subjects who a) attain an investigator-determined CR or b) a VGPR 
and complete treatment with at least one dose of IPI on either Arm of treatment may 
discontinue treatment with IPI with the option of restarting the Second Course Phase if they 
meet the criteria specified in Section 7.1.5.2.1. After discontinuing treatment following 
assessment of CR, these subjects should return to the site for a Safety Follow-up Visit 
(described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.3.2) and SFU (described in Section 7.1.5.3.3).
Withdrawal From Future Biomedical Research
7.1.4.1.1
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
Calibration of Critical Equipment
7.1.4.3
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 
 
 
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reproducible.  Documentation of equipment calibration must be retained with the study 
documentation 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 See Protocol-specific 
Administrative Binder and Site Imaging Manual.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
7.1.5.1
Within 28 days prior to treatment randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Visit 
requirements are outlined in the Trial Flow Chart (Section 6). Screening procedures may be 
repeated.
Written consent must be obtained prior to performing any protocol-specific procedure.  
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:
•
Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment.
•
For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site 
laboratory, will be required.
•
Tumor imaging must be performed within 28 days prior to the first dose of trial 
treatment.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeating a screening test if performed within the specified time frame and the results 
meet the inclusion/exclusion criteria.
Treatment Period
7.1.5.2
Visit requirements are outlined in the Trial Flow Chart (Section 6). Specific procedure-
related details are provided in Section 7.1.
After a screening phase of up to 28 days, eligible subject will receive assigned treatment on 
Day 1 of each dosing cycle and thereafter following a weekly (PEG-IFN) or every 3, 6 or 
 
 
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12 weeks (IPI) schedule, depending on the part and the treatment group in which the subject 
is enrolled. Pembrolizumab will be given q3w. A cycle is 6 weeks. Additional information 
regarding the DLT assessment period can be found in Section 5.2.1.2.1.
Treatment with pembrolizumab + PEG-IFN doublet will continue until up to two years of 
therapy have been administered, documented disease progression, unacceptable AEs, 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance 
with trial treatment or procedure requirements, or administrative reasons. 
In Parts 1A and 1B, treatment with pembrolizumab + IPI doublet will continue for 2 cycles 
(12 weeks), followed by treatment with pembrolizumab single agent until up to 24 months of 
therapy have been administered, documented disease progression, unacceptable AEs, 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance 
with trial treatment or procedure requirements, or administrative reasons. 
In Part 1C, treatment with pembrolizumab + IPI doublet will continue for a maximum of 
4 cycles (24 weeks) or 8 cycles (48 weeks), for Arm 1 and Arm 2, respectively, followed by 
treatment with pembrolizumab single agent until up to 24 months of therapy have been 
administered, documented disease progression, unacceptable AEs, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw the subject, 
subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons. 
Second Course Phase 
7.1.5.2.1
Upon Sponsor consultation, subjects who stop pembrolizumab with SD or better per 
modified RECIST 1.1 may be eligible for retreatment with pembrolizumab + IPI at a dose of 
pembrolizumab of 200 mg q3w or pembrolizumab 200 mg q3w monotherapy if they progress 
after stopping pembrolizumab, at the discretion of the investigator, as long as the Part to 
which the subject was initially enrolled remains open. This retreatment is termed the Second 
Course Phase of this trial. Subjects enrolled in Part 1A who received PEG-IFN and who are 
eligible for the Second Course Phase will only be allowed to receive pembrolizumab 
monotherapy. The Second Course Phase will be administered for a maximum of 17 doses of 
pembrolizumab and 4 doses of IPI. The Second Course Phase of this trial is only available if
the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to modified RECIST 1.1.

Was treated
for at least
24 weeks with
pembrolizumab
before 
discontinuing therapy.

Received at least two treatments with pembrolizumab beyond the date 
when the initial CR was declared.
 
 
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OR
o
Subject had SD, PR or CR and stopped pembrolizumab treatment after 24 months
of study therapy for reasons other than disease progression or intolerability.

AND
o
Experienced 
an 
investigator-determined 
confirmed 
radiographic 
disease 
progression after stopping their initial treatment with pembrolizumab.
o
Did not receive any anti-cancer treatment since the last dose of pembrolizumab.
o
Have a performance status of 0 or 1 on the ECOG Performance Scale.
o
Demonstrate adequate organ function as detailed in Section 5.1.2.
o
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study 
medication.
o
Female subjects of childbearing potential should be willing to adhere to the 
contraception requirements outlined in Section 5.7.2 for the course of the study 
through 120 days after the last dose of study medication. Subjects of child bearing 
potential are those who have not been surgically sterilized or have not been free 
from menses for > 1 year. 
o
Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy.
o
Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might interfere with the subject’s participation for the 
full duration of the trial or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.
Subjects in the Second Course Phase will restart retreatment with pembrolizumab + IPI at a 
dose of pembrolizumab of 200 mg q3w or pembrolizumab 200 mg q3w monotherapy. 
Subjects will not be allowed to restart the Second Course with pembrolizumab + PEG-IFN.
The Second Course Phase will be administered for a maximum of 17 doses of 
pembrolizumab and 4 doses of IPI.
Visit requirements are outlined in Section 6.2 – Trial Flow Chart for Second Course of 
Treatment. Treatment beyond confirmed PD is not permitted for Second Course Phase.
Post-Treatment Visits
7.1.5.3
Safety Follow-up Visit
7.1.5.3.1
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first.  
 
 
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All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an 
AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anticancer therapy, whichever occurs first. Serious AEs that occur within 
90 days of the end of treatment or 30 days following cessation of trial treatment if the subject 
initiates new anticancer therapy should also be followed and recorded.  
Subjects who are eligible for retreatment with pembrolizumab may have up to 2 safety 
follow-up visits, 1 after the Initial Treatment Period and 1 after the Second Course 
Treatment.
Follow-up Visits
7.1.5.3.2
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (± 1 week) for the 
first year after discontinuation, then every 6 months (± 2 weeks) for years two through five, 
and every 12 months (± 4 weeks) after year five to monitor disease status. 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).  Every effort should be made to collect information 
regarding disease status until the start of new anti-cancer therapy, disease progression, death, 
end of trial [or if the subject begins retreatment with pembrolizumab as detailed in 
Section 7.1.5.2.1]. Information regarding post-trial anticancer treatment will be collected if 
new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.2 will move from the Follow-Up Phase to the Second Course Phase when 
they experience disease progression. Details are provided in the Trial Flow Chart (Section 6) 
for retreatment with pembrolizumab.
Survival Follow-up (SFU)
7.1.5.3.3
Subjects who experience confirmed disease progression or start a new anticancer therapy, 
will move into the SFU Phase and should be contacted by telephone approximately every 
12 weeks from the last contact date to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first.  
Survival Status
7.1.5.4
To ensure current and complete survival data are available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee review, interim and/or final analysis. Upon Sponsor notification, all 
subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined time period will be contacted for their survival status (excluding subjects 
that have a previously recorded death event in the collection tool).
 
 
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Assessing and Recording Adverse Events
7.2
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 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical
product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
For purposes of this trial, an overdose is any dose higher than 20% over the prescribed dose 
for pembrolizumab or IPI, or any dose exceeding the prespecified dose of pembrolizumab by 
 
 
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≥1000 mg (5 times the dose) for pembrolizumab 200 mg fixed dosing, or any dose exceeding 
the prescribed dose for PEG-IFN by 50%. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, PEG-IFN should be 
discontinued and the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
trial treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper.  Sponsor Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 16 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of trial treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause other than progression 
of the cancer under study (reference Section 7.2.3.3 for additional details), whether or not 
related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Electronic reporting procedures can be found in the EDC data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent)
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
 
 
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Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90  days 
following cessation of treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any ECI or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
3. In the event a subject develops any of the following AEs, a detailed narrative of the event 
should be reported as an ECI to the SPONSOR within 24 hours of the event:
a.
Grade ≥ 3 diarrhea
b. Grade ≥ 2 colitis
c.
Grade ≥ 2 pneumonitis
d. Grade ≥3 hypo- or hyperthyroidism
e.
Grade ≥ 2 Depression
A separate guidance document has been provided entitled “Pembrolizumab Events of 
Clinical Interest and Immune-Related Adverse Event Guidance Document.” This document 
 
 
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can be found in the administrative binder and provides guidance regarding identification, 
evaluation and management of ECIs and irAEs. Additional ECIs are identified in this 
guidance document and also need to be reported to the SPONSOR within 24 hours of the 
event.
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event. Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiological causes. If lab results or symptoms indicated a 
possible immune-related ECI then additional testing should be performed to rule out other 
etiologic causes. If no other cause was found, then it is assumed to be immune-related.
Protocol-Specific Exceptions to Serious Adverse Event Reporting
7.2.3.3
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3.  
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 16
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to 
Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with 
Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, 
there 
is 
a 
reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable. The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the trial. If, after the
trial has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, along with an explanation as to when and why they 
occurred, will be listed in the Clinical Study Report (CSR) for the trial. Post hoc exploratory 
analyses will be clearly identified in the CSR. No separate SAP will be issued for this trial.
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Part 1
8.1.1
The primary purpose of Part 1A of this trial is to investigate the safety and tolerability of 
MK-3475 in combination with PEG-IFN or IPI in adult subjects with MEL or RCC. The 
primary purpose of Part 1B of this trial is to further characterize the safety, tolerability and 
preliminary efficacy of the MK-3475 in combination with IPI in MEL subjects. Descriptive 
tables that summarize the number and percentage of subjects that experience adverse events 
as categorized in the NCI CTCAE Version 4 will be generated by dose level for the all 
subjects as treated population. 
At the end of the Part 1A of the trial, the dose-response relationship, as the percentage of 
subjects experiencing at least one DLT in Cycle 1, for each dose level in the MK-3475+PEG-
IFN combination will be estimated using a Bayesian pooling of adjacent violators analysis as 
outlined by Ji et al [84] using all DLT data from the trial with a conservative adjustment as 
described in Section 5.2.1.2.  For the MK-3475+IPI combination, the percentage of subjects 
experiencing at least one DLT in Cycle 1 will be summarized for both Part 1A and 1B. The 
dose-response profile, along with other tolerability data, will be used to determine the 
recommended Phase 2 dose (RP2D) for MK-3475+PEG-IFN.  
The Part 1A sample size of the trial depends primarily on clinical considerations rather than 
on statistical considerations. Specifically, the final number of subjects enrolled in the trial 
will depend on empirical safety (DLT) observations. However, it is estimated that a 
maximum of 25 subjects evaluable for safety and tolerability will be enrolled in Part 1A for  
the MK-3475+PEG-IFN combination, and a maximum of 18 subjects will be enrolled in Part 
1A for the MK-3475+IPI combination. 
The Part 1B sample size is driven by the expected number of PD-L1 negative subjects. 
Assuming that the prevalence of PD-L1 negative subjects is ~25%, then 90 subjects would be 
 
 
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expected to provide ~22 subjects with PD-L1 negative MEL. If less than 22 PD-L1 negative 
MEL were enrolled in the MK-3475+IPI arm in Part 1A and 1B combined, enrollment will 
continue until at least 22 PD-L1 negative subjects are enrolled, up to a maximum of 150 
subjects in Part 1B. Historical data has shown a response rate of 15% for PD-L1 negative 
MEL subjects treated with MK-3475 monotherapy. With  22 subjects with PD-L1 negative 
MEL, the study provides 80% power to rule out a lower bound on the ORR of 15% if the true 
ORR for MK-3475+IPI in PD-L1 negative subjects is 40%. If no less than 7 responses are 
observed, 22 PD-L1 negative subjects will allow excluding a 15% ORR lower bound of the 
95% CI. 
The Part 1C sample size provides adequate precision for the estimation of the ORR and the 
rate of grade 3-5 DRAEs for the regimens being assessed, with guidelines provided to assess 
whether the therapies maintain the ORR seen with pembrolizumab and standard dose 
ipilimumab, while substantially reducing the rate of grade 3-5 DRAEs. 
Statistical Analysis Plan
8.2
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is open-label; the subject, the trial site personnel, and the Sponsor are not blinded to 
individual treatment group assignment for Part 1 of the study. The Clinical Biostatistics 
department will generate the randomized allocation schedule(s) for study treatment 
assignment. Subjects in Part 1A and 1C will be randomly assigned to treatment combination 
(pembrolizumab + PEG-IFN or pembrolizumab + IPI) if both combinations are open for
enrollment.
Hypotheses/Estimation
8.2.2
Objectives and hypotheses of the trial are stated in Section 3.
Analysis Endpoints
8.2.3
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
Safety Endpoints
8.2.3.1
Safety measurements of interest are described in Section  4.2.3.1.
Part 1A:  The primary Part 1A safety endpoint is the DLT rate. 
Part 1B and 1C:  For Part 1B and Part 1C, all ECIs listed in the irAE guidance as well as 
Grade ≥2 Depression are prespecified as events of interest (Tier-1 events).
 
 
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Efficacy Endpoints
8.2.3.2
Primary Efficacy Endpoint
The primary efficacy endpoint will be the ORR defined as the proportion of the subjects in 
the analysis population who have best response as CR or partial response (PR). Responses 
are based on central independent review using RECIST 1.1.
Ordinal response score, per RECIST 1.1, defined as the best overall response calculated as 
the following:
1=Complete Response
2=Very Good Partial Response [>60% tumor reduction]
3=Moderate Partial Response [>30% - ≤60% tumor reduction] 
4=Stable Disease
5=Progressive Disease
Ordinal response scores are based on central independent review using RECIST 1.1.
Additional secondary efficacy endpoints include PFS, defined as the time from 
randomization to the first documented disease progression (based on central independent 
review using RECIST 1.1) or death due to any cause, whichever occurs first, duration of 
response among subjects who achieve a best response as CR or PR per RECIST 1.1 and OS.
Pharmacokinetic endpoints include area under the curve (AUC), Cmax, and clearance.
Analysis Populations
8.2.4
Efficacy Analysis Populations
8.2.4.1
ORR, DOR, PFS, and OS analyses will be restricted to those patients with measurable 
disease at baseline based on central independent review.
Safety Analysis Populations
8.2.4.2
For Part 1A safety analyses related to DLT rate, the DLT evaluable population will be used. 
The DLT evaluable population consists of all DLT evaluable subjects. In order to be 
considered evaluable, the subject must complete the first cycle of combination therapy or 
discontinue from the trial due to a DRAE. Subjects who discontinue prematurely due to a non 
drug-related cause are not included in the DLT evaluable population (refer to Section 
5.2.1.2.2 for detailed DLT replacement criteria).
For all other Part 1 safety analyses, the APaT population will be used for the analysis of 
safety data. The APaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the APaT 
population. For most subjects, this will be the treatment group to which they are randomized.
Subjects who take incorrect study treatment for the entire treatment period will be included in 
 
 
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the treatment group corresponding to the study treatment actually received. At least one 
laboratory or vital sign measurement obtained subsequent to at least one dose of trial
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section  8.2.5 Statistical Methods.
Statistical Methods
8.2.5
Statistical Methods for Efficacy Analyses
8.2.5.1
Progression-free Survival (PFS) 
8.2.5.1.1
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve for each 
treatment group in the Part 1B and 1C of the trial.
Overall Survival (OS)
8.2.5.1.2
The Kaplan-Meier method will be used to estimate the OS curve in each treatment group.
Objective Response Rate (ORR)
8.2.5.1.3
Exact 90% confidence intervals for ORR will be calculated for the true ORR for the 
treatments investigated in Part 1C. 
Ordinal Response Score
8.2.5.1.4
The frequency distribution of the ordinal response score will be estimated by calculating 
number of patients in each category divided by the total number of patients in the FAS 
population. Subjects with missing data will be considered non-responders.  
Duration of Response (DOR)
8.2.5.1.5
If sample size permits, duration of response will be summarized descriptively using Kaplan-
Meier curves medians and quartiles. Only the subset of subjects who show a CR or PR will 
be included in this analysis. 
Pharmacokinetic Parameters
8.2.5.1.6
Pharmacokinetic parameters will be summarized using descriptive statistics.
Table 17 summarizes the analysis strategy for primary and secondary efficacy endpoints.
 
 
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Table 17
Summary of Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary Hypothesis:
ORR (Part 1C)
P
Exact 90% 
confidence intervals 
for true ORR
FAS
Subjects with 
missing data are 
considered as 
non-responders
Secondary Objectives:
DOR
P
Summary statistics 
using Kaplan-Meier
method
All responders
Non-responders 
are excluded in 
analysis
ORR (Part 1B)
P
Exact test of 
binomial parameter
FAS
Subjects with 
missing data are 
considered as 
non-responders
PFS
P
Estimation: 
Kaplan-Meier 
method for PFS 
curve estimation in 
each treatment group
ITT
Censored at last 
disease 
assessment
OS
P
Summary statistics 
using Kaplan-Meier 
method
ITT
Censored at last 
date known alive
PK
P
Descriptive Statistics
All treated 
subjects
Missing data 
excluded from 
analysis
Ordinal Response Score (Part 
1B and 1C)
P
Descriptive Statistics 
FAS
Subjects with 
missing data are 
considered as 
non-responders
Statistical Methods for Safety Analyses
8.2.5.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements and physical examinations.
Part 1A
DLTs will be listed. Adverse experiences will be summarized as counts and frequencies for 
each dose level. Laboratory assessments, vital signs, and other safety endpoints will be 
summarized as appropriate.
ECIs of a potential immunologic etiology may be defined as an adverse event of unknown 
etiology, associated with drug exposure and is consistent with an immune phenomenon.
irAEs may be predicted based on the nature of pembrolizumab and IPI, their mechanism of 
action, and reported experience with immunotherapies that have a similar mechanism of 
 
 
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action. Special attention should be paid to AEs that may be suggestive of potential irAEs. An 
irAE can occur shortly after the first dose or several months after the last dose of treatment.
Part 1B and Part 1C
All ECIs listed in irAE guidance and Tier 2 or 3 safety parameters listed in Table 18 will be 
described via inferential and descriptive statistics.
Table 18
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
All ECIs in irAE guidance
X
X
X
Grade ≥ 2 depression
X
X
X
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Grade 3-5 AE
X
X
Onset and Duration of First Grade 3-5 AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Any Grade3-5 and Drug-Related AE
X
X
Dose Modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence 
≥4/1% of subjects in one of the treatment 
groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence 
<4/1% of subjects in all of the treatment 
groups)
X
Change from Baseline Results (Labs, ECGs, 
Vital Signs)
X
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
‡
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
For all subjects enrolled at the RP2D for pembrolizumab + PEG-IFN and Phase 2 Dose for 
pembrolizumab + IPI in Part 1B, the incidence of Grade 3-5 adverse experiences will be 
compared between pembrolizumab + IPI and pembrolizumab + PEG-IFN using the Miettinen 
and Nurminen method [85].
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.2.5.3
Demographic variables (e.g., age, gender), baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by descriptive statistics 
 
 
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or categorical tables. The number and percentage of subjects screened, randomized, the 
primary reasons for screening failure, and the primary reason for discontinuation will be 
displayed.
For Part 1A RCC subjects, individual efficacy listing and/or descriptive statistics (as data 
permits) will be summarized to evaluate the efficacy for pembrolizumab + IPI and 
pembrolizumab + PEG-IFN using the same efficacy endpoints as described in Section 
8.2.5.1. 
Multiplicity
8.2.6
No adjustment will be made for multiplicity in Part 1.
Sample Size and Power Calculations
8.2.7
Part 1
8.2.7.1
The Part 1A sample size of the trial depends primarily on clinical considerations rather than 
on statistical considerations. Specifically, the final number of subjects enrolled in the trial 
will depend on empirical safety (DLT) observations. However, it is estimated that a 
maximum of 25 subjects evaluable for safety and tolerability will be enrolled in Part 1A for
the pembrolizumab + PEG-IFN combination, and a maximum of 18 subjects will be enrolled 
in Part 1A for the pembrolizumab + IPI combination.
The Part 1B sample size is driven by the expected number of PD-L1 negative subjects. 
Assuming that the prevalence of PD-L1 negative subjects is ~25%, then 90 subjects would be 
expected to provide ~22 subjects with PD-L1 negative MEL. If less than 22 PD-L1 negative 
MEL were enrolled in the pembrolizumab + IPI arm in Part 1A and 1B combined, enrollment 
will continue until at least 22 PD-L1 negative subjects are enrolled, up to a maximum of 150 
subjects in Part 1B. Historical data has shown a response rate of 15% for PD-L1 negative 
MEL subjects treated with pembrolizumab monotherapy. With 22 subjects with PD-L1 
negative MEL, the study provides 80% power to rule out a lower bound on the ORR of 15% 
if the true ORR for pembrolizumab + IPI in PD-L1 negative subjects is 40%. With 7 or more
responses out of 22 PD-L1 negative patients, a 95% CI would exclude a 15% or lower ORR.
The Part 1C sample size is designed to provide adequate precision for the estimation of the 
true rate of Grade 3-5 DRAEs and the ORR for the treatments evaluated. The sample size for 
part 1C will be 100 patients (50 patients per treatment arm).
With 50 patients per treatment arm, a 95% upper bound for the true rate of Grade 3-5 DRAE 
would be:
 
 
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Observed number of 
patients experiencing 
Grade 3-5 DRAEs
95% upper bound for true 
rate of 
Grade 3-5 DRAEs
10 (20%)
32%
12 (24%)
36%
13 (26%)
38%
With 50 patients per treatment group, an observed rate of Grade 3-5 DRAEs of 26% or less 
would suggest a meaningful reduction in the rate of DRAEs compared to other combinations 
of IPI and anti-PD-1 inhibitors (pembrolizumab or nivolumab), as the 90% upper bound for 
the true rate of Grade 3-5 DRAEs excludes 40%.
With 50 patients per treatment, a 95% upper bound for the true ORR would be:
Observed number of 
patients experiencing 
an objective response
95% lower 
bound for true 
ORR
95% upper bound 
for true ORR
20 (40%)
28%
53%
22 (44%)
32%
57%
24 (48%)
36%
60%
With 50 patients per treatment group, an observed ORR of 48% or more would suggest that 
the combination ORR was consistent with that of other combinations of IPI and anti-PD-1
inhibitors (pembrolizumab or nivolumab) (as the 90% CI excludes 35%).
Interim Analyses
8.2.8
Part 1A and 1B will be considered complete when all enrolled subjects are a minimum of 24
weeks post initial trial treatment administration. At this point a database lock may occur to 
allow analysis of the data. Part 1C will be considered complete for publication purposes 
when all enrolled subjects are a minimum of 72 weeks post initial treatment administration. 
At this point database lock may occur to allow analysis of the data. If the study remains open, 
additional analyses of the data can occur to monitor the study and report on later subject
follow-up.
Compliance (Medication Adherence)
8.2.9
Drug accountability data for trial treatment will be collected during the trial. Percent 
compliance with drug administration will be calculated for each subject for pembrolizumab, 
IPI, and IFN separately.
 
 
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Percent compliance will be calculated as following: 
For IFN administered once a week, “Number of Doses that Should be Taken” will be 
calculated as 1 plus the number (integer) of 1-week intervals that fit between the date of the 
first dose and the date of the last dose. For pembrolizumab and IPI administered q3w
“Number of Doses Should be Taken” will be calculated as 1 plus the number (integer) of 
3-week intervals that fit between the date of the first dose and the date of the last dose. For 
IPI administered q6w and q12w “Number of Doses Should be Taken” will be calculated as 
1 plus the number (integer) of 6-week or 12-week intervals, respectively, that fit between the 
date of the first dose and the date of the last dose.
Extent of Exposure
8.2.10
For a pembrolizumab regimen, a subject’s extent of exposure to pembrolizumab is defined as 
the total number of doses of pembrolizumab the subject received. A subject’s exposure to a 
dose of IPI or IFN is defined as the total number of days on therapy for that dose.
Summary statistics may be provided on Extent of Exposure for the APaT population in Parts 
1B and 1C.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies utilized in the trial are:
Table 19
Product Descriptions
Product Name & Potency
Dosage Form
pembrolizumab 100 mg/4 mL
Solution for Infusion
Pegylated Interferon alfa-2b 300 mcg
Lyophilized Powder for Injection
Ipilimumab 50 mg and 200 mg
Solution for Infusion
NOTE: The investigator will be responsible for providing the following items: syringes, alcohol swabs, 
and sterile water for injection, USP (vial or ampule). .
 
 
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Pegylated Interferon alfa-2b and IPI will be provided centrally by the Sponsor or locally by 
the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product. The trial site is responsible to record the lot number, 
manufacturer and expiry date for any locally purchased product as per local guidelines unless 
otherwise instructed by the Sponsor. However, as any locally sourced combination therapies 
specified in Table 19 of the protocol are approved drugs in the US, investigational sites 
participating in this trial that are located in the US are not required to collect information 
regarding the source (manufacturer/lot/expiry date) on trial documentation. Drug 
accountability and manufacturer information will be retained with the hospital pharmacy at 
the clinical site.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open-label pembrolizumab 100 mg/ 4mL vials, Pegylated Interferon 
alfa-2b 300 mcg kits, and IPI 50 mg and 200 mg kits for dosing Parts 1A, 1B, and 1C 
subjects.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects 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.
 
 
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Standard Policies
9.6
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects 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.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
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.
Confidentiality of Subject Records
10.1.2
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.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identif ying 
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.
 
 
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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.
Confidentiality of IRB/IEC Information
10.1.4
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.
Compliance with Financial Disclosure Requirements
10.2
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 or through a secure password-protected electronic portal 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.
Compliance with Law, Audit and Debarment
10.3
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.
 
 
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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 Section 12.1 -
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 
when documents may be destroyed.  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 discarding 
trial and/or subject files.  
 
 
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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.
Compliance with Trial Registration and Results Posting Requirements
10.4
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 
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.
 
 
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Quality Management System
10.5
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.
Data Management
10.6
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.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
 
 
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the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol 
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[6]
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[7]
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. 
PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor 
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[8]
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of tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular 
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[9]
Shen Z, Zhou S, Wang Y, Li R, Zhong C, Liang C, et al. Higher intratumoral 
infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with 
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[10]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll 
or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
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Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic factors 
in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[12]
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. 
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lung cancer. Clin Cancer Res 2008;14(16):5220-7.
[13]
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, et 
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[15]
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et 
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predict clinical outcome. Science 2006;313(5795):1960-4.
[16]
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molecular biology. Int J Clin Oncol 2010;15(6):544-51.
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survival of a patient affected by pancreatic adenocarcinoma with massive 
lymphocyte and dendritic cell infiltration after interleukin-2 immunotherapy. Report 
of a case. Tumori 2008;94(3):426-30.
 
 
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[18]
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.
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2009 Sep;10(9):840-1.
[20]
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Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57(1):97-106.
[21]
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic 
implications of type and density of tumour-infiltrating lymphocytes in gastric 
cancer. Br J Cancer 2008;99(10):1704-11.
[22]
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, 
et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58(3):449-59.
[23]
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 Mar 
6;191(5):891-8.
[24]
Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance of 
tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 2009 Apr 
2;9:3.
[25]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated with 
outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer Immunol 
Immunother 2010;59(6):909-19.
[26]
Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. 
Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in 
patients with colorectal cancer. Cancer Immunol Immunother 2010;59:653-61.
[27]
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumor 
microenvironment is associated with superior survival in hepatocellular carcinoma 
patients. J Hepatol 2010;52:370-9.
[28]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Int 2011;107(9):1500-6.
 
 
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[29]
Hamid O, Puzanov I, Dummer R, Schachter J, Daud A, Schadendorf D, et al. 
Melanoma and other skin tumours:  Final overall survival for KEYNOTE-002: 
pembrolizumab (pembro) versus investigator-choice chemotherapy (chemo) for 
ipilimumab (ipi)-refractory melanoma [abstract]. Ann Oncol. 2016;27 Suppl 6. 
Abstract no. 11070.
[30]
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. 
Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 
Jun 25;372(26):2521-32.
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intravenous use: 2014.
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Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 
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Ribas A, Puzanov I, Dummer R, Schadendorf D, Hamid O, Robert C, et al. 
Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory 
melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 
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Eggermont AMM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, et al. 
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resected stage III melanoma: final results of EORTC 18991, a randomised phase III 
trial. Lancet 2008;372:117-26.
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Dummer R, Garbe C, Thompson JA, Eggermont AM, Yoo K, Maier T, Bergstrom 
B. Randomized dose-escalation study evaluating peginterferon alfa-2a in patients 
with metastatic malignant melanoma. J Clin Oncol. 2006 Mar 1;24(7):1188-94.
[37]
Eggermont AMM, Suciu S, Testori A, Kruit WH, Marsden J, Punt CJ, et al. 
Ulceration and stage are predictive of interferon efficacy in melanoma: results of 
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Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. 
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Choueiri TK, Hutson TE, Bukowski RM. Evolving role of pegylated interferons in 
metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2003 Dec;3(6):823-9.
 
 
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[40]
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plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 
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chemotherapy for the treatment of patients with refractory metastatic melanoma. J 
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Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-
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inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
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Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-
label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with 
dacarbazine (DTIC) in previously untreated patients with BRAFV600E mutated 
melanoma [Abstract]. J Clin Oncol 2012;30:abstract 8502.
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survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 2012:1-
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Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, 
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Hauschild A, Grobb J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. An 
update on Overall Survival (OS) and follow-on therapies in BREAK-3, a Phase III, 
randomized trial: dabrafenib (D) vs. dacarbazine (DTIC) in Patients (pts) with 
BRAF V600E mutation-positive metastatic melanoma (MM). Poster session 
presented at: ESMO Annual Meeting; 2014 Sep 29; Madrid.
 
 
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previously untreated melanoma without BRAF mutation. N Engl J Med. 2014 Nov 
16. [Epub ahead of print]
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Med. 2015 May 21;372(21):2006-17.
[52]
Postow M, Chesney J, Pavlick A, Robert C, Grossmann K, McDermott D, et al. 
Initial report of overall survival rates from a randomized phase II trial evaluating 
the combination of nivolumab (NIVO) and ipilimumab (IPI) in patients with 
advanced melanoma (MEL) [abstract]. Abstracts of the 2016 AACR Annual 
Meeting; 2016 Apr 16-20; New Orleans, LA; AACR; 2016. p. 1.
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Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. 
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N 
Engl J Med. 2015 Jul 2;373(1):23-34.
[54]
Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase 
III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell 
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2010;28(13):2144-50.
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Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. 
Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J 
Med. 2007 May 31;356(22):2271-81.
[56]
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. 
Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 
2007 Jan 11;356(2):115-24.
[57]
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib 
in locally advanced or metastatic renal cell carcinoma: results of a randomized 
phase III trial. J Clin Oncol. 2010 Feb 20;28(6):1061-8.
[58]
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. 
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 
2015 Nov 5;373(19):1803-13.
[59]
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and 
Tumor Responses with Lambrolizumab (AntiΓÇôPD-1) in Melanoma. N Engl J 
Med 2013;369(2):134-44.
 
 
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[60]
Drake CG, McDermott DF, Sznol M, Choueiri TK, Kluger HM; Powderly JD, et al. 
Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-
936558; ONO-4538) in a phase I trial in patients with previously treated metastatic 
renal cell carcinoma (mRCC): Long-term patient follow-up. [Abstract 4514]. 2013 
ASCO Annual Meeting, Oral Abstract Session, Poster Discussion Session, 
Genitourinary (Nonprostate) Cancer; 2013.
[61]
Cho DC, Sosman JA, Sznol M, Gordon MS, Hollebecque A, Hamid O, et al. 
Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 
antibody in patients with metastatic renal cell carcinoma (mRCC). [Abstract 4505]. 
2013 ASCO Annual Meeting, Oral Abstract Session, Genitourinary (Nonprostate) 
Cancer; 2013.
[62]
Kirkwood JM, Ernstoff MS. Interferons in the treatment of human cancer. J Clin 
Oncol 1984;2(4):336-52.
[63]
Legha SS, Ring S, Eton O, Bedikian A, Buzaid AC, Plager C, et al. Development of 
a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, 
dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic 
melanoma. J Clin Oncol 1998;16:1752-9.
[64]
Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosma JA, et al. Phase III trial 
comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, 
interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine 
alone in patients with metastatic malignant melanoma (E3695): A trial coordinated 
by the Eastern Cooperative Oncology Group. J Clin Oncol 2008;26(35):5748-54.
[65]
Terawaki S, Chikuma S, Shibayama S, Hayashi T, Yoshida T, Okazaki T, et al. 
IFN-a directly promotes programmed cell death-1 transcription and limits the 
duration of T cell-mediated immunity. J Immunol 2011;186:2772-9.
[66]
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. 
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J 
Med 2010;363(8):711-23.
[67]
Selby M, Engelhardt J, Lu LS, Quigley M, Wang C, Chen B, et al. Antitumor 
activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 
in preclinical models. [Abstract 3061]. 2013 ASCO Annual Meeting, General 
Poster Session, Developmental Theraputics - Immunotherapy; 2013 May 31 - Jun 3. 
Chicago, IL, 2013.
[68]
Sznol M, Callahan MK, Kluger H, Postow MA, Burke M, Hong Q, et al. Combined 
nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab in the treatment 
of advanced melanoma patients: Safety and clinical activity. [Abstract 3734]. 
European Society for Medical Onocology 2013 Annual Meeting; 2013 Sep 27-Oct 
1; Amsterdam, Netherlands, 2013.
 
 
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[69]
Topalian SL, Sznol M, Brahmer JR, McDermott DF, Smith DC, Gettinger SN, et al. 
Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid 
tumors: Survival and longterm safety in a phase I trial [Abstract 3002]. 2013 ASCO 
Annual Meeting; 2013 May 31 - Jun 4. Chicago, IL, 2013.
[70]
Bukowski R, Ernstoff MS, Gore ME, Nemunaitis JJ, Amato A, Gupta SK, et al. 
Pegylated interferon alfa-2b treatment for patients with solid tumors: A phase I/II 
study. J Clin Oncol 2002;20(18):3841-49.
[71]
Talpaz M, O'Brien S, Rose E, Gupta S, Shan J, Cortes J, et al. Phase 1 study of 
polyethylene glycol formulation of interferon alpha-2B (Schering 54031) in 
Philadelphia chromosome-positive chronic myelogenous leukemia. Blood. 2001 
Sep 15;98(6):1708-13.
[72]
Tannir NM, Cohen L, Wang X, Thall P, Mathew PF, Jonasch E, et al. Improved 
tolerability and quality of life with maintained efficacy using twice-daily low-dose 
interferon-a-2b. Cancer 2006;107:2254-61.
[73]
George S, Hutson TE, Mekhail T, Wood L, Finke J, Elson P, et al. Phase I trial of 
PEG-interferon and recombinant IL-2 in patients with metastatic renal cell 
carcinoma. Cancer Chemother Pharmacol 2008;62:347-54.
[74]
Kudchadkar RR, Gibney GT, Weber J, Chen A, Smith K, Merek S, et al. A phase 
IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable 
melanoma. [Abstract 9079]. 2013 ASCO Annual Meeting, Oral Abstract Session, 
General Poster Session, Melanoma/Skin Cancers; 2013.
[75]
Lyrdal D, Stienrner U, Lundstam S. Metastatic renal cell carcinoma treated with 
peg-interferon alfa-2b. Acta Oncol 2009;48:901-8.
[76]
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al.  
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell 
carcinoma: a randomised, double-blind phase III trial.  Lancet 2007;370:2103-11.
[77]
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. 
Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in 
patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008 
Nov 20;26(33):5422-8.
[78]
Melichar B, Bracarda S, Matveev V, Alekseev B, Ivanov S, Zyryanov A, et al. A 
multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-
line treatment of metastatic renal cell carcinoma: BEVLiN. Ann Oncol. "in press" 
2013.
 
 
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Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM. 
Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-
33.
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Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, McDermott DF, et al. 
Combined nivolumab and ipilimumab versus ipilimumab alone in patients with 
advanced melanoma: 2-year overall survival outcomes in a multicentre, 
randomised, controlled, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1558-1568.
[81]
Agrawal S, Feng Y, Roy A, Kollia G, Lestini B. Nivolumab dose selection: 
challenges, opportunities and lessons learned for cancer immunotherapy. J 
Immunother Cancer. 2015 Nov 4;3(2): P141.
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Feng Y, Masson E, Dai D, Parker SM, Berman D, Roy A. Model-based clinical 
pharmacology profiling of ipilimumab in patients with advanced melanoma. Br J 
Clin Pharmacol. 2014 Jul;78(1):106-17.
[83]
Wang DD, Zhang S, Zhao H, Men AY, Parivar K.  Fixed dosing versus body size-
based dosing of monoclonal antibodies in adult clinical trials.  J Clin Pharmacol. 
2009;49:1012-1024.
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Ji Y, Liu P, Li Y, Bekele BN. A modified toxicity probability interval method for 
dose-finding trials. Clin Trials 2010;7:653-63.
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Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 
1985;4:213-26.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
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 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. 
 
 
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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.
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."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The DNA, leftover tumor tissue and leftover blood specimen(s) collected in the current 
trial will be used to study various causes for how subjects may respond to a drug/vaccine.  
The DNA, leftover tumor tissue and leftover blood specimen(s) will be stored to provide 
a resource for future trials conducted by Merck focused on the study of biomarkers 
responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease.  The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
 
 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
 
 
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To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
 
 
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by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
 
 
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international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research. When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
 
 
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analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
12.5
The descriptions and grading scales found in the revised NCI CTCAE Version 4.0 will be 
utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html)
 
 
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Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
12.6
RECIST 1.1* will be used in this study for assessment of tumor response. While either CT or
MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study.
* As published in the European Journal of Cancer [1]
 
 
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List of Abbreviations
12.7
Abbreviation/Term
Definition
ACAR
Aggregate Clinical Activity Rate
AE
Adverse event
ADA
Anti-Drug Antibodies
ADCC
Antibody-Dependent Cell-Mediated Cytotoxicity
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
APC
Antigen Presenting Cells
APaT
All-Patients-as-Treated
aPTT
Activated partial thromboplastin time
AUC
Area Under Curve
AST
Aspartate aminotransferase
β-hCG
Beta human chorionic gonadotropin
BORR
Best objective response rate
CBC
Complete blood count
CI
Confidence interval
CNS
Central nervous system
CR
Complete response
CrCl
Calculated creatinine clearance
CRF
Case report form
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
ctDNA
Circulating tumor DNA
CTL
Cytotoxic T Lymphocytes
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
DL
Dose Level
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DRAE
Drug-related Adverse Event
ECI
Events of clinical interest
ECI-ie
Events of clinical interest with a potential immunologic etiology
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
ERC
Ethics review committee
 
 
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Abbreviation/Term
Definition
FAS
Full analysis set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FLC
Free Light Chain
FT4
Free T4
GCP
Good Clinical Practice
Hb
Hemoglobin
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human immunodeficiency virus
HR
Hazard ratio
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
IgG
Immunoglobulin G
IHC
Immunohistochemistry
IMiD
Immunomodulatory
INR
International normalized ratio
IPI
Ipilimumab
irAEs
Immune-related adverse events
IRB
Institutional Review Board
ISS
International Staging System
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intent-To-Treat
IV
Intravenous
Kg
Kilogram
LDH
Lactate dehydrogenase
LMWH
Low molecular weight heparin
mAb
Monoclonal antibody
MAD
Maximum administered dose 
MC38
Mouse Colorectal Model 38
mcL
Millimeters
MEL
Melanoma 
MG
Milligram
mg/kg
Milligram per kilogram
mL
Milliliter
Μg
Microgram
μg/kg
Microgram per kilogram
 
 
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Abbreviation/Term
Definition
MRI
Magnetic resonance imaging
MPR 
Moderate Partial Response
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
Maximum tolerated dose 
mRNA
Messenger Ribonucleic acid
mTOR
Mammalian target of rapamycin
NA or N/A
Not Applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NK
Natural Killer
NSAID
Non-steroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Objective l response rate
OS
Overall survival
OTC
Over-the-counter
PBMC
Peripheral blood mononuclear cells
PBMC
Peripheral blood mononuclear cells
PD
Progressive disease
PD-1
Programmed-death receptor-1
PD-L1
Programmed-death receptor-ligand 1
PD-L2
Programmed-death receptor-ligand 2
PEG-IFN
Pegylated Interferon Alfa-2b
PET
Positron emission tomography
PFS
Progression-free survival
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK-PD
Pharmacokinetic-Pharmacodynamic
po
orally
PR
Partial response
PT
Prothrombin time
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
RR
Response rate
q2w
Every 2 weeks
q3w
Every 3 weeks
q6w
Every 6 weeks
q12w
Every 2 weeks
 
 
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Abbreviation/Term
Definition
SAE
Serious adverse events
SAP
Statistical Analysis Plan
SC
Subcutaneous
sCR
Stringent Complete Response
SFU
Survival follow-up
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SoC
Standard of Care
SJS
Stevens-Johnson Syndrome
SOP
Standard Operating Procedures
SPEP
Serum protein electrophoresis
TCR
T cell receptor
T1DM
Type 1 Diabetes Mellitus
TIL
Tumor-infiltrating lymphocytes
TPI
Toxicity Probability Interval
TSH
Thyroid stimulating hormone
TTP
Time To Progression
VEGF
Vascular endothelial growth factor 
VGPR
Very Good Partial Response
ULN
Upper limit of normal
US
United States
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol). I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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