Clinical trial NCT02039674
Conditions: Non-small Cell Lung Carcinoma
Keywords: PD-1 PD1 Programmed Cell Death-1 Programmed Cell Death 1 Chemotherapy Pemetrexed Paclitaxel Bevacizumab Erlotinib Gefitinib Ipilimumab Carboplatin
Sponsor: Merck Sharp & Dohme LLC
Start date: 2014-02-21; Completion date: 2021-10-18
Enrollment: 267 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the safety, tolerability, and efficacy of pembrolizumab (MK-3475) in combination with chemotherapy or immunotherapy in participants with unresectable or metastatic non-small cell lung cancer (NSCLC).

Detailed description:

Arms: arm 1: Cohort A participants receive pembrolizumab (2 mg/kg) via intravenous (IV) infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (Aare Under the Curve \[AUC\] 6 \[6 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. arm 2: Cohort B2 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 \[6 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (15 mg/kg) via IV infusion on Day 1 of each 3-week cycle. arm 3: Cohort C2 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 \[5 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. arm 4: Cohort D1 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle. arm 5: Cohort E participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS erlotinib (150 mg) via oral tablet once a day on every day of each 3-week cycle. arm 6: Cohort F participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS gefitinib (250 mg) via oral tablet once a day on every day of each 3-week cycle. arm 7: Cohort G+ participants receive pembrolizumab (200 mg) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 \[5 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle. arm 8: Cohort H participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle (at the recommended Phase II dose determined in Cohort D). arm 9: Cohort A10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 \[mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. arm 10: Cohort B10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS paclitaxel (200 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 6 \[6 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle PLUS bevacizumab (15 mg/kg) via IV infusion on Day 1 of each 3-week cycle. arm 11: Cohort C10 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 \[5 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle. arm 12: Cohort G- participants receive placebo (normal saline solution) via IV infusion on Day 1 of each 3-week cycle PLUS carboplatin (AUC 5 \[5 mg/mL/min\]) via IV infusion on Day 1 of each 3-week cycle PLUS pemetrexed (500 mg/m\^2) via IV infusion on Day 1 of each 3-week cycle PLUS. arm 13: Cohort D2 participants receive pembrolizumab (10 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (3 mg/kg) via IV infusion on Day 1 of each 3-week cycle. arm 14: Cohort D1 participants receive pembrolizumab (2 mg/kg) via IV infusion on Day 1 of each 3-week cycle PLUS ipilimumab (1 mg/kg) via IV infusion on Day 1 of each 3-week cycle.
Interventions: intervention 1: Pembrolizumab intervention 2: Paclitaxel intervention 3: Carboplatin intervention 4: Bevacizumab intervention 5: Pemetrexed intervention 6: Ipilimumab intervention 7: Erlotinib intervention 8: Gefitinib
Intervention descriptions: intervention 1: IV on Day 1 of each 3-week cycle prior to chemo/immunotherapy intervention 2: IV on Day 1 of each 3-week cycle for a maximum of 4 administrations intervention 3: IV on Day 1 of each 3-week cycle for a maximum of 4 administrations intervention 4: IV on Day 1 of each 3-week cycle intervention 5: IV on Day 1 of each 3-week cycle intervention 6: IV on Day 1 of each 3-week cycle for a maximum of 4 administrations intervention 7: Orally tablet once daily intervention 8: Oral tablet once daily

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase I/II Study of MK-3475 (SCH900475) in Combination with 
Chemotherapy or Immunotherapy in Patients with Locally 
Advanced or Metastatic Non-Small Cell Lung Carcinoma
20-Apr-2020
NCT02039674


Product:  MK-3475 
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Protocol/Amendment No.: 021-05 
MK-3475-021-05 Final Protocol
20-Apr-2020
Confidential
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 I/II Study of MK-3475 (SCH900475) in Combination with Chemotherapy or 
Immunotherapy in Patients with Locally Advanced or Metastatic Non-Small Cell Lung 
Carcinoma
IND NUMBER:  116833
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
Definition of Dose-Limiting Toxicities .............................................................. 19
Replacement of Subjects in DLT Observation Period........................................ 20
Trial Diagram........................................................................................................ 21
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 22
Primary Objective(s) & Hypothesis(es).............................................................. 22
Secondary Objective(s) & Hypothesis(es)........................................................... 22
Exploratory Objectives......................................................................................... 23
4.0
BACKGROUND & RATIONALE.......................................................................... 23
Background ........................................................................................................... 23
Pharmaceutical and Therapeutic Background .................................................... 23
Preclinical and Clinical Trials............................................................................. 25
4.1.2.1
Preclinical Background on Combinations ................................................... 26
Information on Other Trial-Related Therapy...................................................... 26
Rationale................................................................................................................ 28
Rationale for the Trial and Selected Subject Population .................................... 28
Rationale for Dose Selection/Regimen............................................................... 29
4.2.2.1
Starting Dose for This Trial......................................................................... 30
4.2.2.2
Maximum Dose/Exposure for This Trial..................................................... 30
4.2.2.3
Rationale for Dose Interval and Trial Design.............................................. 30
Rationale for Endpoints ...................................................................................... 30
4.2.3.1
Efficacy Endpoints....................................................................................... 30
4.2.3.2
Safety Endpoints.......................................................................................... 30
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 30
4.2.3.4
Planned Exploratory Biomarker Research................................................... 31
4.2.3.5
Future Biomedical Research........................................................................ 31
 
 
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5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
Diagnosis/Condition for Entry into the Trial...................................................... 31
Subject Inclusion Criteria.................................................................................... 32
Subject Exclusion Criteria .................................................................................. 34
Trial Treatment(s) ................................................................................................ 36
Dose Selection/Modification .............................................................................. 37
5.2.1.1
Dose Selection ............................................................................................. 37
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 37
5.2.1.2.1
Concomitant Chemotherapeutic Agents ............................................... 37
5.2.1.2.2
MK-3475 Dose Modifications.............................................................. 38
Timing of Dose Administration.......................................................................... 43
5.2.2.1
MK-3475...................................................................................................... 44
5.2.2.2
Paclitaxel...................................................................................................... 44
5.2.2.3
Pemetrexed................................................................................................... 44
5.2.2.4
Carboplatin................................................................................................... 45
5.2.2.5
Bevacizumab................................................................................................ 45
5.2.2.6
Ipilimumab................................................................................................... 45
5.2.2.7
Erlotinib ....................................................................................................... 45
5.2.2.8
Gefitinib....................................................................................................... 45
Trial Blinding/Masking....................................................................................... 45
Randomization or Treatment Allocation............................................................ 45
Stratification.......................................................................................................... 46
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 46
Acceptable Concomitant Medications ................................................................ 46
Prohibited Concomitant Medications.................................................................. 46
Rescue Medications & Supportive Care............................................................. 47
Supportive Care Guidelines ................................................................................ 47
Guidelines for Infusion-Reactions ...................................................................... 48
Diet/Activity/Other Considerations..................................................................... 48
Diet...................................................................................................................... 48
Contraception...................................................................................................... 48
 
 
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Use in Pregnancy ................................................................................................ 50
Use in Nursing Women....................................................................................... 50
Subject Withdrawal/Discontinuation Criteria................................................... 50
Subject Replacement Strategy............................................................................. 52
Beginning and End of the Trial ........................................................................... 53
Clinical Criteria for Early Trial Termination ................................................... 53
Post-progression Treatment................................................................................. 53
Post MK-3475/Chemotherapies........................................................................... 54
6.0
TRIAL FLOW CHART ........................................................................................... 55
Treatment Phase ................................................................................................... 55
Cohort F Dose Separation Treatment Phase...................................................... 59
Post-Treatment Follow-up Phase ........................................................................ 62
Second Course Phase............................................................................................ 64
Second Course Post-Treatment Follow-up Phase.............................................. 66
Crossover Phase .................................................................................................... 68
7.0
TRIAL PROCEDURES ........................................................................................... 70
Trial Procedures ................................................................................................... 70
Administrative Procedures.................................................................................. 70
7.1.1.1
Informed Consent......................................................................................... 70
7.1.1.1.1
General Informed Consent.................................................................... 70
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 71
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 71
7.1.1.3
Subject Identification Card .......................................................................... 71
7.1.1.4
Medical History ........................................................................................... 71
7.1.1.5
Prior and Concomitant Medications Review............................................... 71
7.1.1.5.1
Prior Medications.................................................................................. 71
7.1.1.5.2
Concomitant Medications..................................................................... 71
7.1.1.6
Non-Small Cell Lung Cancer (NSCLC) Disease Details and 
Treatments ................................................................................................... 72
7.1.1.6.1
Disease Details...................................................................................... 72
7.1.1.6.2
Prior Treatment..................................................................................... 72
 
 
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7.1.1.6.3
Subsequent Antineoplastic Therapy Status........................................... 72
7.1.1.7
Assignment of Screening Number............................................................... 72
7.1.1.8
Assignment of Randomization Number....................................................... 72
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)................................... 72
Clinical Procedures/Assessments........................................................................ 73
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 73
7.1.2.2
Physical Exam.............................................................................................. 73
7.1.2.2.1
Full Physical Exam ............................................................................... 73
7.1.2.2.2
Directed Physical Exam........................................................................ 73
7.1.2.3
Vital Signs.................................................................................................... 74
7.1.2.4
12-Lead Electrocardiogram (ECG).............................................................. 74
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 74
7.1.2.6
Pulmonary Function Tests ........................................................................... 74
Laboratory Procedures/Assessments .................................................................. 74
7.1.3.1
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry 
and 
Urinalysis).................................................................................................... 74
7.1.3.2
Pharmacokinetic Evaluations....................................................................... 75
7.1.3.2.1
Blood Collection for Plasma MK-3475................................................ 75
7.1.3.3
Anti-MK-3475 Antibodies........................................................................... 76
7.1.3.4
Molecular Testing........................................................................................ 76
7.1.3.5
Future Biomedical Research........................................................................ 76
Other Procedures................................................................................................. 76
7.1.4.1
Withdrawal/Discontinuation........................................................................ 76
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 76
7.1.4.2
Blinding/Unblinding .................................................................................... 77
7.1.4.3
Tumor Imaging ............................................................................................ 77
7.1.4.4
Tumor Tissue Collection.............................................................................. 78
Visit Requirements.............................................................................................. 78
7.1.5.1
Screening...................................................................................................... 79
7.1.5.2
Treatment Phase........................................................................................... 79
7.1.5.3
Post-Treatment Follow-up Phase................................................................. 79
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 80
 
 
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7.1.5.3.2
Follow-up Visits ................................................................................... 80
7.1.5.3.3
Survival Follow-up ............................................................................... 80
7.1.5.3.4
Survival Status...................................................................................... 81
7.1.5.4
Second Course Phase................................................................................... 81
7.1.5.5
Crossover for Subjects in Cohort G Chemotherapy Arm with 
Documented Disease Progression................................................................ 82
7.1.5.6
Crossover Assessments and Procedures ...................................................... 82
Assessing and Recording Adverse Events .......................................................... 83
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 84
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 84
Immediate Reporting of Adverse Events to the Sponsor.................................... 85
7.2.3.1
Serious Adverse Events ............................................................................... 85
7.2.3.2
Events of Clinical Interest............................................................................ 86
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 87
Evaluating Adverse Events................................................................................. 88
Sponsor Responsibility for Reporting Adverse Events ...................................... 91
TRIAL GOVERNANCE AND OVERSIGHT................................................... 91
Scientific Advisory Committee........................................................................... 91
Clinical Adjudication Committee ....................................................................... 91
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 91
Statistical Analysis Plan Summary ..................................................................... 91
Efficacy Analyses ............................................................................................... 91
Safety Analyses................................................................................................... 92
Power and Sample Size....................................................................................... 92
Subgroup Analyses ............................................................................................. 93
Statistical Analysis Plan ....................................................................................... 93
Responsibility for Analysis/In-House Blinding.................................................. 93
Hypotheses/Estimation ....................................................................................... 94
Analysis Endpoints ............................................................................................. 94
8.2.3.1
Efficacy Endpoints....................................................................................... 94
8.2.3.2
Safety Endpoints.......................................................................................... 95
 
 
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Analysis Populations........................................................................................... 96
8.2.4.1
Efficacy Analysis Populations..................................................................... 96
8.2.4.2
Safety Analysis Populations ........................................................................ 96
Statistical Methods.............................................................................................. 97
8.2.5.1
Statistical Methods for Efficacy Analyses................................................... 97
8.2.5.1.1
Cohorts A-F .......................................................................................... 97
8.2.5.1.2
Cohorts G1 and G2 ............................................................................... 97
8.2.5.1.3
Cohort H ............................................................................................. 101
8.2.5.2
Statistical Methods for Safety Analyses .................................................... 101
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................... 101
Multiplicity ....................................................................................................... 102
Sample Size and Power Calculations................................................................ 102
Subgroup Analyses and Effect of Baseline Factors.......................................... 104
Interim Analyses ............................................................................................... 104
Compliance (Medication Adherence)............................................................... 104
Extent of Exposure............................................................................................ 104
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 104
Investigational Product ...................................................................................... 104
Packaging and Labeling Information ............................................................... 105
Clinical Supplies Disclosure............................................................................... 105
Storage and Handling Requirements................................................................ 105
Returns and Reconciliation................................................................................ 106
Standard Policies................................................................................................. 106
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 106
Confidentiality..................................................................................................... 106
Confidentiality of Data ..................................................................................... 106
Confidentiality of Subject Records................................................................... 106
Confidentiality of Investigator Information...................................................... 107
Confidentiality of IRB/IEC Information........................................................... 107
Compliance with Financial Disclosure Requirements..................................... 107
 
 
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Compliance with Law, Audit and Debarment ................................................. 108
Compliance with Trial Registration and Results Posting Requirements ...... 110
Quality Management System............................................................................. 110
Data Management............................................................................................... 110
Publications ......................................................................................................... 110
11.0
LIST OF REFERENCES....................................................................................... 112
12.0
APPENDICES......................................................................................................... 119
Merck Code of Conduct for Clinical Trials...................................................... 119
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 121
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 128
Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 
by Sample Types ................................................................................................. 139
ECOG Performance Status................................................................................ 140
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 141
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 142
Strong Inhibitors of CYP3A4 ............................................................................ 143
13.0
SIGNATURES......................................................................................................... 144
Sponsor’s Representative................................................................................... 144
Investigator.......................................................................................................... 144
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Lab Values ................................................................ 33
Table 2
Trial Treatment.................................................................................................... 36
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with MK-3475............................................................... 39
Table 4
MK-3475 Infusion Reaction Dose Modification and Treatment Guidelines...... 42
Table 5
Laboratory Tests.................................................................................................. 75
Table 6
Evaluating Adverse Events ................................................................................. 89
Table 7
Summary of Analysis Strategy for Key Efficacy Endpoints in Part 2................ 92
Table 8
Censoring Rules for DOR ................................................................................... 98
Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS .......................... 99
Table 10
Analysis Strategy of Key Efficacy Endpoints of Cohorts G1 and G2 .............. 100
Table 11
Product Descriptions ......................................................................................... 105
 
 
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LIST OF FIGURES
Figure 1
Trial Design ........................................................................................................ 21
Figure 2
Power for primary hypothesis under different effect size assumptions............ 103
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 05
20-APR-2020
To extend the duration of the study, update Future Biomedical Research (FBR) 
language, and change the Follow-up imaging interval.
Amendment 04
18-DEC-2017
To clarify the maximum duration of treatment with MK-3475 in the treatment and 
crossover phases and maintenance pemetrexed, change MK-3475 dosing in the 
Second Course Phase to a fixed dose, provide details regarding the management of 
infusion-related reactions, increase the window for collecting irAEs, and update the 
timing and procedures for survival status assessment.
Amendment 03
18-APR-2016
To update primary objective and hypothesis, efficacy endpoints, analyses, statistical 
methods, multiplicity strategy, and sample size and power based on data from Cohort 
C (Part 1).
Amendment 02
16-APR-2015
To update discontinuation criteria attributed to gefitinib for subjects in Cohort F, and 
clarify time frames to assess and record adverse events.
Amendment 01
15-OCT-2014
To modify MK-3475 or chemotherapy dose regimen in Cohorts D, E, F, and G based 
on safety and efficacy information updates.
Original protocol
08-OCT-2013
 
 
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SUMMARY OF CHANGES
Overall Rationale for the Amendments:
Amended protocol to extend the duration of the study, update Future Biomedical Research (FBR) language, and change the Follow-up 
imaging interval.
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
Trial Summary
Study duration extended 2 additional 
years.
To accommodate subjects on extended 
pemetrexed cycles.
4.2.3.5
Future Biomedical Research
FBR language updated to remove 
references to “sub-trial”.
To clarify that FBR is not a separate 
sub-study with reporting.
7.1.1.1.2
Consent and Collection of 
Specimens for Future 
Biomedical Research
12.2
Collection and Management of 
Specimens for Future 
Biomedical Research
6.0
Trial Flow Chart
Follow-up imaging interval changed
to every 12 weeks during years 1, 2 
and 3, and every 6 months up to the 
end of year 5.
To update imaging interval in subjects 
who discontinue trial treatment for 
reasons other than disease progression 
or new anticancer therapy.
6.3
Post-Treatment Follow-up Phase
6.5
Second Course Post-Treatment 
Follow-up Phase
7.1.4.3
Tumor Imaging
7.1.5.3.2
Follow-up Visits
Throughout
Throughout
Made typographical corrections and 
minor administrative edits.
To correct typographical errors and 
clarify intended meaning.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase I/II Study of MK-3475 Combination with Chemotherapy in NSCLC Subjects
Trial Phase
Phase I-II
Clinical Indication
Treatment of Non-Small Cell Lung Cancer
Trial Type
Interventional
Type of control
Active Control without Placebo
Route of 
administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Part 1:  Cohort A – Carboplatin and Paclitaxel plus MK-3475;  Cohort B – Carboplatin, 
Paclitaxel and Bevacizumab plus MK-3475; Cohort C – Carboplatin and Pemetrexed 
plus MK-3475,  Cohort D – Ipilimumab plus MK-3475, Cohort E – Erlotinib plus MK-
3475, Cohort F – Gefitinib plus MK-3475. Part 2 – Cohort G – Carboplatin and 
Pemetrexed plus/minus MK-3475; Cohort H  - Ipilimumab plus MK-3475
Number of trial 
subjects
Approximately 308 subjects will be enrolled.
Estimated duration 
of trial
The sponsor estimates that the trial will require approximately 84 months from the time 
the first subject signs the informed consent until the last subject’s last visit.
Duration of 
Participation
Each subject will participate in the trial from the time the subject signs the Informed 
Consent Form (ICF) through the final protocol-specified contact (up to approximately 7
years). After a screening phase of up to 28 days, eligible subjects will receive assigned 
treatment on Day 1 of each 3-week (Q3W) dosing cycle. Treatment with MK-3475 will 
continue for a maximum of 35 cycles (approximately 2 years), documented disease 
progression, unacceptable adverse event(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with the trial treatment or 
procedure requirements or administrative reasons. MK-3475 treated subjects who have 
been on therapy for ≥6 months and who attain a complete response may consider 
stopping trial treatment. These subjects, as well as those subjects assigned to the MK-
3475 arm who stop trial therapy after 35 cycles of study medication for reasons other 
than disease progression or intolerability, may be eligible for re-treatment with MK-
3475 in the Second Course Phase after they have experienced radiographic disease 
progression at the discretion of the investigator according to the criteria in Section 
7.1.5.4. After the end of treatment, each subject will be followed for a minimum of 30 
days for adverse event monitoring even if the patient started new antineoplastic 
treatment (serious adverse events will be collected for up to 90 days following cessation 
of Sponsor’s product, or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier). Subjects will have post-treatment follow-
up for disease status, including radiographic imaging every 3 months, initiating a non-
study cancer treatment and experiencing disease progression, until death, withdrawing 
consent, or becoming lost to follow-up.
Once the subject has achieved the study objective or study has ended, the subject is 
discontinued from this study and will be enrolled in an extension study to continue 
protocol defined assessments and treatment. Subjects who may eventually be eligible 
for crossover who have not yet transitioned to pembrolizumab will be considered for the 
extension study on a case-by-case basis.
 
 
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Randomization 
Ratio
Randomized 1:1 in cohorts A, B, C and G. Not randomized in cohorts D, E, F and H
2.0 TRIAL DESIGN
Trial Design
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.
This is a multicenter, open-label, Phase I/II study of intravenous (IV) MK-3475 at 2 dosing 
schedules in combination with chemotherapy or immunotherapy in subjects with locally 
advanced or metastatic non-small cell lung cancer (NSCLC). The study is composed of 2
parts. Part 1 of the study will determine the recommended phase II dose (RP2D) for MK-
3475 in combination with different chemotherapy and/or immunotherapy regimens. Part 2 
includes a randomized comparison of chemotherapy plus or minus MK-3475 based on the 
doses defined in Part 1, as well as a cohort expanding the ipilimumab cohort from Part 1.
Subject’s tumors will be screened at baseline for EGFR mutations, EML4 ALK translocation, 
and PD-L1 expression.  Positive tumor PD-L1 expression will not be required for enrollment; 
however, subjects in Part 2 Cohort G will be stratified based on PD-L1 status. Subjects with 
squamous cell histology will not be required to be screened for EGFR mutations or ALK 
translocations and subjects with known EGFR mutations will not be required to be screened 
for EML4 ALK.  Subjects with known KRAS mutation do not need to be tested for EGFR 
mutations and ALK translocations.  For Part 1, cohorts D, E, and F, the investigator will be 
allowed to select from any of the open cohorts for which the subject is eligible. For Part 1 
cohorts A, B and C, the investigator will be allowed to choose the chemotherapy cohort but 
subjects will be randomized to chemotherapy plus MK-3475 2 mg/kg or chemotherapy plus 
MK-3475 10 mg/kg.  For Part 2, subjects enrolled into cohort G will be randomized at 1:1 
ratio to receive Carboplatin and Pemetrexed plus/minus MK-3475 200mg.  Subjects assigned 
to the chemotherapy arm will have the opportunity to crossover to receive MK-3475 
monotherapy once they experience progression of disease (PD) defined by RECIST 1.1 and 
meet all crossover criteria defined by the protocol. Section 7.1.5.5 provides crossover criteria 
and guidance. Treatment is limited up to 35 cycles for patients who crossover to MK-3475 
monotherapy.  The Sponsor may elect to add an arm to cohort G based on additional data 
available from Part 1 of the study. Opening of cohort H will be determined by the Sponsor 
after a careful review of available safety and efficacy data from cohort D.  
The following applies to all subjects enrolled in Parts 1 and 2.  Subjects will be evaluated 
every 6 weeks (42 ± 7 days) for the first 18 weeks followed by every 9 weeks in Year 1 and 
every 12 weeks subsequently with radiographic imaging to assess response to treatment, until 
the subject experiences PD or initiates a new anticancer therapy. All imaging obtained from 
Part 2 will be submitted for potential independent radiologists’ review who will assess the 
images using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for determination 
 
 
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of objective response rate (ORR) and progression-free survival (PFS).  Adverse events will 
be monitored throughout the trial and graded in severity according to the guidelines outlined 
in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
Treatment with MK-3475 will continue for 35 cycles (approximately 2 years) from the date 
the first dose has been administered, documented disease progression (investigators may 
elect to continue MK-3475 treatment beyond progression in specific circumstances outlined 
in Sections 5.8, and 5.12), unacceptable adverse event(s), 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.  MK-3475 treated subjects who attain an 
investigator-determined confirmed complete response (CR) per RECIST 1.1 may consider 
stopping trial treatment.  These subjects, as well as those subjects assigned to the MK-3475 
arm who stop trial therapy after 35 cycles for reasons other than disease progression or 
intolerability, may be eligible for re-treatment with MK-3475 in the Second Course Phase 
(for up to 17 cycles) after they have experienced radiographic disease progression at the 
discretion of the investigator according to the criteria in Section 7.1.5.4.  Response or 
progression in the Second Course Phase will not count towards the ORR and PFS of the 
primary endpoint in this trial.  
After the end of treatment, each subject will be followed for a minimum of 30 days for 
adverse event monitoring even if the patient started new antineoplastic treatment (serious 
adverse events will be collected for up to 90 days following cessation of Sponsor’s product, 
or 30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier).  Subjects will have post-treatment follow-up for disease status, 
including initiating a non-study cancer treatment and experiencing disease progression, until 
death, withdrawing consent, or becoming lost to follow-up.  
Subjects may have the opportunity to transition to a pembrolizumab extension study if 
available in the future after closure of this study.
Participation in this trial will be dependent upon supplying tumor tissue from either a newly 
obtained formalin-fixed specimen, or an older formalin-fixed, paraffin-embedded specimen 
from locations not radiated prior to biopsy. Newly obtained formalin-fixed specimens are 
strongly encouraged.  If new scientific data emerge that indicate that an existing biopsy or 
surgical specimen is suboptimal for identification of subjects, only new biopsies will be 
acceptable for determination of PD-L1 status.  The specimen will be evaluated at a central 
laboratory facility for expression status of PD-L1 in a prospective manner.  
The design for each of the cohorts is described below:
Part 1
Cohort A (paclitaxel and carboplatin) – First Line subjects who have any histology and who 
have wild type EGFR and negative ALK translocation status.  
 
 
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Twenty-four subjects will be randomized to treatment with MK-3475 at either 2 mg/kg or 
10 mg/kg (12 subjects per dose arm) in combination with paclitaxel and carboplatin every 
3 weeks (Q3W) for 4 cycles as described in the body of the protocol. 
If ≤2 of 12 subjects at 10 mg/kg have DLT during the first cycle, the dose level is considered 
acceptable and will be considered the MTD. If 3 or more of the 12 subjects treated at 10
mg/kg have DLT, the 10 mg/kg dose will be considered unacceptable.  If the 10 mg/kg dose 
has been ruled out and if ≤2 of 12 subjects at 2 mg/kg have DLT, the 2 mg/kg dose will be 
considered acceptable and will be considered the MTD. If 3 or more of the 12 subjects
treated at 2 mg/kg have DLT, the 2 mg/kg dose will be considered unacceptable and the 
cohort discontinued.  After completion of 4 cycles of chemotherapy subjects will continue 
treatment with MK-3475 until progression of disease and or unacceptable toxicity as defined 
in Section 5.2.1.2 up until a maximum of 35 cycles (approximately 2 years).  
Cohort B (paclitaxel, carboplatin and bevacizumab) – First Line subjects who have non-
squamous histology and who have wild type EGFR and negative ALK translocation status.
The design for cohort B will be the same as cohort A except that the chemotherapy will 
consist of paclitaxel, carboplatin and bevacizumab. In addition, subjects should receive 
maintenance bevacizumab at the discretion of the investigator with MK-3475 until 
progression or unacceptable toxicity as defined in Section 5.2.1.2 for a maximum of 
35 cycles (approximately 2 years).
Cohort C (carboplatin and pemetrexed) – First Line subjects who have non-squamous 
histology and who have wild type EGFR and negative ALK translocation status.  
The design for cohort C will be the same as cohort A, except that the chemotherapy will 
consist of carboplatin and pemetrexed.  In addition, subjects should receive maintenance 
pemetrexed at the discretion of the investigator with MK-3475 until progression or 
unacceptable toxicity as defined in Section 5.2.1.2 for a maximum of 35 cycles 
(approximately 2 years).
Cohort D (ipilimumab plus MK-3475) – Subjects with any histology and have failed 
previous treatment.  Subjects with EGFR mutations or ALK translocations must have 
progressed on appropriate targeted therapies (e.g., erlotinib, gefitinib, crizotinib). After 
starting enrollment into cohort D, additional safety information became available from the 
nivolumab and ipilimumab combination study in advanced NSCLC patients which raised 
safety concerns of the combination including treatment-related deaths [67]. Based on the 
data, the Sponsor has decided to decrease the dose of combination to dose level -2;
Ipilimumab 1 mg/kg combined with MK-3475 2 mg/kg. At the time of the decision, a total 
of 6 patients (3 patients at Ipilimumab 1 mg/kg combined with MK-3475 10 mg/kg, and 
3 patients at Ipilimumab 3 mg/kg combined with MK-3475 10mg/kg) had been enrolled and 
treated with the combination and no DLTs have been reported. The cohort will follow a 
3+3 design followed by expansion up to total 12 patients at dose level -2.
 
 
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
The first 3 subjects will be treated with MK-3475 2 mg/kg Q3W in combination with 
ipilimumab 1 mg/kg.  If ≤1 DLTs occur in these 3 subjects during the first cycle (3 
weeks) of treatment, 3 more subjects will be enrolled. If ≤1 DLTs occur in 6 
subjects, the dose level will be declared as the RP2D and 6 additional subjects will be 
enrolled at the dose as an expansion cohort. 

If ≥2/3 or ≥2/6 subjects treated with MK-3475 2 mg/kg Q3W in combination with 
ipilimumab 1 mg/kg have a DLT, the cohort will be discontinued.
Cohort E (erlotinib plus MK-3475) – First Line subjects who have activating EGFR 
mutations, negative ALK translocation and any histology. Treatment will follow 3+3 design 
followed by cohort expansion with MK-3475 2 mg/kg Q3W in combination with erlotinib 
daily. A total of 12 subjects will be treated.  
The first 3 subjects will be treated with MK-3475 2 mg/kg Q3W in combination with 
erlotinib daily as described in the body of the protocol.  If ≤1 DLTs occur in these 3 subjects 
during the first cycle (3 weeks) of treatment, the next 3 subjects will be treated.  If ≤1 of the 6 
subjects have a DLT, the dose level is considered acceptable for phase II.  If ≥2/3 or ≥2/6 
subjects treated have a DLT, the combination will be defined as unacceptable and the cohort 
will be discontinued.  Missing >10% of erlotinib dose in the first cycle for any reason other 
than study drug-related toxicity will be considered noncompliance and the subject will be 
replaced. Erlotinib will be continued as long as the subject is receiving benefits whereas MK-
3475 will be limited to a maximum of 35 cycles (approximately 2 years).  
Cohort F (gefitinib plus MK-3475) – First Line subjects who have activating EGFR 
mutations, negative ALK translocation and any histology. Treatment will follow 3+3 design 
followed by cohort expansion with MK-3475 2 mg/kg Q3W in combination with gefitinib. A 
total of 12 subjects will be treated.  The first 3 subjects will be treated with MK-3475 2 
mg/kg Q3W in combination with gefitinib daily as described in the body of the protocol.  If 
≤1 DLTs occur in these 3 subjects during the first cycle (3 weeks) of treatment, the next 
3 subjects will be treated.  If ≤1 of the 6 subjects have a DLT, the dose level is considered 
acceptable for phase II.  If ≥2/3 or ≥2/6 subjects treated have a DLT, the institution of a dose 
separation phase will be initiated as described below. Missing >10% of gefitinib dose during 
the first cycle for any reason other than study drug-related toxicity will be considered 
noncompliance and the subject will be replaced. Gefitinib will be continued as long as the 
subject is receiving benefits whereas MK-3475 will be limited to a maximum of 35 cycles 
(approximately 2 years).
If the dose combination in Cohort F as described above results in a high level of 
discontinuations at Cycle 2 or 3 the Dose Separation Phase may be initiated even though the 
combination was found to be tolerable as defined by the DLT rules above.
Cohort F Dose Separation Phase (gefitinib plus MK-3475) - Treatment will follow 3+3 
design followed by cohort expansion with gefitinib daily for the first 6 weeks of treatment 
followed by MK-3475 2 mg/kg Q3W in combination with gefitinib daily.  A total of 12 
subjects will be treated.  
 
 
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The first 3 subjects will be treated with gefitinib daily for the first 6 weeks of treatment 
followed by MK-3475 2 mg/kg Q3W in combination with gefitinib daily as described in the 
body of the protocol.  If drug-related toxicities ≥ Grade 3 occur during the first 6 weeks of 
gefitinib monotherapy the patient should be discontinued from the treatment phase and not 
receive gefitinib and MK-3475 combination at Cycle 1.  If ≤ 1 DLTs occur in these 3 
subjects during Cycle 1 and 2 (Weeks 7 – 12) of treatment, the next 3 subjects will be treated.  
If ≤1 of the 6 subjects have a DLT, the dose level is considered acceptable for phase II.  If 
≥2/3 or ≥2/6 subjects treated have a DLT, the combination will be defined as unacceptable 
and the cohort will be discontinued.  Missing >10% of gefitinib dose in the first 9 weeks for 
any reason other than study drug-related toxicity will be considered noncompliance and the 
subject will be replaced. Gefitinib will be continued as long as the subject is receiving
benefits whereas MK-3475 will be limited to 35 cycles (approximately 2 years).  
Part 2
Cohorts G1 and G2 – First Line subjects who are EGFR wild type non-squamous histology. 
Subjects will be screened for the presence of PD-L1 expression, ALK translocation and 
EGFR mutation.  Subjects who are EGFR wild type and do not have ALK translocation and 
otherwise eligible for randomization will be enrolled in cohort G1.  Subjects with non-
squamous histology will be randomized to receive carboplatin and pemetrexed alone for 4
cycles followed by maintenance pemetrexed at the discretion of the investigator until 
progression or unacceptable toxicity as defined in Section 5.2.1.2 or carboplatin and 
pemetrexed plus MK-3475 200mg for 4 cycles followed by maintenance pemetrexed with 
MK-3475 at the discretion of the investigator until progression or unacceptable toxicity as 
defined in Section 5.2.1.2.
MK-3475 is limited to a maximum of 35 treatment cycles. 
Treatment with maintenance pemetrexed does not have a maximum duration and may 
continue within local regulations and the investigator’s judgment until reaching a 
protocol-specified discontinuation criterion (eg, progressive disease, toxicity, withdrawal of 
consent, physician decision, end of study). Subjects assigned to the chemotherapy arm will 
have the opportunity to crossover to receive MK-3475 monotherapy once they experience 
progression of disease (PD) defined by RECIST 1.1 and meet all crossover criteria defined in 
Section 7.1.5.5. Treatment is limited up to 17 cycles for patients who crossover to MK-3475 
monotherapy.  The Sponsor may elect to add additional arm(s) (treatment from Cohort A 
(paclitaxel and carboplatin), or treatment from Cohort B (paclitaxel, carboplatin and 
bevacizumab)) to cohort G1 based on additional data available from Part 1 of the study.  
Cohort G2 will be optional and dependent upon results of G1.  If Cohort G1 does not achieve 
the prespecified target HR, but an analysis suggests a strong correlation between PD-L1 
expression levels and anti-tumor activity then Cohort G2 will initiate with a biomarker-
selected population.  Cohort G2 will randomize 60 subjects to receive either carboplatin and 
pemetrexed alone for 4 cycles followed by maintenance pemetrexed at the discretion of the 
investigator until progression or unacceptable toxicity as defined in Section 5.2.1.2 or 
carboplatin and pemetrexed plus MK-3475 200mg for 4 cycles followed by maintenance 
pemetrexed with MK-3475 at the discretion of the investigator until progression or 
unacceptable toxicity as defined in Section 5.2.1.2 for a maximum of 35 cycles 
 
 
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(approximately 2 years).  Subjects assigned to the chemotherapy arm will have the 
opportunity to crossover to receive MK-3475 monotherapy once they experience progression 
of disease (PD) defined by RECIST 1.1 and meet all crossover criteria defined in Section 
7.1.5.5.  Treatment is limited up to 35 cycles for the patients who crossover to MK-3475 
monotherapy.
Note that subjects receiving chemotherapy only in cohort G will have a slightly modified 
laboratory assessment follow-up.  See Section 6.1 for details.
Cohort H (ipilimumab plus MK-3475) – Subjects with any histology and have failed prior 
treatments.  Subjects with EGFR mutations or ALK translocations must have progressed on 
appropriate targeted therapies (e.g., erlotinib, gefitinib, crizotinib)
Subjects assigned to cohort H will receive ipilimumab at the RP2D from Part 1, cohort D for 
4 cycles in combination with MK-3475 followed by MK-3475 monotherapy.
Definition of Dose-Limiting Toxicities
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.0
(Appendix 12.6).
The DLT window of observation will be one cycle.  
The occurrence of any of the following toxicities will be considered a DLT, if judged by the 
investigator to be possibly, probably or definitely related to study drug administration:
1. Grade 4 non-hematologic toxicity (not laboratory).
2. Grade 4 hematologic toxicity lasting ≥7 days.
3. Grade 3 non-hematologic toxicity (not laboratory, specifically nausea, vomiting and 
diarrhea) lasting >3 days despite optimal supportive care.
4. Any Grade 3 or Grade 4 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.
5. 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
 
 
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
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.
6. 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
7. Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity
8. Missing >10% of erlotinib or gefitinib doses as a result of AE(s) during the DLT window 
of observation.
9. Grade 5 toxicity.
Replacement of Subjects in DLT Observation Period
Subjects who received < 90% of the MK-3475 infusion during the DLT window of 
observation as defined in 2.1.1 (e.g., because the infusion had to be discontinued due to an 
infusion reaction) and did not experience a DLT will not be taken into account in the 
assessment of the overall DLT rate for the particular dose level cohort and need to be 
replaced.
If a subject experiences a DLT during the DLT window of observation as defined in 2.1.1,
study therapy may be discontinued following discussion and agreement between the Sponsor 
and investigator.  An alternative consideration may be dose modification of MK-3475 as 
described in Section 5.2.1.2 with continued therapy.
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.
 
 
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Trial Diagram
The trial design is depicted in Figure 1 below.
Figure 1
Trial Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
1) Primary Objective Part 1:  To determine the recommended Phase II dose for
MK-3475 in combination with chemotherapy or immunotherapy in subjects with 
unresectable or metastatic NSCLC.
2) Primary Objective Part 2: To evaluate anti-tumor activity based on RECIST 1.1 of 
MK-3475 in combination with chemotherapy or immunotherapy in NSCLC subjects
using objective response rate (ORR).
Hypotheses:  

Cohort G1: MK-3475 in combination with chemotherapy improves ORR per 
RECIST 1.1 by blinded independent central review in NSCLC subjects compared 
to chemotherapy alone.

Cohort H: MK-3475 in combination with immunotherapy results in an ORR of 
greater than 20% per RECIST 1.1 by blinded independent central review in 
NSCLC subjects.
Secondary Objective(s) & Hypothesis(es)
1) Objective: To evaluate anti-tumor activity based on RECIST 1.1 of MK-3475 in 
combination with chemotherapy in NSCLC subjects using progression-free survival 
(PFS).
Cohort G1 Hypothesis: MK-3475 in combination with chemotherapy prolongs PFS per 
RECIST 1.1 by blinded independent central review in NSCLC subjects compared to 
chemotherapy alone treatment.
2) Objective: To evaluate duration of response (DOR) per RECIST 1.1 by blinded 
independent central review in subjects with unresectable or metastatic NSCLC treated 
with MK-3475 in combination with chemotherapy or immunotherapy or chemotherapy 
alone.
3) Objective:  To evaluate the overall survival (OS) in subjects with unresectable or 
metastatic NSCLC treated with MK-3475 in combination with chemotherapy or 
immunotherapy or chemotherapy alone.
4) Objective:  To characterize the pharmacokinetic (PK) profile of MK-3475 when given in 
combination with chemotherapy or ipilimumab or TKI (gefitinib or erlotinib).
5) Objective:  To evaluate anti-tumor activity based on modified RECIST 1.1 of MK-3475 
in combination with chemotherapy or immunotherapy or TKI (Part 1). 
 
 
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6) Objective:  To evaluate the correlation between PD-L1 expression levels and anti-tumor 
activity of MK-3475 in cohort G1.
Exploratory Objectives
1) To evaluate PFS and OS following crossover to MK-3475 in subjects treated with 
chemotherapy alone until disease progression.
2) To explore the correlation of tumor measurements (e.g., single longest diameter or 
volume) with PFS and OS in previously treated subjects with NSCLC in subjects
receiving MK-3475 in combination with chemotherapy versus chemotherapy alone.  
3) To investigate other biomarkers that may correlate with tumor response.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3475.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2-37].  In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in solid malignancies such as ovarian, colorectal and 
pancreatic cancer, hepatocellular carcinoma, malignant melanoma (MEL) and renal cell 
carcinoma (RCC).  TILs can be expanded ex vivo and re-infused, inducing durable objective 
tumor responses in cancers such as MEL [38, 39].
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) 
[40; 41].   The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins [42; 34].  PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [43; 44].  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 [42; 
45-47].  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 
 
 
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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 [45].  
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 [48], pancreatic carcinoma 
[49], hepatocellular carcinoma [50], and ovarian carcinoma [51].  Furthermore, PD-1 has 
been suggested to regulate tumor-specific T-cell expansion in subjects with MEL [52].
The observed correlation of clinical prognosis with PD-L expression in multiple cancers 
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.
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-, granzyme B and perforin, indicating 
that the mechanism of action involved local infiltration and activation of effector T-cell 
function in vivo [51; 53-57].  In addition, the combination of gemcitabine and anti-PD-L1 
mAb demonstrated synergy in the rejection of pancreatic mouse tumors [49].  In-house 
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 IB).
Recent data of nivolumab (MDX-1106, BMS-936558), an IgG4 antibody against PD-1, have 
validated PD-1 as an attractive target for clinical therapeutic intervention in NSCLC subjects
[18; 59].  Nivolumab was tested in multiple solid tumors in an open-label Phase I trial and 
promising clinical activity was noted in subjects with MEL, RCC, and NSCLC at multiple 
doses.  After an initial cohort of subjects with previously treated NSCLC were treated at 10 
mg/kg every 2 weeks (Q2W) with nivolumab, the study permitted randomization among 3
dose levels for new subjects in this population 1, 3, and 10 mg/kg Q2W.  Overall, subjects
with progressive NSCLC from prior therapies who were exposed to nivolumab had a 16% 
(20/122) ORR [59].  Those treated with nivolumab at 1 mg/kg administered every 2 weeks 
(Q2W) had only a 3% (1/31) ORR with a response lasting greater than 11 months.  Those 
treated with nivolumab at 3 mg/kg Q2W had a 27% (9/33) ORR with one responder having a 
response of greater than 30 months.  Those treated at 10 mg/kg Q2W had a 17% (10/58) 
ORR, with one response lasting greater than 18 months.  The most common drug-related 
adverse events (AEs), occurring in 5% or more of previously treated subjects with NSCLC, 
included decreased appetite, decreased hemoglobin, diarrhea, nausea, pruritus, fatigue, and 
rash.  The most commonly observed Gr 3-4 drug-related AEs in previously treated subjects 
with NSCLC were elevated aspartate aminotransferase (AST), fatigue, and pneumonitis [58].  
Of note, 3 deaths involving pneumonitis were observed on this trial, 2 of these subjects were 
receiving anti-PD-1 therapy for NSCLC [18].
 
 
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Preclinical and Clinical Trials
An open-label Phase I trial (Keynote 001) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab. The dose escalation portion of this trial 
evaluated 3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W), in subjects with advanced solid tumors. All 3 dose levels were well tolerated and no
dose - limiting toxicities were observed. Based on pharmacokinetic (PK) data showing a 
half-life of 21 days, the protocol was amended to change the dosing frequency in the 
expansion cohort to Q3W. The ongoing expansion cohort in Keynote 001 is enrolling 
subjects with NSCLC.
Keynote 001, Part C enrolled 38 subjects with NSCLC (adenocarcinoma, squamous cell 
carcinoma, and large cell carcinoma) who experienced progression of cancer after initiation 
of their second line of systemic therapy to receive monotherapy pembrolizumab. By 
investigator-assessed irRC (immune-related response criteria), the ORR (confirmed and 
unconfirmed) was 24%. Similar results were obtained using RECIST 1.1, yielding an ORR 
(confirmed and unconfirmed) of 21%. Most responses by irRC were observed by the time of 
first planned assessment at Week 9. The median duration of response by irRC has not been 
reached with a median duration of follow-up of 62 weeks. The median OS for all 38 patients 
treated with pembrolizumab was 51 weeks.
Subjects were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with pembrolizumab
to evaluate for expression of PD-L1, the presumptive predictive
biomarker of pembrolizumab, using a preliminary immunohistochemistry assay. A modified
H-score scoring system of PD-L1 expression was established for NSCLC by analyzing
tumor specimens from resected NSCLC specimens. This scoring system was then applied to
the samples from Keynote 001, Part C.
A total of 35 patients from Keynote 001 had tumor samples evaluable and a clinical response 
assessed. All but 3 patients were from Part C; 3 patients from Part A had NSCLC, submitted 
tumor tissue, and had a clinical response assessment. Seven of the 35 patients had a clinical 
response (20%) by investigator assessed irRC. Six responders (26%) were observed among
the 23 patients whose tumors expressed PD-L1. Of note, these 6 responders clustered at
the higher end of the modified H-score. Six of 9 (67%) patients whose tumors expressed PD-
L1 to an extent above the preliminary cut point had a clinical response. No responses
were noted among the patients whose tumors did not express PD-L1.
Keynote 001 Part F is currently enrolling PD-L1 positive previously untreated subjects with 
advanced NSCLC (Part F1) or previously treated subjected with advanced NSCLC (Part F2).
The planned enrollment for Part F1 is ~88 subjects; preliminary data from 45 subjects 
indicates an ORR by investigator assessed irRC of 36%.   Median OS at 12 months has not 
been reached with an OS rate at 12 months of 79.7%. For the subjects enrolled onto Part F2, 
the median PFS by investigator assessed irRC was 26.4 weeks in the highest PD-L1 positive 
cohort (PD-L1 “strong”); the median OS in the same cohort was 13.7 months.
 
 
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A training set comprised of approximately 140 tumor samples and their associated clinical 
outcome data were used to assess an optimal cut point for PD-L1 positivity. An optimal PD-
L1 cut point was identified by receiver operator characteristic curve analyses and by 
considering clinical implications of false positive and false negative results. Cut points were 
identified based upon a proportions score (PS) method of IHC analysis with the tumors 
expressing at or greater than the highest cut point (PS >50%) referred to as PD-L1
strongly positive tumors, and tumors expressing >1% but less than 50% referred to as
the PD -L1 weak tumors. Outcomes based on irRC were used as the primary outcome for
the analysis. Based on the training set, the Positive Predictive Value for patients in the
strong category was 42% while maintaining a negative predictive value of 92% for patients
in the weak or null category. Given the limited activity in the PD-L1 negative population, 
they will be excluded from the study. Furthermore, preliminary data indicate that the
prevalence of PD - L1 positivity in the previously untreated, Keynote 001, Part F1 cohort is
approximately 78%.
4.1.2.1
Preclinical Background on Combinations
MK-3475 relies upon a functional immune system to exert its anti-tumor effect, as previously 
discussed.  Theoretically, an even greater tumor cell reduction might be achieved by 
enhancing the antigen presentation via administration of MK-3475 in combination with 
standard cytotoxic chemotherapy.  Provided the cytotoxic chemotherapy combination is not 
also immunosuppressive, this coadministration should show increased anti-tumor activity.  
Indeed Figures 9-12 of the IB describe syngeneic colon cancer murine models that 
demonstrate this very principle.  Mice receiving the anti-PD-1 mAb plus 5-FU or 
gemcitabine experienced a greater tumor volume reduction and survival.  So it is reasonable 
to explore such effects in humans, but first a safe dose must be identified.
Information on Other Trial-Related Therapy
Current standard in a first line setting for advanced NSCLC except EGFR mutated type and 
EML4-ALK is platinum-based doublet therapy. While platinum doublets have similar 
outcomes [59; 60], cisplatin/pemetrexed or carboplatin/paclitaxel have been clinically widely
used mainly on the basis of safety. Median survival was 10.3 months of NSCLC subjects
who were treated with cisplatin/pemetrexed in a first line setting. Frequent (>5%) Grade 3 or 
4 drug-related toxicities were neutropenia, anemia, nausea, vomiting, and fatigue [59]. The 
median survival was
12.3 months for
NSCLC subjects
who were treated with 
carboplatin/paclitaxel in a first line setting. Frequent (>5%) Grade 3 or 4 toxicities were
leukopenia, neutropenia, anemia, thrombocytopenia, febrile neutropenia, nausea, vomiting, 
anorexia and constipation [61]. The addition of bevacizumab to carboplatin/paclitaxel
followed by bevacizumab maintenance therapy in subjects who are eligible for treatment has 
been demonstrated in improved overall survival [62].  Despite the responses observed in 
NSCLC subjects with chemotherapy, almost all subjects eventually progress and die as a 
consequence of their NSCLC.
 
 
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For subjects with EGFR mutations, treatment with erlotinib or gefitinib is the standard of 
care as monotherapy.  Despite response rates in excess of 50%, and improved overall 
survival, almost all subjects eventually progress and need additional treatment options. 
Therefore, new therapies are necessary for the treatment of subjects with advanced or 
metastatic NSCLC.  
Nivolumab has been evaluated in combination with chemotherapy in subjects with NSCLC.  
The preliminary data are summarized below:
Nivolumab has been studied in combination with chemotherapy in subjects with NSCLC 
[63].  The study enrolled first line NSCLC patients regardless of PD-L1 status. The study 
explored nivolumab 10 mg/kg Q3W (except one arm at 5 mg/kg as noted below) in 
combination with 3 standard chemotherapy regimens.  The chemotherapy was given for 4 
cycles concurrently with nivolumab followed by nivolumab monotherapy. The preliminary 
results are shown below:
The data indicate that the combination of an anti-PD-1 therapy in combination with 
chemotherapy has demonstrated encouraging response rates and as well as 1 year OS rates; 
however, 45% of the patients in the study experienced treatment-related Grade 3 or 4 AEs. 
Therefore, randomized phase II data with the combination will be necessary to determine the 
relative improvement in benefit/risk compared to chemotherapy alone.  
Given the potential limitations of combinations with chemotherapy, another approach is the 
addition of anti-PD-1 to ipilimumab.  The rationale is that blocking of PD-1 receptors and 
CTLA4 receptors results in T-lymphocytes being fully disinhibited.    Preclinical studies have 
demonstrated synergy between nivolumab and ipilimumab [64] and a clinical trial in first line 
patients with advanced NSCLC has shown anti-tumor activity when combining these 2
treatments. However, increased toxicities were seen from the combination including 
treatment-related deaths (N=3 [7%]) and discontinuation due to AEs (N=16 [35%]) [67]. The 
preliminary efficacy data are shown below:
 
 
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Furthermore, ipilimumab has demonstrated activity in NSCLC in combination with 
chemotherapy [65].
Therefore, combination immunotherapy offers a potential advantage that warrants further 
exploration in NSCLC patients who do not have other effective treatment options.
Rationale
Rationale for the Trial and Selected Subject Population
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying Investigators Brochure (IB) and Informed Consent documents.
Lung cancer has been the most common malignancy in the world for several decades and it 
also has been the leading cause of cancer related mortality. In 2008, there were more than 1.6 
million newly diagnosed lung cancer cases and 1.4 million cases of lung cancer related 
deaths worldwide.
Despite the recent progress in lung cancer treatment, overall survival for advanced NSCLC 
remains short and almost all patients die within 1 year from the initial diagnosis. Advanced
lung cancer subjects without EGFR mutation or EML4-ALK translocation are often treated 
with platinum-based combination chemotherapy with or without bevacizumab. Overall 
response rates and PFS from these first line regimens range 15-35% and 4-6 months 
respectively. For patients with EGFR mutations or EML4-ALK translocations, the 
development of targeted therapies has improved clinical outcomes; however, overall survival 
remains poor with a median less than 2 years. Therapy for patients with this stage of disease 
 
 
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is not curative, and disease progression is expected. Therefore, new therapies are needed for
patients with advanced or metastatic NSCLC.  
Anti-tumor activity of MK-3475 is being tested in NSCLC patients in MK-3475 PN001 and 
preliminary data revealed encouraging response rates. Moreover, when MK-3475 was 
administered in combination with other chemotherapeutic agents in mouse models, 
synergistic anti-tumor effects were observed (refer to the IB, Section 4.1.6 and 4.1.7).  
Therefore, clinical development of MK-3475, an anti-PD-1 antibody, in combination with 
chemotherapy would potentially have a great significance in patients with advanced solid 
tumors including NSCLC.
Rationale for Dose Selection/Regimen
In general, the dose and schedule for MK-3475 used in the study is based on the results of
PN001.  (See IB.)  
Cohorts A, B and C – The chemotherapy regimens are either the approved dose and schedule 
for each regimen or a standard modification of the regimen [62; 66].  In the phase I study, no 
DLTs were seen within the first 4 weeks of treatment when nivolumab was given at 10 
mg/kg Q3W in combination with chemotherapy as mentioned above [63].  Therefore, a 
randomized phase I design will be employed to evaluate MK-3475 at doses of 2 mg/kg vs. 10 
mg/kg for 12 subjects.  
Cohort D - When tested in advanced melanoma patients, ipilimumab at 3 mg/kg in 
combination with nivolumab 1 mg/kg every 3-week schedule demonstrated an acceptable 
safety profile.  However, after starting enrollment into cohort D, additional safety 
information became available from the nivolumab and ipilimumab combination study in 
advanced NSCLC patients which raised safety concerns of the combination including 
treatment-related deaths [67], the Sponsor has decided to decrease the dose of combination to 
dose level -2; Ipilimumab 1mg/kg combined with MK-3475 2mg/kg.  At the time of the 
decision, a total of 6 patients (3 patients at Ipilimumab 1mg/kg combined with MK-3475 
10mg/kg, and 3 patients at Ipilimumab 3mg/kg combined with MK-3475 10mg/kg) had been 
enrolled and treated with the combination in Cohort D and no DLTs have been reported.  
Cohort E and F – Treatment will consist of MK-3475 2 mg/kg Q3W in combination with 
standard doses of gefitinib or erlotinib.  The MK-3475 dose will follow a 3+3 dose escalation 
schema.
Cohort G1 - The rationale for further exploration of lower doses of M K - 3 4 7 5  in solid
tumors is based on: 1) similar efficacy and safety of MK-3475 when dosed at either 2 mg/kg, 
10 mg/kg Q3W, or 10 mg/kg Q2W in melanoma patients, 2) the flat exposure -response 
relationships of MK-3475 for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 
10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior
of MK-3475 (as assessed by the population PK model) and 4) the assumption that the 
dynamics of PD-1 target engagement will not vary meaningfully with tumor type.
 
 
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The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of MK-3475 showing that the fixed
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with
those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe.
4.2.2.1
Starting Dose for This Trial
The starting dose for MK-3475 in this trial is 2 or 10 mg/kg Q3W.  
4.2.2.2
Maximum Dose/Exposure for This Trial
The maximum dose and exposure of MK-3475 allowed in this study is 10 mg/kg Q3W up to 
35 cycles (approximately 2 years). If a subject completes 35 cycles and later experiences 
PD, he/she may be eligible to receive up to 17 additional cycles (approximately 1 year) of 
MK-3475 200mg Q3W, termed Second Course (see Section 7.1.5.4).
4.2.2.3
Rationale for Dose Interval and Trial Design
Please see Section 4.2.2 for the rationale for dose interval and trial design.  
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
The anti-tumor activity will be evaluated as an efficacy endpoint based on radiographic (CT
or MRI). RECIST 1.1 (Section 12.7) will be applied for evaluation of tumor response. For 
the purposes of this study, RECIST 1.1 is modified to include a confirmatory scan for disease 
progression. This modification was a result of regulatory agency feedback and was prompted 
by the clinical observation that some subjects can have a temporary increase in existing 
tumor lesions or the transient occurrence of a new lesion after start of immunotherapy, while 
ultimately experiencing treatment benefit in form of an objective disease response or long-
lasting disease stabilization.
4.2.3.2
Safety Endpoints
The safety primary endpoint in this study is the incidence of DLTs observed in the DLT
evaluation period. Adverse events and laboratory test values observed in this study are also 
safety endpoints. In addition to general laboratory tests, immune laboratory tests will be 
evaluated considering the mode of action of MK-3475. 
4.2.3.3
Pharmacokinetic Endpoints
Pharmacokinetic endpoints will include MK-3475 levels as well as anti-drug antibodies.
 
 
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Pharmacokinetics of pembrolizumab will be explored per existing modeling analysis plan 
(MAP). 
4.2.3.4
Planned Exploratory Biomarker Research
PD-L1 is a ligand for PD-1 and MK-3475 attempts to disrupt the interaction of 2 proteins. 
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, pancreatic 
carcinoma, hepatocellular carcinoma, ovarian carcinoma, and NSCLC.
The correlation between baseline PD-L1 expression levels and tumor response will be
evaluated as an exploratory objective. PD-L1 expression levels will be measured in archival 
tumors or biopsy samples determined to be evaluable by central lab.
4.2.3.5
Future Biomedical Research
Merck will conduct Future Biomedical Research on DNA (blood) or 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. Specimens may be used for future assay development.
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 Future 
Biomedical Research are presented in Section 12.2 - Collection and Management of 
Specimens for Future Biomedical Research.  Additional informational material for 
institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is 
provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with NSCLC ≥18 years of age will be enrolled in this trial.
 
 
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Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1) Have a histologically-confirmed or cytologically confirmed diagnosis of stage IIIB/IV 
NSCLC
a.
Subjects for cohort A, B, C, E, F and G should have received no prior systemic 
treatment for stage IIIb/IV NSCLC.
b. Subjects for cohorts D and H should have received prior treatment for NSCLC which 
should have been platinum based, unless EGFR mutation or ALK translocation was 
present. Subjects who are eligible for specific targeted therapy (e.g., EGFR mutation 
or ALK translocation) should have received prior treatment with the appropriate 
targeted agents.
c.
Subjects for cohorts E and F should have confirmed activating EGFR mutation.
2) Patients who had disease progression >1yr after completing adjuvant therapy for stage I-
IIIA disease are eligible for Cohort A, B, C, G1 and G2, as long as no systemic therapy 
was given for the recurrent disease. 
3) Subject must have at least one radiographically measurable lesion as per RECIST 1.1
defined as a lesion that is ≥10 mm in longest diameter or lymph node that is ≥15 mm in 
short axis imaged by CT scan or MRI
4) Be ≥18 years of age on day of signing informed consent.
5) Have a life expectancy of at least 3 months.
6) Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group
(ECOG) Performance Status (Section 12.4)
7) Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or
less (except alopecia). If subject received major surgery or radiation therapy of > 30 Gy, 
they must have recovered from the toxicity and/or complications from the intervention.
 
 
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8) Have adequate organ function as indicated by the following laboratory values:
Table 1
Adequate Organ Function Lab Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L– 4 weeks without transfusions
Renal
Serum creatinine  OR
calculated creatinine clearance (CrCl)a
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subjects with creatinine levels > 1.5 X 
institutional ULN
Hepatic
Serum total bilirubin
≤  ULN 
AST (SGOT) and ALT (SGPT)
≤ 1.5 X ULN 
Alkaline Phosphatase
≤ 2.5 X ULN 
Endocrine
Thyroid-stimulating hormone (TSH)
Within normal limitsb
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless the subject is receiving anticoagulant therapy
≤1.5 X ULN unless the subject is receiving anticoagulant therapy
a Creatinine clearance should be calculated per institutional standard.  If no local guideline is available, 
Creatinine Clearance should be calculated using the Cockcroft-Gault Method:
CrCl = [(140-age) * weight (kg) * (0.85 for females only)] / (72 * serum creatinine)
b If TSH is not within normal limits at baseline, the subject will still be eligible if total T3 or free T3 and free T4 
are within the normal limits.
9) Female subjects of childbearing potential must have a negative urine or serum pregnancy 
test within 72 hours prior to receiving the first dose of study medication. If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10) Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, for the 
course of the study through 120 days after the last dose of study medication and up to 180 
days after last dose of chemotherapeutic agents or TKIs.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
11) Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception as outlined in Section 5.7.2- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy and up to 
180 days after last dose of chemotherapeutic agents or TKIs.
 
 
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Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
12) Subject has voluntarily agreed to participate by giving 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.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1) Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 
4 weeks prior to administration of MK-3475.
2) a) Within 3 weeks of the first dose of trial treatment:

Has received prior systemic cytotoxic chemotherapy 

Has received antineoplastic biological therapy (e.g., cetuximab)

Had major surgery
b) Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose 
of trial treatment 
c) Received prior tyrosine kinase inhibitor therapy or completed
palliative radiotherapy within 7 days of the first dose of trial treatment.
3) Is expected to require any other form of antineoplastic therapy while on study.
4) Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal 
flu vaccines that do not contain live virus are permitted.
5) Patients with clinically active diverticulitis, intra-abdominal abscess, GI obstruction, 
abdominal carcinomatosis.
6) Has a known history of prior malignancy except if the patient has undergone potentially 
curative therapy with no evidence of that disease recurrence for 5 years since initiation of 
that therapy.  
Note: The time requirement for no evidence of disease for 5 years does not apply to 
the NSCLC tumor for which a subject is enrolled in the study.  The time requirement 
also does not apply to subjects who underwent successful definitive resection of basal 
 
 
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cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the 
skin, in situ cervical cancer, or other in situ cancers.
7) Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are clinically stable for at least 4 weeks and, have no evidence of new or enlarging 
brain metastases and also are off steroids 3 days prior to dosing with study medication.  
Stable brain metastases by this definition should be established prior to the first dose of 
study medication.  
8) Previously had a severe hypersensitivity reaction to treatment with another mAb.
9) Has active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.   
10) Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or 
local steroid injections would not be excluded from the study. Subjects on chronic 
systemic steroids would be excluded from the study.
11) Had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody 
targeting other immuno-regulatory receptors or mechanisms.  Has participated in any 
other MK-3475 trial and has been treated with MK-3475.
Examples of such antibodies include (but are not limited to) antibodies against IDO, 
PD-L1, IL-2R, GITR.
12) Has an active infection requiring therapy.
13) Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14) Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive 
HBsAg result.  Active Hepatitis C is defined by a known positive Hep C Ab result and
known quantitative HCV RNA results greater than the lower limits of detection of the 
assay.
15) Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.
16) Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
 
 
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17) Is, at the time of signing informed consent, a regular user (including “recreational use”) 
of any illicit drugs or had a recent history (within the last year) of substance abuse 
(including alcohol).
18) Has symptomatic ascites or pleural effusion. A subject who is clinically stable following 
treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
19) Has interstitial lung disease or a history of pneumonitis that required oral or intravenous 
glucocorticoids to assist with management.  Lymphangitic spread of the NSCLC is not 
exclusionary.  
20) Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study.
21) Subjects in cohorts E and F that require treatment with a strong inhibitor of CYP3A4 will 
be excluded.  They may be included if there is an alternate treatment available (not a 
strong CYP3A4 inhibitor) and they are willing to switch prior to randomization.  If a 
subject opts to change from a strong CYP 3A4 inhibitor to a weaker CYP 3A4 inhibitor, 
the subject must stop the strong CYP 3A4 inhibitor 7 days before study drug 
administration.
22) 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)
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which treatment is allocated/assigned. The treatments to be used in this trial are outlined 
below in Table 2 and in Section 5.2.2.
Table 2
Trial Treatment
Drug
Dose/ Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Paclitaxel
200 or 175
mg/m2
Q3W
IV infusion
Day 1 of 
each cycle
Treatment of 
cancer
Carboplatin
6 mg/ml/min 
(Cohorts A&B)
Target AUC 
5 mg/mL/min 
(Cohort C and 
G)
Q3W
IV infusion
Day 1 of 
each cycle
Treatment of 
cancer
Bevacizumab
15 mg/kg
Q3W
IV infusion
Day 1 of 
each cycle
Treatment of 
cancer
Pemetrexed
500 mg/m2
Q3W
IV infusion
Day 1 of 
each cycle
Treatment of 
cancer
 
 
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Drug
Dose/ Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Ipilimumab
1 mg/kg
Q3W
IV infusion
Day 1 of 
each cycle
Experimental
Erlotinib
150 mg
Daily
PO
Daily
Treatment of 
cancer
Gefitinib
250 mg
Daily
PO
Daily
Treatment of 
cancer
MK-34751
2 or 10 mg/kg
Q3W
IV infusion
Day 1 of 
each cycle1,
Experimental
MK-34751
200 mg
Q3W
IV infusion
Day 1 of 
each cycle1
Experimental
1MK-3475 to be administered prior to chemo-/immunotherapy. 
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
5.2.1.1
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.
The dose amount required to prepare the MK-3475 infusion solution will be based on the 
subject’s weight in kilograms (kg) for Part 1 of the study and Cohort H in Part 2.  For Part 2, 
Cohort G, the dose amount required to prepare the MK-3475 infusion solution will be based 
on a fixed dose of 200mg.  Details on the dose calculation, preparation and administration are 
provided in the Pharmacy Manual.
Concomitant chemotherapeutic/immunotherapeutic agents will be prepared and administered 
as per the approved product label.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Concomitant Chemotherapeutic Agents
Refer to approved product label.
 
 
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5.2.1.2.2 MK-3475 Dose Modifications
Dose modification and toxicity management for immune-related AEs (irAEs) associated 
with pembrolizumab
AEs associated with pembrolizumab exposure may have an immunologic etiology.  These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of treatment and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications.  Based on 
existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, 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 3.
In addition, subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures, as described in 
Section 5.6.1, are also included in Table 3.
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with MK-3475
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
Pneumonitis -
related AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor 
participants 
for 
signs 
and 
symptoms of pneumonitis

Evaluate 
participants 
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 
participants 
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).

Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune
Pneumonitis -
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
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

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for participants with T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants 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 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
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 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones (eg, levothyroxine or 
liothyronine) 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
Pneumonitis -
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
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
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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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 4.
Table 4
MK-3475 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 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the 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 
MK-3475 with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
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
Other allowed dose interruption for pembrolizumab
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient’s study record.
Dose increase of MK 3475 will not be permitted in individual subjects unless the 2 mg/kg 
dose of MK-3475 is dropped during the trial due to safety and/or efficacy concerns.  If this 
occurs the Sponsor will inform the investigators and recommend to treat patients with 
10mg/kg of MK-3475.
Timing of Dose Administration
MK-3475 will be administered at least 30 minutes prior to premedication for the 
chemotherapies or ipilimumab. 
Trial treatment should be administered on Day 1 of each cycle after all procedures / 
assessments have been completed except for the post-infusion PK sample time points listed 
in the Trial Flow Chart.  Trial treatment can be administered +/- 3 days of the targeted Day 1 
for each cycle due to administrative reasons only.
 
 
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The specific time of MK-3475 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.  MK-3475 should be administered prior to
chemotherapy/immunotherapy.  Please note that Day 1 of MK-3475 for the Dose Separation 
Phase in Cohort F is at Cycle 1 (Weeks 7 – 9) requiring a different schedule for PK/antibody 
samples as noted in the study flow chart (Section 6.2).
All trial treatments will be administered on an out-patient basis.
For subjects who experience disease progression, investigators may elect to interrupt 
treatment by deferring the decision to continue/discontinue treatment in the trial until 
confirmation of disease progression per RECIST 1.1 at least 28 days from the date of 
imaging demonstrating disease progression.  Subjects for whom disease progression is not 
confirmed on subsequent imaging may resume treatment.  Please see Section 5.8 for other 
exceptions.
5.2.2.1
MK-3475
MK-3475 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).  Note that infusion time may 
take longer for subjects who exceed the upper weight boundary as listed in the Procedures 
Manual.
The Pharmacy Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
5.2.2.2
Paclitaxel
Paclitaxel 200 or 175 mg/m2 will be administered as an IV infusion over 3 hours Q3W for 4 
cycles.  All subjects should be premedicated with oral or injectable steroids according to the 
approved product label and/or standard practice.  Additional premedications should be 
administered as per standard practice.  
5.2.2.3
Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes Q3W until 
progression or unacceptable toxicity.  All subjects should receive the appropriate 
supplementation of vitamin B12 and folic acid according to the approved product label 
and/or standard practice.  In addition, all subjects should receive the appropriate 
corticosteroid premedications as per the local approved label.  Additional premedications 
should be administered as per standard practice.
 
 
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5.2.2.4
Carboplatin
Carboplatin AUC 6 (for cohort A and B) or 5 (for cohorts C and G) mL/min will be 
administered as an IV infusion over 15-60 minutes Q3W for 4 cycles immediately after either 
paclitaxel or pemetrexed.  Additional premedications should be administered as per standard 
practice.  
5.2.2.5
Bevacizumab
Bevacizumab, 15 mg/kg, will be administered as an IV infusion over 30-90 minutes based on 
local approved product label Q3W.  Additional premedications should be administered as per 
standard practice.  Bevacizumab should be continued until progression of disease or 
unacceptable toxicity.
5.2.2.6
Ipilimumab
Ipilimumab 1 mg/kg will be administered as a 90-minute IV infusion (starting no sooner than 
30 minutes after completion of MK-3475 infusion and after peak level of MK-3475 
pharmacokinetic blood samples are drawn) for 4 cycles.
5.2.2.7
Erlotinib
Erlotinib 150 mg will be administered as an oral tablet daily.  Additional premedications 
should be administered as per standard practice.  Erlotinib should be continued until 
progression of disease or unacceptable toxicity.
5.2.2.8
Gefitinib
Gefitinib 250 mg will be administered as an oral tablet daily.  Additional premedications 
should be administered as per standard practice. Gefitinib should be continued until 
progression of disease or unacceptable toxicity.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
The subject-level PD-L1 biomarker results will be masked in the database to the investigator.  
Imaging data for the primary analysis will be centrally reviewed by independent 
radiologist(s) without knowledge of subject treatment assignment.
Randomization or Treatment Allocation
Randomization will occur centrally using an interactive voice response system/integrated 
web response system (IVRS/IWRS). There are 4 treatment arms that will be randomized:  A, 
B, C and G.  For cohorts A, B and C, subjects will be assigned randomly in a 1:1 ratio to 
receive chemotherapy plus 2 mg/kg MK-3475 or chemotherapy plus 10 mg/kg MK-3475.  
 
 
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For Cohort G1, subjects will be assigned randomly in a 1:1 ratio to receive carboplatin and 
pemetrexed plus/minus  MK-3475 200 mg. Cohort G2 is optional and will be randomized the 
same as cohort G1.
Stratification
Randomization will be stratified according to the following factors:
Subjects in Cohort G1 will be stratified based on negative or positive PD-L1 tumor 
expression.  Positive PD-L1 tumor expression is defined as Tumor Proportion Score (TPS) 
≥1%.  TPS <1% and PD-L1 unevaluable subjects will be included in the negative group.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date will also be included on the CRF.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Surgery or radiotherapy for tumor control 
is not permitted during the study; however, radiotherapy or procedures for symptom 
management is allowed.
All concomitant medications received within 30 days before the first dose of trial treatment 
through the Safety Follow-up Visit should be recorded.  After the Safety Follow-up Visit 
record all medications taken for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening, 
Treatment, crossover and Second Course Phases of this trial:

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.

Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.

Investigational agents other than MK-3475.

Radiation therapy; radiotherapy for symptom management is allowed.
 
 
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
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chickenpox, yellow fever, nasal seasonal flu, 
nasal H1N1 flu, rabies, BCG, and typhoid vaccine.

Prolonged therapy with systemic glucocorticoids (>7 days) for any purpose other than 
to modulate symptoms from an event of clinical interest or for use as a premedication
for chemotherapeutic agents specified in the protocol. Brief, limited use of systemic 
corticosteroids (≤7 days) are permitted where such use is considered standard of care 
(e.g. as premedication for contrast allergy or for COPD exacerbation). Replacement 
doses of steroids (for example, prednisone 10 mg daily) are permitted while on study.

Strong inhibitors of the CYP3A4 enzymes may not be used on Cohorts E & F (a 
common list of such agents may be found in Section 12.8)
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.  
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines
MK-3475
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined in the dose modification table (Table 
3). Where appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids.  Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to MK-3475. 
Note: if after the evaluation the event is determined not to be related to MK-3475, the 
investigator does not need to follow the treatment guidance. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the dose modification table.
 
 
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Guidelines for Infusion-Reactions
See Section 5.2.1.2, Table 4.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Contraception
MK-3475 may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
MK-3475 has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
 
 
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Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
intrauterine device (IUD)
•
vasectomy of a female subject’s male partner 
•
contraceptive rod implanted into the skin
Combination method (requires use of 2 of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)  
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
•
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 180
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study.
 
 
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Use in Pregnancy
If a female subject inadvertently becomes pregnant while on treatment in this study, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.  If 
a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and followed as described 
above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether MK-3475 is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breastfeeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal 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 continue to be monitored in the trial for 
any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent

Documented disease progression
Note: If a subject has confirmed progression of disease by RECIST 1.1, the subject 
should not receive further trial treatment on study except as indicated below.  If a 
subject has unconfirmed progression of disease and is clinically stable, it is at the 
discretion of the investigator to continue treating the subject with the assigned 
 
 
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treatment per protocol until progression of disease is confirmed at least 28 days from 
the date of the scan suggesting progression of disease.  
Exception 1) A subject who is clinically stable and has progression which is limited 
(defined as 1- 4 progressing lesions amenable to local ablative therapy) may, at the
discretion of the investigator, continue assigned treatment per protocol after ablative 
therapy until further progression of disease is confirmed. No lung or liver lesions may 
be considered for ablation and at least one site of prior measurable disease should not 
be ablated. Protocol therapy will be interrupted until recovery from any toxicities due 
to ablation, not to exceed 12 weeks. 
Exception 2) Subjects assigned to the chemotherapy arm in Cohort G1 will have the 
opportunity to crossover to receive MK-3475 monotherapy once they experience 
progression of disease (PD) defined by RECIST 1.1 and meet all crossover criteria 
defined in Section 7.1.5.5.  
Clinical Stability is defined as:
1) Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) indicating disease progression.
2) No decline in ECOG performance status.
3) Absence of rapid progression of disease or progressive tumor at critical 
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention.

Unacceptable adverse experiences as described in Section 5.2.1.2.

35 cycles (approximately 2 years) of uninterrupted delivery of MK-3475 every 3 
weeks and no documented progression of disease

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Administrative reasons
 
 
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If a MK-3475 treated subject attains an investigator-determined confirmed CR according to 
RECIST 1.1, has been treated for at least 6 months with MK-3475, and has at least 2
treatments with MK-3475 beyond the date when the initial CR was declared OR the
subject has received the maximum administrations of MK-3475 as outlined above, the 
subject and investigator may consider stopping therapy with MK-3475. Subjects who
discontinue MK-3475 and then experience radiographic disease progression according to
RECIST 1.1 may be eligible for re-treatment with MK-3475 in the Second Course
Phase at the discretion of the investigator as described in Section 7.1.5.4.
Subjects will resume therapy at the dose and schedule when they previously stopped trial 
treatment unless that schedule has been discontinued, at which case subjects will resume 
therapy on the remaining schedule.  Subjects who continue into the Second Course Phase 
will be administered MK-3475 at a fixed dose of 200 mg every 3 weeks for a maximum of 17 
cycles.
Chemotherapy may be discontinued when a subject has received the maximum number of 
cycles permitted by the local regulatory authority. Maintenance pemetrexed may continue 
beyond Cycle 35 at the investigator’s discretion and in accordance with local regulations 
until reaching a stopping criterion.

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 a minimum of 30 days for adverse event monitoring even 
if the patient started new antineoplastic treatment (serious adverse events will be 
collected for up to 90 days following cessation of Sponsor’s product, or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier as described in Section 7.2.3.1). Subjects will have post-
treatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent, becoming lost to follow-up or entering the 
Second Course Phase.  After documented disease progression each subject will either 
move into the Second Course Phase or be followed for overall survival until death or 
withdrawal of consent.
Subject Replacement Strategy
Subjects who received <90% of the MK-3475 infusion during the DLT window of 
observation as defined in 2.1.1 (e.g., because the infusion had to be discontinued due to an 
infusion reaction) and did not experience a DLT will not be taken into account in the 
assessment of the overall DLT rate for the particular dose level cohort and need to be 
replaced.
 
 
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Confidential
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall
trial ends when the last subject completes the last trial visit, discontinues from the trial or is 
lost to follow-up (i.e. the subject is unable to be contacted by the investigator).  Upon study 
completion, subjects are discontinued and enrolled in a pembrolizumab extension study.
Note that data cleaning and lock may take place before the end of trial.  Subjects who may 
eventually be eligible for crossover who have not yet transitioned to pembrolizumab will be 
considered for the extension study on a case-by-case basis.
Clinical Criteria for Early Trial Termination
The trial will be stopped early if the risk/benefit ratio to the trial population as a whole is 
unacceptable.
Statistical criteria for stopping the trial are provided in Section 8.0 – Statistical Analysis Plan.
Further recruitment in the trial or at (a) particular trial site(s) may be stopped due to 
insufficient compliance with the protocol, GCP and/or other applicable regulatory 
requirements, procedure-related problems or the number of discontinuations for 
administrative reasons is too high.
Post-progression Treatment
Investigators treating MK-3475 clinically-stable subjects who experience disease progression 
may elect to interrupt treatment by deferring the decision to continue/discontinue treatment in 
the trial until confirmation of disease progression per RECIST 1.1 at least 28 days from the 
date of imaging demonstrating disease progression.  Subjects treated with MK-3475 for 
whom disease progression is not confirmed on subsequent imaging may resume treatment 
with MK-3475.  
A subject who is clinically stable (defined in Section 5.8) and has confirmed progression 
which is limited (defined as 1- 4 progressing lesions amenable to local ablative therapy) may, 
at the discretion of the investigator, continue assigned treatment per protocol after ablative 
therapy until further progression of disease is confirmed. No lung or liver lesions may be 
considered for ablation and at least one site of prior measurable disease should not be 
ablated. Protocol therapy will be interrupted until recovery from any toxicities due to 
ablation, not to exceed 12 weeks.  
Subjects assigned to the chemotherapy arm only in Cohort G will have the opportunity to 
crossover to receive MK-3475 monotherapy if they experience progression of disease (PD) 
defined by RECIST 1.1 and meet all crossover criteria defined in Section 7.1.5.5 for up to 
35 treatment cycles (approximately 2 years) at the investigator’s discretion.
 
 
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Post MK-3475/Chemotherapies
After a subject stops the designated study treatment for one of the reasons described in 
Section 5.8, other than for a CR, the subject may be interested in pursuing other therapies.  If 
investigators assess that the subject is fit for subsequent therapy, it is encouraged.  
The exact subsequent treatment(s) used will be at the discretion of the investigator and 
determined by the interests of the subject.  
 
 
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6.0 TRIAL FLOW CHART
Treatment Phase
Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Treatment Cycle / Scheduled Time
-28 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
through 
35
36+
Discontinuation Visit
Scheduling Window (Days):2
± 3
± 3
± 
3
± 3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 3
Administrative Procedures
Informed Consent 
X
Informed 
Consent 
for 
Future 
Biomedical Research (optional)
X24
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NSCLC Disease Details and Prior 
Treatment
X
Survival Status27
---------------------------------------------------------------------------------------------------------------------------------------------
Clinical Procedures / Assessments
Review Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary Function Testing
and 
DLCO
X
Study Drug Administration
Paclitaxel/Carboplatin16
X
X
X
X
Bevacizumab 14, 23
X
X
X
X
X23
X
X
X
X
X
X
X
X
X
 
 
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Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Treatment Cycle / Scheduled Time
-28 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
through 
35
36+
Discontinuation Visit
Scheduling Window (Days):2
± 3
± 3
± 
3
± 3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 3
Pemetrexed17, 23
X
X
X
X
X23
X
X
X
X
X
X
X
X
X
Carboplatin17
X
X
X
X
Ipilimumab18
X
X
X
X
Erlotinib19, 22
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Gefitinib20, 22
MK-347521
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures / Assessments: analysis performed by local laboratory26
Pregnancy Test - Urine or Serum β-
HCG 3
X
PT/INR and aPTT 4
X 5
CBC with Differential6
X 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry 
Panel6
X 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis6, 7
X 5
X
X
X
X7
X
T3, FT3, FT4 and TSH 6, 8
X 5
X
X
X
X 7
X
ALK Translocation Testing15
X 
EGFR Mutation Testing15
X 
Tumor PDL Expression
X
Blood 
for 
Future 
Biomedical 
Research25 (optional)
X
MK-3475 Treatment Arm only: analysis performed by central laboratory
Pharmacokinetics 9
X
X10
X
X
X
X
X 12
X
Anti-MK-3475 Antibodies 11
X
X
X
X
X
X
X 12
X
Efficacy Measurements
Tumor Imaging 13
X
X
X
X
X
X
X13
X13
X
 
 
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Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Treatment Cycle / Scheduled Time
-28 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
through 
35
36+
Discontinuation Visit
Scheduling Window (Days):2
± 3
± 3
± 
3
± 3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 3
Tumor Biopsies / Archival Tissue Collection
Tumor Tissue Collection 25
X
1
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified.   Treatment cycles are 3 weeks (21-days). 
Imaging will be performed every 6 weeks (± 7 days) from the first dose of trial treatment regardless of any treatment delays.
2
In general, the window for each visit is 3 days unless otherwise specified.
3
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. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
4
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
5
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.  
6
After Cycle 1, lab samples can be collected up to 48 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.  
7
Perform every 4 cycles after Cycle 13.
8
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.
9
MK-3475 treated subjects – Trough (predose) and peak (post-dose) samples will be collected at Cycles 1 and 2.  A trough sample will be collected at Cycle 3, 6, 9, 13, and 17.  All trough samples 
should be drawn within 24 hours before infusion of MK-3475 and at the same time as blood collection for anti-MK-3475 antibodies.  The peak samples in Cycles 1 and 2 should be drawn within 30-
minutes after the end of the infusion. Procedures for sample collection are described in the Procedures Manual.
10 MK-3475 treated subjects – An additional PK sample must be drawn between 24 and 96 hours after Cycle 2 dosing.
11 MK-3475 treated subjects – Draw samples for anti-MK-3475 antibodies within 24 hours before infusion of MK-3475 and at the same time as PK blood sample collection in Cycles 1, 2, 3, 6, 9, 13 
and 17.  After Cycle 17 collect samples every 8 cycles.  Procedures for sample collection are described in the Procedures Manual.
12 Perform every 8 cycles after Cycle 17. 
13 Performed every 6 weeks for the first 18 weeks, then every 9 weeks till the end of Year 1.  Performed every 12 weeks subsequently until the subject experiences PD or initiates a new anticancer
therapy. After the first documentation of progression (if the subject is clinically stable) or response per RECIST 1.1 repeat imaging for confirmation is required. Confirmatory imaging should be 
performed 4 to 6 weeks later.  Timing of imaging scans should follow the calendar and not be adjusted for treatment delays.
14 Cohort B only, see Section 2.1 Trial Design.
15 Site must be able to provide documentation of the subject’s tumor EGFR mutation and ALK translocation status.  If the site is unable to provide this source documentation, then the Sponsor will 
offer this molecular testing of the tumor. See Section 7.1.3.4 for details on EGFR mutation testing.
16 Cohorts A and B only, see Section 2.1 Trial Design.
17 Cohort C and G only, see Section 2.1 Trial Design.
18 Cohorts D and H only, see Section 2.1 Trial Design.
19 Cohort E only, see Section 2.1 Trial Design. 
20 Cohort F only, see Section 2.1 Trial Design.
21   Cohorts A, B, C, D, E, F and H.  Chemotherapy + MK-3475 arm (exclude chemotherapy only arm) in Cohort G. 
22 Tablets to be taken daily; will be dispensed at the beginning of each cycle.
23 May be continued as maintenance therapy after Cycle 4 at discretion of investigator.
24 Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn.  DNA sample for analysis should be obtained predose, on Day 1 (or with the 
next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This sample should only be taken once from each 
subject.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
 
 
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Screening
(Visit 1)
Treatment Cycles1
End of Treatment
Treatment Cycle / Scheduled Time
-28 to -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 
through 
35
36+
Discontinuation Visit
Scheduling Window (Days):2
± 3
± 3
± 
3
± 3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 
3
± 3
± 3
25 Tumor tissue for biomarker analysis from an archival tissue sample or fresh biopsy of a tumor lesion not previously irradiated must be provided.  Detailed instructions for tissue collection, 
processing and shipment are provided in the Procedures Manual. Any leftover tumor tissue will be stored for future research if the subject signs the optional FBR consent.
26 Subjects receiving chemotherapy only in cohort G1: require only CBC and chemistry panel after Cycle 6 (Week 18).  This should be collected at the time of clinic visit for radiological scan.
27 After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be requested 
by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants 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 participants that have a death event previously recorded).
 
 
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Cohort F Dose Separation Treatment Phase
Screening
(Visit 1)
Treatment Cycles(C)1
End of 
Treatment
Treatment Cycle / 
Scheduled Time
-28 to -1
1 
Day 
1
1 
Week 
3
1 
Week 
6
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru 
35
Discon-
tinuation
Visit
Scheduling Window 
(Days):2
±3
±3
± 3
±3
±3
± 3
±3
± 3
± 3
±3
± 3
± 3
± 3
±3
± 3
Administrative Procedures
Informed Consent 
X
Informed Consent for Future 
Biomedical 
Research 
(optional)
X19
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical 
History
X
Prior 
and 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
NSCLC Disease Details and 
Prior Treatment
X
Survival Status20
-------------------------------------------------------------------------------------------------------------------------------------------------------
Clinical Procedures / Assessments
Review Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed 
Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulmonary Function Testing
and DLCO
X
 
 
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Screening
(Visit 1)
Treatment Cycles(C)1
End of 
Treatment
Treatment Cycle / 
Scheduled Time
-28 to -1
1 
Day 
1
1 
Week 
3
1 
Week 
6
2
3
4
5
6
7
8
9
10
11
12
13
14 
thru 
35
Discon-
tinuation
Visit
Scheduling Window 
(Days):2
±3
±3
± 3
±3
±3
± 3
±3
± 3
± 3
±3
± 3
± 3
± 3
±3
± 3
Study Drug Administration
Gefitnib16, 18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MK-347517
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures / Assessments: analysis performed by local laboratory
Pregnancy Test - Urine or 
Serum β-HCG 3
X
PT/INR and aPTT 4
X 5
CBC  with Differential6
X 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive 
Serum 
Chemistry Panel5
X 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis6,7
X 5
X
X
X
X7
X
T3, FT3, FT4 and TSH 6,8
X 5
X
X
X
X
X
X 7
X
ALK Translocation Testing14
X 
EGFR Mutation Testing14
X 
Tumor PDL Expression
X
Blood for Future Biomedical 
Research23 (optional)
X
MK-3475 Treatment Arm only: analysis performed by central laboratory
Pharmacokinetics 9
X
x10
X
X
X
X
X 12
X
Anti-MK-3475 Antibodies 11
X
X
X
X
X
X 
X 12
X
Efficacy Measurements
Tumor Imaging 13
X
X
X
X
X
X
X
X
X
Tumor Biopsies / Archival Tissue Collection
Tumor Tissue Collection 19
X
 
 
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1
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment unless otherwise specified.  Patients will be treated with Gefitinib only for the first 6 
weeks followed by the combination treatment of Gefitinib and MK-3475.  Treatment cycles are 3 weeks (21-days) with the exception of Cycle 1 (42 days). Imaging will be performed every 6 
weeks (± 7 days) from the first dose of trial treatment regardless of any treatment delays.
2
In general, the window for each visit is 3 days unless otherwise specified.
3
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. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines.
4
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
5
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.  
6
After screening, lab samples can be collected up to 48 hours prior to the scheduled time point.   Laboratory results must be known and acceptable prior to dosing at each cycle.  See Section 7.1.3 
for details regarding laboratory tests.  
7
Perform every 4 cycles after Cycle 13.
8
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.9
MK-3475 treated subjects – Trough (predose) and peak (post-
dose) samples will be collected at Cycles 1 and 2.  A trough sample will be collected at Cycle 3, 6, 9, 13, and 17.  All trough samples should be drawn within 24 hours before infusion of MK-
3475 and at the same time as blood collection for anti-MK-3475 antibodies.  The peak samples in Cycles 1 and 2 should be drawn within 30-minutes after the end of the infusion. Procedures for 
sample collection are described in the Procedures Manual.
10 MK-3475 treated subjects – An additional PK sample must be drawn between 24 and 96 hours after Cycle 2 dosing.
11 MK-3475 treated subjects – Draw samples for anti-MK-3475 antibodies within 24 hours before infusion of MK-3475 and at the same time as PK blood sample collection in Cycles 1, 2, 3, 6, 9, 
13 and 17.  After Cycle 17 collect samples every 8 cycles.  Procedures for sample collection are described in the Procedures Manual.
12 Perform every 8 cycles after Cycle 17. 
13 Performed every 6 weeks for the first 24 weeks, then every 9 weeks till the end of Year 1.  Performed every 12 weeks subsequently until the subject experiences PD or initiates a new anticancer
therapy.  After the first documentation of progression (if the subject is clinically stable) or response per RECIST 1.1 repeat imaging for confirmation is required. Confirmatory imaging should be 
performed 4 to 6 weeks later.  Timing of imaging scans should follow the calendar and not be adjusted for treatment delays.
14 Site must be able to provide documentation of the subject’s tumor EGFR mutation and ALK translocation status.  If the site is unable to provide this source documentation, then the Sponsor will 
offer this molecular testing of the tumor. See Section 7.1.3.3 for details on EGFR mutation testing.
15 Patients will receive Gefitinib monotherapy for the first 6 weeks of treatment followed by the combination treatment of Gefitinib and MK-3475 (Cycle 1), see Section 2.1 Trial Design.
16 Patients will receive MK-3475 combined with Gefitinib (Cycle 1) after receiving 6 weeks of Gefitinib monotherapy, see Section 2.1 Trial Design.
17 Tablets to be taken daily; will be dispensed at the beginning of each treatment visit.
18 Informed consent for Future Biomedical Research (FBR) samples must be obtained before the DNA sample is drawn.  DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw), as the last sample drawn, on allocated subjects only, or at a later date as soon as the informed consent is obtained. This sample should only be taken once from 
each subject.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
19 Tumor tissue for biomarker analysis from an archival tissue sample or fresh biopsy of a tumor lesion not previously irradiated must be provided.  Detailed instructions for tissue collection, 
processing and shipment are provided in the Procedures Manual. Any leftover tumor tissue will be stored for future research if the subject signs the optional FBR consent.
20 After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be 
requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants 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 participants that have a death event previously recorded).
 
 
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Post-Treatment Follow-up Phase
Trial Phase
Safety Follow-up 1
Follow-up 2
Survival 
Follow-up3
Time from Last Dose of Trial Treatment
30 Days
3 Months
6 Months
Every 12 Weeks after 
Month 6 
Every 12 Weeks
Visit
Safety Follow-up Visit
Follow-up Visit 1
Follow-up Visit 2
Follow-up Visit 3 and 
beyond
Survival Follow-up Visit 1 
and beyond
Scheduling Window
± 3 days
± 7 days
± 7 days
± 7 days
14 days
Administrative Procedures
Review Medications
X
Subsequent antineoplastic therapy Status
X
X
X
X
X
Survival Status 3
-------------------------------------------------------------------------------------------------------------------------------------------
Clinical Procedures/Assessments
Review Adverse Events 4
X
X
X
X
ECOG Performance Status
X
X
X
Directed Physical Examination
X
X
X
Vital Signs and Weight 5
X
X
X
Efficacy Measurement
Tumor Imaging 6
X 
X
X
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
CBC with Differential 7
X
Comprehensive Serum Chemistry Panel 7
X
T3, FT3, FT4 and TSH 8
X
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 antineoplastic treatment, whichever comes 
first.  Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.  Subjects who 
are eligible per the requirements in Section 7.1.5.4 for treatment with MK-3475 during the Second Course Phase may have up to two Safety Follow-up Visits, one after the Treatment Phase and the 
second after the Second Course Phase.
2
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed by radiologic imaging to monitor disease status.  
Follow-up Visit 1 should be scheduled approximately 3 months after the last dose of trial treatment.  Follow-up Visit 2 should occur 6 months after the last dose of trial treatment. After Follow-up 
Visit 2, follow-up visits should occur every 12 weeks (± 7 days).  Unless otherwise noted in the flow chart, every effort should be made to collect subject information until the start of new 
antineoplastic therapy, disease progression, death or entering the Second Course Phase, whichever occurs first. 
3
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be requested 
by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants 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 participants that have a death event previously recorded).
4
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) occurring within 90 days following cessation of treatment or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  After this time, report only SAEs that are considered related to trial treatment.
 
 
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5
Vital signs to include temperature, pulse, respiratory rate, blood pressure and weight. 
6
The same imaging technique should be used in a subject as was used earlier in the trial.  Unless a subject enters the Second Course Phase, imaging should continue until the start of a new 
antineoplastic therapy, documented disease progression, or death, whichever occurs first, as follows: every 12 weeks during year 1, 2 and 3, and every 6 months up to the end of year 5. Thereafter, 
imaging frequency will be based on local standards.
7
See Section 7.1.3 for list of laboratory tests.
8
Analysis will be performed by a central laboratory only if the local laboratory is unable to perform this service.
 
 
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Second Course Phase
Trial Phase
Second Course Treatment Cycles1
End of 
Treatment
Treatment Cycle / Scheduled 
Time
1
2
3
4
5
6
7
8
9
10
11
12
13
14-17
Discon-
tinuation 
Visit
Scheduling Window (Days):2
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Administrative Procedures
Eligibility Criteria
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MK-3475 Administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival Status10
----------------------------------------------------------------------------------------------------------------------------------------------------------------
Clinical Procedures / Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
X
X
X
X7
Directed Physical Examination
X
X
X
X
X
X
X
X
X7
X
Vital Signs and Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures / Assessments: analysis performed by local laboratory5
Pregnancy Test - Urine or Serum β-
HCG 3
X
PT/INR and aPTT 4
X
CBC with Differential 6
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry 
Panel 5
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis 6
X 
X
X
X
X 7
X
T3, FT3, FT4 and TSH 6, 8
X 
X
X
X
X 7
X
Efficacy Measurements
Tumor Imaging 9
X
X
X
X
X
X 12
X
1
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified.   Treatment cycles are 3 weeks (21-days).  
Imaging will be performed every 9 weeks (63 ± 7 days) from the first dose of trial treatment regardless of any treatment delays.
2
In general, the window for each visit is 3 days unless otherwise specified.
3
For women of reproductive potential, a urine pregnancy test will be performed within 72 hours prior to the first Second Course dose.  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.
 
 
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4
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
5
Laboratory tests for determining eligibility for Second Course Phase are to be performed within 10 days prior to the first dose of MK-3475. See Section 7.1.3 for details regarding laboratory tests.  
6
After the first dose, lab samples can be collected up to 48 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.  
7
Perform at Cycle 13 and 17.  Thyroid function tests should be performed at Cycle 14.
8    Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.
9   The Second Course Cycle 1 scan may have been performed up to 30 days prior to the first dose of trial treatment in the Second Course Phase.  Imaging will be performed every 9 weeks (63 7 days) 
after the first dose of Second Course Phase trial treatment.  The timing of imaging should follow calendar days and should not be adjusted for delays in cycle starts of MK-3475 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 for subject management; Sponsor 
may collect radiological assessments for retrospective analysis by a central vendor.  The processes for image collection and transmission to the central vendor are in the Investigator Imaging 
Operations Manual (IIOM). 
10  After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be requested 
by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants 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 participants that have a death event previously recorded).
 
 
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Second Course Post-Treatment Follow-up Phase
Trial Phase
Safety Follow-up 1
Follow-up 2
Survival 
Follow-up3
Time from Last Dose of Trial Treatment
30 Days
3 Months
6 Months
Every 12 Weeks after 
Month 6 
Every 12 Weeks
Visit
Safety Follow-up Visit
Follow-up Visit 1
Follow-up Visit 2
Follow-up Visit 3 and 
beyond
Survival Follow-up Visit 1 
and beyond
Scheduling Window
± 3 days
±  7 days
± 7 days
± 7 days
14 days
Administrative Procedures
Review Medications
X
Subsequent antineoplastic therapy Status
X
X
X
X
X
Survival Status 3
-------------------------------------------------------------------------------------------------------------------------------------------
Clinical Procedures/Assessments
Review Adverse Events 4
X
X
X
X
ECOG Performance Status
X
X
X
Directed Physical Examination
X
X
X
Vital Signs and Weight 5
X
X
X
Efficacy Measurement
Tumor Imaging 6
X 
X
X
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
CBC with Differential 7
X
Comprehensive Serum Chemistry Panel 7
X
T3, FT3, FT4 and TSH 8
X
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 antineoplastic treatment, whichever comes 
first.  Subjects with an AE of Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first.  Subjects who 
are eligible per the requirements in Section 7.1.5.4 for treatment with MK-3475 during the Second Course Phase may have up to two Safety Follow-up Visits, one after the Treatment Phase and the 
second after the Second Course Phase.
2
Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-up Phase and should be assessed by radiologic imaging to monitor disease status.  
Follow-up Visit 1 should be scheduled 3 months after the last dose of trial treatment.  Follow-up Visit 2 should occur 6 months after the last dose of trial treatment. After Follow-up Visit 2, follow-
up visits should occur every 12 weeks (± 7 days).  Unless otherwise noted in the flow chart, every effort should be made to collect subject information until the start of new antineoplastic therapy, 
disease progression or death, whichever occurs first. 
3
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be requested 
by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants 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 participants that have a death event previously recorded). 
4
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) occurring within 90 days following cessation of treatment or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  After this time, report only SAEs that are considered related to trial treatment.
 
 
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5
Vital signs to include temperature, pulse, respiratory rate, blood pressure and weight. 
6
The same imaging technique should be used in a subject as was used earlier in the trial.  Subjects who discontinue trial treatment due to reasons other than disease progression should continue to be 
assessed by radiologic imaging until the start of a new antineoplastic therapy, documented disease progression, or death, whichever occurs first, as follows: every 12 weeks during year 1, 2 and 3, 
and every 6 months up to the end of year 5. Thereafter, imaging frequency will be based on local standards.
7
See Section 7.1.3 for list of laboratory tests.
8
Analysis will be performed by a central laboratory only if the local laboratory is unable to perform this service.
 
 
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Crossover Phase
(Only applicable for subjects randomized to Cohort G chemotherapy arm that have confirmation of PD and qualified for the crossover 
phase).
Treatment Cycles1
End of 
Treatment
Treatment Cycle / Scheduled 
Time
17
2
3
4
5
6
7
8
9
10
11
12
13
14 through 
35
Discontinuation 
Visit
Scheduling Window (Days):2
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
Administrative Procedures
Prior 
and 
Concomitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival Status10
------------------------------------------------------------------------------------------------------------------------------------------------------------------
Clinical Procedures / Assessments
Review Adverse Events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures / Assessments: analysis performed by local laboratory
CBC with Differential 9
X3
X
X
X
X
X
X
X
X
X
X
X
X
PT/INR and aPTT 
X3
Comprehensive Serum Chemistry 
Panel 9
X3
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis4
X3
X
X
X
X4
X
T3, FT3, FT4 and TSH 4,5
X3
X
X
X
X
X
X
X 4
X
Efficacy Measurements
Tumor Imaging 6
X
X
X
X
X6
Study Drug Administration
MK-34758
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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1
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of trial treatment for each cycle unless otherwise specified.   Treatment cycles are 3 weeks (21-days).  
Imaging will be performed every 9 weeks (± 7 days) from the first dose of trial treatment for the first 6 months, and subsequently every 12 weeks, regardless of any treatment delays.
2
In general, the window for each visit is 3 days unless otherwise specified. 
3
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.  
4
Perform every 4 cycles beginning at Cycle 14 (Cycle 18, 22, 26, 30, and 34).
5
Thyroid function tests will be performed by a central laboratory only if the local laboratory is unable to perform this service.
6
Progressive disease is: 1) required for crossover, without exception, and 2) is based on RECIST 1.1. It is recommended that tumor response assessment be obtained every 9 weeks for the first 6 
months and then every 12 weeks until PD or initiation of a new anticancer therapy. The image used to determine progressive disease can be used as the new baseline image for the crossover phase if 
1) 30 days prior to  receiving the first dose of MK-3475 monotherapy and 2) No study treatment between the image and first dose of MK-3475 monotherapy, otherwise a new baseline image must 
be performed prior to treatment of MK-3475 monotherapy.  Timing of imaging scans should follow the calendar and not be adjusted for treatment delays.
7
Screening can initiate once progressive disease have been confirmed.   Treatment with MK 3475 may not initiate until at least 21 days from the date of last dose of chemotherapy. Screening 
procedures may be completed during these 21 days.  All procedures and assessments completed at the time of withdrawal from the main study may be used as appropriate for the start of the 
Crossover Phase of the study.
8
Treatment with MK 3475 may not initiate until at least 21 days from the last dose of chemotherapy. MK-3475 can be administered for up to 35 cycles (approximately 2 years).
9
After Cycle 1, lab samples can be collected up to 48 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.
10 After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. Updated survival status may be requested 
by the Sponsor at any time during the course of the study. Upon Sponsor notification, all participants 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 participants that have a death event previously recorded).
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator 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
7.1.1.1
Informed Consent
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.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
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 Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
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 after the subject provides written 
informed consent.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator.  In addition, record any prior 
cancer other than NCSLC even if diagnosed greater than 10 years prior to Visit 1.  NSCLC 
history will be recorded separately and not listed as Medical History.  Medical history will 
also include an assessment of smoking history.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial.  In addition, record all treatments for a prior cancer 
other than NSCLC even if taken greater than 30 days prior to Visit 1.  Prior treatments for 
NSCLC will be recorded separately and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the 30-day Safety Follow-up Visit.  After the Safety Follow-up Visit 
record all medications related to reportable SAEs and ECIs as defined in Section 7.2.
 
 
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7.1.1.6
Non-Small Cell Lung Cancer (NSCLC) Disease Details and Treatments
7.1.1.6.1 Disease Details
The investigator or qualified designee will obtain prior and current NSCLC disease details.
7.1.1.6.2 Prior Treatment
The investigator or qualified designee will review all prior treatments for NSCLC including 
systemic treatments, radiation and surgeries.
7.1.1.6.3 Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new antineoplastic 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 antineoplastic therapy has been initiated 
the subject will move into survival follow-up.
7.1.1.7
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to 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.  
7.1.1.8
Assignment of Randomization Number
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.
7.1.1.9
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol-specified treatment plan for > 12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
 
 
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The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.
The instructions for preparing and administering MK-3475 will be provided in the Pharmacy
Manual.
Standard of care therapy will be prepared and administered as per the approved product label.
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.5). Toxicities 
will be characterized in terms including seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.
An immune-related adverse event (irAE) may be defined as an adverse event of unknown 
etiology, associated with drug exposure and is consistent with an immune phenomenon.  
Efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic 
causes prior to labeling an adverse event immune-related.  Immunological, serological and 
histological (biopsy) data should be used to support the diagnosis of an immune-related 
toxicity.  
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
7.1.2.2
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history. The timepoints for full physical exam are described in Section 6 - Trial Flow Chart. 
After the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs.
7.1.2.2.2 Directed Physical Exam
For cycles that do not required a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.  New clinically significant abnormal findings should be 
recorded as AEs.
 
 
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7.1.2.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and during the Follow-up period as specified in 
the Trial Flow Chart.  Vital signs include temperature, pulse, respiratory rate, weight and 
blood pressure.  Height will be measured at Visit 1 only.
7.1.2.4
12-Lead Electrocardiogram (ECG)
A standard 12-lead ECG will be performed using local standard procedures once at 
screening.  Clinically significant abnormal findings should be recorded as medical history.  
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.4) 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.
7.1.2.6
Pulmonary Function Tests
Pulmonary function tests should include an assessment of forced vital capacity, forced 
expiratory flow between 25 and 75 percent of FVC (FEF25-75), forced expiratory volume in 
one second and peak expiratory flow (PEF) and diffusing capacity of the lungs for carbon 
monoxide (DLCO).  Additionally, oxygen saturation as assessed by pulse oximetry is 
required. These tests should be performed at baseline and subsequently at the discretion of 
the investigator. Hemoglobin must be obtained within 3 days of pulmonary function testing.  
Laboratory Procedures/Assessments
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 Procedures 
Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.
 
 
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Table 5
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Hemoglobin
Alkaline phosphatase
Glucose
Serum 
β-human 
chorionic gonadotropin 
(β-hCG)
Platelet count
Alanine 
aminotransferase 
(ALT)
Protein
Follicle 
stimulating 
hormone (FSH)
WBC (total and 
differential)*
Aspartate aminotransferase 
(AST)
Serum 
Triiodothyronine (T3)
Bicarbonate
or 
Carbon 
Dioxide
Microscopic exam, 
if abnormal results 
are noted
Free Triiodothyronine 
(FT3)
Calcium
Free Thyroxine (FT4)
Chloride
Serum 
thyrotropin 
(TSH)
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Total protein
Blood Urea Nitrogen
*Absolute or percentage acceptable
7.1.3.2
Pharmacokinetic Evaluations
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently 
planned as shown in the Trial Flowchart. Blood samples for PK and ADA collected may be 
stored only at this time. Further analysis may be performed if required. If ongoing PK and/or 
ADA sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued. 
7.1.3.2.1 Blood Collection for Plasma MK-3475
Sample collection, storage and shipment instructions for serum samples will be provided in 
the operations/laboratory manual.
The timepoints for PK blood sampling are described in Section 6 - Trial Flow Chart.
 
 
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7.1.3.3
Anti-MK-3475 Antibodies
Sample collection, storage and shipment instructions will be provided in the 
procedure/laboratory manual.
7.1.3.4
Molecular Testing
Site must be able to provide documentation of subject’s tumor EGFR mutation and ALK 
translocation status. Patients with known EGFR mutations do not need to get tested for ALK 
translocation.  If the site is unable to provide this source documentation, then the Sponsor 
will offer this molecular testing of the tumor.  Documentation of EGFR mutation status 
should include the specific test used (Roche cobas, Qiagen Therascreen, other lab-developed 
test), and the specific mutation detected.  If an LDT is used, documentation should also 
describe which mutations are detected by the test.  Detailed instructions for tissue collection, 
processing and shipment are provided in the Procedures Manual.
7.1.3.5
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Leftover Fresh Tumor Biopsy and/or Archival Tumor Tissue
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from study treatment prior to completion of the trial
should be encouraged to continue to be followed for all remaining study visits and survival 
follow-up contacts.
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 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 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 
 
 
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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.
7.1.4.2
Blinding/Unblinding
This is an open-label trial; there is no blinding for this trial.
7.1.4.3
Tumor Imaging
The initial tumor imaging will be performed within 30 days prior to the first dose of trial 
treatment.  CT scans are the required modality for measurable disease unless a subject has a 
clinical condition e.g. severe contrast allergy, or the lesions are significantly better visualized 
through the use of an MRI.  The same imaging technique must be used for a subject 
throughout the study.  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 30 days 
prior to the first dose of trial treatment.  On-study imaging will be performed every 6 weeks 
through Cycle 6 and every 9 weeks for the remainder of Year 1 after the first dose of trial 
treatment or more frequently if clinically indicated.  On-study imaging will subsequently 
change to every 12 weeks until the subject experiences PD or initiates a new anticancer
therapy.  CT timing should follow calendar days and should not be adjusted for delays in 
cycle starts or extension of MK-3475 cycle frequencies.  
After the first documentation of progression (if the subject is clinically stable) or response 
per RECIST 1.1, confirmatory scans should be performed 4 to 6 weeks later. 
After the first documentation of progression it is at the discretion of the investigator to keep a 
clinically-stable subject on trial treatment or to stop trial treatment until repeat imaging 
performed at least 28 days later confirms progression.  Clinical Stability is defined as:
1) Absence of symptoms and signs indicating clinical significant progression of disease 
(including worsening of laboratory values) indicating disease progression.
2) No decline in ECOG performance status.
3) Absence of rapid progression of disease or progressive tumor at critical anatomical sites 
(e.g., cord compression) requiring urgent alternative medical intervention.
 
 
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Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation. If progression is confirmed, then the subject will be discontinued from trial 
treatment (See exceptions in Section 5.8).  If progression is not confirmed, then the subject 
should resume/continue trial treatment and have their next scan approximately 6 weeks from 
the date of the scan that first showed progression.  When feasible, subjects should not be 
discontinued until progression is confirmed.
Subjects who move into the Second Course Phase will continue to have scans performed 
every 9 weeks.
Subjects who discontinue trial treatment for reasons other than disease progression should 
receive tumor imaging until confirmed disease progression or the start of a new 
antineoplastic therapy, whichever occurs first, as follows: every 12 weeks during year 1, 2 
and 3, and every 6 months up to the end of year 5. Thereafter, imaging frequency will be 
based on local standards.
Disease progression for trial eligibility will be according to RECIST 1.1 criteria; Local
reading (investigator assessment with site radiology reading) will be used to determine 
eligibility and for subject management.
The processes for image collection, processing and transmission to the central vendor are in 
the Site Imaging Manual (SIM).
7.1.4.4
Tumor Tissue Collection
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 10 unstained slides and received by 
the central vendor before randomization.  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.  A fine needle aspirate or 
cytologic specimen will not be acceptable.  Needle or excisional biopsies, or resected tissue 
is required.  Newly obtained formalin-fixed specimens are encouraged.  Note that if a tumor 
biopsy of a target lesion is obtained during eligibility assessment, it is preferred to obtain a 
new baseline scan.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.  Older biopsy material or surgical specimens may be used to assess 
EGFR mutation status and ALK translocation status, if not already known when the subject
signs informed consent.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
 
 
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7.1.5.1
Screening
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Approximately 28 days prior to randomization, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1.  Screening 
procedures may be repeated after consultation with the Sponsor.
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 30 days prior to the first dose of trial 
treatment.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of repeating a screening test if performed within the specified time frame and the results meet 
the inclusion/exclusion criteria.
7.1.5.2
Treatment Phase
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.3
Post-Treatment Follow-up Phase
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.  If the subject experienced a CR, 
PR, or SD during the treatment Phase on MK-3475, and then experiences PD at any time 
during that two-year follow-up period, he/she will be eligible to receive up to 12 months of 
therapy with MK-3475 in the Second Course Phase.  After the Second Course Phase subjects 
should be followed for up to 2 years, with no option for re-treatment with MK-3475 on study.
 
 
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7.1.5.3.1 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic treatment, 
whichever comes first.  Subjects with an AE of Grade >1 will be further followed until the 
resolution of the AE to Grade 0-1 or until beginning of a new antineoplastic therapy,
whichever occurs first.  Subjects who are eligible per the requirements in Section 7.1.5.4 for 
treatment with MK-3475 during the Second Course Phase may have up to 2 safety follow-up 
visits, one after the Treatment Phase and the second after the Second Course Phase.
7.1.5.3.2 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-up Phase and should continue to be assessed by radiologic imaging to 
monitor disease status.  Follow-up Visit 1 should be scheduled approximately 3 months after 
the last dose of trial treatment.  Assessment for drug-related immune-related adverse events 
should occur at Follow-up Visit 1.  Follow-up Visit 2 should occur 6 months after the last 
dose of trial treatment. After Follow-up Visit 2, subjects should continue to be assessed by 
radiologic imaging to monitor disease status and initiation of new antineoplastic therapy.  
Unless otherwise noted in the flow chart, every effort should be made to collect subject 
information on the start of new antineoplastic therapy, disease progression, death.
Subjects who are eligible to receive treatment with MK-3475 in the Second Course Phase 
according to the criteria in Section 7.1.5.4 will move from the follow-up phase to the Second 
Course Phase when they experience disease progression.  Subjects who discontinue trial 
treatment from the Second Course Phase for a reason other than disease progression will 
move into the Follow-up Phase and should continue to be assessed by radiologic imaging to 
monitor disease status.  Follow-up Visit 1 should be scheduled approximately 3 months after 
the last dose of trial treatment.  Assessment for drug-related immune-related adverse events 
should occur at Follow-up Visit 1.  Follow-up Visit 2 should occur 6 months after the last 
dose of trial treatment. After Follow-up Visit 2 subjects should continue to be assessed by 
radiologic imaging to monitor disease status, and initiation of new antineoplastic therapy.  
Unless otherwise noted in the flow chart, every effort should be made to collect subject 
information on the start of new antineoplastic therapy, disease progression, and death
7.1.5.3.3 Survival Follow-up
Once a subject experiences disease progression by site assessment and verified by central 
imaging vendor review or starts a new anticancer therapy, the subject moves into the 
Survival Follow-Up Phase and should be contacted by telephone at least Q12W (more 
frequently if needed) from the last contact date to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
 
 
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7.1.5.3.4 Survival Status
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.  
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 previously recorded a death event in the collection tool).
7.1.5.4
Second Course Phase
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. Subjects who were randomized 
to receive MK-3475 may be eligible to receive MK-3475 in the Second Course Phase of this 
study for up to 17 cycles (approximately 1 year) if the subject:

Stopped their initial treatment with MK-3475 after attaining an investigator-
determined confirmed CR according to RECIST 1.1, were treated for at least 6
months with MK-3475, and received at least 2 treatments with MK-3475 beyond the 
date when the initial CR was declared.  A CR by RECIST 1.1 means that all index 
lesions have resolved (none have bidimensional measurements), all non-index lesions 
have disappeared, and no new lesions have been identified.  These findings must be 
confirmed on subsequent imaging at least 4 weeks later for the call of CR by RECIST 
1.1 to be appropriate.  So the subject will have no evidence of metastatic cancer in 
order for the subject and his/her physician to consider the subject’s participation in 
this Second Course Phase.

Experienced an investigator-determined confirmed radiographic disease progression 
according to RECIST 1.1 after stopping their initial treatment with MK-3475 due to 
achievement of a confirmed CR.
OR

Had SD, PR or CR and stopped MK-3475 treatment after 35 cycles (approximately 
2 years) of study therapy for reasons other than disease progression or intolerability
AND

Did not receive any anticancer treatment since the last dose of MK-3475.

Continues to meet inclusion criteria 4, 5, 6, 7, 8 and 9.  

Does not meet exclusion criteria 2, 3, 4, 7, 9 to 15 and/or 19.
Subjects will be re-treated with MK-3475 200 mg every 3 weeks.  An objective response or 
progression of disease that occurs during the Second Course Phase for a subject will not be 
counted as an event for the primary analysis of either endpoint in this trial.
 
 
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7.1.5.5
Crossover for Subjects in Cohort G Chemotherapy Arm with Documented 
Disease Progression 
Subjects in Cohort G who are randomized into the chemotherapy arm will have the 
opportunity to crossover to receive MK-3475 once they experience disease progression from 
the chemotherapy. Subjects who permanently discontinue chemotherapy due to an adverse 
event, withdraw consent, or for any reason other than progressive disease, will not be eligible 
for crossover. Crossover subjects must not initiate treatment with MK-3475 any earlier than 
21 days after their last dose of chemotherapy regardless of the time of progression.
Crossover Qualifications
Subjects in Cohort G on the chemotherapy arm will be considered for crossover to MK-3475 
after documented, progressive disease assessed based on RECIST 1.1 by the investigator 
followed by confirmation with the Sponsor. Crossover is optional and is at the discretion of 
the investigator (with the SPONSORs agreement). Subjects who meet the following criteria 
are eligible for crossover:

Documentation of progressive disease will be defined as investigator assessment with 
confirmation with Sponsor per RECIST version 1.1

Patients who have ablation due to limited PD as defined in Section 5.8 must have 
documented further progressive disease defined as investigator assessment with 
confirmation with Sponsor per RECIST version 1.1

Chemotherapy induced adverse events (except alopecia) must have improved to CTCAE
(Version 4.0) ≤Grade 1

If a subject is unstable as a result of a new or progressing brain metastasis(es), the subject
will not be eligible for crossover.

ECOG Performance Status 0-1

Subject has not received any other systemic chemotherapy other than the chemotherapy 
administered during the treatment phase.

Received palliative radiotherapy of 30Gy or less ≥7 days before the first dose of 
crossover trial treatment.

Patient has adequate organ function as indicated by the laboratory values in Section 5.1.2.
7.1.5.6
Crossover Assessments and Procedures 
Crossover subjects must not initiate treatment with MK-3475 any earlier than 21 days after 
their last dose of chemotherapy regardless of the time of progression. The subject will then 
start the crossover phase as outlined in Crossover Flow Chart in Section 6.6. Screening 
procedures need to be completed within 28 days of confirmed progressive disease. All 
 
 
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procedures and assessments completed at the time of withdrawal from the main study may be 
used as appropriate for the start of the Crossover Phase of the study.  The tumor image used 
to determine progressive disease can be used as the new baseline image for the Crossover 
phase if 1) 30 days prior to receiving the first dose of MK-3475 monotherapy and 2) No 
study treatment between the image and first dose of MK-3475 monotherapy, otherwise a new 
baseline image must be performed prior to MK-3475 monotherapy treatment. Subjects who 
crossover and then achieve a CR per RECIST 1.1 have the option to hold MK -3475 while 
continuing in the trial. Additional details are provided in Second Course Phase Section 
7.1.5.4. Subjects who permanently discontinue the Crossover Phase will follow the same 
Post-Treatment Follow-up Phase Flow Chart provided in Section 6.3.
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
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 
 
 
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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 EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
In this trial, an overdose is any dose higher than 20% over the prescribed dose.
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 by the 
investigator 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).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator. All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
 
 
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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. 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).
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject’s female partner 
that occurs during the trial or within 14 days of completing the trial.  All subjects and female 
partners 
of 
male 
subjects 
who 
become 
pregnant 
must 
be 
followed 
to 
the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
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).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
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);
 
 
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●
Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow-up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow-up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the 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.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be 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 30 days 
following cessation of treatment, 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).
 
 
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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).
Subjects should be assessed for possible ECIs prior to each dose. ECIs that occur to any 
subject from the date of first dose through 30 days following cessation of treatment whether 
or not related to the Sponsor’s product, 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.
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints outlined in this section will not be reported to the Sponsor as described in 
Section 7.2.3 Immediate Reporting of Adverse Experiences to the Sponsor.
Specifically, the suspected/actual events (as opposed to endpoints or endpoint components) 
covered in this exception are as follows: any event that is disease progression of the cancer 
under study which meets the criteria described in section 7.2.3.1.  Note: as described in 
Section 7.2.3.1, any secondary primary cancer needs to be reported as a SAE.
For this protocol, the following MedDRA Preferred Term is considered suspected efficacy 
endpoint/endpoint event:

Malignant Neoplasm Progression
The Sponsor will monitor aggregated and blinded suspected efficacy/efficacy endpoint event 
and other safety data to ensure the safety of subjects in the trial.  Any suspected endpoint
which upon review is not progression of the cancer under study will be forwarded to global 
safety as a SAE within 24 hours of determination that the event is not progression of the 
cancer under study.
 
 
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Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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 6
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 
CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of 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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (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
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
Clinical Adjudication Committee
Clinical adjudication is not used in the study. For Cohort G1, all imaging will be collected for 
potential independent radiologists’ review.  Images will be assessed using RECIST 1.1 for 
determination of objective response rate (ORR) and progression-free survival (PFS). The use 
of independent radiologists’ review will be determined based on the investigator assessed 
ORR and PFS.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
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).
Efficacy Analyses
The intention-to-treat (ITT) population that includes all randomized subjects will serve as the 
primary population for the analyses of efficacy data from randomized cohorts A, B, C, G1 
and G2.  The All-Subjects-as-Treated (ASaT) population that includes all treated subjects 
will serve as the primary population for the analyses of efficacy data from non-randomized 
cohorts D, E, F and H.
Part 1: Descriptive analyses will be provided. It is expected that 12 subjects will be treated at 
the RP2D. 
Part 2: The primary efficacy endpoint is objective response rate (ORR) per RECIST 1.1 
based on blinded independent central review.  For cohort G1 only, the key secondary efficacy 
endpoint is progression-free survival (PFS) per RECIST 1.1 based on blinded independent 
central review. The Type I error rate alpha=2.5% (one-sided) over the multiple endpoints 
(primary ORR and key secondary PFS) will be controlled by a fixed-sequence, closed-testing 
procedure [73], stepping down from ORR to PFS.  For cohort H, only the primary hypothesis
 
 
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will be tested at alpha=5% (one-sided), and no multiplicity adjustment is planned.  An 
outline of the analysis strategy for key efficacy endpoints is in Table 7.
Table 7
Summary of Analysis Strategy for Key Efficacy Endpoints in Part 2
Endpoint
(Description, Time 
Point)
Statistical Method‡
Analysis 
Population
Missing Data 
Approach
Cohorts G1 and G2
Objective response rate
(RECIST 1.1) by 
blinded independent 
central review
Stratified Miettinen and Nurminen method
ITT
Subjects with 
missing data are 
considered as non-
responders
PFS (RECIST 1.1) by 
blinded independent 
central review
Testing:  Stratified Log-rank test
Estimation: Stratified Cox model with Efron’s 
tie handling method
Kaplan-Meier method for PFS curve 
estimation in each treatment group
ITT
Censored according 
to Table 9.
Cohort H
Objective response rate
(RECIST 1.1) by 
blinded independent 
central review
Testing: exact Binomial test
Estimation: Empirical proportion
ASaT
Subjects with 
missing data are 
considered as non-
responders
Safety Analyses
The All-Subjects-as-Treated (ASaT) population will be employed for safety analyses. The 
ASaT population, consisting of all subjects who received at least 1 dose of study treatment, 
will be defined separately for Part 1 and Part 2 of the study. DLT will be summarized for Part 
1 by dose level for each cohort. Descriptive tables that summarize the number and percentage 
of subjects that experience adverse events as categorized in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0 will be generated for each cohort in Part 2.
Power and Sample Size
In Cohorts A-F, the sample sizes depend primarily on clinical considerations rather than on 
statistical considerations. The details of the design are presented in Section 2.0. In summary, 
a randomized dose finding design will be used in Cohorts A, B and C with 12 subjects 
assigned to each of the 2 dose levels of MK-3475 combined with the chemotherapy.   
Cohort G1 will randomize approximately 108 subjects with 1:1 ratio to either the MK-3475 
in combination with chemotherapy arm or to the chemotherapy alone arm. The analysis will 
be conducted after all subjects have a minimum of 6 months follow-up.  The study has at 
least 89% power to detect a 30% difference in ORR (30% in chemotherapy alone versus 60% 
 
 
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in MK-3475 in combination with chemotherapy) at α=2.5% (one-sided).  An observed ORR 
difference of approximately 18.4% is needed to achieve a positive ORR outcome.
Cohort G2 is optional and event-driven by PFS (i.e., the number of subjects and follow-up 
time are subject to change but number of events is not); and plans to randomize 
approximately 60 subjects with 1:1 ratio to either the MK-3475 in combination with 
chemotherapy arm or to the chemotherapy alone arm, and will complete after approximately 
44 events have been observed between the combination arm and the chemotherapy alone 
arm. With 44 events, the study has at least 84% power to detect a 0.4 hazard ratio at 
alpha=2.5% (one-sided) after taking a 5% discount for loss of information due to interval 
censoring.
Cohort H will enroll 32 subjects in a single arm of the MK-3475 and ipilimumab 
combination. The 12 subjects from cohort D expansion will be combined with subjects from 
cohort H in the analysis of objective response rate.  With a total of 44 subjects, the study has 
approximately 90% power to detect a 20% difference (40% vs. 20% in historical control, 
obtained from MK-3475 PN001 data) in objective response rate at the 5% type I error rate 
(one-sided). A p-value of 5% approximately corresponds to an empirical objective response 
rate of 31% (14/44).
Subgroup Analyses
Subjects with high PD-L1 expression level are of special interest in this study. The treatment 
effect estimate and its 95% confidence interval for the primary and key secondary endpoints
will be provided in the subgroup of subjects who are PD-L1 positive and PD-L1 negative.
Other classification of interest will be explored as well
Statistical Analysis Plan
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study 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 study.  Post hoc 
exploratory analyses will be clearly identified in the CSR.  No separate Statistical Analysis 
Plan (SAP) will be issued for this Study.
Responsibility for Analysis/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is an open-label study. For Part 1, subjects, investigators, and Sponsor personnel 
will be aware of subject treatment assignments after each subject is enrolled and treatment is 
assigned.  For Part 2 randomized cohorts, analyses or summaries generated by randomized 
treatment assignment and actual treatment received will be limited and documented. In 
 
 
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addition, the independent radiologist(s) will perform the central imaging review without 
knowledge of treatment group assignment.  
The IVRS vendor will generate the randomized allocation schedule for study treatment 
assignment of cohort G1, and the Clinical Biostatistics department of the SPONSOR will 
generate the randomized allocation schedules for study treatment assignment of other cohorts 
for this protocol, and the randomization will be implemented in IVRS.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3. 
Analysis Endpoints
8.2.3.1
Efficacy Endpoints
Primary
Objective response rate (ORR) – RECIST 1.1 by blinded independent central review
ORR is defined as the proportion of subjects who have achieved complete response (CR) or 
partial response (PR) according to RECIST 1.1 by blinded independent central review. 
Subjects with missing outcome on objective response will be considered non-responders.
Secondary
Progression-free Survival (PFS) – RECIST 1.1 by blinded independent central review
PFS is defined as the time from randomization (or the start of treatment when there is no 
randomization) to progressive disease (PD) or death, whichever occurs earlier, based upon 
RECIST 1.1 by blinded independent central review. Subjects without documented PD/death 
will be censored at the last disease assessment date.  For cohorts G1 and G2, more censoring 
rules for sensitivity analyses are considered.  See Section 8.2.5.1.2 for definition of 
censoring.
Duration of Response (DOR) – RECIST 1.1 by blinded independent central review
For subjects who demonstrate CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first. 
Overall survival (OS)
OS is defined as the time from randomization (or the start of treatment when there is no 
randomization) to death due to any cause. Subjects without documented death at the time of 
analysis will be censored at the date last known to be alive.
 
 
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PFS/ORR – RECIST 1.1 by investigator assessment
PFS and ORR per RECIST 1.1 by investigator assessment are defined as specified for the 
respective endpoint. 
PFS/ORR – modified RECIST 1.1 by investigator assessment
PFS and ORR per modified RECIST 1.1 are defined as specified for the respective endpoints 
using RECIST 1.1 above, with the exception that a confirmation assessment of PD (at least 4 
weeks after the initial PD assessment) is required for subjects who remain on treatment 
following a documented PD per RECIST 1.1. Subjects who discontinue treatment following 
a documented PD assessment per RECIST 1.1 will be counted as having disease progression 
on the date of the documented PD assessment.  See Section 8.2.5.1.2 for definition of 
censoring.
Exploratory
For cohort G1 only: exploratory endpoints will also include PFS2, PFS and OS following 
crossover to MK-3475.
In subjects who are randomized to chemotherapy only in cohort G1, PFS2 is defined as the 
time from randomization to subsequent disease progression following crossover to MK-3475, 
or death from any cause, whichever first. If progression after crossover to MK-3475 cannot 
be measured, a PFS event is defined as end or discontinuation of MK-3475 or death from any 
cause, whichever occurs first. Subjects alive and for whom a PFS event has not been 
observed will be censored at last disease assessment after crossover.
Time to progression following crossover to MK-3475 is defined as the time from the first 
dose of crossover therapy to the earliest documented disease progression (with respect to the 
last available tumor assessment prior to crossover). OS following crossover to MK-3475 is 
defined as the time from the first dose of crossover therapy to death due to any cause.
8.2.3.2
Safety Endpoints
The primary safety endpoint in Part 1 of the study is DLT. Safety will be monitored by 
cumulative data reviews throughout the trial. The toxicities and grades experienced by 
subjects who have received study treatment, including adverse events (AEs), serious adverse 
events (SAEs) and events of clinical interest (ECIs). Other safety measures evaluated in all 
parts of the study include laboratory safety assessments, ECGs, and vital signs and physical 
examinations. Safety measurements are as described in Section 7.
 
 
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Analysis Populations
8.2.4.1
Efficacy Analysis Populations
The Intent-to-Treat (ITT) population will serve as the primary population for randomized 
cohorts A, B, C, G1 and G2.  The ITT population consists of all randomized subjects with 
subjects analyzed in the treatment group to which they were randomized.  
The All-Subjects-as-Treated (ASaT) population will serve as the primary population for non-
randomized cohorts D, E, F and H. The ASaT population consists of all subjects who 
received at least one dose of study treatment with subjects analyzed in the treatment group 
corresponding to the study treatment they actually received.  
Analysis of duration of response is based on all responders.
8.2.4.2
Safety Analysis Populations
The All-Subjects-as-Treated (ASaT) populations will be used for the analysis of safety data 
in this study. The ASaT 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 ASaT 
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 
the treatment group corresponding to the study treatment actually received.   
In Cohort G1, the primary safety comparison will be performed between MK-3475 in 
combination with chemotherapy arm and chemotherapy alone arm. Subjects who crossover 
to MK-3475 monotherapy will be censored at time of crossover and AEs occurred during 
treatment with MK-3475 monotherapy will be excluded from the primary safety analysis.  
An exploratory safety analysis will be conducted for the crossover population including all 
safety events from the date of first dose of MK-3475 after crossover.  
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
For safety analysis 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 therapy or discontinue from the trial
due to a drug-related adverse event.  Subjects who discontinue prematurely due to a non 
drug-related cause are not included in the DLT evaluable population.
 
 
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Statistical Methods
8.2.5.1
Statistical Methods for Efficacy Analyses
8.2.5.1.1 Cohorts A-F
Subjects’ ORR and PFS based on blinded independent central review and the investigator 
assessment per RECIST 1.1 along with other baseline characteristics will be analyzed using 
descriptive statistics.
8.2.5.1.2 Cohorts G1 and G2
The analysis strategy of key efficacy endpoints of Cohorts G1 and G2 are presented in 
Table 10. 
Objective Response Rate (ORR)
ORR will be estimated as the number of responders as a percent of the number of participants 
in the ITT population. Its 95% confidence interval will be estimated using the
Clopper-Pearson method [74]. For cohort G1, the stratified Miettinen and Nurminen’s
method [75] will be used to estimate the treatment difference and its 95% confidence interval 
with strata weighting by sample size. The stratification factor used for randomization of 
cohort G1 (i.e. PD-L1 expression positive vs. negative) will be applied to the analysis.  For 
cohort G2, the non-stratified analyses will be provided.  Subjects with missing outcome will 
be considered non-responders.
Duration of Response (DOR)
The non-parametric Kaplan-Meier plots/estimates and descriptive statistics will be provided.
Subjects who are alive, have not yet progressed, have not initiated new anticancer treatment, 
have not had ≥ 2 consecutive missed disease assessments and have not been determined to be 
lost to follow-up are considered ongoing responders at the time of analysis. Censoring rules 
for DOR are summarized in Table 8 below.
 
 
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Table 8
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment before 
new anticancer therapy initiated
Censor
(non-event)
≥ 2 consecutive missed disease 
assessments at any time prior to 
progression or death
Last adequate disease assessment prior to ≥ 
2 missed adequate disease assessments
Censor
(non-event)
Death or progression after ≤ 1 
missed disease assessments
PD or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.  
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not started 
a new anticancer therapy, have not had ≥ 2 consecutive missed disease assessments, and have not been 
determined to be lost to follow-up.
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. For Cohort G1, the stratified log-rank test will be used to test for treatment 
difference in PFS at one-sided alpha level of 2.5%. Stratified Cox proportional hazard model 
with Efron’s tie handling method will be used to estimate the hazard ratio and its 95% 
confidence interval between the 2 arms. The same stratification factor used for randomization 
(i.e. PD-L1 expression positive vs. negative) will be applied to both the stratified log-rank 
test and the stratified Cox model. For cohort G2, no stratification will be applied in the 
analyses using the log-rank test or Cox proportional hazard model.
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of the first assessment 
at which PD is objectively documented per RECIST 1.1, regardless of discontinuation of 
study drug. Death is always considered as a confirmed PD event.
In order to evaluate the robustness of the PFS endpoint, 3 sensitivity analyses will be 
performed with a different set of censoring rules. Sensitivity analysis 1 is the same as the 
primary analysis except that it censors a subject’s data at the last disease assessment without 
PD when there are 2 or more consecutive missed disease assessments. Sensitivity analysis 2 
is the same as the primary analysis except that it considers discontinuation of treatment or 
initiation of new anticancer treatment, whichever occurs later, to be a PD event for subjects 
without documented PD or death. Sensitivity analysis 3 is the same as the primary analysis 
except that it censors a subject’s data at the last disease assessment for subjects without 
 
 
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documented PD or death, regardless of initiation of new anticancer treatment.  The censoring 
rules for primary and sensitivity analyses are summarized in Table 9. Additional PFS 
sensitivity analyses may be performed, including a PFS analysis using time to scheduled 
tumor assessment visit from randomization as opposed to actual tumor assessment time.
Table 9
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary 
Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
Sensitivity
Analysis 3
No PD and no 
death; new 
anticancer treatment 
is not initiated
Censored at last 
disease 
assessment 
Censored at last 
disease assessment 
Censored at last 
disease assessment if 
still on study therapy; 
progressed at 
treatment 
discontinuation 
otherwise
Censored at last 
disease 
assessment 
No PD and no 
death; new 
anticancer treatment 
is initiated
Censored at last 
disease 
assessment before 
new anticancer 
treatment
Censored at last 
disease assessment 
before new 
anticancer treatment
Progressed at date of 
new anticancer 
treatment
Censored at last 
disease 
assessment
No PD and no 
death; ≥ 2 
consecutive missed 
disease assessments
Censored at last 
disease 
assessment
Censored at last 
disease assessment 
prior to ≥2 
consecutive missed 
visits
Censored at last 
disease assessment
Censored at last 
disease 
assessment
PD or death 
documented after ≤ 
1 missed disease 
assessment
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or 
death
Progressed at date 
of documented PD 
or death
PD or death 
documented after ≥ 
2 consecutive 
missed disease 
assessments
Progressed at date 
of documented PD 
or death
Censored at last 
disease assessment 
prior to the ≥ 2 
consecutive missed 
disease assessment
Progressed at date of 
documented PD or 
death
Progressed at date 
of documented PD 
or death
Overall Survival
The Kaplan-Meier method will be used to estimate the survival curves. For Cohort G1, the 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the 
magnitude of the treatment difference (i.e., the hazard ratio). The hazard ratio and its 95% 
confidence interval from the stratified Cox model with a single treatment covariate will be 
reported. The same stratification factors used for randomization (i.e. PD-L1 expression 
positive vs. negative) will be applied to both the stratified log-rank test and the stratified Cox 
model.  For cohort G2, no stratification will be applied in the analyses using the log-rank test 
or Cox proportional hazard model.
 
 
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Since subjects in the control arm are expected to discontinue from the study earlier compared 
to subjects in the MK-3475 plus chemotherapy arm because of earlier onset of PD and they 
may switch to the MK-3475 treatment after the progressive disease, adjustment for the effect 
of crossover on OS may be performed based on recognized methods, e.g., the Rank 
Preserving Structural Failure Time (RPSFT) model proposed by Robins and Tsiatis (1989)
[68], two stage model [69], etc., based on an examination of the appropriateness of the data 
to the assumptions required by the methods.
PFS and OS after Crossover
The same approaches as previously described for the primary PFS and primary OS analyses 
will be applied to subjects who crossover to MK-3475 after disease progression on the 
control arm (chemotherapy) in this study. The reference start time of PFS and OS is the time 
of first dose crossover therapy.  Time to progression while on the control arm will be 
compared to the time to progression following crossover, where the time to progression 
following crossover is defined as the time from time of crossover to the earliest documented 
disease progression. The last available tumor assessment before crossover will serve as the 
baseline for disease assessment post crossover. If the number of events permits, time to 
progression before and after crossover will be summarized descriptively using the 
Kaplan-Meier method.
PFS2
The same approach as previously described for the primary PFS will be applied to compare 
PFS in subjects randomized to the MK-3475 in combination with chemotherapy arm and 
PFS2 in subjects randomized to chemotherapy alone arm.
Table 10
Analysis Strategy of Key Efficacy Endpoints of Cohorts G1 and G2
Endpoint/Variable
(Description, Time 
Point)
Primary or 
Supportive 
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
ORR (RECIST 1.1) by 
blinded independent 
central review 
P
Stratified Miettinen and 
Nurminen method
ITT
Subjects with missing 
data are considered 
non-responders
PFS (RECIST 1.1) by 
blinded independent 
central review
P
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron’s 
tie handling method 
ITT
Censored according to 
rules in Table 9
DOR (RECIST 1.1) by 
blinded independent 
central review
P
Summary statistics using 
Kaplan-Meier method
All 
responders 
Non-responders are 
excluded in analysis
OS
P
Testing: Stratified Log-
rank test
Estimation: Stratified 
Cox model with Efron’s 
tie handling method
ITT
Model based (censored 
at last date)
 
 
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8.2.5.1.3 Cohort H
ORR will be the primary endpoint for efficacy assessment. The exact Binomial test will be
used for testing ORR greater than the historical control rate of 20% at α=5% (one-sided). A 
90% confidence interval and point estimate for ORR will be provided using the Clopper-
Pearson method [74]. In addition, Kaplan-Meier plots and descriptive statistics of PFS, OS 
and DOR will be provided. 
8.2.5.2
Statistical Methods for Safety Analyses
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.
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.
Immune-related adverse events (irAEs) that are designated as AEs of special interest will be 
summarized in separate tables from other AEs, regardless of causality to study medication.
To properly account for the potential difference in follow-up time between the study arms, 
since the follow-up time is expected to be longer in the MK-3475 plus chemotherapy arm, 
AE incidence density adjusted for treatment exposure analyses may be performed as 
appropriate. 
Time to Grade 3-5 AE
Exploratory analysis of Grade 3-5 AE may be performed on the time to first event. Time to 
first Grade 3-5 AE is defined as the time from the first day of study drug to the first event of 
Grade 3-5 AE. The Kaplan-Meier method will be used to estimate the curve of time to first 
Grade 3-5 AE.  The treatment difference in time to first Grade 3-5 AE will be assessed by 
log-rank test.  A Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., the hazard ratio).  
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Baseline characteristics will be assessed by the use of tables and/or graphs.  No statistical 
hypothesis tests will be performed on these characteristics.  The number and percentage of 
subjects screened, randomized, the primary reasons for screening failure, and the primary 
reason for discontinuation will be displayed.  Demographic variables (e.g., age, gender), 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized by descriptive statistics or categorical tables.
The correlation between PD-L1 expression levels and anti-tumor activity of MK-3475 in G1 
will be explored, and a candidate cutoff point for PD-L1 expression level will be identified 
for enrollment of G2 based on both statistical and clinical considerations if a strong
correlation between PD-L1 expression levels and anti-tumor activity is demonstrated.
 
 
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Specifically, Kendal’s Tau statistics will be used to explore the correlation between PD-L1 
expression levels and tumor size reductions. Harrell’s c-index [70, 71] will be used to explore 
the correlation between PD-L1 expression levels and PFS. Other methods as appropriate will 
also be considered. 
Multiplicity
The overall type I error rate for cohort G1 is strictly controlled at 2.5% (one-sided) by fixed-
sequence, a closed-testing procedure [73].  The closed-testing procedure will be applied to 
the primary hypothesis of ORR first.  If the primary hypothesis is rejected at the α=2.5%
level (one-sided), then testing will continue to the key secondary hypothesis of PFS.  
Nominal p-value for each endpoint will be reported, where applicable, regardless of the 
outcome of the closed-testing procedure dictated by the multiplicity strategy.
No multiplicity adjustment is planned for cohort H, as only one hypothesis of ORR is to be 
tested.
Sample Size and Power Calculations
Cohorts A, B, C, D, E and F
The sample size of the study depends primarily on clinical considerations rather than on 
statistical considerations. Specifically, the final number of subjects enrolled in the study will 
depend on empirical DLT observations. However, it is estimated that around 144 subjects 
evaluable for safety and tolerability will be enrolled in the dose escalation and dose 
confirmation part (i.e., Part 1) of this study to adequately assess toxicity of MK-3475 in 
combination with chemotherapy, ipilimumab or TKI.
Cohort G1
Cohort G1 will randomize approximately 108 subjects with 1:1 ratio to either the MK-3475 
in combination with chemotherapy arm or to the chemotherapy alone arm. The ORR 
analysis will be conducted after all subjects have a minimum of 6 months follow-up.  The 
study has at least 89% power to detect a 30% difference in ORR (30% in chemotherapy alone 
versus 60% in MK-3475 in combination with chemotherapy) at α=2.5% (one-sided).  The 
calculation is based on an asymptotic method proposed by Farrington and Manning (1990) 
[76]. An observed ORR difference of approximately 18.4% is needed to achieve a positive 
ORR outcome.  Figure 2 summarizes power calculations for the primary hypothesis under 
various ORR difference assumptions.  
 
 
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Figure 2
Power for primary hypothesis under different effect size assumptions
At the time of the analysis, it is expected that approximately 68 PFS events will have been 
observed, and the study has overall ~81.5% power to detect a hazard ratio of 0.5 in MK-3475 
in combination with chemotherapy vs. chemotherapy alone at alpha = 2.5% (one-sided). The 
power calculation is based on the following assumptions: 1) progression-free survival 
follows an exponential distribution with a median of 5.5 months in the chemotherapy alone
arm, 2) hazard ratio between MK-3475 in combination with chemotherapy arm and 
chemotherapy alone arm is 0.5, 3) an enrollment period of 13 months, 4) at least 6 months 
follow-up after enrollment completion, and 5) a yearly dropout rate of 5%.  A one-sided p-
value of 2.5% approximately corresponds to an observed hazard ratio of 0.62 or less 
(approximately a 3.4-month or greater improvement over the median PFS from 5.5 months in 
the chemotherapy alone arm).
The sample size and power calculations of cohort G1 were performed using EAST 6.
Cohort G2
Cohort G2 is optional and event-driven by PFS (i.e., the number of subjects and follow-up 
time are subject to change but number of events is not); and plans to randomize 
approximately 60 subjects with 1:1 ratio to either the MK-3475 in combination with
chemotherapy arm or to the chemotherapy alone arm, and will complete after approximately 
44 events have been observed between the combination arm and the chemotherapy alone 
arm. With 44 events, the study has at least 84% power to detect a 0.4 hazard ratio at 
 
 
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alpha=2.5% (one-sided) after taking a 5% discount for loss of information due to interval 
censoring.  The sample size and power were calculated using the normal approximation of 
log-rank test. 
Cohort H
A total of 32 subjects will be enrolled in a single arm of the MK-3475 and ipilimumab 
combination (cohort H). Note that subjects from Cohort D expansion will be eligible to be 
combined with subjects from Cohort H in the analysis. With 44 subjects, the study has 
approximately 90% power to detect a 20% difference (40% vs. 20% in historical control) in 
objective response rate at the 5% type I error rate (one-sided). A p-value of 5% 
approximately corresponds to an empirical objective response rate of 31% (14/44).
Subgroup Analyses and Effect of Baseline Factors
The treatment effect within each of the following classification variables will be explored for 
G1 and G2: Age (≤ 65 vs. > 65 years), Sex (female vs. male), Race (white, non-white), and 
ECOG status (0 vs. 1). The consistency of the treatment effect will be assessed descriptively 
via summary statistics by category for the classification variables listed above. 
Interim Analyses
No interim analysis is planned for this study.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure for 
the ASaT population.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 11.
 
 
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Table 11
Product Descriptions
Product Name & Potency
Dosage Form
MK-3475 25 mg/ml, 4 mL
Solution for infusion
Pemetrexed 500 mg / vial
Lyophilized powder for injection
Pemetrexed 100 mg / vial
Lyophilized powder for injection
All other supplies not indicated in Table 11 above will be provided locally by the trial site, 
subsidiary or designee, depending on local country operational or regulatory requirements. 
Pemetrexed 500 or 100 mg / vial will be provided centrally by the Sponsor or locally by the 
trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
All other supplies not indicated in Table 11 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. 
Per local guidelines the trial site may be responsible for recording the lot number, 
manufacturer and expiry date of any locally purchased product.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Open-label vials will be provided for this study.  No kitting is required.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. MK-3475 (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
 
 
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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
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.
Standard Policies
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign MK-3475 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
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
 
 
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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
By signing this protocol, the investigator recognizes that certain personal identifying
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.  
 
 
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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
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 Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and
other generally accepted standards of good clinical practice); and all applicable federal, state 
and local laws, rules and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in 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.
 
 
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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.  
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 multicenter 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 
 
 
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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
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.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided by the Sponsor.
Publications
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 
 
 
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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, 
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 
 
 
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submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1.
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.  
2. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800.  
3. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.  
4. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.  
5. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.  
6. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.  
7. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, et al. Tumor cell 
expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant 
melanoma. Cancer 2010;116:1757-66.  
8. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance 
and therapeutic potential of the programmed death-1 ligand/programmed death-1 
pathway in human pancreatic cancer. Clin Cancer Res 2007;13(7):2151-7.  
9. Gao Q, Wang X-Y, Qiu S-J, Yamato I, Sho M, Nakajima Y, et al. Overexpression of PD-
L1 significantly associates with tumor aggressiveness and postoperative recurrence in 
human hepatocellular carcinoma. Clin Cancer Res 2009;15(3):971-9.  
10. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. 
Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are 
prognostic factors of human ovarian cancer. PNAS 2007;104(9):3360-5.  
11. Fourcade J, Kudela P, Sun Z, Shen H, Land SR, Lenzner D, et al. PD-1 is a regulator of 
NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 
2009;182:5240-9.  
12. Cai G, Karni A, Oliveira EML, Weiner HL, Hafler DA, Freeman GJ. PD-1 ligands, 
negative regulators for activation of naïve, memory, and recently activated human CD4+ 
T cells. Cell Immunol 2004;230(2):89-98.  
 
 
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13. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: 
and update on implications for chronic infections and tumor evasion. Cancer Immunol 
Immunother 2007;56:739-45.  
14. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on 
tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 
blockade. PNAS 2002;99(19):12293-7.  
15. Tsushima F, Tanaka K, Otsuki N, Youngnak P, Iwai H, Omura K, et al. Predominant 
expression of B7-H1 and its immunoregulatory roles in oral squamous cell carcinoma. 
Oral Oncol 2006;42:268-74.  
16. Korman A, Chen B, Wang C, Wu L, Cardarelli P, Selby M. Activity of anti-PD-1 in 
murine tumor models: role of "host" PD-L1 and synergistic effect of anti-PD-1 and anti-
CTLA-4 [Abstract]. J Immunol 2007;178:48.37.  
17. Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma:  prognostic 
factors. Cancer Control 2005;12(4):223-9.  
18. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of AntiPD-1 antibody in cancer. N Engl J Med 
2012:doi: 10.1056/NEJMoa1200690.  
19. Patnaik A, Kang SP, Tolcher AW, Rasco DW, Papadopoulos KP, Beeram M, et al. 2012 
ASCO Annual Meeting:  Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in 
patients with advanced solid tumors, 2012.   
20. 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.  
21. Chapman PB, Hauschild A, Robert C, Hannen JB, Ascierto P, Larkin J, et al. Improved 
survival with vemurafenib in melanoma with BRAF V600E mutation. New Engl J Med 
2011;346(26):2507-16.  
22. Robert C, Thomas L, Bondarenko I, O'Day S, Weber J, Garbe C, et al. Ipilimumab plus 
dacarbazine for previously untreated metastatic melanoma. N Engl J Med 
2011;364(26):2517-26.  
23. Bellati F, Visconti V, Napoletano C, Antonilli M, Frati L, Benedetti Panici P, et al. 
Immunology of gynecologic neoplasms: analysis of the prognostic significance of the 
immune status. Curr Cancer Drug Targets 2009;9(4):541-65.  
24. Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer development: 
polarization towards pro-tumor immunity. Cytokine Growth Factor Rev 2010;21:3-10.  
 
 
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25. Shirabe K, Motomura T, Muto J, Toshima T, Matono R, Mano Y, et al. Tumor-
infiltrating lymphocytes and hepatocellular carcinoma: pathology and clinical 
management. Int J Clin Oncol 2010;15:552-8.  
26. Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. The 
prognostic value of intraepithelial and stromal CD3-, CD117- and CD138-positive cells 
in non-small cell lung carcinoma. APMIS 2010;118:371-82.  
27. Clark CE, Beatty GL, Vonderheide RH. Immunosurveillance of pancreatic 
adenocarcinoma: insights from genetically engineered mouse models of cancer. Cancer 
Lett 2009;279:1-7.  
28. Diederichsen ACP, Hjelmborg JvB, Christensen PB, Zeuthen J, Fenger C. Prognostic 
value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer 
and HLA-DR expression on tumour cells. Cancer Immunol Immunother 2003;52:423-8.  
29. Gao Q, Qiu S-J, Fan J, Zhou J, Wang X-Y, Xiao Y-S, et al. Intratumoral balance of 
regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma 
after resection. J Clin Oncol 2007;25(18):2586-93.  
30. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.  
31. Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, et al. CD3+ cells at the 
invasive margin of deeply invading (pT3-T4) colorectal cancer and risk of post-surgical 
metastasis: a longitudinal study. Lancet Oncol 2009;10:877-84.  
32. Li JF, Chu YW, Wang GM, Zhu TY, Rong RM, Hou J, et al. The prognostic value of 
peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 
expression in clear cell renal cell carcinoma. BJU Intern 2008;103:399-405.  
33. Nemolato S, Fanni D, Naccarato AG, Ravarino A, Bevilacqua G, Faa G. 
Lymphoepithelioma-like hepatocellular carcinoma: a case report and a review of the 
literature. World J Gastroenterol 2008;14(29):4694-6.  
34. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 
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;94:426-30.  
35. Oshikiri T, Miyamoto M, Shichinohe T, Suzuoki M, Hiraoka K, Nakakubo Y, et al. 
Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma 
as essential immune response. J Surg Oncol 2003;84:224-8.  
 
 
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36. Piersma SJ, Welters MJP, van der Burg SH. Tumor-specific regulatory T cells in cancer 
patients. Human Immunol 2008;69:241-9.
37. Rao UNM, Lee SJ, Luo W, Mihm Jr. MC, Kirkwood JM. Presence of tumor-infiltrating 
lymphocytes and a dominant nodule within primary melanoma are prognostic factors for 
relapse-free survival of patients with thick (T4) primary melanoma: pathologic analysis 
of the E1690 and E1694 intergroup trials. Am J Clin Pathol 2010;133:646-53.
38. Sasaki A, Tanaka F, Mimori K, Inoue H, Kai S, Shibata K, et al. Prognostic value of 
tumor-infiltrating FOXP3+ regulatory T cells in patients with hepatocellular carcinoma. 
EJSO 2008;34:173-9.  
39. 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 adverse prognosis in 
resectable gastric cancer. J Cancer Res Clin Oncol 2010;136:1585-95.  
40. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.  
41. Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
42. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.  
43. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53.  
44. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10(840):841.  
45. 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.  
46. 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;58:449-59.  
47. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.  
48. Oble DA, Loewe R, Yu P, Mihm Jr. MC. Focus on TILs: prognostic significance of 
tumor infiltrating lymphocytes in human melanoma. Cancer Immunity 2009;9:3.  
 
 
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49. 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;59:909-19.  
50. 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.  
51. 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.  
52. 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 Intern 2010;107:1500-6.
53. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value of 
tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-24.  
54. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. 
Adoptive cell transfer therapy following non-myeloablative but lymphodepleting 
chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.  
55. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703.  
56. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits 
B cell receptor-mediated signaling by recruiting src homology 2-domain-containing 
tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71.  
57. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48.
58. Gettinger S, Horn L, Antonia SJ, Spigel DR, Gandhi L, Sequist LV, et al. Clinical 
activity and safety of anti-programmed death-1 (PD-1) (BMS-936558/MDX-1106/ONO-
4538) in patients (PTS) with advanced non-small cell lung cancer (NSCLC) [Abstract 
1237PD].  European Society for Medical Oncology 2012 Annual Meeting; 2012 Sep 28-
2012 Oct 2. Vienna, Austria, 2012.
59. Scagliotti GV, Parikh P, Pawel JV, Biesma B, Vansteenkiste J, et al. Phase III study 
comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy -
naive patients with advanced -stage non-small-cell lung cancer. J Clin Oncol 
2008;26:3543–51.
 
 
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60. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison 
of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 
2002;346:92–8.
61. Ohe Y, Ohashi Y, Kubota K, Tamura T, Nakagawa K, Negoro S, et al., Randomized 
phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin 
plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: 
Four-Arm Cooperative Study in Japan.  Ann Oncol. 2007 Feb;18(2):317-23.
62. Sandler S, Gray R, Perry M Brahmer J, et al., Paclitaxel-carboplatin alone or with 
bevacizumab for non-small-cell lung cancer. NEJM 2006 355:2542-50.
63. Rizi N, Antonia S, Quan Man Chow L, Brahmer JR, et al., (2013, June) A phase I study 
of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus platinum-based doublet 
chemotherapy (PT-doublet) in chemotherapy-naive non-small cell lung cancer (NSCLC) 
patients. Poster presented at the annual meeting of the American Society of Clinical 
Oncology, 
Chicago 
IL. 
Abstract 
retrieved 
from 
http://meetinglibrary.asco.org/content/113504-132
64. Selby M, Engelhardt J, Lu LS, Quigley M, et al., (2013 June) Antitumor activity of 
concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical 
models. Poster presented at the annual meeting of the American Society of Clinical 
Oncology, 
Chicago 
IL. 
Abstract 
retrieved 
from 
http://meetinglibrary.asco.org/content/113653-132
65. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, et al., Ipilimumab in combination with 
paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung 
cancer: results from a randomized, double-blind, multicenter Phase II study. J Clin Oncol 
2012;30:2046-2054.
66. Zukin M, Barrios C, Rodrigues Pereira J, De Albuquerque Ribeiro, de Mendonca Beato 
A, et al., Randomized Phase III trial of single-agent pemetrexed versus carboplatin and 
pemetrexed in patients with advanced non-small-cell lung cancer and Eastern 
Cooperative Oncology Group Performance Status of 2.  J Clin Oncol 2012; 31(23)2849-
53.
67. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: 
Interim phase I results; ASCO Abstract number 8023
68. Robins JM, Tsiatis AA. Correcting for non-compliance in randomized trials using rank 
preserving structural failure time models. Communication in Statistics – Theory and 
Methods 1991;20(8):2609-2631.
69. Uno, H., et al. Moving Beyond the Hazard Ratio in Quantifying the Between-Group 
Difference in Survival Analysis. J Clin Oncol. 2014; 32 (22): 2380-2385.
 
 
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70. Harrell, FE, Califf, RM, Pryor, DB, Lee, KL, Rosati, RA. Evaluating the yield of medical 
tests.  The Journal of the American Medical Association 1982;247: 2543-2546,
71. Harrell, FE, Lee, KL, Mark DB. Multivariable prognostic models: issues in developing 
models, evaluating assumptions and adequacy, and measuring and reducing errors.  
Statistics in Medicine 1996;15: 361-387.:
72. Weickhardt AJ, Camidge DR, Gan G, Xian L, Aisner DL, et al., Local ablative therapy of 
oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in 
oncogene addicted NSCLC. Journal of Thoracic Oncology 2012 Dec; 7(12): 1807–1814.
73. Marcus, R. Et al.  On closed testing procedures with special reference to ordered analysis 
of variance.  Biometrika, 1976: 63: 655-60.
74. Clopper C, Pearson E.  The use of confidence on fiducial limits illustrated in the case of 
the Binomial. Biometrika 1934;26:404-13.
75. Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985;4:213-226.
76. Farrington CP, Manning G. Test statistics and sample size formulae for comparative 
binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. 
Statistics in Medicine 1990; 9: 1447-54.
77. Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating 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
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 and leftover tumor tissue 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 and 
leftover tumor tissue 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 Future 
Biomedical Research.
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 
 
 
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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 
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 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 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.
 
 
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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.
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.
 
 
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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 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in Future Biomedical Research protocol and 
consent.  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 
writing to 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 
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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 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 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, and 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 
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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. 
Therefore, there will not be an additional risk for the subject.
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 
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.
 
 
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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 
IRBs/IECs and Investigational Site Staff
 
 
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Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by 
Sample Types
For approximate blood and tissue volumes, see Procedures Manual.
 
 
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ECOG Performance Status
GRADE ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. 
Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair.
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html)
 
 
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response.  While 
either CT or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging 
technique in this study.  
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. 
Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 2009 
Jan;45(2):228-47.
In addition, volumetric analysis may be used for response assessment (so-called enhanced 
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Strong Inhibitors of CYP3A4
Strong inhibitors of CYP3A4 include:

Clarithromycin

Indinavir

Itraconazole

Ketoconazole

Nefazodone

Nelfinavir

Ritonavir

Saquinavir
This appendix is not intended to be a comprehensive list of strong CYP3A4 inhibitors, but to 
provide a practical list of commonly prescribed medications that should be avoided in 
subjects participating in this study.  Additional guidance for investigators on potential strong 
CYP3A4 inhibitors of clinical significance may be found at 
http://medicine.iupui.edu/flockhart/.
The web-based resources are intended as guidance for the investigators and not necessarily as 
a list of prohibited medications.
 
 
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13.0 SIGNATURES
Sponsor’s Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
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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