Conditions: Solid Tumor Non-small Cell Lung Cancer Small Cell Lung Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 57
Healthy volunteers: no

Brief summary:
This study using pembrolizumab (MK-3475) will be done in 5 parts. In Part A, successive participant cohorts with advanced solid tumors will receive pembrolizumab to assess the safety and tolerability of monotherapy. In Parts B, C, and D, participants with advanced non-small cell lung cancer (NSCLC) will receive pembrolizumab in combination with either cisplatin/pemetrexed or carboplatin/pemetrexed (Part B); with either carboplatin/paclitaxel or carboplatin/nab-paclitaxel (Part C); or with ipilimumab (Part D) by non-random assignment to assess the safety and tolerability of the combination therapy. In Part E, participants with untreated Extensive-disease (ED) Small Cell Lung Cancer (SCLC) will receive pembrolizumab in combination with either cisplatin/etoposide, carboplatin/etoposide, or cisplatin/etoposide with prophylactic use of granulocyte colony-stimulating factor (lasting G-CSF \[pegfilgrastim\]) by non-random assignment to assess the safety and tolerability of the combination therapy.

Detailed description:

Arms:
arm 1: In Part A, participants receive intravenous (IV) Pembrolizumab 2 mg/kg on Day 1 of Cycle 1 (28 days), Cycle 2 and any additional cycles (14 days). arm 2: In Part A, participants receive IV Pembrolizumab 10 mg/kg on Day 1 of Cycle 1 (28 days), Cycle 2 and any additional cycles (14 days). arm 3: In Part B, participants receive IV Pembrolizumab 200 mg + IV Cisplatin 75 mg/m\^2 + IV Pemetrexed 500 mg/m\^2 on Day 1 of each 21-day cycle for a maximum of 4 cycles. After completion of the initial therapy, maintenance therapy with IV pemetrexed in combination with IV pembrolizumab is permitted per standard of care, followed by IV pembrolizumab 200 mg every 3 weeks. arm 4: In Part B, participants receive IV Pembrolizumab 200 mg + IV Carboplatin Area Under The Curve (AUC) 5 mg/mL/minute + IV Pemetrexed 500 mg/m\^2 on Day 1 of each 21-day cycle for a maximum of 4 cycles. After completion of the initial therapy, maintenance therapy with IV pemetrexed in combination with IV pembrolizumab is permitted per standard of care, followed by IV pembrolizumab 200 mg every 3 weeks. arm 5: In Part C, participants receive IV Pembrolizumab 200 mg + IV Carboplatin AUC 6 mg/mL/minute + IV Paclitaxel 200 mg/m\^2 on Day 1 of each 21-day cycle for a maximum of 4 cycles. After completion of the initial therapy, maintenance therapy with IV pembrolizumab 200 mg every 3 weeks. arm 6: In Part C, participants receive IV Pembrolizumab 200 mg + IV Carboplatin AUC 6 mg/mL/minute on Day 1 of each 21-day cycle + IV Nab-paclitaxel 100 mg/m\^2 on Days 1, 8, and 15 of each 21-day cycle for a maximum of 4 cycles. After completion of the initial therapy, maintenance therapy with IV pembrolizumab 200 mg every 3 weeks. arm 7: In Part D, participants receive IV Pembrolizumab 200 mg on Day 1 of each 21-day cycle + IV Ipilimumab 1 mg/kg on Day 1 of every other 21-day cycle (every 42 days) for a maximum of 18 cycles of Ipilimumab (35 doses of Pembrolizumab). arm 8: In Part E, participants receive IV Pembrolizumab 200 mg + IV Cisplatin 75 mg/m\^2 on Day 1 of each 21-day cycle + IV Etoposide 100 mg/m\^2 on Days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles. After completion of the initial therapy, maintenance therapy with IV pembrolizumab 200 mg every 3 weeks. arm 9: In Part E, participants receive IV Pembrolizumab 200 mg + IV Carboplatin AUC 5 mg/mL/minute on Day 1 of each 21-day cycle + IV Etoposide 100 mg/m\^2 on Days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles. After completion of the initial therapy, maintenance therapy with IV pembrolizumab 200 mg every 3 weeks. arm 10: In Part E, participants receive IV Pembrolizumab 200 mg + IV Cisplatin 75 mg/m\^2 on Day 1 of each 21-day cycle + IV Etoposide 100 mg/m\^2 on Days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles + lasting granulocyte colony-stimulating factor (G-CSF) (pegfilgrastim) 3.6 mg on Day 4 of Cycle 1. After completion of the initial therapy, maintenance therapy with IV pembrolizumab 200 mg every 3 weeks.

Interventions: intervention 1: Pembrolizumab 2 mg/kg intervention 2: Pembrolizumab 10 mg/kg intervention 3: Pembrolizumab 200 mg intervention 4: Cisplatin 75 mg/m^2 intervention 5: Pemetrexed 500 mg/m^2 intervention 6: Carboplatin AUC 5 mg/mL/min intervention 7: Carboplatin AUC 6 mg/mL/min intervention 8: Paclitaxel 200 mg/m^2 intervention 9: Nab-paclitaxel 100 mg/m^2 intervention 10: Ipilimumab 1 mg/kg intervention 11: Etoposide 100 mg/m^2 intervention 12: G-CSF (pegfilgrastim) 3.6 mg
Intervention descriptions: intervention 1: Administered as an intravenous (IV) infusion on Day 1 of Cycle 1 (28 days), Cycle 2 (14 days), and Cycle 3 (14 days) intervention 2: Administered as an IV infusion on Day 1 of Cycle 1 (28 days), Cycle 2 (14 days), and Cycle 3 (14 days) intervention 3: Administered as an IV infusion on Day 1 of each 21-day cycle intervention 4: Administered as an IV infusion on Day 1 of each 21-day cycle intervention 5: Administered as an IV infusion on Day 1 of each 21-day cycle intervention 6: Administered as an IV infusion on Day 1 of each 21-day cycle intervention 7: Administered as an IV infusion on Day 1 of each 21-day cycle intervention 8: Administered as an IV infusion on Day 1 of each 21-day cycle intervention 9: Administered as an IV infusion on Days 1, 8, and 15 of each 21-day cycle intervention 10: Administered as an IV infusion on Day 1 of every other 21-day cycle (every 42 days) intervention 11: Administered as an IV infusion on Days 1, 2, and 3 of each 21-day cycle intervention 12: Administered as a subcutaneous injection on Day 4 of Cycle 1

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase I Study of MK-3475 Alone in Subjects with Advanced 
Solid Tumors and in Combination with Platinum-Doublet 
Chemotherapy or immunotherapy in Subjects with Advanced Non-
Small Cell Lung Cancer/ Extensive-Disease Small Cell Lung 
Cancer.
24-Sep-2019
NCT01840579


Product:  MK-3475
1
Protocol/Amendment No.: 011-08 
MK-3475-011-08 Final Protocol
24-Sep-2019
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.
This protocol amendment is applicable only to Japan.
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.
TITLE:
A Phase I Study of MK-3475 Alone in Subjects with Advanced Solid Tumors and in 
Combination with Platinum-Doublet Chemotherapy or immunotherapy in Subjects with 
Advanced Non-Small Cell Lung Cancer/ Extensive-Disease Small Cell Lung Cancer.
IND NUMBER:  Not Applicable
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
2.1
Trial Design ........................................................................................................... 15
2.2
Trial Diagram........................................................................................................ 18
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
3.1
Primary Objective(s) & Hypothesis(es).............................................................. 20
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 20
3.3
Exploratory Objectives......................................................................................... 21
4.0
BACKGROUND & RATIONALE.......................................................................... 21
4.1
Background ........................................................................................................... 21
4.1.1
Pharmaceutical and Therapeutic Background .................................................... 21
4.1.2
Ongoing Clinical Trials....................................................................................... 24
4.2
Rationale................................................................................................................ 25
4.2.1
Rationale for the Trial and Selected Subject Population .................................... 25
4.2.2
Rationale for Dose Selection/Regimen............................................................... 26
4.2.3
Rationale for Endpoints ...................................................................................... 27
4.2.3.1
Safety Endpoints.......................................................................................... 27
4.2.3.2
Efficacy Endpoints....................................................................................... 27
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 28
4.2.3.4
Immunogenicity Endpoints.......................................................................... 28
4.2.3.5
Planned Exploratory Biomarker Research................................................... 28
4.2.3.6
Future Biomedical Research........................................................................ 29
5.0
METHODOLOGY ................................................................................................... 30
5.1
Entry Criteria........................................................................................................ 30
5.1.1
Diagnosis/Condition for Entry into the Trial...................................................... 30
5.1.2
Subject Inclusion Criteria.................................................................................... 30
5.1.3
Subject Exclusion Criteria .................................................................................. 33
5.2
Trial Treatments................................................................................................... 35
 
 
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5.2.1
Dose Selection/Tolerability Evaluation Rules/Definition of Dose-Limiting 
Toxicity/Modification......................................................................................... 37
5.2.1.1
Dose Selection ............................................................................................. 37
5.2.1.2
Tolerability Evaluation Rules ...................................................................... 37
5.2.1.3
Definition of Dose-Limiting Toxicity.......................................................... 40
5.2.1.4
Dose Modification ....................................................................................... 41
5.2.2
Timing of Dose Administration.......................................................................... 47
5.2.3
Trial Blinding/Masking....................................................................................... 50
5.3
Randomization or Treatment Allocation............................................................ 50
5.4
Stratification.......................................................................................................... 50
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)..................... 50
5.5.1
Allowed Concomitant Medications .................................................................... 51
5.5.2
Prohibited Concomitant Medication................................................................... 51
5.6
Rescue Medications & Supportive Care............................................................. 52
5.6.1
Supportive Care Guidelines ................................................................................ 52
5.7
Diet/Activity/Other Considerations..................................................................... 53
5.7.1
Diet...................................................................................................................... 53
5.7.2
Contraception...................................................................................................... 53
5.7.3
Use in Pregnancy ................................................................................................ 54
5.7.4
Breast-feeding..................................................................................................... 55
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 55
5.8.1
Discontinuation of Treatment ............................................................................. 55
5.8.2
Withdrawal from the Trial .................................................................................. 56
5.9
Subject Replacement Strategy............................................................................. 57
5.10
Beginning and End of the Trial ........................................................................... 57
5.11
Clinical Criteria for Early Trial Termination ................................................... 57
6.0
TRIAL FLOW CHART ........................................................................................... 58
6.1
Part A..................................................................................................................... 58
6.2
Combination Therapy .......................................................................................... 61
6.2.1
Part B and C- treatment phase ............................................................................ 61
6.2.2
Part D- treatment phase....................................................................................... 65
6.2.3
Part E- treatment phase ....................................................................................... 68
6.2.4
Follow-up phase-Part B, C, D and E................................................................... 72
 
 
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6.2.5
Part B, C and E- Second Course phase and Follow-up phase ............................ 74
6.2.6
Part D- Second Course phase and Follow-up phase ........................................... 76
7.0
TRIAL PROCEDURES ........................................................................................... 78
7.1
Trial Procedures ................................................................................................... 78
7.1.1
Administrative Procedures.................................................................................. 78
7.1.1.1
Informed Consent......................................................................................... 78
7.1.1.1.1
General Informed Consent.................................................................... 78
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 79
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 79
7.1.1.3
Subject Identification Card .......................................................................... 79
7.1.1.4
Medical History ........................................................................................... 79
7.1.1.5
Demographics .............................................................................................. 79
7.1.1.5.1
Molecular Testing................................................................................. 79
7.1.1.6
Prior and Concomitant Medications Review............................................... 80
7.1.1.6.1
Prior Medications.................................................................................. 80
7.1.1.6.2
Concomitant Medications..................................................................... 80
7.1.1.7
Solid Tumor and NSCLC/SCLC Disease Details and Prior Treatments..... 80
7.1.1.7.1
Disease Details...................................................................................... 80
7.1.1.7.2
Prior Treatment..................................................................................... 80
7.1.1.8
Subsequent Antineoplastic Therapy Status.................................................. 80
7.1.1.9
Assignment of Screening Number............................................................... 80
7.1.1.10 Assignment of Randomization Number....................................................... 81
7.1.1.11 Trial Compliance (Medication/Diet/Activity/Other)................................... 81
7.1.2
Clinical Procedures/Assessments........................................................................ 81
7.1.2.1
Adverse Event Monitoring........................................................................... 81
7.1.2.2
Physical Exam.............................................................................................. 82
7.1.2.3
Height, Weight, and Vital Signs .................................................................. 82
7.1.2.4
12-lead ECG................................................................................................. 82
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 83
7.1.2.6
Pulse Oximetry (SpO2) ................................................................................ 83
7.1.3
Laboratory Procedures/Assessments .................................................................. 83
 
 
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis and 
Other)........................................................................................................... 83
7.1.3.2
Pharmacokinetic / Anti-pembrolizumab Antibodies /Evaluations .............. 85
7.1.3.2.1
Blood Collection for Serum Pharmacokinetics of MK-3475 ............... 85
7.1.3.2.2
Blood Collection for Serum Anti-pembrolizumab Antibodies............. 87
7.1.3.3
Tumor Marker.............................................................................................. 88
7.1.3.4
Tumor Imaging and Assessment of Disease (irRC and irRECSIT) ............ 88
7.1.3.5
Pulmonary Radiographic Evaluation for pembrolizumab-Induced 
Pneumonitis ................................................................................................. 91
7.1.3.6
Tumor Tissue Collection.............................................................................. 91
7.1.3.7
Blood Collection for Correlative Studies and Biomarker Samples ............. 92
7.1.3.8
Planned Genetic Analysis Sample Collection.............................................. 92
7.1.3.9
Future Biomedical Research........................................................................ 92
7.1.4
Other Procedures................................................................................................. 92
7.1.4.1
Withdrawal/Discontinuation........................................................................ 92
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 93
7.1.4.1.2
Lost to Follow-up.................................................................................. 93
7.1.4.2
Blinding/Unblinding .................................................................................... 93
7.1.4.3
Domiciling ................................................................................................... 93
7.1.5
Visit Requirements.............................................................................................. 94
7.1.5.1
Screening...................................................................................................... 94
7.1.5.2
Treatment Period.......................................................................................... 94
7.1.5.3
Discontinuation............................................................................................ 94
7.1.5.4
Follow-up phase........................................................................................... 95
7.1.5.4.1
Mandatory Safety Follow-Up Visit ...................................................... 95
7.1.5.4.2
Observation visit................................................................................... 95
7.1.5.4.3
Follow-Up Visit 1 and 2 ....................................................................... 95
7.1.5.5
Survival Follow-up (Part B, C, D and E)..................................................... 95
7.1.5.6
Second Course Phase (Part B, C, D and E only) ......................................... 95
7.1.5.7
Critical Procedures Based on Trial Objectives: Timing of Procedure......... 97
7.2
Assessing and Recording Adverse Events .......................................................... 97
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 98
 
 
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7.2.2
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 98
7.2.3
Immediate Reporting of Adverse Events to the Sponsor.................................... 99
7.2.3.1
Serious Adverse Events ............................................................................... 99
7.2.3.2
Events of Clinical Interest.......................................................................... 100
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 101
7.2.4
Evaluating Adverse Events............................................................................... 101
7.2.5
Sponsor Responsibility for Reporting Adverse Events .................................... 104
7.3
TRIAL GOVERNANCE AND OVERSIGHT................................................. 104
7.3.1
Efficacy and Safety Evaluation Committee...................................................... 104
7.3.2
Independent Pulmonary Radiographic Adviser................................................ 104
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 104
8.1
Statistical Analysis Plan Summary ................................................................... 104
8.2
Statistical Analysis Plan ..................................................................................... 105
8.2.1
Responsibility for Analyses .............................................................................. 105
8.2.2
Trial Objectives................................................................................................. 105
8.2.3
Variables/Time Points of Interest ..................................................................... 105
8.2.3.1
Safety Endpoints........................................................................................ 105
8.2.3.2
Efficacy Endpoints..................................................................................... 106
8.2.3.3
Pharmacokinetic Endpoints ....................................................................... 106
8.2.3.4
Immunogenicity Endpoints........................................................................ 107
8.2.4
Analysis Populations......................................................................................... 107
8.2.4.1
Safety Analysis Populations ...................................................................... 107
8.2.4.2
Efficacy Analysis Populations................................................................... 107
8.2.5
Statistical Methods............................................................................................ 107
8.2.5.1
Safety Analyses.......................................................................................... 107
8.2.5.2
Pharmacokinetics Analyses ....................................................................... 108
8.2.5.3
Efficacy Analyses ...................................................................................... 108
8.2.6
Multiplicity ....................................................................................................... 108
8.2.7
Sample Size and Power Calculation ................................................................. 108
8.2.8
Interim Analysis................................................................................................ 109
8.2.9
Accounting for Missing Data............................................................................ 109
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 109
 
 
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9.1
Investigational Product ...................................................................................... 109
9.2
Packaging and Labeling Information ............................................................... 110
9.3
Clinical Supplies Disclosure............................................................................... 110
9.4
Storage and Handling Requirements................................................................ 110
9.5
Returns and Reconciliation................................................................................ 110
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 111
10.1
Confidentiality..................................................................................................... 111
10.1.1 Confidentiality of Data ..................................................................................... 111
10.1.2 Confidentiality of Subject Records................................................................... 111
10.1.3 Confidentiality of Investigator Information...................................................... 111
10.1.4 Confidentiality of IRB/IEC Information........................................................... 112
10.2
Compliance with Financial Disclosure Requirements..................................... 112
10.3
Compliance with Law, Audit and Debarment ................................................. 112
10.4
Compliance with Trial Registration and Results Posting Requirements...... 114
10.5
Quality Management System............................................................................. 115
10.6
Data Management............................................................................................... 115
10.7
Publications ......................................................................................................... 115
11.0
LIST OF REFERENCES....................................................................................... 117
12.0
APPENDICES......................................................................................................... 120
12.1
Merck Code of Conduct for Clinical Trials...................................................... 120
12.2
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 122
12.3
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 128
12.4
ECOG Performance Status................................................................................ 139
12.5
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 140
12.5.1 irRECIST Assessment of Disease..................................................................... 140
12.6
Immune Related Response Criteria .................................................................. 143
13.0
SIGNATURES......................................................................................................... 145
13.1
Sponsor's Representative ................................................................................... 145
13.2
Investigator.......................................................................................................... 145
 
 
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LIST OF TABLES
Table 1
Trial Treatment ..................................................................................................... 35
Table 2
Dose Escalation/Tolerability Evaluation Rules in Part A..................................... 38
Table 3
Dose Evaluation Rules in Part B, C, D and E....................................................... 39
Table 4
Dose modification and toxicity management guidelines for immune-
related AEs associated with pembrolizumab........................................................ 42
Table 5
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines ............................................................................................................. 45
Table 6
Maximum dose of Carboplatin ............................................................................. 50
Table 7
Laboratory Tests ................................................................................................... 83
Table 8
Sampling Points for Pharmacokinetics in Part A.................................................. 85
Table 9
Sampling Points for Pharmacokinetics in Part B, C and E................................... 86
Table 10
Sampling Points for Pharmacokinetics in Part D.................................................. 86
Table 11
Sampling Points for Anti-pembrolizumab Antibodies in Part A.......................... 87
Table 12
Sampling Points for Anti-pembrolizumab Antibodies in Part B, C, and E .......... 87
Table 13
Sampling Points for Anti-pembrolizumab Antibodies in Part D.......................... 88
Table 14
Imaging and Treatment Determinations After First Radiological Evidence 
of PD (based on irRC in Part A or RECIST 1.1 in Part B, C, D and E)............... 90
Table 15
Evaluating Adverse Events................................................................................. 102
Table 16
Product Descriptions........................................................................................... 109
 
 
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LIST OF FIGURES
Figure 1
Study Design Diagram.......................................................................................... 20
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-011-08
24-SEP-2019
Remove 2nd course treatment phase and follow up phase including survival follow up.
MK-3475-011-07
16-OCT-2017
Add part E cohort 3 to evaluate regimen (pembrolizumab + cisplatin + etoposide) with
prophylactic use of granulocyte colony-stimulating factor (lasting G-CSF).
MK-3475-011-06
12-DEC-2016
Add New parts [Part D (pembrolizumab + ipilimumab for NSCLC) and Part E
(pembrolizumab + cisplatin/carboplatin + etoposide for SCLC)] 
MK-3475-011-05
05-JUL-2016
Addition of SpO2 and SP-D measurements for screening and on treatment period.
MK-3475-011-04
15-APR-2016
Add Part C; In the Part C (combination), 6 to 9 subjects with advanced squamous 
NSCLC will receive MK-3475 200mg Q3W in combination with carboplatin/paclitaxel 
(Cohort 1), or carboplatin/nab-paclitaxel (Cohort 2), respectively.
MK-3475-011-03
14-JUL-2015
Changed dose of MK-3475 in Part B from 10 mg/kg to 200 mg fixed dose.
Changed the drugs of chemotherapy in Cohort 2 from carboplatin/ paclitaxel to 
carboplatin/pemetrexed.
MK-3475-011-02
04-APR-2013
Subject exclusion criteria #1 was changed from 4 weeks to 2 weeks prior to the first 
dose of trial treatment for palliative radiotherapy and kinase inhibitors.
Added a section for demographics as Section 7.1.1.5 to collect information regarding 
cancer related gene mutation/translocation etc.
Section 8.2.5.1 was changed; 90% confidence interval” is changed into “90% Bayesian 
prediction interval” to keep the consistent with TPI designs used in study.
 
 
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Document
Date of Issue
Overall Rationale
MK-3475-011-01
14-MAR-2013
Add part B; MK-3475 and cytotoxic chemotherapy administration will be staggered in 
Cycle 1 only. 10 mg/kg of MK-3475 will be administered on Day 1 in Cycle 1 without 
the accompanying cytotoxic chemotherapy.
On 
Day 
8 
in 
Cycle 
1, 
either 
cisplatin/pemetrexed 
(Cohort 
1) 
or 
carboplatin/paclitaxel(Cohort 2) will be administered while MK-3475 will be withheld.
MK-3475-011-00
04-FEB-2013
Initial version.
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1
5.8.1
6.2.4
6.2.5
6.2.6
7.1.1.8
7.1.3.4
7.1.5.4.2
7.1.5.5
7.1.5.6
TRIAL SUMMARY
Trial Design
Discontinuation of Treatment
Follow-up phase-Part B, C, D and E
Part B, C and E- Second Course 
phase and Follow-up phase
Part D- Second Course phase and 
Follow-up phase
Subsequent Antineoplastic Therapy 
Status
Tumor Imaging and Assessment of 
Disease (irRC and irRECSIT)
Observation visit
Survival Follow-up (Part B, C, D and 
E)
Second Course Phase (Part B, C, D 
and E only)
Patients who have already started the second 
course phase of administration before the 
approval of the protocol version 08, may 
continue in the second course phase (up to 12 
months) if applicable.  For other patients, the 
second course phase is not applicable.
After the approval of the protocol version 08, 
the final visit of this study will be a safety 
follow-up visit, and imaging follow-up and 
survival follow-up will not be performed. 
Participants in the follow-up phase or survival 
follow-up phase will discontinue the study and 
no further visits are required.
The primary objective of 
this study was achieved 
and additional data is not 
required.
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.1.3.2.1
Blood 
Collection 
for 
Serum 
Pharmacokinetics of MK-3475
Serum samples collection for pharmacokinetic 
measurements will be discontinued after the 
completion of discontinuation visit
after 
approval of the protocol version 08.
Based 
on 
the 
results 
already 
obtained, 
no 
further data is required. 
7.1.3.2.2
Blood Collection for Serum Anti-
pembrolizumab Antibodies
Blood 
samples 
collection 
for 
anti-
pembrolizumab antibodies measurements will 
be discontinued after the completion of 
discontinuation visit after approval of the 
protocol version 08.
Based 
on 
the 
results 
already 
obtained, 
no 
further data is required.
7.1.3.4
7.1.3.5
Tumor Imaging and Assessment of 
Disease (irRC and irRECSIT)
Pulmonary Radiographic Evaluation 
for 
pembrolizumab-Induced 
Pneumonitis
Images taken after July 20, 2019 need not be 
submitted to the central vendor nor Sponsor.
Based 
on 
the 
results 
already 
obtained, 
no 
further data is required.
7.1.5.4.3
Follow-Up Visit 1 and 2
After the approval of the protocol version 08, 
all follow-up visits, including serum or blood 
sample collection for pharmacokinetic or anti-
MK-3475 antibody 
assessment, will be 
discontinued after the 30 day of follow-up
visit.
The primary objective of 
this study was achieved 
and additional data is not 
required.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase I study of MK-3475 in subjects with advanced solid tumors and 
NSCLC/ED-SCLC
Trial Phase
Phase I
Clinical Indication
Advanced solid tumors and non-small cell lung cancer (NSCLC)/Small Cell 
Lung Cancer (SCLC)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
IV infusion
Trial Blinding
Unblinded Open-label
Treatment Groups 
In the Part A (monotherapy, 3+3 design), 3 or 6 subjects with advanced 
solid tumors will receive escalating doses of pembrolizumab 2 mg/kg 
(Dose level 1) or 10 mg/kg (Dose level 2) every 2 weeks (Q2W), 
respectively.
In the Part B (combination), 6 to 9 subjects with advanced NSCLC will 
receive pembrolizumab 200 mg every 3 week (Q3W) in combination with 
cisplatin/pemetrexed (Cohort 1), or carboplatin/ pemetrexed (Cohort 2), 
respectively.
In the Part C (combination), 6 to 9 subjects with advanced squamous 
NSCLC will receive pembrolizumab 200 mg Q3W in combination with 
carboplatin/paclitaxel (Cohort 1), or carboplatin/nab-paclitaxel (Cohort 2), 
respectively.
In the Part D (combination), 6 to 9 subjects with advanced NSCLC will 
receive pembrolizumab 200 mg (Q3W) in combination with 1 mg/kg 
ipilimumab [every 6 weeks (Q6W)]. 
In the Part E (combination), 6 to 9 subjects with untreated Extensive-
Disease (ED) Small Cell Lung Cancer (SCLC) will receive pembrolizumab
200 mg Q3W in combination with cisplatin/etoposide (Cohort 1), or 
carboplatin/ etoposide (Cohort 2), respectively. Three to 9 subjects with 
untreated ED-SCLC will receive pembrolizumab 200 mg Q3W in 
combination with cisplatin/etoposide (Cohort 3). Subjects, who enrolled 
into cohort 3, will take prophylactic use of granulocyte colony-stimulating 
factor (lasting G-CSF) (pegfilgrastim).
Number of trial subjects
Approximately 84 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 6 years from 
the time the first subject signs the informed consent until the last subject’s 
last visit.
 
 
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Duration of Participation
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through the final protocol-specified contact.  
After a screening phase of 28 days, subjects will continue the treatment of 
study drugs until completion of 2 years of trial therapy, documented 
disease progression, unacceptable adverse event(s) etc. Pembrolizumab (in 
part D, pembrolizumab+ipilimumab) treated subjects who attain a complete 
response may consider stopping trial treatment. These subjects who attain
Complete Response or stop trial therapy after 2 years of treatments for 
reasons other than disease progression or intolerability may be eligible for 
re-treatment if they meet the criteria for Second Course Phase. Patients 
who have already started the second course phase of administration before 
the approval of the protocol version 08, may continue the second course 
phase (up to 12 months) if applicable.  For other patients, the second course 
phase is not applicable. After the end of treatment, each subject will be 
followed for a minimum of 30 days for adverse event monitoring [serious 
adverse events (SAE) will be collected for up to 90 days following 
cessation of treatment or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier]. Subjects in 
Part B, C, D and E will have 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. After the approval of the protocol version 08, the final visit of this 
study will be a safety follow-up visit, and imaging follow-up and survival 
follow-up will not be performed. Participants in the follow-up phase or 
survival follow-up phase will discontinue the study and no further visits are 
required.
2.0 TRIAL DESIGN
2.1
Trial Design
This study is an open-label, non-randomized, multi-center Phase I study of pembrolizumab 
alone in subjects with advanced solid tumors, and in combination with platinum-doublet
chemotherapy or immunotherapy in subjects with previously untreated advanced Non-Small 
Cell Lung Cancer/ ED-SCLC.  This study is designed to evaluate the safety and tolerability, 
and pharmacokinetics of pembrolizumab alone and in combination with platinum-doublet 
chemotherapy selected by each cohort or immunotherapy.  As exploratory objectives, the 
presence of anti- pembrolizumab antibodies, anti-tumor activity, overall survival, correlation 
between objective response and PD-L1 expression levels, and pulmonary radiographic
changes and its features will also be evaluated.  The study has 5 parts; Part A, (monotherapy, 
3+3 design), and Part B, C, D and E (combination).
In Part A, pembrolizumab will be administered as an IV infusion in repeating 2-week cycles, 
and 4 weeks period in the only first cycle (Cycle 1: 4 weeks, Cycle 2 and subsequent cycles: 
2 weeks).  3 or 6 subjects will be enrolled sequentially to receive escalating doses of 2 mg/kg 
(Dose level 1) and 10 mg/kg (Dose level 2) of pembrolizumab, respectively.
In Part B, 200 mg of pembrolizumab and cytotoxic chemotherapy will be administered. A 
maximum of 4 cycles of cisplatin/pemetrexed (Cohort 1) or carboplatin/ pemetrexed (Cohort 
2) will be administered along with pembrolizumab.  After completion of the platinum-
 
 
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containing doublet, maintenance therapy with pemetrexed in combination with 
pembrolizumab is permitted if the investigator thinks it is appropriate per standard of care 
(SOC), followed by a single agent of pembrolizumab. 6 to 9 subjects in each Cohort will be 
enrolled
In Part C, 200 mg of pembrolizumab and cytotoxic chemotherapy will be administered. A 
maximum of 4 cycles of carboplatin/paclitaxel (Cohort 1) or carboplatin/nab-paclitaxel 
(Cohort 2) will be administered along with pembrolizumab followed by pembrolizumab as 
maintenance therapy. 6 to 9 subjects in each Cohort will be enrolled.
In Part D, 200 mg (Q3W) of pembrolizumab and 1 mg/kg ipilimumab (Q6W) will be 
administered. Pembrolizumab plus ipilimumab will be administered up to 18 cycles of 
ipilimumab (35 times of pembrolizumab). 6 to 9 subjects will be enrolled.
In Part E, 200 mg of pembrolizumab and cytotoxic chemotherapy will be administered. A 
maximum of 4 cycles of cisplatin/etoposide (Cohort 1 and 3) or carboplatin/etoposide 
(Cohort 2) will be administered along with pembrolizumab followed by pembrolizumab as 
maintenance therapy. 6 to 9 subjects in each Cohort will be enrolled. Three to 9 subjects with 
untreated ED-SCLC will receive pembrolizumab 200 mg Q3W in combination with 
cisplatin/etoposide and prophylactic lasting G-CSF (pegfilgrastim).  Patients who achieve a 
partial or complete response with platinum/etoposide plus 200 mg pembrolizumab for 4 cycle 
may be offered prophylactic cranial radiation (PCI) at the discretion of the Investigator; if 
given, PCI would begin within 4 to 6 weeks after the last with platinum/etoposide plus 
pembrolizumab 200 mg treatment.  At least 2 weeks following completion of PCI, patients 
will continue 200 mg pembrolizumab Q3W as maintenance therapy.
6 subject in each cohort at part C and E (cohort 1 and 2) or in part D will be enrolled for PK 
sample evaluation even if 0/3 subjects develop a DLT and it is considered to be tolerated.
There are 3 cohorts in Part E. Preliminary data of the DLT assessment, no DLT was reported 
in Cohort 2, however in Cohort 1, Grade 3 febrile neutropenia (DLT) has been reported in 3 
out of 6 patients in Cycle 1 [Grade 4 laryngeal stenosis has been reported in 1 out of 6 
patients in Cycle 1, also]. Prophylactic use of G-CSF in SCLC patients is allowed based on a 
subject’s condition in Japan clinical practice. A lasting G-CSF is used for prophylaxis of 
neutropenia due to chemotherapies. To minimize a patient's burden, only lasting G-CSF 
prophylactic use of G-CSF during DLT assessment period was selected to evaluate the safety 
and tolerability for untreated ED-SCLC patients treated with pembrolizumab 200 mg Q3W in 
combination with cisplatin/etoposide and prophylactic G-CSF.
Subjects will continue trial therapy until they meet 5.8 Subject Withdrawal/Discontinuation 
Criteria such as, documented disease progression, unacceptable adverse event(s) etc.
Pembrolizumab (in part D, pembrolizumab+ipilimumab) treated subjects who attain a 
complete response may consider stopping trial treatment. These subjects and who stopped 
trial therapy after 2 years of treatments for reasons other than disease progression or 
intolerability may be eligible for re-treatment if they meet the criteria for Second Course 
Phase. Patients who have already started the second course phase of administration before the 
approval of the protocol version 08, may continue the second course phase (up to 12 months) 
 
 
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if applicable.  For other patients, the second course phase is not applicable. After the end of 
treatment, each subject will be followed for a minimum of 30 days for adverse event 
monitoring [serious adverse events(SAE) will be collected for up to 90 days following 
cessation of treatment or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier] Subjects in Part B, C, D and E will be followed-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. After the 
approval of the protocol version 08, the final visit of this study will be a safety follow-up 
visit, and imaging follow-up and survival follow-up will not be performed. Participants in the 
follow-up phase or survival follow-up phase are completed and no further visits are required.
The Dose limited toxicity (DLT) evaluation period will be defined as the first 4 weeks (in 
Part A), 3 weeks (in Part B, C and E) or 6 weeks (in Part D) after initiation of study treatment.  
As a general rule, all of the study procedures in the DLT evaluation period will be performed 
under hospitalization.  In the DLT assessments of Part A, if 0 of the 3 subjects or ≤ 1 of the 6 
subjects experience a DLT at a dose level, it will be considered to be tolerated.  In Part B, C, 
D and E, if 0 of the 3 subjects or ≤ 2 of the 6 subjects or ≤ 4 of the 9 subjects experience a 
DLT at each combination cohort/part, it will be considered to be tolerated.
Time points of serum pharmacokinetics of pembrolizumab are described in section 7.1.3.2.1. 
The anti-tumor activity will be assessed by radiographic (CT or MRI), and standard tumor 
markers evaluations (as appropriate for a given tumor type) approximately every 6 (in Part 
A) calendar weeks or every 6 calendar weeks for the first 24 weeks and every 9 calendar
weeks from the date of imaging assessment at the week 24 (in Part B, C, D and E).  Tumor 
response will be assessed using the immune related Response Criteria (irRC, See Section
12.6) for Part A or irRECIST for Part B, C, D and E by investigator, and tumor volumetric 
analysis for Part A or RECIST 1.1 (See Section 12.5) for Part B and C by central imaging 
vendor. Time points of serum anti- pembrolizumab antibodies are described in section
7.1.3.2.2.
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.
Combination medications for Part B and, that with carboplatin/paclitaxel for Part C and with 
ipilimumab for part D were determined based on the results of ongoing overseas Phase I/II 
study (PN021).  In PN021, tolerability, safety and efficacy were evaluated with 2 mg/kg or 
10 mg/kg of pembrolizumab in combination with chemotherapy or immunotherapy and the 
triple combination were well tolerated. An ongoing overseas phase 1b/2 study (KEYNOTE-
026) is exploring the combination of pembrolizumab with carboplatin and nab-paclitaxel.
Combination medications for Part E were determined based on ongoing overseas Phase II 
study (REACTION, ClinicalTrials.gov Identifier: NCT02580994).
 
 
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2.2
Trial Diagram
The trial design is depicted in Figure 1
 
 
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MK-3475
Ipilimumab
Part D
DLT evaluation 
period
Treatment
Safety 
Follow-up
Screening
Follow-up
Cycle 1
Day 1
1 to 28 days
3 weeks
3 weeks
Last dose
30 days
Follow
-up 1
Follow
-up 2
Follow
-up 3･･･
Survival Follow
-up 1･･･
Survival  
Follow-up
6 months
Every
9 weeks
Every
2 months
MK-3475
Ipilimumab
MK-3475
3 weeks
MK-3475
Ipilimumab
MK-3475
Cycle 2
Day 1
 
 
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Figure 1
Study Design Diagram
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
1)
Objective: To evaluate the tolerability and safety profile of pembrolizumab alone in 
subjects with advanced solid tumors and in combination with platinum-doublet 
chemotherapy in subjects with advanced NSCLC or ED-SCLC, or in combination with
immunotherapy in subjects with advanced NSCLC.
3.2
Secondary Objective(s) & Hypothesis(es)
1)
Objective: To evaluate the pharmacokinetic profiles of pembrolizumab alone and in 
combination with platinum-doublet chemotherapy or immunotherapy.
Survival 
Follow-up
Screening
Cycle 1
1 to 28 days
Cycle 2
Last Dose
3 weeks
3 weeks
30 days
Survival 
Follow-up 1
MK-3475
Cisplatin
MK-3475
Cisplatin
MK-3475
Cohort 1
Cohort 2
Treatment
Safety 
Follow-up
6 months
Every 
9 weeks
Every 
2 months
Follow
-up1
Follow
-Up 3
Follow
-up 2
DLT
evaluation 
period
Part E
Follow-up
Day 1,2,3
Etoposide
Etoposide
3 weeks
Cycle 5
MK-3475
Day 1
Prophylactic Cranial Irradiation 
(Investigator’s choice)
Day 1,2,3
MK-3475
Carboplatin
MK-3475
Carboplatin
MK-3475
Etoposide
Etoposide
MK-3475
Cohort 3
Day 4
Lasting G-CSF (Pegfilgrastim) (Cohort 3 only)
 
 
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3.3
Exploratory Objectives
1)
Objective: To evaluate the presence of anti- pembrolizumab antibodies.
2)
Objective: To evaluate the anti-tumor activity of pembrolizumab alone in advanced 
solid tumors and in combination with platinum-doublet chemotherapy in advanced 
NSCLC or ED-SCLC, or in combination with immunotherapy in subjects with advanced 
NSCLC.
3)
Objective: To evaluate the correlation between PD-L1 expression levels and tumor 
response of pembrolizumab.
4)
Objective: To evaluate the pulmonary radiographic changes and its features for a  
diagnosis of pembrolizumab-induced pneumonitis
5)
Objective: To identify molecular (genomic, metabolic and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic activity, 
and/or the mechanism of action of pembrolizumab and other treatments (Part B, C, D
and E only).
4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3475.
4.1.1
Pharmaceutical and Therapeutic Background
Pembrolizumab is a potent and highly selective humanized monoclonal anti-PD-1 antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1
(programmed cell death-1) and its ligands PD-L1 and PD-L2.  This blockade enhances 
functional activity of the target lymphocytes to facilitate tumor regression and ultimately 
immune rejection.
The PD-1 pathway represents a major immune control switch which may be engaged by 
tumor cells to overcome active T cell immune surveillance.  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 
is an Ig superfamily member which has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [1, 2].  Although healthy 
organs express little (if any) PD-L1, a variety of cancers were demonstrated to express 
abundant levels of this T cell inhibitor.  High expression of PD-L1 on tumor cells (and to a 
lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in 
various cancer types including renal cell carcinoma (RCC), pancreatic carcinoma [3], 
hepatocellular carcinoma [4], ovarian carcinoma [5] and NSCLC [6].  The high expression 
of PD-L1 on tumor cells has been found to correlate with poor prognosis and survival in 
various cancers. The observed correlation of clinical prognosis with PD-L1 expression in 
multiple cancers suggests that the PD-1/PD-L1 pathway plays a critical role in tumor evasion 
 
 
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and is thus an attractive target for therapeutic intervention. Actually in the clinical trial using 
other anti-PD-1 antibody, nivolumab, objective response were observed in subjects with 
NSCLC, melanoma, and other advanced solid tumors and the safety profile does not appear 
to preclude its use [7]. Nivolumab was also well tolerated up to the dose of 20 mg/kg in 
phase I study in Japanese subjects with advanced solid tumors, and showed anti-tumor 
activities in melanoma, CRC, and thyroid carcinoma [8].
Lung cancer has the highest incidence of malignancies in 2008 with more than 1.6 million 
cases in world wide.  Mortality from lung cancer was similar with over 1.4 million deaths 
from lung cancer.  In Japan also, lung cancer is the leading cause of cancer death.
The 
incidence of lung cancer in 2007 is more than 90 thousands cases and around 70 thousands 
patients die annually from lung cancer.  Most lung cancer patients, approximately 85%, have 
NSCLC. Of those, approximately 40%-60% have adenocarcinoma histology; 10%-15%, 
squamous histology; 5%, neuroendocrine histology; and the rest, “not otherwise specified”
[9, 10]. 
Current standard in a first-line for advanced NSCLC except EGFR mutated type and EML4-
ALK is platinum-based doublet therapy.  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 [11]. While platinum doublets
have similar outcomes [12, 13], cisplatin/pemetrexed or carboplatin/paclitaxel have been 
clinically well used mainly on the basis of safety. Carboplatin/pemetrexed is more often used 
in clinical practice in recent years. Median survival months were 10.3 months of NSCLC 
patients who were treated with cisplatin/pemetrexed in a first line therapy.  Key (>5%) grade 
3 or 4 drug-related toxicities were neutropenia, anemia, nausea, vomiting, and fatigue [12].  
The median survival months were 10.5 months of NSCLC patients who were treated with 
carboplatin/pemetrexed in a first therapy. 
Key (>5%) grade 3 or 4 toxicities were
neutropenia, anemia, thrombocytopenia and any hemorrhagic events [14].
A randomized phase III trial compared the efficacy and safety of albumin-bound paclitaxel 
(nab-paclitaxel) plus carboplatin with solvent-based paclitaxel (sb-paclitaxel) plus 
carboplatin in advanced NSCLC. A total of 1,052 untreated subjects with stage IIIB to IV 
NSCLC were randomly assigned 1:1 to receive 100 mg/m2 nab-paclitaxel weekly and 
carboplatin at AUC of 6 Q3W (nab-paclitaxel) or 200 mg/m2 sb-paclitaxel plus carboplatin 
AUC 6 Q3W (sb- paclitaxel). The primary end point was objective response rate (ORR). The 
ORR of nab-paclitaxel arm and sb-paclitaxel arm was 33% v 25%, respectively, (response 
rate ratio, 1.313; 95% CI, 1.082 to 1.593) in overall population and 41% v 24%, respectively,
(response rate ratio, 1.680; 95% CI, 1.271 to 2.221) in patients with squamous histology [15].
When pembrolizumab was administrated in combination with other chemotherapeutic agents 
in mouse models, synergistic antitumor effects were observed (refer to the IB)
Ipilimumab is a fully human monoclonal antibody (IgG1) that blocks CTLA-4, which down-
regulates pathways of T-cell activation but not the distinct mechanisms of PD-1, to promote 
anti-tumor immunity [16]. Ipilimumab is approved in more than 50 countries including Japan 
 
 
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since it was approved in the USA in March, 2011 for the treatment of patients with
unresectable or metastatic melanoma.
As for combination of anti-PD-1 and anti-CTLA-4 antibody, nivolumab in combination with 
ipilimumab was approved in Oct, 2015 for the treatment of patients with BRAF V600 wild-
type unresectable or metastatic melanoma in US. In addition, recent clinical study 
demonstrated that the combination of PD-1 and CTLA-4 blockade has demonstrated durable 
responses with untreated NSCLC patients. A phase I trial was conducted to evaluate the 
safety and efficacy of first-line nivolmab and ipilimumab in advanced NSCLC (CheckMate 
012). A total of 129 untreated subjects with stage IIIB/IV NSCLC were received nivolmab 3 
mg/kg Q2W + ipilimumab 1 mg/kg (Q6W or Q12W) or nivolmab 3 mg/kg Q2W. The 
confirmed ORR (confirmed) was 39% (n=39, nivolmab 3 mg/kg Q2W + ipilimumab 1 mg/kg 
Q6W), 47% (n=38, nivolmab 3 mg/kg Q2W + ipilimumab 1 mg/kg Q12W) and 23 % (n=52, 
nivolmab 3 mg/kg Q2W) respectively. One year OS rate was 69% (95%CI: 52-81%), Not 
Reached, and 73% (95%CI: 59-83%). PFS was 3.9 months (95%CI: 2.6-13.2 months), 8.1
month (95%CI: 5.6-13.6 months) and 3.6 months (95%CI: 2.3-6.6 months), respectively. The 
Efficacy with nivolmab plus ipilimumab was enhanced with increasing PD-L1 expression. 
The rate of grade 3-4 treatment-related AEs was 33%,
37%
and
19% in 
Nivolumab+Ipilimumab (Q6W) arm, Nivolumab+Ipilimumab (Q12W) arm and Nivolumab 
monotherapy arm respectively. There was no treatment-related death [17].
SCLC is characterized by a rapid high growth fraction and a high frequency of somatic 
mutations [18]. SCLC is also characterized early development of widespread metastases. 
Most patients with SCLC present with hematogenous metastases (ED-SCLC); approximately 
one third present with limited disease confined to the chest. SCLC is highly sensitive to 
initial chemotherapy and radiotherapy; however, most patients have recurrent disease and 
eventually die [19, 20].
Current standard in a first-line for ED-SCLC is platinum-based doublet therapy with 
etoposide and irinotecan in Japan.  Small randomized trials and a meta-analysis of 4 
randomized studies compared cisplatin-based versus carboplatin-based regimens in patients 
with SCLC have suggested similar efficacy of cisplatin and carboplatin in patients with 
SCLC [21, 22].
The combination of irinotecan and a platinum agent has provided the greatest challenge to EP. 
Initially, a small phase III trial performed in Japan reported that patients with ED-SCLC who 
were treated with irinotecan plus cisplatin experienced a median survival of 12.8 months 
compared with 9.4 months for patients treated with etoposide with a platinum agent [23]. 
However, 2 subsequent large phase III trials performed in the United States comparing 
irinotecan plus cisplatin with etoposide with a platinum agent failed to show a significant 
difference in response rate or OS between the regimens [24, 25].
Therefore, clinical development of pembrolizumab, an anti-PD-1 antibody, would have a 
great significance in patients with advanced solid tumors including NSCLC/SCLC.
 
 
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4.1.2
Ongoing Clinical Trials
Refer to the latest IB for detailed information of clinical trials of pembrolizumab.
In overseas Phase I/II study (PN021), subject with stage IIIB/IV NSCLC and no prior 
systemic therapy were randomized 1:1 to pembrolizumab 2 or 10 mg/kg Q3W plus 
carboplatin/ paclitaxel (cohort A) or carboplatin/pemetrexed (cohort C) in phase I cohort. 
Subjects with IIIB/IV NSCLC who have failed previous treatment were randomized to 
pembrolizumab 2 or 10 mg/kg Q3W plus ipilimumab 1 mg/kg or 3 mg/kg (cohort D and H).
Twenty-five subjects (pembrolizumab 2 mg/kg; n=13 and pembrolizumab 10 mg/kg; n=12) 
in cohort A, 24 subject (2 mg/kg; n=12 and 10 mg/kg; n=12) in cohort C, and 51 subjects 
(pembrolizumab 2 mg/kg/ipilimumab 1 mg/kg; n=45, pembrolizumab 10 mg/kg/ipilimumab 
3 mg/kg; n=3, pembrolizumab 10 mg/kg/ipilimumab 1 mg/kg; n=3) in cohort D and H 
received study therapy. One DLT was reported (Grade 3 rash in cohort C, pembrolizumab 10 
mg/kg).  
Grade 3 or 4 toxicities in part A were anemia and febrile neutropenia (n=2 each), fatigue, 
hypertension, Infectious pleural effusion, leukopenia, neutropenia, rash, urticaria and white 
blood cell count decreased (n=1 each). Grade 3 or 4 toxicities in part C were AST increased 
(n = 3), ALT increased (n=2), anemia, atrial fibrillation, colitis, diarrhea, drug eruption and 
hyponatremia (n=1 each). Grade 3 or 4 toxicities reported by in cohort D and H were 
syncope and diarrhea (n=3 each), dyspnea, fatigue, hypokalemia, pneumonia (n=2 each), 
diabetic ketoacidosis, large intestine perforation, pancytopenia, pericardial effusion, sepsis, 
adrenal insufficiency, ALT increased, AST increased, back pain, cardiac failure, cerebral 
ischemia, colitis, constipation, drug eruption, gastroenteritis, hepatocellular injury, 
hypoglycemia, hyponatremia, hypoxia, noncardiac chest pain, pneumonitis, pulmonary 
embolism, rash maculopapular, rash pruritic, retroperitoneal hematoma, intestinal 
perforation, lymphocyte count decreased (n=1 each). The rate of grade 3-5 treatment-related 
AEs was 49%, 33% and 67% in MK-3475 2 mg/kg + ipilimumab1 mg/kg arm, MK-3475 10 
mg/kg + ipilimumab 3 mg/kg arm and MK-3475 10 mg/kg + ipilimumab1 mg/kg arm 
respectively. One treatment-related death (pancreatitis) was reported (MK-3475 2 mg/kg +
ipilimumab 1 mg/kg).
ORR (confirmed and unconfirmed) was 28 % (n=7: 2 mg/kg; n=5 and 10 mg/kg; n=2) in 
cohort A and 58%  (n=14: 2 mg/kg; n=5 and 10 mg/kg; n=9) in cohort C. Disease control rate 
(DCR) was 84% (n=21: 2 mg/kg; n=12 and 10 mg/kg; n=9) in A and 100% (n=24: 2 mg/kg; 
n=12 and 10 mg/kg; n=12) in cohort C. The efficacy results are encouraging a flat dose–
exposure relationship since no difference was observed across pembrolizumab dose level in 
each cohort. Based on the promising ORR observed for pembrolizumab in combination with 
carboplatin and pemetrexed, this combination is being further explored - in a prespecified 
phase 2 cohort of PN021.
In cohort D and H, ORR was 25% and DCR was 64% in overall population (n=44, MK-3475 
2 mg/kg/ipilimumab 1 mg/kg) and ORR was 20% and DCR was 70% in PD-L1 negative 
population (n=20, MK-3475 2 mg/kg/ipilimumab 1 mg/kg).
 
 
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An ongoing overseas phase 1b/2 study (KEYNOTE-026) is exploring the combination of 
pembrolizumab with carboplatin and nab-paclitaxel.
For chemotherapy-naïve patients with ED-SCLC, ongoing overseas Phase II study 
(REACTION, ClinicalTrials.gov Identifier: NCT02580994) is exploring the combination of 
pembrolizumab with cisplatin/carboplatin and etoposide. 
In ongoing international multicohort phase Ib studies [KEYNOTE-028 (KN-028) and 
KEYNOTE-158 (KN-158)] are exploring the mono-therapy of pembrolizumab for relapsed 
SCLC patients (ClinicalTrials.gov Identifier: NCT02054806 and NCT02628067).  KN-028 is 
a study of pembrolizumab in patients with PD-L1 positive advanced solid tumors. 
Preliminary data of KN-028 was released in ASCO 2015 annual meeting; pembrolizumab 
monotherapy is generally well tolerated and has promising antitumor activity in patients with 
PD-L1 positive SCLC who have progressed on prior platinum-based therapy. ORR was 35%. 
[26].  
4.2
Rationale
4.2.1
Rationale for the Trial and Selected Subject Population
As described in 4.1 Background, non-clinical and clinical data obtained so far supports 
clinical development of pembrolizumab in Japan.  This phase I study is the first in Japanese 
study using pembrolizumab. In the Part A (monotherapy), subjects with advanced solid 
tumors who have failed established standard medical anti-cancer therapies for a given tumor 
type or have been intolerant to such a therapy will be selected according to the “Guideline for 
clinical evaluation method of anti-malignant tumor agents [27]”.  In Part B, C and D
(combination), the selected subject population is chemotherapy-naïve patients with advanced
NSCLC. In Part E (combination), the selected subject population is chemotherapy-naïve 
patients with ED-SCLC. NSCLC and SCLC are considered to be one of the promising 
indications of potential tumors (refer to 4.1.1 Pharmaceutical and Therapeutic Background). 
Given the safety profile of pembrolizumab observed thus far, it is not believed that there will 
be considerable overlapping toxicities with standard of care cytotoxic chemotherapy. In Part 
B, C and E of this study, pembrolizumab will be added to common platinum-containing 
doublet chemotherapy in chemotherapy-naïve patients with advanced NSCLC/ED-SCLC
based on ethical considerations for the subjects.
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.
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
 
 
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4.2.2
Rationale for Dose Selection/Regimen
The dosing regimens of pembrolizumab in this study were mainly determined based on 
results from the overseas phase I study (PN001) in subjects with advanced solid tumors.  No 
DLTs were observed at 1 mg/kg (n=4), 3 mg/kg (n=3), and 10 mg/kg (n=10) of 
pembrolizumab in the dose-escalation part (Part A) of the study.  Up to 10 mg/kg of 
pembrolizumab was well tolerated in non-Japanese subjects.  In the study, pembrolizumab
showed evidence of target engagement and objective evidence of tumor size reduction at all 
dose levels.  Therefore, translational PK-PD evaluation that a surrogate PD-1 antibody was 
dosed to a syngeneic mouse tumor model and tumor growth was determined together with 
blood and tissue sampling for PK and receptor occupancy was conducted. This model was 
then updated with human relevant parameters on human PK from PN001, MK-3475 affinity 
and melanoma growth patterns to perform in silico predictions.  The predictions concluded 
that the lowest dose of pembrolizumab with the potential to be equivalent to 10 mg/kg of 
pembrolizumab was 2 mg/kg for subjects with melanoma.  Based on these results, 
randomized phase II and III studies are planned to evaluate the efficacy and safety profiles of 
2 mg/kg and 10 mg/kg of pembrolizumab in melanoma and NSCLC.
This study is the first clinical trial of MK-3475 in Japan.  Based on the above results, 
2 mg/kg of pembrolizumab was selected as the initial dose considering safety and efficacy in 
Japanese subjects in Part A. After confirming the safety and tolerability of 2 mg/kg, the 
safety and tolerability of 10 mg/kg will be evaluated in Part A.
The rationale for further exploration of lower doses of pembrolizumab in solid tumors is 
based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or10 
mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab 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, indication or tumor type on distribution behavior 
of pembrolizumab (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. In addition, 
preliminary data from 45 previously treated, advanced or metastatic NSCLC patients treated 
at the 2 mg/kg Q3W dose/schedule indicates a 20% BOR by RECIST (35% by irRC). This is 
in comparison to the 22.4% ORR observed at the 10 mg/kg Q2W, suggesting lack of dose 
responsiveness and additional justification of inclusion of a low dose of pembrolizumab in 
Part B, C, D and E.
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally similar to
those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma and NSCLC as associated with 
maximal efficacy response and 3) will maintain individual patients exposure in the e 
exposure range established in melanoma and NSCLC that are well tolerated and safe.
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity 
 
 
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in the logistical chain at treatment facilities and reduce wastage. Thus, 200 mg Q3W was 
selected in Part B, C, D and E in this study.
The PK profile obtained in the overseas phase I study (PN001) shows slow systemic 
clearance, limited volume of distribution, and a dose related increase in exposure.  The long 
half-life (t1/2) (13-21 days) supports dosing intervals of every 2 weeks (Q2W) and every 3 
weeks (Q3W).
The dose of ipilimumab (1 mg/kg Q6W) was based upon KEYNOTE-021(cohort D and H)
and CheckMate 012 study. The results of these studies are described in section 4.1.1 and 
4.1.2.
4.2.3
Rationale for Endpoints
4.2.3.1
Safety Endpoints
The safety primary endpoint in this study is the incidence of DLTs observed in the DLT 
evaluation period in Japanese subjects according to the “Guideline for clinical evaluation 
method of anti-malignant tumor agents [27]”. Adverse events and laboratory tests values 
observed in this study are also safety endpoints.  In addition to general laboratory tests, 
immune laboratory test will be evaluated considering the mode of action of pembrolizumab.  
Since pneumonitis has been previously reported in clinical studies of anti-PD-1 antibodies 
including pembrolizumab, pulmonary radiographic changes and its features will be evaluated 
by investigators or their designees, and an independent radiologist from a potential risk of 
pneumonitis.
4.2.3.2
Efficacy Endpoints
The anti-tumor activity will be evaluated as an efficacy endpoints based on imaging (CT or 
MRI), and tumor markers evaluations (as appropriate for a given tumor type).  The immune 
related Response Criteria (irRC) (Part A only, Section 12.6), irRECIST (Part B, C, D and E) 
and RECIST 1.1 (Section 12.5) will be applied for evaluation of tumor response. irRC is a 
recently published set of guidelines proposed for immunotherapies in solid tumors [28]. 
RECIST 1.1 will also be used by the local site for treatment decisions for the study. However 
RECIST 1.1 will be adapted to account for the unique tumor response profile seen with 
immunotherapies such as pembrolizumab. Immunotherapeutic agents such as pembrolizumab
may produce antitumor effects by potentiating endogenous cancer-specific immune 
responses which may be functionally anergic. The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. Standard RECIST criteria may not provide a complete response 
assessment of immunotherapeutic agents such as pembrolizumab. Therefore, irRC will be 
used in Part A, and RECIST 1.1 will be used in Part B, C, D and E with the following 
adaptation, outlined in Section 7.1.3.4 termed irRECIST. When feasible, subjects should not 
be discontinued until progression is confirmed. This allowance to continue treatment despite 
initial radiologic progression takes into account the observation that some subjects can have a 
 
 
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transient tumor flare in the first few months after the start of immunotherapy, but with 
subsequent disease response.
Tumor response will also be evaluated using tumor volumetric analysis at the central imaging 
vendor in Part A.
4.2.3.3
Pharmacokinetic Endpoints
Serum samples will be obtained to measure pharmacokinetics of pembrolizumab alone and in 
combination with platinum-doublet chemotherapy or immunotherapy in Japanese subjects 
based on the “Guide line for clinical evaluation methods of anti-malignant tumor agents” 
[27].  As pharmacokinetics endpoints, pharmacokinetic parameters (AUC0-28days, Cmax, Tmax, 
Ctrough, t1/2, etc.) of pembrolizumab will be evaluated. In part B, C, D and E, pharmacokinetic 
parameters (Cmax, Tmax, Ctrough, etc.) of pembrolizumab will be evaluated.
4.2.3.4
Immunogenicity Endpoints
Serum samples will be obtained to evaluate the presence of anti- pembrolizumab antibodies 
in Japanese subjects.  In general, human anti-humanized antibodies may have an effect on 
study results such as the pharmacokinetics, efficacy and safety of pembrolizumab though it is 
unknown for pembrolizumab.
4.2.3.5
Planned Exploratory Biomarker Research
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 by 
immunohistochemistry (IHC) in archival tumors or biopsy samples.  PD-L1 is a ligand for 
PD-1 and pembrolizumab attempts to disrupt the interaction of two 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 renal cell 
carcinoma, pancreatic carcinoma, hepatocellular carcinoma, ovarian carcinoma, and NSCLC.
Additional biomarker research to identify factors important for pembrolizumab (MK-3475) 
therapy may also be pursued.  For example, tumor samples from this study may undergo 
proteomic, genomic, metabolomics and transcriptional analyses.  Additional research may 
evaluate factors important for predicting responsiveness or resistance to pembrolizumab 
therapy and other immunologic targets.
Assays may include but are not be limited to:
Immunohistochemistry
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab (MK-3475).  Other biomarkers contributing to the PD-1/PD-L1 axis may 
also be explored.
 
 
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Transcriptional Analyses
Messenger RNA (mRNA) expression profiling in archival material will be completed to 
assess expression of approximately 700 genes and attempt to define a gene set critical for 
clinical response to pembrolizumab (MK-3475).  The hypothesis to be tested is that 
pembrolizumab (MK-3475) induces responses in tumors that reflect an inflamed/ immune 
phenotype based on gene expression signatures capturing PD-L1 and interferon-gamma 
transcriptional programs.  Global profiling will also be pursued.  Expression of individual 
genes related to the immune system may also be evaluated such as immune signatures and 
critical cytokines (e.g., IL-10).  
Proteomic analysis
Tissue samples can be subjected to proteomic profiling studies using a variety of platforms 
that could include but are not limited to immunoassay, liquid chromatography/mass 
spectrometry.  This approach could identify novel protein biomarkers that could aid in patient 
selection for pembrolizumab (MK-3475) therapy.
Gene Analyses
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to define certain tumor types at the genetic level as being 
‘hypermutated’ or it can detect the presence of specific t-cell clones within the tumor 
microenvironment.  There is a potential that this hypermutated state and the detection of 
increased T-cell clonality may correlate with response to pembrolizumab therapy, and/or that 
the converse, ‘hypomutated’ state or lack of t-cells clones may correlate with non-response.
Planned Genetic Analysis 
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
4.2.3.6
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 analyses.  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 
 
 
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pharmacogenetics 
(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, and/or to ensure that subjects 
receive the correct dose of the correct drug at the correct time.  The details of this Future 
Biomedical Research sub-trial are presented in Section 12.2, Collection and Management of 
Specimens for Future Biomedical Research.  Additional informational material for 
institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is 
provided in Section 12.3.
5.0 METHODOLOGY
5.1
Entry Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with advanced solid tumor or advanced NSCLC or ED-SCLC of at 
least 20 years of age will be enrolled in this trial.
5.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Meet the following corresponding requirements for the part of the study they will 
enroll into;
In Part A (monotherapy), subjects must have a histological or cytological diagnosis of
solid tumor, progressive metastatic disease, or progressive locally advanced disease 
not amenable to local therapy:

Subjects must have failed established standard medical anti-cancer therapies for a
given tumor type or have been intolerant to such therapy, or in the opinion of the
Investigator have been considered ineligible for a particular form of standard
therapy on medical grounds.
In Part B, C and D (combination), subjects must have a histologically-confirmed or 
cytologically confirmed diagnosis of NSCLC, for stage IIIB/IV.

(This criterion is applicable to Part C) Has a histological or cytological diagnosis 
of squamous cancer.

Subject must be naïve to systemic therapy.
 
 
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
Subject who had disease progression >6 months after completing adjuvant 
therapy for stage I -IIIA disease are eligible, as long as no systemic therapy was 
given for the recurrent disease.

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.
In Part E (combination), subjects must have a histologically-confirmed or 
cytologically confirmed diagnosis of SCLC for ED stage; American Joint Committee 
on Cancer (AJCC) (7th edition) Stage IV (T any, N any, M 1a/b), or T3-4 due to 
multiple lung nodules that are too extensive.

Subject must be naïve to systemic therapy. 

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.
2. Be male or female and ≥20 years of age on day of signing informed consent.
3. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Status (Section 12.4).
4. Have adequate organ function as indicated by the following laboratory 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– without transfusion
Renal
Serum creatinine 
or calculated creatinine clearance a
≤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
≤ 1.5 X ULN 
OR
Direct bilirubin ≤ ULN for subjects with total bilirubin 
levels >1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases
Endocrine
Adrenocorticotropic hormone (ACTH) level b
Within normal limits
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
 
 
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System
Laboratory Value
a Creatinine clearance (Ccr) should be calculated per institutional standard or from one of the following 
numerical formulas:
Men: Ccr (mL/min) = {(140–age) x Body weight (kg)}/{72 x Serum Creatinine (mg/dL)}
Women: Ccr (mL/min) = {(140–age) x Body weight (kg) x 0.85}/{72 x Serum Creatinin (mg/dL)}
Ccr (mL/min) = {Urine Creatinin (mg/dL)}x{Urine volume (mL/day)/1440 (min/day)} x{1.73 / body surface 
area (m2)}/ Serum Creatine (mg/dL)
b ACTH: Part D only
5. (This criterion is applicable to Part B, C and D) Have resolution of toxic effect(s) of 
the most recent prior antineoplastic chemotherapy (such as neoadjuvant/adjuvant 
therapy) 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.
6. (This criterion is applicable to Part B and C only) Have provided a formalin fixed 
tumor tissue sample from a biopsy of a tumor lesion from a site not previously 
irradiated to assess for PD-L1 status. Fine needle aspirates, Endobronchial 
Ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or cell blocks are 
not acceptable. Needle or excisional biopsies, or resected tissue is required.
7. Female subject 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.
8. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an
adequate  method of contraception as outlined in Section 5.7.2 – Contraception, for
the course of the study 120 days after the last dose of study medication and through
180 days after last dose of chemotherapeutic agents.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
9. Male subjects of childbearing potential (Section 5.7.2) 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 
through 180 days after last dose of chemotherapeutic agents.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
10. 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.
 
 
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5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has had the following cancer therapy within 4 weeks (2 weeks in Part E) (2 weeks for 
palliative radiotherapy and kinase inhibitors) prior to the first dose of study therapy, 
or who has not recovered from the adverse events due to previous agents 
administered more than 4 weeks prior to the first dose of study therapy.  If the subject 
has residual toxicity from prior treatment, toxicity must be ≤ Grade 1 or baseline,
except for alopecia.
Part A: Chemotherapy, radiation therapy, biological therapy or kinase inhibitors
Part B, C, D and E: Radiation therapy
2. (This criterion is applicable to Part B only) Has a histological diagnosis of squamous 
cancer.
3. Is currently participating or has participated in a study of an investigational agent or 
using an investigational device within 30 days of administration of pembrolizumab.
4. Is expected to require any other form of antineoplastic therapy while on study 
(including maintenance therapy with another agent for NSCLC or SCLC).
5. Is on chronic systemic steroid therapy within two weeks prior to the first dose of trial 
treatment or on any other form of immunosuppressive medication.
6. Has a history of acute diverticulitis, intra-abdominal abscess, GI obstruction, 
abdominal carcinomatosis which are known risks factors for bowel perforation.
7. (This criterion is applicable to Part B, C, D and E only) Has a known history of a 
hematologic malignancy, primary brain tumor or sarcoma, or of another primary solid 
tumor, unless the subject has undergone potentially curative therapy with no evidence 
of that disease for 5 years.
Note: The time requirement for no evidence of disease for 5 years does not apply to the 
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 cell 
carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the 
skin, in situ cervical cancer, or other in situ cancers.
8. 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 8 (in Part A) or 4 (in Part B, C and D)
or 2 (in Part E) 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 confirmed using MRI or CT images prior to 
the first dose of study medication by the investigator.  Subject with asymptomatic 
 
 
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brain metastases (ie., no neurological symptoms, norequirements for corticosteroids, 
and no lesion > 1.5 cm) may participate but will require regular imaging of the brain 
as a site of disease.
9. (This criterion is applicable to Part C only) Has pre-existing peripheral neuropathy 
that is ≥ Grade 2 by CTCAE version 4 criteria.
10. Previously had a hypersensitivity reaction to the study drug substance or another mAb.
11. 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.
12. Has prior therapy with an anti-PD-1, PD-L1, or PD-L2 agent or an antibody targeting 
other immuno-regulatory receptors or mechanisms.

Examples of such antibodies include (but are not limited to) antibodies against 
IDO, IL-2R, GITR, CD137, CTLA-4.
13. Has received a live-virus vaccination within 4 weeks of planned treatment start.  
Seasonal flu vaccines that do not contain live virus are permitted.
14. Has an active infection requiring systemic intravenous therapy.
15. Has interstitial lung disease detected by chest CT, or a history of pneumonitis that 
required oral or intravenous glucocorticoids to assist with management.  
Lymphangitic spread of the NSCLC is not exclusionary.
16. Is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), Hepatitis 
B (HBsAg reactive) or Hepatitis C [HCV RNA (qualitative) is detected].
17. 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.
18. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
19. Is, at the time of signing informed consent, known to be actively abusing alcohol or 
drug.
20. Has symptomatic ascites or pleural effusion. A subject who is clinically stable 
following treatment for these conditions (including therapeutic thoraco-
or 
paracentesis) is eligible.
 
 
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21. Is pregnant or breast-feeding, or expecting to conceive or father children within the 
projected duration of the study, starting with screening visit through 120 days after 
the last dose of trial treatment and through 180 days after last dose of 
chemotherapeutic agents. Subjects who stop breast-feeding prior to initiation of trial 
treatment and not expecting to resume of breast-feeding will not be excluded from the 
study.
22. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this trial, 
unless prospective IRB approval (by chair or designee) is given allowing exception to 
this criterion for a specific subject.
5.2
Trial Treatments
Trial treatments to be used in this trial are outlined below in Table 1.
Table 1
Trial Treatment
Drug, Biologic, 
Device, etc.
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Part A, Dose level 1 (n= 3 or 6)
Pembrolizumab
2 mg/kg
Q2W‡
IV infusion
(30 min)
Day 1 of each cycle
Experimental
Part A, Dose level 2 (n= 3 or 6)
MK-3475
10 mg/kg
Q2W‡
IV infusion
(30 min)
Day 1 of each cycle
Experimental
Part B*, Cohort 1 (n= 6-9)
Pembrolizumab
200 mg
Q3W
IV infusion
(30 min)
Day 1 of each cycle§
Experimental
Cisplatin
75 mg/m2
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Pemetrexed
500 mg/m2
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Part B*, Cohort 2  (n= 6-9)
Pembrolizumab
200 mg
Q3W
IV infusion
(30 min)
Day 1 of each cycle§
Experimental
Carboplatin
AUC 
of 
5
mg/mL/min
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Pemetrexed
500 mg/m2
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Part C**, Cohort 1 (n= 6-9)
Pembrolizumab
200 mg
Q3W
IV infusion
(30 min)
Day 1 of each cycle§
Experimental
Carboplatin
AUC 
of 
6
mg/mL/min
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Paclitaxel
200 mg/m2
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
 
 
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Drug, Biologic, 
Device, etc.
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Part C**, Cohort 2  (n= 6-9)
Pembrolizumab
200 mg
Q3W
IV infusion
(30 min)
Day 1 of each cycle§
Experimental
Carboplatin
AUC 
of 
6
mg/mL/min
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Nab-paclitaxel
100 mg/m2
Q1W
IV infusion†
Day 1, 8, 15 of each 
cycle
Standard of 
care
Part D***, (n=6-9)
Pembrorizumab
200 mg
Q3W
IV infusion
(30 min)
Day 1 and 22 of each 
cycle||
Experimental
Ipilimumab¶
1mg/kg
Q6W
IV infusion
(90 min)
Day 1 of each cycle ||
Experimental
Part E****, Cohort 1 (n=6-9)
Pembrorizumab
200 mg
Q3W
IV infusion
(30 min)
Day 1 of each cycle§
Experimental
Cisplatin
75 mg/ m2
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Etoposide
100 mg/m2
Q3W
IV infusion†
Day 1, 2, 3 of each 
cycle
Standard of 
care
Part E****, Cohort 2 (n=6-9)
Pembrorizumab
200 mg
Q3W
IV infusion
(30 min)
Day 1 of each cycle§
Experimental
Carboplatin
AUC 
of 
5
mg/mL/min
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Etoposide
100 mg/m2
Q3W
IV infusion†
Day 1, 2, 3 of each 
cycle
Standard of 
care
Part E****, Cohort 3 (n=3-9)
Pembrorizumab
200 mg
Q3W
IV infusion
(30 min)
Day 1 of each cycle§
Experimental
Cisplatin
75 mg/ m2
Q3W
IV infusion†
Day 1 of each cycle
Standard of 
care
Etoposide
100 mg/m2
Q3W
IV infusion†
Day 1, 2, 3 of each 
cycle
Standard of 
care
Pegfilgrastim
3.6 mg
one time
Subcutaneous
Injection
Day 4 of  cycle 1††
Concomitant 
medication
* In Part B, pemetrexed may be administered every 3 weeks after finishing the treatment of combination therapy for 4 
cycles by investigation’s judgment as clinically significant.
**
In Part C, pembrolizumab will be administered every 3 weeks after finishing the treatment of combination therapy 
for 4 cycles.
*** In Part D, pembrolizumab and ipilimumab will be administered up to 18 cycles of ipilimumab (35 times of 
pembrolizumab).
**** In Part E, pembrolizumab will be administered every 3 weeks after finishing the treatment of combination therapy 
for 4 cycles.
† Infusion of combination regimens and pre-medications will follow local institutional practice.
‡ The doing interval is 4 weeks for Cycle 1 only
§ Pembrolizumab to be administered prior to chemotherapy.
|| Pembrolizumab to be administered prior to ipilimumab.
¶ ipilimumab has not been approved for NSCLC.
†† Use of Pegfilgrastim after cycle 2 and later is in section 5.5.1.
 
 
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5.2.1
Dose Selection/Tolerability Evaluation Rules/Definition of Dose-Limiting 
Toxicity/Modification
5.2.1.1
Dose Selection
In Part A, the dose amount required to prepare the pembrolizumab infusion solution will be 
based on the dose level (2 mg/kg or 10 mg/kg) and the subject’s weight in kilograms (kg).  If 
a subject’s weight at screening does not fluctuate by more than 10%, this weight can be used 
to calculate dose.
In Part B, C, D and E, a fixed dose of 200 mg of pembrolizumab will be used. A dose amount 
required to prepare the cisplatin (75 mg/m2), pemetrexed (500 mg/m2), carboplatin (AUC of 
5, for Part B and E, or 6, for Part C, mg/mL/min), paclitaxel (200 mg/m2) , nab-paclitaxel 
(100 mg/m2), ipilimumab (1 mg/kg) or etoposide (100 mg/m2) infusion solution will be based 
on the standard practice in each site.
Details on the dose calculation, preparation and administration are provided in the Pharmacy
Manual.
(Part E Cohort 3 only) Dose of lasting G-CSF (pegfilgrastim) 3.6 mg (via subcutaneous
injection) is decided by a regulatory approved dose following the local prescribing 
information. Preparation and administration is also following the local prescribing 
information.
5.2.1.2
Tolerability Evaluation Rules
As a general rule, all of the study procedures in the DLT evaluation period will be performed 
under hospitalization.
Part A (Monotherapy) – 3+3 design
DLTs observed during the DLT evaluation period (the first 4 weeks after initiation of study 
treatment) will be used to determine escalation to the next dose level and the tolerability of 
the dose level using a TPI (toxicity profile interval) design [29] (target DLT rate: 20%).  The 
dose escalation/tolerability evaluation rules (Table 2) are as follows:
Dose level 1 (2 mg/kg)

An initial cohort of 3 subjects is enrolled.

If 0/3 subjects develops a DLT, the doles level 1 will be considered tolerated, 
then escalation to the dose level 2 (10 mg/kg) will occur.

If 1/3 subjects develops a DLT, other 3 subjects will be enrolled at the dose 
level 1.

If ≤1/6 subjects develop a DLT then the dose level 1 is considered to be 
tolerated, then escalation to the dose level 2 (10 mg/kg) will occur.
 
 
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
If ≥2/6 subjects develop a DLT, the dose level 1 will be considered to be 
not tolerated.

If ≥2/3 subjects develop a DLT, the dose level 1 will be considered to be not 
tolerated.
Dose level 2 (10 mg/kg)

An initial cohort of 3 subjects is enrolled.

If 0/3 subjects develops a DLT, the doles level 2 will be considered tolerated. 
Other 3 subjects will be enrolled at the dose level 2.

If 1/3 subjects develops a DLT, other 3 subjects will be enrolled at the dose 
level 2.

If ≤1/6 subjects develop a DLT then the dose level 2 is considered to be 
tolerated.

If ≥2/6 subjects develop a DLT, the dose level 2 will be considered to be 
not tolerated.

If ≥2/3 subjects develop a DLT, the dose level 2 will be considered to be not 
tolerated.
Table 2
Dose Escalation/Tolerability Evaluation Rules in Part A
Number of subjects treated at current dose
Number of toxicities
3
6
0
E
E
1
S
E
2
DU
D
3
DU
DU
4
DU
5
DU
6
DU
E = Escalate to the next higher dose (do not escalate from 
Dose level 2)
S = Stay at the current dose
D = De-escalate to the next lower dose (do not de-escalate 
from Dose level 1)
DU = The current dose is unacceptably toxic, no more 
subjects to be treated at this dose
 
 
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Part B, C, D and E (Combination)
DLTs observed during the DLT evaluation period [the first 3 weeks after initiation of study 
treatment (part B, C and E), the first 6 weeks after initiation of study treatment (Part D)] will 
be used to determine the tolerability of the combination regimen using a TPI design (target 
DLT rate: 30%). The tolerability evaluation rules (Table 3) are as follows:

Six to 9 subjects are enrolled based on TPI design in the combination regimen; (Six 
to 9 subjects each for Cohort 1 and Cohort 2 of part B, C and E, and 3 to 9 subjects 
are enrolled based on TPI design in part E cohort 3) (respectively parallel enrollment 
is allowed).

If 0/3 subjects or ≤2/6 subjects or ≤4/9 subjects develop a DLT at the 
combination regimen, then it is considered to be tolerated.

If ≥3/6 or ≥5/9 subjects develop a DLT, the regimen will be considered to be 
not tolerated.
Table 3
Dose Evaluation Rules in Part B, C, D and E
Number of subjects treated at current dose
Number of 
toxicities
3
6
9
0
E
E
E
1
A
E
E
2
DU
E
E
3
DU
DU
E
4
DU
E
5
DU
DU
6
DU
DU
7
DU
8
DU
9
DU
E = Evaluable
A = Add further 3 patients
DU = The current dose is unacceptably toxic, no more subjects to be treated at 
this dose
 
 
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5.2.1.3
Definition of Dose-Limiting Toxicity
All toxicities will be graded using National Cancer Institute (NCI) CTCAE Version 4.0. 
The occurrence of any of the following toxicities during the DLT evaluation period will be 
considered a DLT, if judged by the Investigator to be related to study drug administration:
1. Grade 4 neutropenia lasting >7 days.
2. Grade 3 and Grade 4 febrile neutropenia:

Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C or a sustained temperature of ≥38 degrees C for more than one 
hour

Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C or a sustained temperature of ≥38 degrees C for more than one 
hour, with life-threatening consequences and urgent intervention indicated.
3. Grade 4 thrombocytopenia (<25,000/mm3)
4. Grade 4 anemia
5. Grade 4 non-hematologic toxicity (not laboratory)
6. Grade 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal 
supportive care.
7. Any Grade 3 non-hematologic laboratory value if:

M
edical intervention is required to treat the subject, or

The abnormality persists for >7 days.
8.
(Part D only) Missing the 2nd dose of pembrolizumab (Cycle1 Day 22) due to drug-
related adverse event.
If a subject experiences a DLT in DLT evaluation period, the subject may be discontinued
from the study or refer to Section 5.2.1.4 in detail.
The SPONSOR and the investigator will decide the appropriateness of the DLT, and 
enrollment of additional subjects in consultation with the Efficacy and Safety Evaluation 
Committee as needed.
 
 
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5.2.1.4
Dose Modification
Pembrolizumab
Dose reduction or dose increase of pembrolizumab will not be permitted in individual 
subjects.
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab, administration of corticosteroids and/or other 
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, 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 4.
 
 
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Table 4
Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot 
be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper

Monitor subjects for signs and symptoms of 
pneumonitis

Evaluate subjects with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or recurrent 
grade 2
Permanently 
discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer corticosteroids 
(initial dose of 1-2mg/kg 
prednisone or equivalent) 
followed by taper

Monitor subjects for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without 
fever) and of bowel perforation (ie, 
peritoneal signs and ileus).

Subjects with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Subjects with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST / ALT elevation 
or Increased Bilirubin
Grade 2
Withhold

Administer corticosteroids 
(initial dose of 0.5- 1mg/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 1-2mg/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 subjects with 
T1DM 

Administer anti-
hyperglycemic in subjects 
with hyperglycemia 

Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
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 
liothyroinine) per standard 
of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and renal 
dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2mg/kg or 
equivalent) followed by 
taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
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
 
 
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Immune-related AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
All Other immune-
related AEs
Grade 3, or intolerable/ 
persistent Grade 2
Withhold

Based on severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology or exclude other causes
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 subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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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 5. 
Table 5
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption 
not 
indicated; 
intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires 
therapy 
or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(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 
pembrolizumab 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 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. 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.
(In Part E only) If PCI which is specified in the study design is conducted, pembrolizumab
dosing should be postponed during the PCI conducted period.  At least 2 weeks following 
completion of PCI, patients will continue 200 mg pembrolizumab Q3W as maintenance 
therapy.
Chemotherapy regimen 
(For Part B, C and E only) Dose modification of cytotoxic chemotherapy will conform to the 
site’s standards procedures.  Dose modification of chemotherapy will not be permitted in 
DLT evaluation period.
(For Part B only) Subject has the option, in the event of toxicity, to change the choice of 
platinum (cisplatin and carboplatin) administered.
 
 
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Immunotherapy regimen 
(For Part D only) Dose reduction or dose increase of Ipilimumab will not be permitted in 
individual subjects. If a toxicity is observed with pembrolizumab in combination with 
ipilimumab and requires a dose modification, pembrolizumab and ipilimumab should be 
withheld and toxicities treated as per criteria outlined in Table 4. Subjects who experience an 
unacceptable toxicity that is attributed to combination therapy and not pembrolizumab 
monotherapy in the opinion of the investigator may permanently discontinue ipilimumab and 
continue with pembrolizumab as monotherapy, upon improvement of toxicity as per Table 4.
Ipilimumab may not be continued under any circumstances if pembrolizumab is discontinued 
or while pembrolizumab is held.
5.2.2
Timing of Dose Administration
Trial treatment can be administerd+/- 3 days of the targeted Day 1 for each cycle due to 
administrative reasons only.
The specific time of trial treatment infusion (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.
Pembrolizumab
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Subjects enrolled in the Parts A, B, C and E will receive pembrolizumab at the following
timing:
1. Pembrolizumab will be administered on Day 1 of each cycle as a 30-minute IV 
infusion (25-40 min).
Subjects enrolled in the Parts D will receive pembrolizumab at the following timing:
1. Pembrolizumab will be administered on Day 1 and Day 22 of each cycle up to 35 
times as a 30-minute IV infusion (25-40 min).
In Part B, C and E, pembrolizumab will be administered at least 30 minutes prior to 
premedication for the following chemotherapies.
Trial treatmentcan be administerd+/- 3 days of the targeted Day 1 for each cycle due to 
administrative reasons only.
The specific time of trial treatment infusion (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.
 
 
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Combination Regimens for Part B
All subjects should receive the appropriate pre-medications per site’s standard practice.
Subjects enrolled in Cohort 1 will receive cisplatin/pemetrexed at the following timing:
1. Pemetrexed 500 mg/m2 will be administered as an IV infusion on Day 1 of each cycle 
(every 3 weeks) up to 4 cycles.  Subjects should also receive appropriate vitamin 
supplementation of vitamin B12 and folic acid.
2. Cisplatin 75 mg/m2 will be administered as an IV infusion after Pemetrexed infusion 
on Day 1 of each cycle (every 3 weeks) up to 4 cycles.
Subjects enrolled in the Cohort 2 will receive carboplatin/pemetrexed at the following
timing:
1. Pemetrexed 500 mg/m2 will be administered as an IV infusion on Day 1 of each cycle 
(every 3 weeks) up to 4 cycles.  Subjects should also receive appropriate vitamin 
supplementation of vitamin B12 and folic acid.
2. Carboplatin AUC of 5 mg/mL/min will be administered as an IV infusion after 
pemetrexed infusion on Day 1 of each cycle (every 3 weeks) up to 4 cycles.
Pemetrexed 500 mg/m2 may be administered as an IV infusion on Day 1 of each cycle (3 
weeks) with pembrolizumab after finishing the treatment of combination therapy for 4 cycles
by investigation’s judgment as clinically significant in both cohorts 1 and 2.   Subjects should 
also receive appropriate vitamin supplementation of vitamin B12 and folic acid.
Combination Regimens for Part C
All subjects should receive the appropriate pre-medications per site’s standard practice.
Subjects enrolled in Cohort 1 will receive carboplatin/paclitaxel at the following timing:
1.
Paclitaxel 200 mg/m2 will be administered as an IV infusion on Day 1 of each cycle 
(every 3 weeks) up to 4 cycles. Paclitaxel should be completely administered before 
initiating carboplatin dose.
2.
Carboplatin AUC of 6 mg/mL/min will be administered as an IV infusion after 
paclitaxel infusion on Day 1 of each cycle (every 3 weeks) up to 4 cycles.
Subjects enrolled in the Cohort 2 will receive carboplatin/nab-paclitaxel at the following 
timing:
1.
Nab-paclitaxel 100 mg/m2 will be administered as an IV infusion on Day 1, 8 and 15 
of each cycle (every 3 weeks) up to 4 cycles. Nab-paclitaxel should be completely 
administered before initiating carboplatin dose. 
 
 
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2.
Carboplatin AUC of 6 mg/mL/min will be administered as an IV infusion after nab-
paclitaxel infusion on Day 1 of each cycle (every 3 weeks) up to 4 cycles.
Pembrolizumab will be administered as an IV infusion on Day 1 of each cycle (3 weeks) 
after finishing the treatment of combination therapy for 4 cycles in both cohorts 1 and 2.
Combination Regimens for Part E
All subjects should receive the appropriate pre-medications per site’s standard practice.
Subjects enrolled in Cohort 1 and 3 will receive cisplatin/etposide at the following timing:
1.
Etposide 100 mg/m2 will be administered as an IV infusion on Day 1, 2 and 3 of each 
cycle (every 3 weeks) up to 4 cycles. Etoposide should be completely administered 
before initiating cisplatin dose.
2.
Cisplatin 75 mg/m2 will be administered as an IV infusion after Etoposide infusion on 
Day 1 of each cycle (every 3 weeks) up to 4 cycles.
3.
(Cohort 3 only) Subject who enrolled into cohort 3 should take prophylactic use of 
lasting G-CSF (pegfilgrastim) 3.6 mg via subcutaneous injection following the local 
prescribing information. A lasting G-CSF (pegfilgurastim) should administer at least 24 
hours after from the end of infusion of etoposide on Cycle 1 Day 3.
Subjects enrolled in the Cohort 2 will receive carboplatin/etoposide at the following timing:
1.
Etposide 100 mg/m2 will be administered as an IV infusion on Day 1, 2 and 3 of each 
cycle (every 3 weeks) up to 4 cycles. Etoposide should be completely administered 
before initiating carboplatin dose.
2.
Carboplatin AUC of 5 mg/mL/min will be administered as an IV infusion after 
etoposide infusion on Day 1 of each cycle (every 3 weeks) up to 4 cycles.
Pembrolizumab will be administered as an IV infusion on Day 1 of each cycle (3 weeks) 
after finishing the treatment of combination therapy for 4 cycles in each cohort.
(For Part C and E only) Carboplatin: AUC is using Calvert formula.
Calvert Formula
Total Dose (mg) = (target AUC) x (CrCl + 25)
The estimated GFR used in the Calvert formula should not exceed 125 mL/min.
 
 
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Table 6
Maximum dose of Carboplatin
AUC
Maximum dose of Carboplatin
6
900 mg
5
750 mg
4
600 mg
Combination Regimens for Part D
Subjects enrolled in Part D will receive ipilimumab at the following timing:
Ipilimumab will be administered on day 1 in each cycle as a 90-minute IV infusion Q6W up 
to 18 cycles. Sites should make every effort to target infusion timing to be as close to 90 
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 90 minutes:  5 
min/+10 min). infuse pembrolizumab first followed by ipilimumab on the same day. Use 
separate infusion bags and filters for each infusion.
5.2.3
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
5.3
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated to trial treatment by non-random 
assignment. 
5.4
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  Listed below are some specific restrictions for concomitant therapy 
or vaccination during the course of the trial.  If there is a clinical indication for one of these 
or other medications or vaccinations specifically prohibited during the trial, discontinuation 
from trial therapy or vaccination may be required.  The investigator should discuss any 
questions regarding this with the local Clinical Monitor.  The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the subject's primary 
physician.  However, the decision to continue the subject on trial therapy or vaccination 
schedule requires the mutual agreement of the investigator, the Sponsor and the subject.
 
 
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5.5.1
Allowed 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 study period, documentation of drug dosage, 
frequency, route, and date will also be included on the CRF.
All prior/concomitant medications received within 30 days before the first dose of study
mediation and 30 days after the last infusion of study medication should be recorded.
Palliative and supportive care is permitted during the course of the trial for underlying 
medical conditions and management of symptoms. Radiotherapy to a symptomatic solitary 
lesion or to the brain may be allowed after consultation with the Sponsor.
Colony-Stimulating Factors
Prophylactic use of colony-stimulating factors including Granulocyte Colony-Stimulating 
Factor (G-CSF) during DLT assessment period is NOT allowed, except part E cohort 3 (See 
Section 5.5.2). Subject who enrolled into cohort 3 should take prophylactic use of lasting G-
CSF (pegfilgrastim) (See Table 1 and section 5.2.2). Treatment use of G-CSF is allowed
during treatment period. After a DLT assessment period, there is no specific limitation for 
use of G-CSF (investigators may follow the latest guidelines for use of Colony-Stimulating 
Factor).
5.5.2
Prohibited Concomitant Medication
Subjects may receive other medications that the Investigator deems to be medically 
necessary. The following medication will be prohibited during screening and treatment 
period and second course period:

Non-protocol specified chemotherapy 

Radiation therapy
Note: Radiotherapy to a symptomatic solitary lesion or to the brain may be allowed 
after consultation with the Sponsor.  In Part E, PCI which is specified in the study 
design is acceptable.

Non-protocol specified Immunotherapy

Antineoplastic biological therapy 

Investigational agents other than pembrolizumab and ipilimumab
 
 
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
Live vaccines within 4 weeks prior to the first dose of trial treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, 
H1N1 flu, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for 
injection aregenerally killed virus vaccines and are allowed.

Prophylactic use of colony-stimulating factors including G-CSF during DLT 
assessment period (except part E cohort 3).

Initiation of bisphosphonate or anti-RANKL mAb after the initiation of study drug
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 study.  
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
In Part B, C and E, subjects will receive platinum-doublet chemotherapy, in part D subjects 
will receive ipilimumab (details are in Table 1) in combination with pembrolizumab. For 
prohibited medication for the chemotherapy and ipilimumab, refer to the approved labeling.
5.6
Rescue Medications & Supportive Care
5.6.1
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.4, Table 4.  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to Table 4 in Section 
5.2.1.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
 
 
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5.7
Diet/Activity/Other Considerations
5.7.1
Diet
Subjects should maintain a normal unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.
5.7.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if
pembrolizumab has transient adverse effects on the composition of sperm.
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

intrauterine device (IUD)
 
 
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
vasectomy of a female subject’s male partner 

contraceptive rod implanted into the skin
Combination method (requires use of two of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)  

contraceptive sponge (nulliparous women only) 

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy and through 180 days after last dose of 
chemotherapeutic agents. 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.
5.7.3
Use in Pregnancy
If a female subject inadvertently becomes pregnant while on treatment with pembrolizumab, 
the subject will immediately be removed from the study. The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor 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 
 
 
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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. 
5.7.4
Breast-feeding
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the
nursing infant, subjects who are breast-feeding are not eligible for enrollment. Subjects who 
stop breast-feeding prior to initiation of trial treatment and not expecting to resume of breast-
feeding will be eligible for the study.
5.8
Subject Withdrawal/Discontinuation Criteria
5.8.1
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation are important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment 
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 - Trial Flow Chart and Section 7.1.5.3 – Discontinuation.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment 
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
o
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Documented disease progression.
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 
7.1.3.4
o
Unacceptable adverse experiences as described in Section 5.2.1.4
o
Intercurrent illness that prevents further administration of treatment.
o
Completed 24 months of treatment with pembrolizumab [In Part D, Completion of 18 
cycles of ipilimumab (35 times of pembrolizumab)].
 
 
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o
Investigator’s decision to withdraw the subject.
o
The subject has a confirmed positive serum pregnancy test.
o
Noncompliance with trial treatment or procedure requirements.
o
The subject is lost to follow-up.
o
Administrative reasons.
If a pembrolizumab
treated subject attains an investigator-determined confirmed CR 
according to irRC (in Part A) or RECIST 1.1 (in Part B, C, D and E), has been treated for at 
least 6 months with pembrolizumab, and has at least two treatments with pembrolizumab 
beyond the date when the initial CR was declared, OR the subject has received the maximum 
administrations of pembrolrizumab as outlined above, investigator may consider stopping 
therapy with pembrolizumab (In part D, pembrolizumab + ipilimumab). Subjects who 
discontinue pembrolizumab (In part D, pembrolizumab + ipilimumab) and then experience 
radiographic disease progression according to irRC or RECIST 1.1 may be eligible for re-
treatment with pembrolizumab (In part D, pembrolizumab + ipilimumab) in the Second 
Course Phase at the discretion of the investigator as described in Section 7.1.5.6.  The subject 
will resume therapy at the same dose and schedule at the time of initial discontinuation.
Patients who have already started the second course phase of administration before the 
approval of the protocol version 08, may continue the second course phase (up to 12 months) 
if applicable.  For other patients, the second course phase is not applicable.
Note: After the approval of the protocol version 08, the final visit of this study will be a 
safety follow-up visit, and imaging follow-up and survival follow-up will not be performed. 
Participants in the follow-up phase or survival follow-up phase are completed and no further 
visits are required.
5.8.2
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
 
 
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5.9
Subject Replacement Strategy
In order for a subject to be considered evaluable for the analysis of DLT, the subject must 
have had a DLT in the DLT evaluation period, and had received at least 90% of the 
prescribed dose of pembrolizumab and the combination regimen and completed all safety 
evaluations in the DLT evaluation period without experiencing a DLT. A subject without a 
DLT will replaced if he/she did not adequately complete the evaluation period associated 
with the first cycle of study therapy (i.e., discontinue prematurely due to a reason unrelated to 
study therapy) or if that subject received <90% of the prescribed dose.
If a subject discontinues from the trial, a replacement subject may be enrolled if deemed 
appropriate by the investigator and Sponsor.  The replacement subject will generally receive 
the same treatment or treatment sequence (as appropriate) as the subject being replaced.  The 
replacement subject will be assigned a unique randomization number.  The trial site should 
contact the Sponsor for the replacement subject’s randomization number.
5.10 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).
A trial may be paused during review of newly available preclinical/clinical safety, 
pharmacokinetic, pharmacodynamic, efficacy or biologic data or other items of interest, prior 
to a final decision on continuation or termination of the trial.  It may be necessary to keep the 
trial open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the trial.  If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated.  The overall trial end will then not be 
identified until the Sponsor has made the decision to end the trial following this review 
period.  The Competent Authority(ies) and Institutional Review Board(s)/Independent Ethics 
Committee(s) [IRB(s)/IEC(s)] will be appraised of the maximum duration of the trial beyond 
the last subject out and the justification for keeping the trial open.
5.11 Clinical Criteria for Early Trial Termination
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
6.1
Part A
Part A
Screening1
(-28 to -
1days)
Cycle 1(28 days)
Cycle 2 and 
Additional Cycles
(14 Days)
Discontinuation 
Visit
Safety 
Follow-up
Follow-up 1
Follow-up 2
Cycle Day
1
2
3
8
15
22
1
30 days after 
last dose
3 months 
after last 
dose
6 months 
after last 
dose
Visit Number
1
2
3
4
5
6
7
N
Windows (days)
-28～-1
±2
±3
±7
±7
Study Procedures
Informed Consent
X
Informed Consent for Future Biomedical 
Research (optional)
X
Inclusion/Exclusion Criteria
X
Demographics/Medical 
History/Prior 
Medications
X
Height, Weight and Vital Signs2
X
X
X
X
X
X
X
X
ECOG Performance Status3
X
X
X
X
X
Physical Examination3
X
X
X
X
X
12-lead ECG4
X
X
X
X
Review Adverse Events
 X------------------------------------------------------------------------------------------X
Review Concomitant Medications
X------------------------------------------------------------------------------------------X
Hematology1, 5
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panel1, 5
X
X
X
X
X
X
X
X
Coagulation Parameters1
X
Urinalysis1, 5
X
X
X
X
X
X
X
X
Pregnancy Test - Urine or Serum β-HCG6
X
Thyroid Function1, 5, 7
X
X
X
X
Blood 
for 
Future 
Biomedical 
Research 
(optional)8
X
Anti-pembrolizumab Antibodies9
X
X
X
X
X
X
Pharmacokinetics10
X
X
X
X
X
X
X
X
X
X
X
HIV, HBV and HCV11
X
KL-6, β-D glucan1, 12
X
Pulmonary Radiographic Evaluation13
X
X
Tumor Imaging14, Serum Tumor Markers1, 14
X
X
 
 
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Part A
Screening1
(-28 to -
1days)
Cycle 1(28 days)
Cycle 2 and 
Additional Cycles
(14 Days)
Discontinuation 
Visit
Safety 
Follow-up
Follow-up 1
Follow-up 2
Cycle Day
1
2
3
8
15
22
1
30 days after 
last dose
3 months 
after last 
dose
6 months 
after last 
dose
Visit Number
1
2
3
4
5
6
7
N
Administer pembrolizumab
X
X
Archival Tumor Tissues/ Fresh tumor biopsy 
(optional)15 (additional consent required)
X
 
 
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Part A
Screening1
(-28 to -
1days)
Cycle 1(28 days)
Cycle 2 and 
Additional Cycles
(14 Days)
Discontinuation 
Visit
Safety 
Follow-up
Follow-up 1
Follow-up 2
Cycle Day
1
2
3
8
15
22
1
30 days after 
last dose
3 months 
after last 
dose
6 months 
after last 
dose
Visit Number
1
2
3
4
5
6
7
N
1.
Laboratory tests (hematology, serum chemistry and urinalysis, etc.) for screening should be performed within 14 days prior to the first dose of trial treatment.
2.
Vital signs include temperature, pulse (in a sitting position), respiratory rate and blood pressure (in a sitting position). Weight and vital signs will be measured at predose in 
every cycle and the scheduled time point in Cycle 1. Height will be measured at screening visit. only
3.
These procedures will be conducted at predose.
4.
Electrocardiogram (12-lead ECG) should be performed at screening, predose in every other cycle, discontinuation visit, and safety follow-up visit.
5.
See Table 7 for list of laboratory tests.  Laboratory tests may be collected up to 48 hours prior to dosing in every cycle and the scheduled time point in Cycle 1.
6.
For women of reproductive potential, a urine/serum pregnancy test will be performed within 72 hours of the first dose.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required. 
7.
FT3, FT4, TSH; at screening, at predose in every cycle, discontinuation visit, and safety follow-up visit.
8.
Signing the informed consent for future biomedical research (FBR) samples is optional. Informed consent for future biomedical research (FBR) samples must be obtained 
before the DNA sample.  DNA sample for analysis should be obtained predose, on Day 1 (or with the next scheduled blood draw), as the last sample drawn, on allocated
subjects only, or at a later date as soon as the informed consent is obtained.  See Section 12.2 for guidance regarding the collection and management of specimens for FBR.
9.
Blood for anti-pembrolizumab antibodies should be collected within 24 hours prior to  start of infusion in Cycle 1 and Cycle 2 then in every other subsequent cycles (during 
the first 12 months of study therapy), at discontinuation visit and at safety follow-up visit.  Every effort should be made to collect additional blood samples for anti-
pembrolizumab antibodies after discontinuation visit for up to 6 months from the last dose of pembrolizumab or until start of a new anti-cancer therapy, whichever occurs 
first.
10. The time points for blood sampling for serum concentrations of pembrolizumab are as follows.
Cycle 1 Day 1: pre-dose (-60 min to 0), post-dose (to +30 min), 6 (±30 min), 24 , 48, 168, 336, and 504 (±2 hr for 24 to 504 hr) after completion of MK-3475 infusion. 
Cycle 2 and additional Cycles (during the first 12 months of study therapy) Every other cycle Day 1: pre-dose (-60 min to 0), post-dose (to +30 min) after completion of 
pembrolizumab infusion.
Discontinuation, safety follow-up Visit and follow-up visit 1 and 2: Every effort should be made to collect additional blood samples for serum concentration of 
pembrolizumab after Discontinuation Visit for up to 6 months from the last dose of MK-3475 or until start of a new anti-cancer therapy, whichever occurs first.
11. Include HCV RNA (qualitative), HBsAg, and HIV 1/2 antibodies.  If results of these test obtained within 3 months before screening are available, they can be used even 
before consent is obtained.
12. KL-6 and β–D glucan will be measured for pulmonary evaluation at screening and thereafter if a subject develops suspected pneumonitis, an additional test will be 
performed as needed by investigator’s judgment.
13. A chest CT performed for tumor imaging will be used for pulmonary radiographic evaluation.
14. Tumor imaging (CT or MRI) will be performed within 28 days prior to enrollment. In Part A, tumor imaging should be performed every 6 calendar weeks (42 days ±7 days) 
after the first dose of study treatment in treatment period.  Tumor imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or 
extension of pembrolizumab cycle frequencies. Tumor response on trial will be assessed using irRC and RECIST ver.1.1 by the study site. Standard tumor markers (as 
appropriate for a given tumor type) will be collected at screening (within 14 days prior to the first dose of study treatment), and at the same timing as tumor imaging 
thereafter.
15. Collection of archival/fresh tumor tissue for purpose of PD-L1 expression analysis.  Access to archival/fresh tumor tissue is highly desirable but not mandatory.  Written 
subject consent is required for collection of tumor tissue. Specific instructions for tissue collection and shipment are provided in the Procedures Manual.   If the subject 
signs the FBR consent, an aliquot of the tissue specimens will be designated for FBR.  In addition, any leftover archival/fresh tissue specimens at the end of the main study 
that would ordinarily be discarded will be retained for FBR providing the subject has signed the FBR consent.
 
 
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6.2
Combination Therapy
6.2.1
Part B and C- treatment phase
Part B and C
Screening1, 
(-28 to -
1days)
Cycle 1(21 days)
Cycle 2 and Additional 
Cycles
(21 Days)
Discontinuation Visit20
Cycle Day
1
2
5
8
15
1
8
15
Visit Number
1
2
3
4
5
6
N
N+1
N+2
Windows (days) 2
-28～-1
±3
±1
±1
Study Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics/Medical History/Prior Medications
X
Height, Weight and Vital Signs4, 5
X
X
X
X
X
X23
X23
X
SpO25
X
X
X
X
X
X23
X23
X
ECOG Performance Status5
X
X
X
X
Physical Examination5
X
X
X
X
12-lead ECG6
X
X6
Review Adverse Events
X----------------------------------------------------------------------------------------X21
Review Concomitant Medications
X----------------------------------------------------------------------------------------X
Hematology3, 7
X
X
X
X
X
X23
X23
X
Comprehensive Serum Chemistry Panel3, 7
X
X
X
X
X
X
Coagulation Parameters3, 7
X
Urinalysis3, 7
X
X
X
X
X
X
Pregnancy Test - Urine or Serum β-HCG8
X
Thyroid Function3, 7, 9
X
X
X
Blood for Genetics10
X
Anti-pembrolizumab Antibodies11
X
X
X
Pharmacokinetics12
X
X
X
X
X
X
HIV, HBV and HCV13
X
KL-6, SP-D3, 14
X
X
X
X
X
X
β-D glucan3, 14
X
Pulmonary Radiographic Evaluation15
X
X
Tumor Imaging16, Serum Tumor Markers3, 16
X
X
Administer pembrolizumab
X
X
Administer Chemotherapy (except for nab-paclitaxel)17
X
X
 
 
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Part B and C
Screening1, 
(-28 to -
1days)
Cycle 1(21 days)
Cycle 2 and Additional 
Cycles
(21 Days)
Discontinuation Visit20
Cycle Day
1
2
5
8
15
1
8
15
Visit Number
1
2
3
4
5
6
N
N+1
N+2
Windows (days) 2
-28～-1
±3
±1
±1
Administer nab-paclitaxel17, 22
X
X
X
X
X
X
Archival Tumor Tissues/ Fresh tumor biopsy 18
X
Blood for Correlative Studies (DNA and RNA) 19
X
X
X
Biomarker Samples (Plasma and Serum) 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 for each cycle unless otherwise specified. Treatment cycles are 
3 weeks (21-days). If treatment cycles are adjusted all procedures except imaging will be completed according to the Cycle number and not weeks on treatment; imaging 
will be performed every 6 calendar weeks (± 7days) after the first dose for the first 24 weeks, and every 9 calendar weeks (± 7 days) from the date of imaging assessment at 
the week 24 regardless of any treatment delays.
2.
In general, the window for each visit is +/- 3 days unless otherwise specified.
3.
Laboratory tests (hematology, serum chemistry and urinalysis, etc.) for screening should be performed within 14 days prior to the first dose of trial treatment.
4.
Vital signs include temperature, pulse (in a sitting position), respiratory rate and blood pressure (in a sitting position). Weight and vital signs will be measured at predose in 
every cycle and the scheduled time point in Cycle 1. Height will be measured at screening visit. only
5.
These procedures will be conducted at pre-dose.
6.
Electrocardiogram (12-lead ECG) should be performed at screening and end of cycle 1 (pre-dose of cycle 2). An additional measurement will be performed as needed by 
investigator’s judgment.  
7.
See Table 7 for list of laboratory tests.  Laboratory tests may be collected up to 48 hours prior to dosing in every cycle and the scheduled time point in Cycle 1.
8.
For women of reproductive potential, a urine/serum pregnancy test will be performed within 72 hours of the first dose.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required. 
9.
FT3, FT4, TSH; at screening, at pre-dose in every cycle, discontinuation visit, and safety follow-up visit.
10. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but 
FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
11. Blood for anti-MK-3475 antibodies should be collected within 24 hours prior to start of infusion in Cycle 1, 2, 4, 6, 8 and every 4 cycles thereafter, at discontinuation visit 
and at safety follow-up visit.  Every effort should be made to collect additional blood samples for anti-MK-3475 antibodies after discontinuation visit for up to 6 months 
from the last dose of MK-3475 or until start of a new anti-cancer therapy, whichever occurs first. See 7.1.3.2 in detail.
12. The time points for blood sampling for serum concentrations of MK-3475 are as follows. See 7.1.3.2 in detail.
Cycle 1 Day 1: pre-dose (-24hr to 0hr), post-dose (to +30 min), 24hr, 96hr (96hr is preferable, although 72hr or 120hr is also acceptable, ±2 hr) and 336hr (±24 hr) after 
completion of MK-3475 infusion. 
Cycle 2, 4, 6, 8 and every 4 cycles thereafter: pre-dose (-24 hr to 0)
Cycle 8: post-dose (to +30min) after completion of MK-3475 infusion.
Discontinuation, safety follow-up Visit and follow-up visit 1 and 2: Every effort should be made to collect additional blood samples for serum concentration of MK-3475 
after Discontinuation Visit for up to 6 months from the last dose of MK-3475 or until start of a new anti-cancer therapy, whichever occurs first.
13. Include HCV RNA (qualitative), HBsAg, and HIV 1/2 antibodies. If results of these test obtained within 3 months before screening are available, they can be used even 
before consent is obtained.
14. KL-6, SP-D and β–D glucan will be measured for pulmonary evaluation. If a subject develops suspected pneumonitis, an additional test will be performed as needed by 
investigator’s judgment.
15. A chest CT performed for tumor imaging will be used for pulmonary radiographic evaluation.
16. Tumor imaging (CT or MRI) will be performed within 28 days prior to enrollment. In Part B and C, tumor imaging should be performed every 6 calendar weeks (± 7days) 
for the first 24 weeks, and every 9 calendar weeks (63 days ±7 days) from the date of imaging assessment at the week 24.  Tumor imaging timing should follow calendar 
days and should not be adjusted for delays in cycle starts or extension of MK-3475/chemotherapy cycle frequencies. The same imaging technique should be used in a 
subject as was used earlier in this trial. Tumor response on trial will be assessed using irRECIST by the study site. Local reading (investigator assessment with site 
radiology reading) will be used to for subject management; In Part B and C, sponsor will 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). Standard tumor markers (as appropriate 
for a given tumor type) will be collected at screening (within 14 days prior to the first dose of study treatment), and at the same timing as tumor imaging thereafter.
17. Subjects will receive platinum-doublet chemotherapy [cisplatin/pemetrexed (cohort 1) or carboplatin/pemetrexed (cohort 2) for Part B, and carboplatin/paclitaxel (cohort 1) 
or carboplatin/nab-paclitaxel (cohort 2) for Part C] in combination with MK-3475 for 4 cycles.  Subjects may receive MK-3475 Q3W as maintenance therapy (for Part B 
 
 
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MK-3475-011-08 Final Protocol
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Confidential 
only, in combination with pemetrexed) once the first 4 cycles of the platinum containing (either carboplatin/pemetrexed or cisplatin/pemetrexed for Part B, and either 
carboplatin/paclitaxel or carboplatin/nab-paclitaxel for Part C) doublet have completed.
18. Collection of archival/fresh tumor tissue for purpose of PD-L1 expression analysis is mandatory for part B and C. EGFR/ALK testing is performed at central laboratory if 
the site is unable to provide this source document (Part B only).   Specific instructions for tissue collection and shipment are provided in section 7.1.3.6 and the Procedures 
Manual.   If the subject signs the FBR consent, an aliquot of the tissue specimens will be designated for FBR.  In addition, any leftover archival/fresh tissue specimens at 
the end of the main study that would ordinarily be discarded will be retained for FBR providing the subject has signed the FBR consent.
19.
Whole blood samples for correlative studies (DNA and RNA) should be collected pre-dose on Day 1 of cycle 1, Cycle 2, and Cycle 3, and again at treatment 
discontinuation. Whole blood for Biomarker Samples (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only. See Procedure Manual.
20. The Discontinuation Visit should occur at the time study drug is discontinued for any reason. If the Discontinuation Visit occurs 30 days from the last dose of study 
treatment, at the time of the mandatory Safety Follow up Visit, procedures do not need to be repeated.
21. Once a subject discontinues study 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.
22. Dosing for nab-paclitaxel is on Day 1, Day 8 and Day 15 of each Q3W cycle.
23. If a subject receives nab-paclitaxel, hematology tests/weight and vital signs, and SpO2 are performed/measured before each dose of nab-paclitaxel on Day 8 and Day 15 of 
each Q3W cycle.
 
 
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6.2.2
Part D- treatment phase
Part D
Screening,          (-28 
to -1days)
Cycle 1
(42 days)
Cycle 2 to 18 Cycles
(42 Days)
Discontinuation 
Visit19
Cycle Day 1
1
22
1
22
Visit Number
1
2
3
N
N+1
Windows (days) 2
-28～-1
±3
±3
±3
Study Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics/Medical History/Prior Medications
X
Height, Weight and Vital Signs4, 5
X
X
X
X
X
X
SpO25
X
X
X
X
X
X
ECOG Performance Status5
X
X
X
X
X
X
Physical Examination5
X
X
X
X
X
X
12-lead ECG6
X6
X6
Review Adverse Events
X---------------------------------------------------------------------X20
Review Concomitant Medications
X---------------------------------------------------------------------X
Hematology3, 7
X
X
X
X
X
X
Comprehensive Serum Chemistry Panel3, 7
X
X
X
X
X
X
Coagulation Parameters3
X
Urinalysis3, 7
X
X
X
X
X
X
Pregnancy Test - Urine or Serum β-HCG8
X
Thyroid Function3, 9
X
X
X
X
X
adrenocorticotropic hormone (ACTH) level 3,22
X
X
X
Blood for Genetics10
X
Anti-MK-3475 Antibodies11
X
X
X
X
Pharmacokinetics12
X
X
X
X
HIV, HBV and HCV13
X
KL-6, SP-D3, 14
X
X
X
X
X
X
β-D glucan3, 14
X
Pulmonary Radiographic Evaluation15
X
X
X
Tumor Imaging16, Serum Tumor Markers3, 16
X
X
X
Administer MK-3475
X
X
X
X
Administer Ipilimumab21
X
X
Archival Tumor Tissues/ Fresh tumor biopsy (optional)17
X
Blood for Correlative Studies (DNA and RNA) 18
X
X
X
Biomarker Samples (Plasma and Serum) 18
X
 
 
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Product:  MK-3475
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Protocol/Amendment No.: 011-08 
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24-Sep-2019
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1.
In general, assessments/procedures are to be performed on Day 1 and Day 22 prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment 
cycles are 6 weeks (42-days). If treatment cycles are adjusted, all procedures except imaging will be completed according to the cycle number and not weeks on treatment; 
imaging will be performed every 6 calendar weeks (± 7days) after the first dose for the first 24 weeks, and every 9 calendar weeks (± 7 days) from the date of imaging 
assessment at the week 24 thereafter regardless of any treatment delays.
2.
In general, the window for each visit is +/- 3 days unless otherwise specified.
3.
Laboratory tests (hematology, serum chemistry and urinalysis, etc.) for screening should be performed within 14 days prior to the first dose of trial treatment.
4.
Vital signs include temperature, pulse (in a sitting position), respiratory rate and blood pressure (in a sitting position). Weight and vital signs will be measured at pre-dose in 
Day 1 and Day 22 of each cycle. Height will be measured at screening visit. only
5.
These procedures will be conducted at pre-dose.
6.
Electrocardiogram (12-lead ECG) should be performed at screening and end of cycle 1 (pre-dose of cycle 2). An additional measurement will be performed as needed by 
investigator’s judgment.
7.
See Table 7 for list of laboratory tests.  Laboratory tests may be collected up to 48 hours prior to dosing of Day 1 and Day 22 in every cycle.
8.
For women of reproductive potential, a urine/serum pregnancy test will be performed within 72 hours of the first dose.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required. 
9.
FT3, FT4, TSH; at screening, up to 48 hours prior to pre-dose in day 22 of cycle 1, at pre-dose in day 1 and day 22 of cycle 2 to 18 and discontinuation visit.
10. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but 
FBR is approved and consent is given, this sample will be collected for the purpose of FBR.
11. Blood for anti-MK-3475 antibodies should be collected within 24 hours prior to start of infusion in Day 1 of Cycle 1, Day 22 of Cycle 1, Day 22 of Cycle 2, Day 22 of 
Cycle 3, Day 22 of Cycle 4 and Day 22 of every 2 cycles thereafter, and at discontinuation visit and at safety follow-up visit.  Every effort should be made to collect 
additional blood samples for anti-MK-3475 antibodies after discontinuation visit for up to 6 months from the last dose of MK-3475 or until start of a new anti-cancer 
therapy, whichever occurs first. See 7.1.3.2 in detail.
12. The time points for blood sampling for serum concentrations of MK-3475 are as follows. See 7.1.3.2 in detail.
Cycle 1 Day 1: pre-dose (-24hr to 0hr), post-dose (to +30 min), 24hr, 96hr (96hr is preferable, although 72hr or 120hr is also acceptable, ±2 hr) and 336hr (±
24 hr) after completion of MK-3475 infusion. 
Day 22 of Cycle 1, Day 22 of Cycle 2, Day 22 of cycle 3, Day 22 of Cycle 4 and Day 22 of every 2 cycles thereafter: predose (-24 hr to 0)
Day 22 of Cycle 4: post-dose (to +30min) after completion of MK-3475 infusion.
Discontinuation, safety follow-up Visit and follow-up visit 1 and 2: Every effort should be made to collect additional blood samples for serum concentration of 
MK-3475 after Discontinuation Visit for up to 6 months from the last dose of MK-3475 or until start of a new anti-cancer therapy, whichever occurs first.
13. Include HCV RNA (qualitative), HBsAg, and HIV 1/2 antibodies. If results of these test obtained within 3 months before screening are available, they can be used even 
before consent is obtained.
14. KL-6, SP-D and β–D glucan will be measured for pulmonary evaluation. If a subject develops suspected pneumonitis, an additional test will be performed as needed by 
investigator’s judgment.
15. A chest CT performed for tumor imaging will be used for pulmonary radiographic evaluation.
16. Tumor imaging (CT or MRI) will be performed within 28 days prior to enrollment. The tumor imaging should be performed every 6 calendar weeks (± 7days) for the first 
24 weeks, and every 9 calendar weeks (63 days ±7 days) from the date of imaging assessment at the week 24 thereafter.  Tumor imaging timing should follow calendar 
days and should not be adjusted for delays in cycle starts or extension of pembrolizumab/ipilimumab cycle frequencies. The same imaging technique should be used in a 
subject as was used earlier in this trial. Tumor response on trial will be assessed using irRECIST by the study site. Local reading (investigator assessment with site 
radiology reading) will be used to for subject management; In Part D, sponsor will collect radiological assessments, but retrospective analysis by a central vendor will not 
be conducted. Standard tumor markers (as appropriate for a given tumor type) will be collected at screening (within 14 days prior to the first dose of study treatment), and 
at the same timing as tumor imaging thereafter.
 
 
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17. Collection of archival/fresh tumor tissue for purpose of PD-L1 expression analysis is optional. Specific instructions for tissue collection and shipment are provided in 
section 7.1.3.6 and the Procedures Manual. If the subject signs the FBR consent, an aliquot of the tissue specimens will be designated for FBR.  In addition, any leftover 
archival/fresh tissue specimens at the end of the main study that would ordinarily be discarded will be retained for FBR providing the subject has signed the FBR consent.
18.
Whole blood samples for correlative studies (DNA and RNA) should be collected pre-dose on Day 1 of cycle 1, Day 1 of Cycle 2, and Day 1 of Cycle 3, and again at 
treatment discontinuation. Whole blood for Biomarker Samples (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only. See Procedure Manual in detail.
19. The Discontinuation Visit should occur at the time study drug is discontinued for any reason. If the Discontinuation Visit occurs 30 days from the last dose of study 
treatment, at the time of the mandatory Safety Follow up Visit, procedures do not need to be repeated.
20. Once a subject discontinues study 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.
21. Ipilimumab will be administered at Day 1 in every cycle up to Cycle 18.
22. ACTH will be measured at screening, up to 48 hours prior to pre-dose of Day 1 of Cycle 2 to Cycle 18 and discontinuation visit. An additional test will be performed as 
needed by investigator’s judgment.
 
 
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6.2.3
Part E- treatment phase
Part E
Screening
(-28 to -1days)
Cycle 1(21 days)
Cycle 2 and 
Additional Cycles (21 
Days)
Discontinuation 
Visit20
Cycle Day1
1
2
3
4
5
8
15
1
2
3
Visit Number
1
2
3
4
5
6
7
8
N
N+1
N+2
Windows (days) 2
-28～-1
±3
Study Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics/Medical History/Prior Medications
X
Height, Weight and Vital Signs4, 5
X
X
X
X
X
X
X
X22
X22
X
SpO25
X
X
X
X
X
X
X
X22
X22
X
ECOG Performance Status5
X
X
X
X
Physical Examination5
X
X
X
X
X
X22
X22
X
12-lead ECG6
X6
X6
Review Adverse Events
X--------------------------------------------------------------------------------------------------------X21
Review Concomitant Medications
X--------------------------------------------------------------------------------------------------------X
Hematology3, 7
X
X
X
X
X
X
Comprehensive Serum Chemistry Panel3, 7
X
X
X
X
X
X
Coagulation Parameters3
X
Urinalysis3, 7
X
X
X
X
X
X
Pregnancy Test - Urine or Serum β-HCG8
X
Thyroid Function3, 7, 9
X
X
X
Blood for Genetics10
X
Anti-pembrolizumab Antibodies11
X
X
X
Pharmacokinetics12
X
X
X
X
X
X
HIV, HBV and HCV13
X
KL-6, SP-D3, 14
X
X
X
X
X
X
β-D glucan3, 14
X
Pulmonary Radiographic Evaluation15
X
X
 
 
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Part E
Screening
(-28 to -1days)
Cycle 1(21 days)
Cycle 2 and 
Additional Cycles (21 
Days)
Discontinuation 
Visit20
Cycle Day1
1
2
3
4
5
8
15
1
2
3
Visit Number
1
2
3
4
5
6
7
8
N
N+1
N+2
Windows (days) 2
-28～-1
±3
Study Procedures
Tumor Imaging16, Serum Tumor Markers3, 16
X
X
Administer pembrolizumab
X
X
Administer Cisplatin or Carboplatin17
X
X
Administer Etoposide17
X
X
X
X
X
X
Administer lasting G-CSF (pegfilgrastim)23
X
Archival Tumor Tissues/ Fresh tumor biopsy (optional) 18
X
Blood for Correlative Studies (DNA and RNA) 19
X
X
X
Biomarker Samples (Plasma and Serum) 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 for each cycle unless otherwise specified. Treatment cycles are 3 
weeks (21-days). If treatment cycles are adjusted all procedures except imaging will be completed according to the Cycle number and not weeks on treatment; imaging will be 
performed every 6 calendar weeks (± 7days) after the first dose for the first 24 weeks, and every 9 calendar weeks (± 7 days) from the date of imaging assessment at the week 
24 regardless of any treatment delays.
2.
In general, the window for each visit is +/- 3 days unless otherwise specified.
3.
Laboratory tests (hematology, serum chemistry and urinalysis, etc.) for screening should be performed within 14 days prior to the first dose of trial treatment.
4.
Height will be measured at screening visit only. Vital signs include temperature, pulse (in a sitting position), respiratory rate and blood pressure (in a sitting position). Weight 
and vital signs will be measured at pre-dose in every cycle and the scheduled time point in Cycle 1. In addition, weight and vital signs will be measured before dosing 
etoposide on Day 2 and 3 of each cycle.
5.
These procedures will be conducted at pre-dose.
6.
Electrocardiogram (12-lead ECG) should be performed at screening and end of cycle 1 (pre-dose of cycle 2). An additional measurement will be performed as needed by 
investigator’s judgment.
7.
See Table 7 for list of laboratory tests.  Laboratory tests may be collected up to 48 hours prior to dosing in every cycle and the scheduled time point in Cycle 1.
8.
For women of reproductive potential, a urine/serum pregnancy test will be performed within 72 hours of the first dose.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required. 
9.
FT3, FT4, TSH; at screening, at pre-dose in every cycle, discontinuation visit, and safety follow-up visit.
10. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR 
is approved and consent is given, this sample will be collected for the purpose of FBR.
11. Blood for anti-pembrolizumab antibodies should be collected within 24 hours prior to start of infusion in Cycle 1, 2 4, 6, 8 and every 4 cycles thereafter, at discontinuation 
visit and at safety follow-up visit.  Every effort should be made to collect additional blood samples for anti-pembrolizumab antibodies after discontinuation visit for up to 6 
months from the last dose of MK-3475 or until start of a new anti-cancer therapy, whichever occurs first. See 7.1.3.2 in detail.
12. The time points for blood sampling for serum concentrations of pembrolizumab are as follows. See 7.1.3.2 in detail.
Cycle 1 Day 1: pre-dose (-24hr to 0hr), post-dose (to +30 min), 24hr (±2 hr), 96hr (96hr is preferable, although 72hr or 120hr is also acceptable, ±2 hr) and 336hr (±24 hr) 
after completion of pembrolizumab infusion. 
Cycle 2, 4, 6, 8 and every 4 cycles thereafter: pre-dose (-24 hr to 0)
Cycle 8: post-dose (to +30 min) after completion of pembrolizumab infusion.
Discontinuation, safety follow-up Visit and follow-up visit 1 and 2: Every effort should be made to collect additional blood samples for serum concentration of 
pembrolizumab after Discontinuation Visit for up to 6 months from the last dose of pembrolizumab or until start of a new anti-cancer therapy, whichever occurs first.
13. Include HCV RNA (qualitative), HBsAg, and HIV 1/2 antibodies. If results of these test obtained within 3 months before screening are available, they can be used even 
before consent is obtained.
14. KL-6, SP-D and β–D glucan will be measured for pulmonary evaluation. If a subject develops suspected pneumonitis, an additional test will be performed as needed by 
investigator’s judgment.
15. A chest CT performed for tumor imaging will be used for pulmonary radiographic evaluation.
16. Tumor imaging (CT or MRI) will be performed within 28 days prior to enrollment, the tumor imaging should be performed every 6 calendar weeks (± 7days) for the first 24 
weeks, and every 9 calendar weeks (63 days ±7 days) from the date of imaging assessment at the week 24.  Tumor imaging timing should follow calendar days and should not 
be adjusted for delays in cycle starts or extension of pembrolizumab/chemotherapy cycle frequencies. The same imaging technique should be used in a subject as was used 
earlier in this trial. Tumor response on trial will be assessed using irRECIST by the study site.  Local reading (investigator assessment with site radiology reading) will be 
used to for subject management; Sponsor will collect radiological assessments, but retrospective analysis by a central vendor will not be conducted. Standard tumor markers 
(as appropriate for a given tumor type) will be collected at screening (within 14 days prior to the first dose of study treatment), and at the same timing as tumor imaging 
thereafter.
 
 
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17. Subjects will receive platinum-doublet chemotherapy [cisplatin/etoposide (cohort 1) or carboplatin/etoposide (cohort 2)] in combination with pembrolizumab for 4 cycles.  
Subjects may receive pembrolizumab Q3W as maintenance therapy once the first 4 cycles of the platinum containing doublet have completed.
18. Collection of archival/fresh tumor tissue for purpose of PD-L1 expression analysis is optional. Specific instructions for tissue collection and shipment are provided in section 
7.1.3.6 and the Procedures Manual.  If the subject signs the FBR consent, an aliquot of the tissue specimens will be designated for FBR.  In addition, any leftover 
archival/fresh tissue specimens at the end of the main study that would ordinarily be discarded will be retained for FBR providing the subject has signed the FBR consent.
19. Whole blood samples for correlative studies (DNA and RNA) should be collected pre-dose on Day 1 of cycle 1, Cycle 2, and Cycle 3, and again at treatment discontinuation.
Whole blood for Biomarker Samples (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only. See Procedure Manual.
20. The Discontinuation Visit should occur at the time study drug is discontinued for any reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, 
at the time of the mandatory Safety Follow up Visit, procedures do not need to be repeated.
21. Once a subject discontinues study 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. 
22. If a subject receives etoposide, Physical Examination, weight, vital signs, and SpO2 are performed/measured before each dose of etoposide on Day 2 and Day 3 of each Q3W 
cycle
23. (Cohort 3 only) Subject who enrolled into cohort 3 should take prophylactic use of lasting G-CSF (pegfilgrastim) 3.6 mg via subcutaneous injection following the local 
prescribing information. A lasting G-CSF (pegfilgurastim) should administer at least 24 hours after from the end of infusion of etoposide on Cycle 1 Day 3.
 
 
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6.2.4
Follow-up phase-Part B, C, D and E
After the approval of the protocol version 08, the final visit of this study will be a safety follow-up visit, and imaging follow-up and 
survival follow-up will not be performed. Participants in the follow-up phase or survival follow-up phase will discontinue the study
and no further visits are required.
post- treatment follow-up period
Visit
Safety  Follow-up Visit 1
Time from Last Dose of Trial Treatment
30 Days
Scheduling Window
± 3 days
Administrative Procedures
Review Medications
X
Subsequent antineoplastic therapy Status
X
Review Adverse Events 2
X
ECOG Performance Status
X
Physical Examination
X
Vital Signs and Weight 3
X
SpO2
X
12-Lead ECG
X6
Tumor Imaging
X5
CBC with Differential 5
X
Comprehensive Serum Chemistry Panel 5
X
adrenocorticotropic hormone (ACTH) level7
X
KL-6, SP-D5
X
FT3, FT4 and TSH 5
X
 
 
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1. All subjects will conduct the procedures at Safety Follow-Up Visit.  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.
2. Record all AEs and ECIs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) occurring within 90 days of 
the last dose of trial treatment or 30 days following cessation of treatment if the subject initiates new anti-cancer treatment, whichever comes first.  After this time, report 
only SAEs that are considered related to trial treatment.
3. Vital signs to include temperature, pulse (in a sitting position), respiratory rate, blood pressure (in a sitting position) and weight. 
4. The same imaging technique should be used in a subject as was used earlier in the trial.  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, 
then a scan at Safety Follow-up Visit isn’t mandatory.
5. See Section 7.1.3 for list of laboratory tests.
6. 12-lead ECG will be performed as needed by investigator’s judgment.
 
 
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6.2.5
Part B, C and E- Second Course phase and Follow-up phase
Patients who have already started the second course phase of administration before the approval of the protocol version 08, may 
continue the second course phase (up to 12 months) if applicable.  For other patients, the second course phase is not applicable.
Second Course Phase1
Follow-up for second course 
phase
Treatment Cycle / Scheduled Time
1
2
3
4
5
6
7
8
9
10 and 
beyond
Discontinuation 
Visit
Safety Follow-up Visit 17
Scheduling Window (Days):2
± 3
± 3
± 3
±3
±3
±3
±3
±3
±3
30 Days ± 3 days from last dose
Eligibility Criteria3
X
Concomitant Medications4
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
X
X
Review Adverse Events 5, 6
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination7, 9
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs and Weight 8, 9
X
X
X
X
X
X
X
X
X
X
X
X
SpO29
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status 9
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test - Urine or Serum β-HCG 10
X
PT/INR and aPTT 11
X12
CBC with Differential13
X12
X
X
X
X
X
X
X
X
X
X
X
Comprehensive Serum Chemistry Panel13
X12
X
X
X
X
X
X
X
X
X
X
X
KL-6, SP-D13
X12
X
X
X
X
X
X
X
X
X
X
X
Urinalysis13,14
X12
X
X
X
X
X
FT3, FT4 and TSH 13, 14
X12
X
X
X
X
X
Tumor Imaging 15, 16
X
X
X
X
X
X
Subsequent antineoplastic therapy Status
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.   If treatment cycles 
are delayed all procedures except imaging will be completed according to the Cycle number and not weeks on treatment.  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.
Review Secord Course Phase eligibility criteria in Section 7.1.5.6 prior to administering the first dose of trial treatment. 
4.
Concomitant Medications - Enter new medications started during the trial through the Safety Follow-up Visit for treatment phase.  After the Safety Follow-up Visit record 
all medications taken for SAEs as defined in Section 7.2.
5.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness. 
6.
All AEs of unknown etiology associated with trial treatment exposure should be evaluated  In the follow-up phase, record all AEs and ECIs occurring within 30 days after 
the last dose of trial treatment or until the initiation of the new therapy for cancer.  Report all SAEs (related and unrelated to trial treatment) occurring within 90 days of 
the last dose of trial treatment or 30 days following cessation of treatment if the subject initiates new anti-cancer treatment, whichever comes first.  After this time, report 
only SAEs that are considered related to trial treatment.
7.
Perform physical examinations at pre-dose on the day of the study treatment visit. 
8.
Vital signs to include temperature, pulse (in a sitting position), respiratory rate, weight and blood pressure (in a sitting position).
9.
These procedures will be conducted at pre-dose.
10.
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.
11.
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
12.
Laboratory tests for determining eligibility for Second Course Phase are to be performed within 10 days prior to the first dose. See Section 7.1.3 for details regarding 
laboratory tests.  
13.
After the 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. 
14.
Thyroid function tests should be performed every 4 cycles after Cycle 10.  Urinalysis tests should be performed at pre-dose of Day 1 in every 4 cycle after cycle 9.
15.
The Second Course Cycle 1 scan may have been performed up to 28 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 or more frequently if clinically indicated.  The timing of imaging should follow 
calendar days and should not be adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies. The same imaging technique should be used in a 
subject throughout the trial.  Local reading (investigator assessment with site radiology reading) will be used to for subject management; in part B and C, sponsor will 
collect radiological assessments for retrospective analysis by a central vendor. In Part E, sponsor will collect radiological assessments, but retrospective analysis by a 
central vendor will not be conducted. The processes for image collection and transmission to the central vendor are in the Investigator Imaging Operations Manual 
(IIOM). 
16.
After the first documentation of progression (if the subject is clinically stable) or responses per RECIST 1.1, confirmatory imaging may be performed as early as 28 days 
later; alternately, the scan performed at the next scheduled time point (e.g. every 63 ±7 days) may be used as confirmation
17.
All subjects will conduct the procedures at Safety Follow-Up Visit.  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.  
 
 
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6.2.6
Part D- Second Course phase and Follow-up phase
Patients who have already started the second course phase of administration before the approval of the protocol version 08, may 
continue the second course phase (up to 12 months) if applicable.  For other patients, the second course phase is not applicable.
Second Course Phase
Follow-up for second course phase
Treatment Cycle / Scheduled Time1
Cycle 1
(42 Days)
Cycle 2 to 9 Cycles
(42 Days)
Discontinuation 
Visit
Safety Follow-up Visit 18
Cycle Day
1
22
1
22
Scheduling Window (Days):2
± 3
± 3
± 3
30 Days ± 3 days from last dose
Eligibility Criteria3
X
Concomitant Medications4
X
X
X
X
X
Administer pembrolizumab
X
X
X
X
Administer Ipilimumab120
X
X
Review Adverse Events 5, 6
X
X
X
X
X
X
Physical Examination7, 9
X
X
X
X
X
X
Vital Signs and Weight 8, 9
X
X
X
X
X
X
SpO29
X
X
X
X
X
X
ECOG Performance Status 9
X
X
X
X
X
X
Pregnancy Test - Urine or Serum β-HCG 10
X
PT/INR and aPTT 11
X12
CBC with Differential13
X12
X
X
X
X
X
Comprehensive Serum Chemistry Panel13
X12
X
X
X
X
X
KL-6, SP-D13
X12
X
X
X
X
X
Urinalysis13,14
X12
X14
X
X
FT3, FT4 and TSH 13,15
X12
X15
X
X
adrenocorticotropic hormone (ACTH) level 19
X12
X
X
X
Tumor Imaging 16, 17
X
X
X
X
X
Subsequent antineoplastic therapy Status
X
 
 
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1.
In general, assessments/procedures are to be performed on Day 1 and Day 22 prior to the first dose of trial treatment for each cycle unless otherwise specified. Treatment 
cycles are 6 weeks (42-days). If treatment cycles are delayed all procedures except imaging will be completed according to the Cycle number and not weeks on treatment.  
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.
Review Secord Course Phase eligibility criteria in Section 7.1.5.6 prior to administering the first dose of trial treatment. 
4.
Concomitant Medications - Enter new medications started during the trial through the Safety Follow-up Visit for treatment phase.  After the Safety Follow-up Visit record 
all medications taken for SAEs as defined in Section 7.2.
5.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
seriousness. 
6.
All AEs of unknown etiology associated with trial treatment exposure should be evaluated  In the follow-up phase, record all AEs and ECIs occurring within 30 days after 
the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) occurring within 90 days of the last dose of trial treatment or 30 days following 
cessation of treatment if the subject initiates new anti-cancer treatment, whichever comes first.  After this time, report only SAEs that are considered related to trial 
treatment.
7.
Perform physical examinations at pre-dose on the day of the study treatment visit. 
8.
Vital signs to include temperature, pulse (in a sitting position), respiratory rate, weight and blood pressure (in a sitting position).
9.
These procedures will be conducted at pre-dose.
10.
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.
11.
Coagulation factors (PT/INR and aPTT) should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.
12.
Laboratory tests for determining eligibility for Second Course Phase are to be performed within 10 days prior to the first dose. See Section 7.1.3 for details regarding 
laboratory tests.  
13.
After the 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. 
14.
Urinalysis tests should be performed at pre-dose of Day 1 in every 2 cycle after cycle 1
15.
Thyroid function tests should be performed at pre-dose of Day 1 in cycle 1, cycle 2 and every 2 cycles thereafter.
16.
The Second Course Cycle 1 scan may have been performed up to 28 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 or more frequently if clinically indicated.  The timing of imaging should follow 
calendar days and should not be adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies. The same imaging technique should be used in a 
subject throughout the trial.  Local reading (investigator assessment with site radiology reading) will be used to for subject management; Sponsor will collect radiological 
assessments, but retrospective analysis by a central vendor will not be conducted.
17.
After the first documentation of progression (if the subject is clinically stable) or responses per RECIST 1.1, confirmatory imaging may be performed as early as 28 days 
later; alternately, thre scan performed at the next scheduled time point (e.g. every 63 ±7 days) may be used as confirmation
18.
All subjects will conduct the procedures at Safety Follow-Up Visit.  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.  
19.
ACTH will be measured at pre-dose of Day 1 of each cycle, discontinuation visit and safety follow up visit. An additional test will be performed as needed by 
investigator’s judgment.
20.
Ipilimumab will be administered at Day 1 in every cycle up to Cycle 9.
 
 
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the 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.
7.1.1
Administrative Procedures
7.1.1.1
Informed Consent
The investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial or Future Biomedical Research.
The 2nd cycle and thereafter are positioned as the continuation administration study. Consent 
should be obtained again from the subjects in writing before starting the 2nd cycle (Part A).
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 the Future Biomedical Research sub-trial.  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. Record any prior cancer other 
than the current cancer evaluated in this study even if diagnosed greater than 10 years prior to 
screening visit. History of the current cancer will be recorded separately and not listed as 
Medical History (See Section 7.1.1.7.1).
7.1.1.5
Demographics
Demographics (including smoking history, cancer-related gene mutation/translocation status, 
expression of cancer-related gene products, and cancer-related viral infection, etc.) will be 
obtained by the investigator or qualified designee.
7.1.1.5.1 Molecular Testing
Site must be able to provide documentation of subject’s tumor EGFR mutation and ALK 
translocation status (Part B and D only). If the site is unable to provide this source 
documentation, then the Sponsor will offer this molecular testing of the tumor (Part B only). 
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
 
 
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7.1.1.6
Prior and Concomitant Medications Review
7.1.1.6.1 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 therapy. In addition, record all treatments for a prior 
cancer other than the current cancer even if taken greater than 30 days prior to starting the 
trial therapy. Prior treatments for the current cancer will be recorded separately and not 
listed as a prior medication (See Section 7.1.1.7.2).
7.1.1.6.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial from start of study treatment through the 30-day safety follow-up visit. After 
the safety follow-up visit record all medications related to reportable SAEs as defined in 
Section 7.2.
7.1.1.7
Solid Tumor and NSCLC/SCLC Disease Details and Prior Treatments
7.1.1.7.1 Disease Details
The investigator or qualified designee will obtain prior and current solid tumor and 
NSCLC/SCLC disease details.
7.1.1.7.2 Prior Treatment
The investigator or qualified designee will review all prior treatments for current solid tumor 
and NSCLC/SCLC including systemic treatments, radiation and surgeries.
7.1.1.8
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. After the approval of the protocol version 08, 
the final visit of this study will be a safety follow-up visit 30 days after the last dose, and 
survival follow-up will not be performed. Participants in the follow-up phase or survival 
follow-up phase will discontinue the study and no further visits are required.
7.1.1.9
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 treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.  Any subject who is screened multiple times will retain the original 
screening number assigned at the initial screening visit.
 
 
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7.1.1.10 Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, to trial treatment and will 
receive a randomization number.  The randomization number identifies the subject for all 
procedures occurring after treatment allocation.  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.
7.1.1.11 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.
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 pembrolizumab will be provided in the
Pharmacy Manual.
Cisplatin, pemetrexed, carboplatin, paclitaxel, nab-paclitaxel, etoposide and ipilimumab will 
be prepared and administered as per the approved product label.
7.1.2
Clinical Procedures/Assessments
7.1.2.1
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new
or worsening adverse Events as specified in the Trial Flow Chart and more frequently if 
clinically indicated. Adverse events will be graded and recorded throughout the study and 
during the follow-up period according to NCI CTCAE Version 4.0. 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. Certain irAEs should also be reported to the Sponsor. 
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
 
 
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7.1.2.2
Physical Exam
The investigator or qualified designee will perform a complete physical exam at screening, 
prior to the administration of trial treatment (including Day 22 of each cycle in part D), 
discontinuation visit, safety follow-up visit and follow up visit 1 and 2. In addition, in Part E, 
the investigator or qualified designee will perform a complete physical exam before dosing 
etoposide on Day 2 and 3 of each cycle. Clinically significant abnormal findings at screening 
should be recorded as medical history. After the first dose of trial treatment new clinically 
significant abnormal findings should be recorded as AEs.
7.1.2.3
Height, Weight, and Vital Signs
The investigator or qualified designee will take weight and vital signs at screening, Cycle 1 
Day 1 (pre-dose), Day 8, Day 15, Day 22 (Part A and Part D), and pre-dose of trial treatment
in every cycle (including Day 22 of each cycle in Part D), discontinuation visit, and safety 
follow-up visit. In addition, in Part E, the investigator or qualified designee will take weight 
and vital signs before dosing etoposide on Day 2 and 3 of each cycle.

Height (screening visit only)

Weight 
o
If a subject’s weight at screening does not fluctuate by more than 10%, this 
weight can be used to calculate dose.

Vital signs
o
Temperature
o
Pulse (in a sitting position)
o
Respiratory rate 
o
Blood pressure (in a sitting position)
7.1.2.4
12-lead ECG
A standard 12-lead ECG will be performed using local standard procedures.
Part A: at screening, pre-dose in every other cycle, discontinuation visit, and safety follow-up 
visit.
Part B, C, D and E: at screening and end of cycle 1 (pre-dose of cycle 2). An additional 
measurement will be performed as needed by investigator’s judgment.
Clinically significant abnormal findings at screening should be recorded as medical history.  
After the first dose of trial treatment new clinically significant abnormal findings should be 
recorded as AEs.
 
 
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7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG status (see Section 12.4) at 
screening, prior to the Day 1 administration of trial treatment in every cycle (part A, B, C and 
E), prior to the Day 1 and Day 22 administration of trial treatment in every cycle (part D), 
discontinuation visit, safety follow-up visit, and Follow up visit 1 and 2..
7.1.2.6
Pulse Oximetry (SpO2)
Pulse oximetry (SpO2) will be performed using local standard procedures once at screening, 
prior to the administration of each dose of trial treatment (including Day 22 of every cycle in 
Part D), at discontinuation visit, at safety follow-up visit, at Follow-up Visit 1 and at Follow-
up visit 2.
7.1.3
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The approximate blood/tissue volumes drawn/collected by visit and by 
sample type per subject can be found in Procedure manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis and Other)
Laboratory tests for hematology, chemistry, urinalysis and others are specified in Table 7.
Table 7
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Adrenocorticotropic 
hormone (ACTH) level*
Blood
PT (INR)
Hemoglobin
Albumin
Glucose
aPTT
Platelet count
Alkaline phosphatase
Protein
Free triiodothyronine
(T3)
WBC (total and 
differential)
Alanine 
aminotransferase (ALT)
Specific gravity 
Free thyroxine (T4)
Red blood cell count
Aspartate 
aminotransferase (AST)
Microscopic exam, if 
abnormal results are 
noted
Thyroid stimulating 
hormone (TSH)
Absolute neutrophil
Count
Lactate dehydrogenase
(LDH)
Serum/Urine β-human 
chorionic gonadotropin (β-
hCG)
Absolute lymphocyte 
count
CRP
HIV antibody
Creatinine or calculated
creatinine clearance 
(CrCl)
HBsAg
Uric acid
HCV RNA
Calcium
KL-6
Chloride
SP-D
Glucose
-D glucan
Phosphorus
 
 
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Hematology
Chemistry
Urinalysis
Other
Potassium
Sodium
Magnesium
Total bilirubin
Direct and indirect
Bilirubin
Total protein
Blood urea nitrogen
Total cholesterol
Triglycerides
* ACTH; Part D only
Laboratory tests (hematology, serum chemistry, urinalysis, coagulation parameters, thyroid
function, KL-6, SP-D and β-D glucan) for screening should be performed within 14 days 
prior to the first dose of trial treatment. Laboratory tests (hematology, serum chemistry, 
urinalysis, thyroid function, KL-6 and SP-D) may be collected up to 48 hours prior to dosing 
[if a subject receives nab-paclitaxel, laboratory tests on Day 8 and Day 15 of each Q3W 
cycle is required only for hematology. If a subject participates in Part D includes laboratory 
tests (except ACTH) on Day 22 of each cycle (refer to 6.2.2 in detail).] in every cycle and the 
scheduled time point in Cycle 1.  The investigator or qualified designee must review the 
result and confirm acceptability of continuation of trial treatment at pre-dose in every cycle.
PT/INR and aPTT will be collected as coagulation parameters.
TSH, FT3, and FT4 will be measured for thyroid function test.
Testing for HCV RNA (qualitative), HBsAg, and HIV 1/2 antibodies will be performed at 
screening. If results of these tests obtained within 3 months before screening are available, 
they can be used even before consent is obtained.
For women of reproductive potential, a urine/serum pregnancy test will be performed within 
72 hours of the first dose.  If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required.
KL-6 and SP-D is a lung-specific marker for pneumonitis [30, 31]. β-D glucan is a marker 
for fungus infectious disease [32], and is used for the differential diagnosis for pneumonitis.  
KL-6, SP-D and β-D glucan will be measured at screening and prior to dosing in every 
cycle(In Part D, Day 1 and Day 22 in each cycle) (only for KL-6 and SP-D), and if a subject 
develops suspected pneumonitis, an additional test will be performed as needed by 
investigator’s judgment. 
(Part D only) ACTH will be measured at screening, pre-dose of Day 1 of Cycle 2 to Cycle 18,
discontinuation visit and Safety Follow-up Visit. An additional test will be performed as 
needed by investigator’s judgment.
 
 
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7.1.3.2
Pharmacokinetic / Anti-pembrolizumab Antibodies /Evaluations
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure in this 
indication, and also to evaluate exposure of the proposed dosing regimen, sample collections 
for analysis of anti-drug antibodies (ADA) and PK are currently planned as shown in Section 
7.1.3.2.1 and 7.1.3.2.2. If ongoing ADA and PK results continue to be consistent with 
existing ADA and PK data from other pembrolizumab clinical trials, it may be decided to 
discontinue or reduce further sample collection in this study, which will be communicated by 
administrative memo.
7.1.3.2.1 Blood Collection for Serum Pharmacokinetics of MK-3475
Serum samples for pharmacokinetics will be obtained at the following points. 3.5 mL blood 
will be collected at each point. Every effort should be made to collect additional blood 
samples for pharmacokinetics after the discontinuation visit for up to 6 months from the last 
dose of pembrolizumab or until start of a new anti-cancer therapy, whichever occurs first.
Serum samples for pharmacokinetic measurements will be discontinued after the completion 
of discontinuation visit after the final dose after approval of the protocol version 08. Serum 
sample preparation, storage and shipment instructions for serum samples will be provided in 
the Procedure Manual.
Table 8
Sampling Points for Pharmacokinetics in Part A
Sampling Point
Time window
Cycle 1
Pre-dose (Day 1)
Within 60 min prior to start of infusion
30 mins after completion of infusion (Day 1)
Within 30 min after completion of 
infusion
6 hours after completion of infusion (Day 1)
±30 min
24 hours after completion of infusion (Day 2)
±2 hours
48 hours after completion of infusion (Day 3)
±2 hours
168 hours after completion of infusion (Day 8)
±2 hours
336 hours after completion of infusion (Day 15)
±2 hours
504 hours after completion of infusion (Day 22)
±2 hours
Cycle 2 and the additional Cycles during the first 12 months of study therapy
Pre-dose (Day 1) in every other cycle
Within 60 min prior to start of infusion
Post-dose (Day 1) in every other cycle
Within 30 min after completion of infusion
Discontinuation
Safety follow-up visit
30 days after the last dose
±3 days 
Fol1ow-up visit 1
3 months after the last dose
±7 days
Follow-up visit 2
6 months after the last dose
±7 days
 
 
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Table 9
Sampling Points for Pharmacokinetics in Part B, C and E
Sampling Point
Time window
Cycle 1
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
30 minutes after completion of infusion (Day 1)
Within 30 min after completion of infusion
24 hours after completion of infusion (Day 2)
±2 hours
96 hours after completion of infusion (Day 5)
(72 or 120 hours is acceptable) 
±2 hours
336 hours after completion of infusion (Day 15)
±24 hours
Cycle 2
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Cycle 4
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Cycle 6
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Cycle 8 and every 4 cycles thereafter
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
30 minutes after completion of infusion (Cycle 8 Day 1
only)
Within 30 minutes after completion of infusion
Discontinuation
Table 10
Sampling Points for Pharmacokinetics in Part D
Sampling Point
Time window
Cycle 1
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
30 minutes after completion of infusion (Day 1)
Within 30 minutes after completion of infusion
24 hours after completion of infusion (Day 2)
±2 hours
96 hours after completion of infusion (Day 5)(72 or 
120 hours is acceptable) 
±2 hours
336 hours after completion of infusion (Day 15)
±24 hours
Pre-dose (Day 22)
±24 hours
Cycle 2
Pre-dose (Day 22)
±24 hours
Cycle 3
Pre-dose (Day 22)
±24 hours
Cycle 4
Pre-dose (Day 22)
±24 hours
30 minutes after completion of infusion (Day22)
Within 30 minutes after completion of infusion
Every 2 cycle thereafter
Pre-dose (Day 22)
±24 hours
Discontinuation
 
 
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7.1.3.2.2 Blood Collection for Serum Anti-pembrolizumab Antibodies
Serum samples for serum anti-pembrolizumab antibodies will be obtained at the following
points. 5 mL blood will be collected at each point. Every effort should be made to collect 
additional blood samples for anti-pembrolizumab antibodies after the discontinuation visit for 
up to 6 months from the last dose of pembrolizumab or until start of a new anti-cancer 
therapy, whichever occurs first.  Blood samples collection for anti-pembrolizumab antibodies
measurements will be discontinued after the completion of discontinuation visit after 
approval of the protocol version 08. Serum sample preparation, storage and shipment 
instructions for serum samples will be provided in the Procedure Manual.
Table 11
Sampling Points for Anti-pembrolizumab Antibodies in Part A
Sampling Point
Time window
Cycle 1
Pre-dose on Day 1
Within 24 hours prior to start of infusion
Cycle 2 and the additional Cycles during the first 12 months of study therapy
Pre-dose on Day 1 in every other cycle
Within 24 hours prior to start of infusion
Discontinuation
Safety follow-up visit
30 days after the last dose
±3 days 
Follow-up visit 1
3 months after the last dose
±7 days
Follow-up visit 2
6 months after the last dose
±7 days
Table 12
Sampling Points for Anti-pembrolizumab Antibodies in Part B, C, and E
Sampling Point
Time window
Cycle 1
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Cycle 2
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Cycle 4
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Cycle 6
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Cycle 8 and every 4 cycles thereafter
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Discontinuation
 
 
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Table 13
Sampling Points for Anti-pembrolizumab Antibodies in Part D
Sampling Point
Time window
Cycle 1
Pre-dose (Day 1)
Within 24 hours prior to start of infusion
Pre-dose (Day 22)
Within 24 hours prior to start of infusion
Cycle 2
Pre-dose (Day 22)
Within 24 hours prior to start of infusion
Cycle 3
Pre-dose (Day 22)
Within 24 hours prior to start of infusion
Cycle 4
Pre-dose (Day 22)
Within 24 hours prior to start of infusion
Every 2 cycle thereafter
Pre-dose (Day 22)
Within 24 hours prior to start of infusion
Discontinuation
7.1.3.3
Tumor Marker
Standard tumor markers (as appropriate for a given tumor type) will be collected within 14 
days prior to the first dose of study treatment, and at the same timing as tumor imaging 
thereafter.
7.1.3.4
Tumor Imaging and Assessment of Disease (irRC and irRECSIT)
The tumor imaging (CT or MRI) for screening should be performed within 28 days prior to 
the first dose of trial treatment in Part A, B, C, D and E. Scans performed as part of routine 
clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the first dose of trial treatment. The same 
imaging technique must be used for a subject throughout the study.
In Part A, tumor imaging should be performed every 6 calendar weeks (42 days±7 days) after 
the first dose of study treatment in treatment period.  In Part B, C, D and E, tumor imaging 
should be performed every 6 calendar weeks (± 7days) for the first 24 weeks, and every 9 
calendar weeks (± 7 days) from the date of imaging assessment at the week 24. Tumor 
imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts or extension of pembrolizumab (ipilimumab in part D) cycle frequencies.  Tumor 
response by the study sites will be assessed using irRC (see Section 12.6) and RECIST ver. 
1.1 (see Section 12.5) in Part A, and irRECIST in Part B, C, D and E.  In irRECIST, after 
initial PD based on RECIST 1.1 is identified, a subject may continue treatment if clinically 
stable, at the discretion of the investigator. An additional imaging ≥4 week later is needed to 
confirm PD.  If PD is not confirmed, treatment can continue.  Please see below and Section 
12.5.1 for more precise instruction.
After the first documentation of progression per irRC (Part A) or RECIST 1.1 (Part B, C, D 
and E), 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 4 weeks later 
 
 
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confirms progression using irRECIST.  When feasible, subjects should not be discontinued 
until progression is confirmed per irRC (Part A) or irRECIST (Part B, C, D and E).  
NOTE:  If a subject with confirmed the first radiographic progression based on irRC (Part 
A) or RECIST 1.1 (Part B, C, D and E) is clinically stable or clinically improved, and 
there is no further increase in the tumor dimensions at the confirmatory scan, an 
exception may be considered to continue treatment.  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.
4）Absence of rapid progression of disease
Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation. If progression is confirmed at the subsequent scan, then the subject will be 
discontinued from trial treatment unless, if in the opinion of the investigator, the subject is 
deriving clinical benefit and upon consultation with the Sponsor. If progression is not 
confirmed at the subsequent scan, then the subject should resume/continue trial treatment and 
have their next scan according to the every 6 week (42 ± 7 days, in Part A) or every 6 
calendar weeks (63 ± 7 days) for the first 24 weeks, and every 9 calendar weeks (63 days ±7 
days) from the date of imaging assessment at the week 24 thereafter (in Part B, C, D and E) 
schedule.
Regarding imaging and treatment determinations after the first radiological evidence of 
progression, see Table 14.
 
 
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Table 14
Imaging and Treatment Determinations After First Radiological Evidence of 
PD (based on irRC in Part A or RECIST 1.1 in Part B, C, D and E)
Imaging and Treatment Determinations After First Radiological Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st
radiologic 
evidence of PD
Repeat imaging at 

4 
weeks 
to 
confirm PD
May continue study 
treatment 
at 
the 
Investigator’s 
discretion 
while 
awaiting 
confirmatory scan
Repeat imaging at 

4 
weeks 
to 
confirm 
PD 
if 
possible.
Discontinue treatment
Repeat 
scan 
confirms PD
No 
additional 
imaging 
required 
if 
Investigator 
does 
not 
see 
benefit. 
 
If 
Investigator 
sees 
benefit, 
continue 
regularly 
scheduled imaging 
assessments 
May 
continue 
treatment 
if 
Investigator considers 
subject 
deriving 
clinical benefit
No 
additional 
imaging required
N/A
Repeat 
scan 
shows SD, PR or 
CR
Continue regularly 
scheduled imaging 
assessments
Continue 
study 
treatment 
at 
the 
Investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments
May 
restart 
study 
treatment if condition has 
improved and/or clinically 
stable per Investigator’s 
discretion.
Next 
tumor 
image 
should 
occur 
according to the regular 
imaging schedule outlined 
in the protocol
In Part B, C, D and E, subjects who discontinued study treatment due to other than disease 
progression should be obtained imaging every 6 calendar weeks (± 7days) after the first dose 
for the first 24 weeks, and every 9 calendar weeks (± 7 days) from the date of imaging 
assessment at the week 24 by radiologic imaging to monitor disease status until the subject 
experiences disease progression or initiation of a new therapy for cancer. After the approval 
of the protocol version 08, all follow-up including imaging follow-up will be discontinued 
after the completion of the 30 days follow-up visit.
Subjects who move into the Second Course Phase will continue to have scans performed 
every 9 weeks (63 ± 7 days) after the first dose of Second Course Phase trial treatment for 
Year 1 and every 12 weeks (84 ± 7 days) thereafter.
Central imaging vendor will receive radiographic images for tumor volumetric analysis (in 
Part A) and RECIST 1.1 (in Part B and C). However, images taken after July 20, 2019 need 
not be submitted to the central vendor.
 
 
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7.1.3.5
Pulmonary Radiographic Evaluation for pembrolizumab-Induced Pneumonitis
Pulmonary radiographic imaging is used in a diagnosis of pembrolizumab-induced 
pneumonitis.  A chest CT performed for tumor imaging may be used for pulmonary 
radiographic evaluation. For a subject with suspected pneumonitis based on respiratory
symptoms, other clinical findings or laboratory findings, a chest CT should be performed 
immediately.  If a finding on pneumonitis is observed, the subject should be followed every 
month with chest imaging to monitor the pneumonitis.
Pulmonary radiographic evaluation will be performed according to the table in Section 6.0. 
The investigator or sub-investigator will judge whether the variation after the study drug 
administration is an adverse experience or not and record it in the Case Report Form.
Additionally, an independent radiologist will review chest CTs of all subjects for pulmonary 
radiographic evaluation.  For that purpose, the chest CT imaging will be submitted to the 
SPONSOR. However, images taken after July 20, 2019 need not be submitted.
In Part C, D and E, the sponsor will confirm the eligibility for exclusion criteria 15 in section 
5.1.3 before randomization. After obtaining consent by the subject, the site staff will send the 
screening scan to the sponsor. Refer to the Procedures manual for details.
7.1.3.6
Tumor Tissue Collection
Part A 
Tumor tissue from an archival tissue sample or fresh biopsy of a tumor lesion not previously 
irradiated will be used for PD-L1expression analysis by IHC.
A fine needle aspirate or 
cytological specimen will not be acceptable.
If the subject signs the Future Biomedical 
Research (FBR) consent, an aliquot of the tissue biopsies will be designated for FBR.
Part B, C, D and E
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 unstained slides and received by the central 
vendor for PD-L1 expression analysis by IHC (mandatory for part B and C. optional for part 
D and E). Fine needle aspirates, Endobronchial Ultrasound-guided transbronchial needle
aspiration (EBUS-TBNA) or cell blocks are not 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 (Part B and D only).
 
 
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7.1.3.7
Blood Collection for Correlative Studies and Biomarker Samples 
Details regarding time points for blood collection are outlined in the Trial Flow Chart –
Section 6.2.1, 6.2.2 and 6.2.3.
Detailed instructions for blood collection, processing and shipment are provided in the 
Procedures Manual.
7.1.3.8
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedure Manual.
7.1.3.9
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:
Part A

Blood for genomics use

An aliquot of the Fresh Tumor Biopsy and/or Archival Tumor Tissue collected from 
the main study.

Leftover Fresh Tumor Biopsy and/or Archival Tumor Tissue from the main study.
Part B, C, D and E

Leftover DNA for future research

Leftover Fresh Tumor Biopsy and/or Archival Tumor Tissue from the main study.
7.1.4
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
The investigator or trial coordinator must notify the Sponsor when a subject has been 
discontinued/withdrawn from the trial.  If a subject discontinues for any reason at any time 
during the course of the trial, the subject may be asked to return to the clinic (or be 
contacted) for a post-trial visit (approximately 14 days after the last dose of trial drug is 
performed to have the applicable procedures conducted.  However, the investigator may 
decide to perform the post-trial procedures at the time of discontinuation or as soon as 
possible after discontinuation.  If the post-trial visit occurs prior to 14 days after the last dose 
of trial drug is performed, the investigator should perform a follow-up phone call at 14 days 
post the last dose of trial drug to determine if any adverse events have occurred since the 
post-trial clinic visit.  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.
 
 
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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 
writing to the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit. If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (e.g. phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the pre-specified data handling and analysis guidelines
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Domiciling
In principle, subjects will be hospitalized for DLT evaluation period.
 
 
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7.1.5
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
UP to 28 days prior to first dose of trial treatment, 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 (hematology, serum chemistry, urinalysis, coagulation parameters, 
thyroid function test, KL-6, SP-D and β-D glucan) for screening should be performed 
within 14 days prior to the first dose of trial treatment.

Standard tumor markers (as appropriate for a given tumor type) will be collected within 
14 days prior to the first dose of study treatment.

For women of reproductive potential, a urine/serum 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 will be required.

If results of HCV RNA (qualitative), HBsAg, and HIV 1/2 antibodies test obtained 
within 3 months before screening are available, they can be used even before consent is 
obtained.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.
Results from assessments performed during the initial screening period are acceptable in lieu
of a repeating a screening test if performed within the specified time frame and the results
meet the inclusion/exclusion criteria.
7.1.5.2
Treatment Period
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related
details are provided above in Section 7.1 - Trial Procedures.  Subject will be received study 
treatment until the subject meets 5.8 Discontinuation criteria.
7.1.5.3
Discontinuation
If a subject discontinues trial treatment, procedures for discontinuation will be conducted.
 
 
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7.1.5.4
Follow-up phase
7.1.5.4.1 Mandatory Safety Follow-Up Visit
The mandatory safety follow-up visit will 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.
7.1.5.4.2 Observation visit
Subjects who discontinue trial treatment for a reason other than disease progression during 
Treatment Phase or Second Couse Phase will move into the Observation Phase. The subject 
should continue the tumor imaging every 6 calendar weeks (± 7days) for the first 24 weeks, 
and every 9 calendar weeks (± 7 days) from the date of imaging assessment at the week 24
thereafter (Part B, C, D and E) to monitor disease status until radiologic progression. Once 
the subject stops the imaging assessments and then initiates a new antineoplastic therapy, the 
subject moves into the survival follow-up phase. After the approval of the protocol version 
08, all follow-up including imaging follow-up will be discontinued after the completion of 
the 30 days of follow-up visit.
7.1.5.4.3 Follow-Up Visit 1 and 2
Subjects who completed the safety follow-up visit will move to follow-up visit 1 and 2 to 
collect serum samples for pharmacokinetics and anti-pembrolizumab antibodies. Follow-up 
visit 1 and 2 will be conducted 3 months and 6 months after the last dose of trial treatment, 
respectively, or until beginning of a new antineoplastic treatment, whichever comes first.
After the approval of the protocol version 08, all follow-up, including serum or blood sample 
collection for pharmacokinetic or anti-MK-3475 antibody assessment, will be discontinued 
after the 30 days follow-up visit.
7.1.5.5
Survival Follow-up (Part B, C, D and E)
Once a subject experiences PD or initiates new antineoplastic therapy, the subject moves to 
survival follow-up phase and followed by telephone every 2 months from the last contact in 
the study for survival. Post-study treatments and the subject’s response to them will also be 
collected. The Sponsor may request survival status to be assessed and its respective entry into 
the database at additional time points during the course of the study (ex. around the projected 
analysis). After approval of the protocol version 08, the final visit of this trial will be a safety 
follow-up visit and no follow-up for survival will be conducted. Participants in the follow-up 
phase or survival follow-up phase will discontinue the study and no further visits are required.
7.1.5.6
Second Course Phase (Part B, C, D and E only)
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related
details are provided above in Section 7.1 - Trial Procedures. Patients may be eligible to 
receive MK-3475 only (in part D, MK-3475 +ipilimumab) in the Second Course Phase of 
 
 
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this study for up to 12 months if the subject meet the following conditions.  Patients who 
have already started the second course phase of administration before the approval of the 
protocol version 08, may continue in the second course phase (up to 12 months) is applicable.  
For other patients, the second course phase is not applicable.

Stopped their initial treatment with pembrolizumab(in part D, pembrolizumab
+ipilimumab) after attaining an investigator determined confirmed CR according to 
RECIST 1.1, were treated for at least six months with pembrolizumab, and received at 
least two treatments with pembrolizumab beyond the date when the initial CR was 
declared. A CR by RECIST 1.1 means that all target lesions have resolved, all non-target
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. 
OR 

Had SD, PR or CR and stopped pembrolizumab treatment after 24 months (In Part D, 35 
times) of study therapy for reasons other than disease progression or intolerability 
AND

Experienced an investigator-determined radiographic disease progression after stopping 
their initial treatment with pembrolizumab (in part D, pembrolizumab +ipilimumab)  

Did not receive any-cancer treatment since the last dose of pembrolizumab (in part D, 
pembrolizumab+ ipilimumab)  

Continues to meet inclusion criteria 3, 4, 7 to 9.

Does not meet exclusion criteria 4, 5, 11, 13 to 20
Subjects who receive pembrolizumab plus ipilimumab may be eligible to receive up to 17 
additional trial treatments of pembrolizumab plus 9 cycles of ipilimumab in the Second 
Course Phase; subjects will receive the treatment regimen that was assigned at the last 
administration in initial treatment (i.e., if ipilimumab was discontinued early in initial 
treatment at the investigator’s discretion and the subject continued on pembrolizumab 
monotherapy for any length of time, they would only be eligible for monotherapy 
pembrolizumab in Second Course Phase). Additionally, investigators may choose to 
administer pembrolizumab only for the Second Course Phase treatment and forego the 
ipilimumab for the entire Second Course Phase even if the 18 course of ipilimumab and
pembrolizumab is completed..
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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7.1.5.7
Critical Procedures Based on Trial Objectives: Timing of Procedure 
For this trial, the blood sample for MK-3475 is the critical procedure. 
At any post-dose time points, the blood sample for MK-3475 needs to be collected as close to 
the exact time point as possible.  All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Trial procedures can be performed prior or after the 
prescribed/scheduled time.  
The order of priority can be changed during the trial with joint agreement of the investigator 
and the Sponsor Clinical Monitor.  
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures.  
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
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 
 
 
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will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
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.
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for study therapy: five times the pembrolizumab and three times the ipilimumab dose or 
more than 20 % of the chemotherapy regimen. No specific information is available on the 
treatment of overdose of study therapy. In the event of overdose, study therapy should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported 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).
7.2.2
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 
 
 
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not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor 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).
7.2.3
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);
●
Is associated with an overdose.
Refer to Table 15 for additional details regarding each of the above criteria.
 
 
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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:
2. 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. 
3. 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.
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study
7.2.4
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
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 15
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 
test drug 
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 U.S. CLINICAL 
MONITOR 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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7.2.5
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
7.3
TRIAL GOVERNANCE AND OVERSIGHT
7.3.1
Efficacy and Safety Evaluation Committee
The Efficacy and Safety Evaluation Committee (ESEC) will be established for the purpose of 
evaluating the safety information of this study from the specialist and objective viewpoints to 
ensure the safety of subjects.
The details of the ESEC are prescribed by separate instructions.
7.3.2
Independent Pulmonary Radiographic Adviser
An independent pulmonary radiographic adviser will review pulmonary radiographic 
changes and its features using chest CT imaging.
The details of the independent pulmonary radiographic adviser are prescribed by separate 
instructions.
8.0 STATISTICAL ANALYSIS PLAN
8.1
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).
The primary purpose of this study is to evaluate the safety and tolerability of pembrolizumab
alone in subjects with advanced solid tumors and in combination with platinum-doublet 
chemotherapy in subjects with advanced NSCLC or ED-SCLC, or in combination with 
immunotherapy in subjects with advanced NSCLC.
DLT will be tabulated. Summary statistics for frequency, duration, grade, and time to onset 
of first DLT in each dose level will be provided. Adverse events will be summarized by 
tabulating the number (%) of subjects experiencing at least one adverse event within each 
system organ class and within each preferred term. Additionally, ECOG performance status, 
laboratory tests, vital signs, physical examinations, chest CT imaging, and 12-lead ECGs 
parameters will be summarized for each dose level/ cohort.
Summary statistics will be provided by dose levels/ cohort for the pharmacokinetic 
parameters (AUC0-28days, Cmax, Tmax, Ctrough, t1/2, etc.) of pembrolizumab.  Response categories 
for target and non-target lesions for subjects with advanced solid tumors or NSCLC/ED-
SCLC (complete response, partial response, progressive disease, and stable disease) will be 
 
 
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tabulated across the various doses levels/ cohort. Exploratory analysis will be provided on 
the correlation between PD-L1 expression levels and tumor response.
There will be totally approximately 84 subjects [9-12 for Part A , 12-18 each for Part B, C 
and E (cohort 1 and 2), 6-9 for part D, 3-9 for Part E cohort 3] enrolled in this study for 
safety and tolerability assessment.
8.2
Statistical Analysis Plan
There are no plans to issue a separate Statistical Analysis Plan (SAP) for this trial. If, after
the trial has begun, important changes are made that affect principal features of the primary 
or key secondary analyses, then the protocol will be amended, as appropriate (consistent with 
ICH Guideline E-9). Any other changes made to the planned analyses after the protocol has 
been finalized, along with an explanation as to when and why they occurred, will be listed in 
the Clinical Study Report (CSR) for the trial. Post hoc exploratory analyses will be clearly 
identified in the CSR.
8.2.1
Responsibility for Analyses
The statistical analysis of the data obtained from this trial will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This trial is being conducted as an open-label trial (i.e. subjects, investigators, and 
SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned).
8.2.2
Trial Objectives
See Section 3.0 for primary objectives.
8.2.3
Variables/Time Points of Interest
8.2.3.1
Safety Endpoints
Safety and tolerability will be assessed by a clinical review of all relevant adverse 
experiences and monitoring variables relates to complete blood count, chemistry panel,
urinalysis, 12-lead ECG, pulmonary radiographic findings, vital signs, physical examinations
and ECOG performance status.
Primary Endpoints
The primary endpoint in this study is the incidence of DLTs observed in the DLT evaluation 
period in Japanese subjects according to the “Guideline for clinical evaluation method of 
anti-malignant tumor agents [27]”.
 
 
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Other Major Variables

Vital signs

Physical examination

ECOG performance status

12-lead ECG

Pulmonary radiographic findings

Adverse events

CBC with differential

Serum chemistry

Urinalysis
All toxicities will be graded and recorded according to the NCI-CTCAE version 4.0.
8.2.3.2
Efficacy Endpoints

Overall Response Rate (ORR): defined as the proportion of the subjects in the
analysis population who have a complete response (CR) or partial response (PR).

Duration of Overall Response (DOR): defined as the time from first documented
evidence of CR or PR until disease progression or death.

Progression–free survival (PFS): defined as the time from allocation to the first 
documented disease progression or death due to any cause, whichever occurs first. 

Overall Survival (OS): defined as the time from allocation to death due to any
cause.

Correlation between PD-L1 expression levels and tumor response 
The immune related Response Criteria (irRC, in Part A), irRECIST (Part B, C, D and E), the 
RECIST ver.1.1, and tumor volumetric analysis (Part A) will be applied for evaluation of 
tumor response. 
8.2.3.3
Pharmacokinetic Endpoints

Pharmacokinetic parameters of pembrolizumab (AUC0-28days, Cmax, Tmax, Ctrough, t1/2, 
etc.) 

In part B, C, D and E, pharmacokinetic parameters of pembrolizumab (Cmax, Tmax, 
Ctrough, etc.)
 
 
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8.2.3.4
Immunogenicity Endpoints

Anti-pembrolizumab antibody
8.2.4
Analysis Populations
8.2.4.1
Safety Analysis Populations
The All Treated Set (ATS) population will be used for the analysis of safety data in this trial. 
The ATS population consists of all allocated subjects who received at least one dose of 
treatment dose. Subjects will be included in the dose level corresponding to the treatment
dose they actually received for the analysis of safety data using the ATS population.  
At least one laboratory, 12-lead ECG or vital sign measurement obtained subsequent to at 
least one dose of treatment dose is required for inclusion in the analysis of each specific
parameter. To assess change from baseline, a baseline measurement is also required.
8.2.4.2
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this trial. The FAS population is a subset of all allocated subjects with 
subjects excluded for the following reasons:

Failure to receive at least one dose of treatment dose
The pharmacokinetics analyses will be based on subjects who have evaluable PK
measurements at baseline and at least once during treatment. No explicit imputation was 
made for missing data.
8.2.5
Statistical Methods
The following analysis is applied to both Part A, B, C, D and E.
8.2.5.1
Safety Analyses
Frequencies of DLTs during the DLT evaluation period [the first 4 weeks (Part A) or 3 weeks 
(Part B, C and E) or 6 weeks (Part D) after initiation of study treatment] will be summarized by 
tabulating by Part (by dose level in Part A and by cohort in Part B, C and E). Tables of summary 
statistics (mean, standard deviation, median, and range) for time to onset and duration of the first 
grade DLT AEs will be provided. Laboratory assessments will be summarized.  Adverse events 
will be summarized by tabulating the number (%) of subjects experiencing at least one adverse 
event within each system organ class and within each preferred term. Complete blood count, 
chemistry panel, urinalysis,
pulmonary radiographic change
findings, adverse events, 
electrocardiogram, vital signs, physical examination and ECOG PS will be summarized.
 
 
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8.2.5.2
Pharmacokinetics Analyses
In part A, summary statistics (mean, standard deviation, and range) will be provided for
pharmacokinetics measures (AUC0-28days, Cmax, Tmax, Ctrough, t1/2, etc.) of MK-3475 and 
appropriate plots will be generated on pharmacokinetic profiles. In part B, C, D and E, 
summary statistics (mean, standard deviation, and range) will be provided for 
pharmacokinetics measures (Cmax, Tmax, Ctrough, etc.) of pembrolizumab and appropriate 
plots will be generated on pharmacokinetic profiles.  A population pharmacokinetic analysis 
will be conducted using the serum concentration of pembrolizumab obtained in the study as 
needed.
8.2.5.3
Efficacy Analyses
Overall objective response rate and its 95% confidence interval using the exact method will 
be provided. Response categories for target and non-target lesions for subjects with advanced 
solid tumors or NSCLC/ED-SCLC (complete response, partial response, progressive disease, 
and stable disease), PFS and OS will be tabulated across the various doses levels/cohorts.
Response duration will be summarized descriptively using Kaplan-Meier method.
An exploratory analysis of a potential correlation between PD-L1 expression levels and 
tumor response will be performed as appropriate. 
8.2.6
Multiplicity
Since the primary objective of this trial is to estimate safety and tolerability of 
pembrolizumab alone in subjects with advanced solid tumors and in combination with 
platinum-doublet chemotherapy or immunotherapy in subjects with advanced NSCLC/ED-
SCLC, no formal statistical hypothesis is tested. Therefore, no adjustment for multiplicity is 
needed.
8.2.7
Sample Size and Power Calculation
The primary objective for the study is to evaluate the tolerability and safety profile of 
pembrolizumab alone in subjects with advanced solid tumors and in combination with 
platinum-doublet chemotherapy or immunotherapy in subjects with advanced NSCLC/ED-
SCLC.  The primary endpoints for the study are DLT rate. A TPI (toxicity profile interval)
design suggested by Ji et al [29] targeting a 20% DLT rate for Part A and 30% for Part B, C, 
D and E will be employed in safety assessment.  Dose escalation/tolerability evaluation rules
for Part A and Part B, C, D and E were described in 5.2.1.2.  For DLT evaluation, 3 to 6
subjects for each dose level in Part A and 3 to 9 subjects for each part/cohort are required in 
Part B, C, D and E. The total number of evaluable subjects is approximately 84 [9-12 for Part 
A, 12-18 each for Part B, C and Part E (cohort 1 and 2), 6-9 for Part D, 3-9 for Part E cohort 
3]. 
With 6 subjects, the probability of no more than 2 subject developing DLTs will be about 
90.1% and 74.4% for assumed DLT rate 20% and 30% respectively.
 
 
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8.2.8
Interim Analysis
No interim analysis is planned.
8.2.9
Accounting for Missing Data
Analyses will be based on subjects with data available. No explicit imputations will be
made.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 16.  
Table 16
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional 
Information
MK-3475 50 mg *
Lyophilized Powder for 
Infusion
Provided by the Sponsor
MK-3475 100 mg/4 mL *
Solution for Injection
Provided by the Sponsor
Ipirimumab 50 mg/10 mL
Solution for Injection
Provided by the Sponsor
* MK-3475 50 mg and/or 100 mg/4 mL will be provided to the site.
All supplies indicated in Table 16 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 16 will be provided by the trial 
site. Every attempt will be made to source these supplies from a single lot/batch number. The 
trial site will be responsible for recording the lot number, manufacturer and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
 
 
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9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
In Part A, subjects will receive open label pembrolizumab vials every 4 weeks at Cycle 1 and 
every 2 weeks at Cycle 2 and subsequent. In Part B, C, D and E, subjects will receive open 
label vials of pembrolizumab every 3 weeks. In Part D, subjects will receive open label vials 
of ipilimumab every 6 weeks.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.5
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.
 
 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
10.1.1 Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
10.1.2 Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
10.1.3 Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1) name, address, telephone number and e-mail address;
2) hospital or clinic address and telephone number;
3) curriculum vitae or other summary of qualifications and credentials; and
4) other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
 
 
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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.
10.1.4 Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.2 Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor 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.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
 
 
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The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The sponsor also recognizes that documents may need 
to be retained for a longer period if required by local regulatory requirements. All trial 
documents shall be made available if required by relevant regulatory authorities. The 
investigator must consult with and obtain written approval by the Sponsor prior to discarding 
trial and/or subject files.  
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.
 
 
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
 
 
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10.5 Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
10.6 Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided by the Sponsor.
10.7 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 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
 
 
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the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
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of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell 
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Med 1995; 152: 1860-1866.
32. Obayashi T, Yoshida M, Tamura H, et al. Determination of plasma (1/3)- . -D-glucan: a 
new diagnostic aid to deep mycosis. J Med Vet Mycol. 1992; 30: 275–80.
 
 
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12.0 APPENDICES
12.1 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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12.2 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 response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimen(s) collected in this trial as outlined in Section 7.1.3.9 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug. Future Biomedical Research 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 enters and is removed by the body, how a drug works, other 
pathways a drug 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, enhance our understanding of human disease and ultimately improve 
public health through development of novel treatments targeted to populations with the 
greatest need.  All specimens will be used by Merck or designees and research will be 
monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 
to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
 
 
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Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens 
for which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
[Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes.] Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an objective 
to the main trial, this analysis is detailed in the main body of this protocol (Section 8.0 –
Statistical Analysis Plan).  These specimens will be processed, analyzed, and the 
remainder of the specimen will be destroyed.  The results of these analyses will be 
reported along with the other trial results.  A separate specimen will be obtained from 
properly-consented subjects in this protocol for storage in the biorepository for Future 
Biomedical Research.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
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. 
 
 
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At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
 
 
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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 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Merck designated biorepository.  The specimens will be stored under strict 
supervision in a limited access facility which operates to assure the integrity of the 
specimens.  Specimens will be destroyed according to Merck policies and procedures and 
this destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database 
thereby maintaining a separation of subject number and these results.  The separate 
databases are accessible only to the authorized Sponsor and the designated trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
 
 
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data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and 
will be advised that counseling should be made available for all who choose to participate 
in this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
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 
 
 
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obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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12.3 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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12.4 ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically 
strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light housework, 
office work).
2
In bed <50% of the time. Ambulatory and capable of all 
self-care, but unable to carry out any work activities. Up and 
about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any 
selfcare. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group,
Robert Comis M.D., Group Chair.
 
 
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12.5 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.
REFERENCE
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 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
In addition, volumetric analysis will be used for response assessment (so-called enhanced
RECIST).
12.5.1 irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment efficacy 
based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively in part B and C.
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment.  This allowance to continue treatment despite 
initial radiologic progressive disease (PD) takes into account the observation that some 
subjects can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat tumor imaging for confirmation of PD. 
Tumor flare includes any of the following scenarios:
•
Worsening of existing target lesion(s)
•
Worsening of existing non-target lesion(s)
•
Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1.1 as verified by 
central imaging vendor, it is at the discretion of the PI whether to continue a subject on study 
treatment until repeat imaging is obtained (using irRECIST for subject management, see 
Table 14.  This clinical judgment decision by the site investigator should be based on the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.  Subjects may receive study treatment and tumor assessment should be 
repeated ≥ 4 weeks later in order to confirm PD by irRECIST per site assessment.  Clinical 
stability is defined as the following: 
 
 
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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  
4)
Absence of rapid progression of disease
Any subjects deemed clinically unstable should be discontinued from trial treatment and is 
not required to have repeat imaging for PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s).
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST: 
•
Target lesion sum of diameters is < 20 % or < 5 mm absolute increase compared 
to nadir
•
Non-target disease resulting in initial PD is stable or qualitatively improved
•
New lesion resulting in initial PD is stable or qualitatively improved 
•
No incremental new lesion(s) since last evaluation
•
No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the subject continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule. 
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur by 
irRECIST:
•
Target lesion sum of diameters remains ≥ 20% and at least 5 mm absolute 
increase compared to nadir
•
Non-target disease resulting in initial PD is qualitatively worse
•
New lesion resulting in initial PD is qualitatively worse
•
Additional new lesion(s) since last evaluation
•
Additional new non-target lesion progression since last evaluation
 
 
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Confidential 
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
NOTE: If a subject has confirmed radiographic progression (i.e. 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered 
following consultation with the Sponsor. In this case, if treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in sections 6.0
Study Flowchart.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1.1 and 
irRECIST.
 
 
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MK-3475-011-08 Final Protocol
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12.6 Immune Related Response Criteria
For all patients who experience disease progression on study, the date noted for of disease
progression is the time of the scan where it is originally detected, and not the following date
of the confirmatory scan.
Definitions of measurable and non-measurable disease
Measurable disease: Neoplastic masses that can be precisely measured in 2 in-plane
perpendicular diameters. Both its longest diameter and its longest perpendicular must be
greater than or equal to 10 mm or 2 times the axial slice thickness, whichever is greater. 
Lymph nodes must have a short-axis line-length of ≥ 15 mm. Malignant lymph nodes must 
be measurable in 2 perpendicular diameters. Both its longest diameter and its longest 
perpendicular must be greater than or equal to 15 mm or 2 times the axial slice thickness. The 
quantitative endpoint will be defined as the product of the longest diameter with its longest 
perpendicular.
Non-measurable disease: Non-measurable lesions are those that are not suitable for
quantitative assessment over time. These include:
1.
Neoplastic masses that are too small to measure, because their longest uninterrupted
diameter or longest perpendicular are less than 10 mm or two times the axial slice
thickness.
2.
Neoplastic masses whose boundaries cannot be distinguished. This includes masses
which cannot be demarcated from surrounding tissue because of inadequate contrast,
masses with overly complex morphology, or those with highly heterogeneous tissue
composition.
3.
Other types of lesions that are confidently felt to represent neoplastic tissue, but 
difficult to quantify in a reproducible manner. These include bone metastases, 
leptomeningeal
metastases, 
malignant 
ascites, 
pleural/pericardial 
effusions, 
inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, ill defined 
abdominal masses, etc.
For irRC, only target lesions selected at baseline and measurable new lesions are 
taken into account.
At the baseline tumor assessment, the sum of the products of the two largest 
perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 
visceral lesions and five cutaneous index lesions) is calculated.
At each subsequent tumor assessment, the SPD of the index lesions and of new, 
measurable lesions (≥ 5 X 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions 
and 10 visceral lesions) are added together to provide the total time-point tumor burden.
 
 
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Protocol/Amendment No.: 011-08 
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24-Sep-2019
Confidential 
Overall response using irRC:

Complete Response (irCR): Complete disappearance of all tumor lesions (whether
measureable or not, and no new lesions). CR must be confirmed by repeated,
consecutive assessments made no less than 4 weeks from the date first documented.

Partial Response (irPR): Decrease in SPD of 50% or greater by a consecutive
assessment at least 4 weeks after first documentation.

Stable Disease (irSD): Failure to meet criteria for irCR or irPR, in absence of irPD.

Progressive Disease (irPD): At least 25% increase in SPD relative to nadir (minimum 
recorded tumor burden) Confirmation by a repeat, consecutive assessment no less 
than 4 weeks from the data first documented.
Please note other key differences between irRC and the original WHO criteria:

New measurable lesions will be incorporated into the SPD

New non measurable lesions do not define progression but preclude irCR

Non-index lesions contribute to defining irCR (complete disappearance required).
*REFERENCE
IrRC for the current protocol is adopted from the following reference:
Wolchok, JD, Hoos, A, O’Day S, et al., Guidelines for the Evaluation of Immune Therapy
Activity in Solid Tumors: Immune-Related Response Criteria. Clinical Cancer Research,
2009 Dec 1;15(23):7412-20. Epub 2009 Nov 24.
 
 
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Confidential 
13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
13.2 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                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
 
 
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