Clinical trial NCT04967417
Conditions: Non-small Cell Lung Cancer
Sponsor: Samsung Medical Center
Start date: 2022-05-26; Completion date: 2024-12-02
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase II single center, open-label, single arm study in patients with advanced non-small cell lung cancer (stage IV) with brain metastases.

This study will be treated with combination of Pembrolizumab 200mg plus platinum doublet based on histology subtypes.

Detailed description:
This is a Phase II single center, open-label, single arm study in patients with advanced non-small cell lung cancer (stage IV) with brain metastases. Patients will be treated with combination of Pembrolizumab 200mg plus platinum doublet based on histology subtypes. After the 4 cycles of combination phase with cytotoxic chemotherapy, maintenance phase will be followed for maximum of 35 cycles. If the disease progression is observed in CNS only which can be controlled with local treatment, systemic treatment can be continued as beyond disease progression.

Non-squamous cell carcinoma:

4 cycles of pemetrexed 500mg/m2 + carboplatin AUC 5.0 + pembrolizumab 200mg every 3 weeks Followed by pemetrexed 500mg/m2 + pembrolizumab 200mg every 3 weeks up to 35 cycles

Squamous cell carcinoma:

4 cycles of paclitaxel 200mg/m2 + carboplatin AUC 6.0 + pembrolizumab 200mg every 3 weeks Followed by pembrolizumab 200mg every 3 weeks up to 35 cycles

Arms: arm 1: * 4 cycles of pemetrexed 500mg/m2 + carboplatin AUC 5.0 + pembrolizumab 200mg every 3 weeks
* Followed by pemetrexed 500mg/m2 + pembrolizumab 200mg every 3 weeks up to 35 cycles arm 2: * 4 cycles of paclitaxel 200mg/m2 + carboplatin AUC 6.0 + pembrolizumab 200mg every 3 weeks
* Followed by pembrolizumab 200mg every 3 weeks up to 35 cycles
Interventions: intervention 1: Pemetrexed, Carboplatin, Pembrolizumab intervention 2: Paclitaxel, Carboplatin, Pembrolizumab
Intervention descriptions: intervention 1: * Pemetrexed 500mg/m2
* Carboplatin AUC 5.0
* Pembrolizumab 200mg intervention 2: * Paclitaxel 200mg/m2
* Caboplatin AUC 6.0
* Pembrolizumab 200mg

Protocol documents:
Prot_000.pdf: 
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SPONSOR: Myung-Ju Ahn, M.D. 
 
 
TITLE: Pembrolizumab with standard cytotoxic chemotherapy in treatment naïve non -small 
cell lung cancer patients with asymptomatic brain metastases 
 
 
 
 


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Documentation History Page 
 
Version 
Date 
Amendment 
Summary of Amendment 
1.3 
22 February 2021 
Original 
 
2.0 
10 August 2021 
Non-Substantial 
amendment 
Modifications to the 
pregnancy test, 
Addition to Visiting  
2.1 
31 March 2022 
Non-Substantial 
amendment 
Change of Sample 
Collection 
2.2 
26 April 2023 
Non-Substantial 
amendment 
Change of Tumor Imaging, 
Sample Collection 


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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 8 
2.0 
TRIAL DESIGN.......................................................................................................... 8 
2.1 
Trial Design ............................................................................................................. 8 
2.2 
Trial Schema ........................................................................................................... 9 
2.3 
Schedule of Activities ............................................................................................ 10 
3.0 
OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) ............................... 12 
3.1 
Primary Endpoint:  Intracranial response rate by RECIST v1.1 .................... 12 
3.2 
Secondary Endpoint(s) ......................................................................................... 12 
3.3 
Exploratory Objective(s) ...................................................................................... 12 
4.0 
BACKGROUND & RATIONALE .......................................................................... 13 
4.1 
Background ........................................................................................................... 13 
4.1.1 
Pharmaceutical and Therapeutic Background .................................................... 13 
4.1.2 
Preclinical and Clinical Trial Data ...................................................................... 14 
4.2 
Rationale ................................................................................................................ 14 
4.2.1 
Rationale for the Trial and Selected Population ................................................. 14 
4.2.2 
Justification for Dose .......................................................................................... 23 
4.2.3 
Rationale for Endpoints ...................................................................................... 25 
4.2.3.1 
Efficacy Endpoints ....................................................................................... 25 
4.2.3.2 
Planned Exploratory Biomarker Research ................................................... 26 
5.0 
METHODOLOGY ................................................................................................... 27 
5.1 
Study Population ................................................................................................... 27 
5.1.1 
Participant Inclusion Criteria .............................................................................. 27 


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5.1.2 
Participant Exclusion Criteria ............................................................................. 29 
5.1.3 
Lifestyle Considerations ..................................................................................... 31 
5.1.3.1 
Meals and Dietary Restrictions .................................................................... 31 
5.1.3.2 
Contraception ............................................................................................... 31 
5.1.4 
Pregnancy ............................................................................................................ 31 
5.2 
Trial Intervention(s) ............................................................................................. 32 
5.2.1 
Timing of Dose Administration .......................................................................... 32 
5.2.2 
Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab ................................................................................................... 34 
5.3 
Randomization or Treatment Allocation ............................................................ 41 
5.4 
Stratification .......................................................................................................... 41 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 41 
5.5.1 
Acceptable Concomitant Medications ................................................................ 41 
5.5.2 
Prohibited Concomitant Medications.................................................................. 41 
5.5.3 
Rescue Medications & Supportive Care ............................................................. 42 
5.6 
Participant Discontinuation Criteria .................................................................. 43 
5.7 
Participant withdrawal From Study ................................................................... 43 
5.8 
Clinical Criteria for Early Trial Termination ................................................... 44 
6.0 
TRIAL ASSESSMENTS AND PROCEDURES .................................................... 45 
6.1 
Trial Procedures ................................................................................................... 45 
6.1.1 
Administrative and General Procedures ............................................................. 45 
6.1.1.1 
Informed Consent......................................................................................... 45 
6.1.1.3 
Inclusion/Exclusion Criteria ........................................................................ 46 
6.1.1.4 
Medical History ........................................................................................... 46 
6.1.1.5 
Prior and Concomitant Medications Review ............................................... 46 


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6.1.1.5.1 
Prior Medications .................................................................................. 46 
6.1.1.5.2 
Concomitant Medications ..................................................................... 46 
6.1.1.6 
Disease Details and Treatments ................................................................... 46 
6.1.1.6.1 
Disease Details ...................................................................................... 46 
6.1.1.6.2 
Prior Treatment Details ......................................................................... 46 
6.1.1.6.3 
Subsequent Anti-Cancer Therapy Status .............................................. 47 
6.1.2 
Clinical Procedures/Assessments ........................................................................ 47 
6.1.2.1 
Adverse Event (AE) Monitoring .................................................................. 47 
6.1.2.2 
Physical Exam .............................................................................................. 47 
6.1.2.3 
Full Physical Exam ...................................................................................... 47 
6.1.2.4 
Directed Physical Exam ............................................................................... 48 
6.1.2.5 
Vital Signs .................................................................................................... 48 
6.1.2.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 48 
6.1.2.7 
Electrocardiograms ...................................................................................... 48 
6.1.3 
Clinical Safety Laboratory Assessments............................................................. 48 
6.1.3.1 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 49 
6.1.3.2 
Pregnancy Testing ........................................................................................ 49 
6.1.4 
Tumor Imaging and Assessment of Disease ....................................................... 49 
6.1.4.1   Initial Tumor Imaging ................................................................................... 49 
6.1.4.2   Tumor Imaging During the Study ............................................................. 50 
6.1.4.3   End of Treatment and Follow-up Tumor Imaging .................................... 50 
6.1.4.5   RECIST 1.1 Assessment of Disease ......................................................... 50 
6.1.5 
Tumor Tissue Collection and Correlative Studies Blood Sampling ................... 50 
6.1.6 
Other Procedures ................................................................................................. 50 
6.1.6.1 
Discontinuation and withdrawal .................................................................. 50 


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6.1.7 
Visit Requirements .............................................................................................. 51 
6.1.7.1 
Screening...................................................................................................... 51 
6.1.7.1.1 
Screening Period ................................................................................... 51 
6.1.7.2 
Treatment Period .......................................................................................... 51 
6.1.7.3 
Post-Treatment Visits................................................................................... 51 
6.1.7.3.2 Follow-up Visits ...................................................................................... 51 
6.1.7.3.3 Survival Follow-up Contacts ................................................................... 51 
6.1.7.3.4  Post Study ............................................................................................... 51 
6.2 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety 
Events ..................................................................................................................... 52 
6.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information ......................................................................................................... 52 
6.2.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events ................ 53 
6.2.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information ............. 53 
6.2.4 Sponsor Responsibility for Reporting Adverse Events ......................................... 54 
6.2.5 Pregnancy and Exposure During Breastfeeding .................................................... 54 
6.2.6 Events of Clinical Interest (ECIs) .......................................................................... 54 
7.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 55 
7.1 
Statistical Analysis Plan Summary ..................................................................... 55 
7.2 
Statistical Analysis Plan ....................................................................................... 55 
8.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
..................................................................................................................................... 55 
8.1 
Investigational Product ........................................................................................ 55 
8.2 
Packaging and Labeling Information ................................................................. 56 
8.3 
Clinical Supplies Disclosure ................................................................................. 56 
8.4 
Storage and Handling Requirements .................................................................. 56 


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8.5 
Returns and Reconciliation .................................................................................. 56 
9.0 
References .................................................................................................................. 56 
10.0 
APPENDICES ........................................................................................................... 58 
Appendix 1: ECOG Performance Status ........................................................................ 58 
Appendix 2: Clinical Laboratory Tests .......................................................................... 59 
Appendix 3: Contraceptive Guidance and Pregnancy Testing .................................... 61 
Contraception Requirements ........................................................................................... 61 
Pregnancy Testing ........................................................................................................... 63 
Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .................................................................................... 64 
10.1.1 Definition of AE ................................................................................................. 64 
10.1.2 Definition of SAE ............................................................................................... 65 
10.1.3 Additional Events Reported in the Same Manner as SAE .................................. 66 
10.1.4 Recording AE and SAE ...................................................................................... 66 
10.1.5 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Principal 
investigator .......................................................................................................... 70 
 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab in non-small cell lung cancer patients with brain 
metastases 
Trial Phase 
II 
Clinical Indication 
Non-small cell lung cancer 
Trial Type 
Prospective single arm single center study 
Type of control 
Historical control 
Route of administration 
Intravenous 
Treatment Groups  
Non-small cell lung cancer  
Number of trial participants 
50  
Estimated enrollment period 
Mar 2022 – Sep 2024 
Estimated duration of trial 
42 months 
Duration of Participation 
18 months 
Estimated average length of 
treatment per patient 
7 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 Trial Design 
This is a Phase II single center, open-label, single arm study in patients with advanced non-small cell 
lung cancer (stage IV) with brain metastases. Patients will be treated with combination of 
Pembrolizumab 200mg plus platinum doublet based on histology subtypes. After the 4 cycles of 
combination phase with cytotoxic chemotherapy, maintenance phase will be followed for maximum of 
35 cycles. If the disease progression is observed in CNS only which can be controlled with local 
treatment, systemic treatment can be continued as beyond disease progression. 
Non-squamous cell carcinoma:  
4 cycles of pemetrexed 500mg/m2 + carboplatin AUC 5.0 + pembrolizumab 200mg every 3 weeks 
Followed by pemetrexed 500mg/m2 + pembrolizumab 200mg every 3 weeks up to 35 cycles 
Squamous cell carcinoma: 
4 cycles of paclitaxel 200mg/m2 + carboplatin AUC 6.0 + pembrolizumab 200mg every 3 weeks 
Followed by pembrolizumab 200mg every 3 weeks up to 35 cycles 
 


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2.2 Trial Schema 
 
 
 
 
 
 
 
 
 
KEY INCLUSION CRITERIA
• Treatment naïve stage IV 
NSCLC
• Subjects with CNS lesion.
• Subjects with 
asymptomatic brain 
metastases without CNS 
treatment
• No EGFR or ALK alteration
Non-squamous 
cell carcinoma
Primary endpoint: Intra cranial response rate
Secondary endpoint: 
Progression-free survival, Intracranial progression-free survival, intracranial duration of 
response, overall survival, objective response rate
Exploratory analysis: Exploratory biomarker study based on WES, WTS and PD-L1 expression
Pemetrexed 500mg/m2
Carboplatin AUC 5.0
Pembrolizumab 200mg
3 wk
3 wk
3 wk
3 wk
3 wk
3 wk
3 wk
Up to 35 cycles
Maintenance Phase
Combination Phase
Squamous 
cell carcinoma
3 wk
3 wk
3 wk
3 wk
3 wk
3 wk
3 wk
Up to 35 cycles
Maintenance Phase
Combination Phase
Paclitaxel 200mg/m2
Carboplatin AUC 6.0


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2.3 Schedule of Activities 
Table 1 Study Flow Chart 
Study Period: 
Screening 
 
Treatment cycles 
Post-treatment 
Visit Number/Title: 
Screening 
 
Combination phase  
(C1 to C4) 
Maintenance phase (To be 
repeated to C35) 
EOT 
(Safety F/U) 
Follow up visit 
Survival F/U 
C1 D1 
C1 D8 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
Scheduled Hour, Day, Week, etc., and Window: 
-28 to -1 
 
 
± 3 
± 3 
±3  
± 3 
± 3 
± 3 
± 3 
28 day post 
discontinue 
Every 12 weeks 
post EOT 
Every 12 weeks 
post EOT 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent  
(Including consent for the treatment of beyond disease 
progression) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Trial treatment administration 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Post study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Proceduresa 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor imaging  
(Chest +/- Abdomen CT) 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
PET-CT  
(Optional) 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Brain MRI 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Laboratory procedure and Safety Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Directed Physical Examination 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital Signs (heart rate, blood pressure), ECOG 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
 
 
X 
 
 
 
 
 
 
 
 
 
 
HIV, hepatitis B and C screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
(every 4 cycles during the maintenance phase) 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
Comprehensive serum chemistry profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
hCG test for female patients with possibility of pregnancyb 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
 


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Study Period: 
Screening 
 
Treatment cycles 
Post-treatment 
Visit Number/Title: 
Screening 
 
Combination phase  
(C1 to C4) 
Maintenance phase (To be 
repeated to C35) 
EOT 
(Safety F/U) 
Follow up visit 
Survival F/U 
C1 D1 
C1 D8 
C2 
C3 
C4 
C5 
C6 
C7 
C8 
Scheduled Hour, Day, Week, etc., and Window: 
-28 to -1 
 
 
± 3 
± 3 
±3  
± 3 
± 3 
± 3 
± 3 
28 day post 
discontinue 
Every 12 weeks 
post EOT 
Every 12 weeks 
post EOT 
Thyroid Function Tests (TSH, T3, free T4; periodically) (every 4 
cycles during the maintenance phase) 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
PT and aPTT (baseline only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Exploratory biomarker studyc 
 
 
PD-L1 status, Correlative studies blood collection (Optional) 
X 
 
X 
X 
X 
 
 
 
 
 
X (Disease 
Progression) 
 
 
Correlative studies tissue collection (optional) 
X 
 
 
 
 
 
 
 
 
 
X (Disease 
Progression) 
 
 
 
 
 
a. CT/PET-CT/Brain MRI will be conducted with window period of ± 7 days.  
CT and Brain MRI will be conducted every 2 cycles(6 weeks) for the first 12 months and every 3 cycles(9 weeks) thereafter.  
PET-CT during the study can be conducted based on investigator’s decision as optional method. 
At the time of treatment discontinuation(±4 weeks window). Every 12 weeks for follow up visit. 
b. WOCBP should be a maximum of 24-hours before the first dose/vaccination. 
c. Blood Sample(Optional): 30cc blood at the time of screening. 20cc blood at the time of C1D8, C2D1, C3D1, and disease progression 
Tissue Sample(Optional): Fresh tumor tissue sample or up to 15 Unstained slide at the screening and disease progression 
 
 
 
 


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3.0 OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) 
3.1 
Primary Endpoint:  Intracranial response rate by RECIST v1.1 
3.2 
Secondary Endpoint(s) 
Progression-free survival 
Overall survival 
Intracranial duration of response 
Intracranial progression-free survival 
 
Objective response rate 
Safety profile 
3.3 
Exploratory Objective(s) 
 
Exploratory analyses based on PD-L1 expression 
- Subgroup analysis of clinical efficacy based on PD-L1 result 
Exploratory analysis based on genomic profile 
- Exploratory analysis using scRNA and TCR sequencing from tissue and blood to identify the 
subset of immune cells correlated with clinical outcomes 
Drug sensitivity test based on organoid culture 
- Develop patient derived organoid pre-clinical model to validate the drug sensitivity and 
explore the tumor characteristics in-depth using organoid.


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4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Despite the recent advance in cancer therapy, central nervous system (CNS) metastases remain a 
devasting complication and major hurdles for the treatment selection. Especially, brain metastases 
occur in up to 30% of non-small cell lung cancer (NSCLC) at the time point of initial diagnoses. The 
current treatment of NSCLC with CNS metastases can be different based on molecular profiles and 
neurology symptoms. To date, if the patients have neurology symptom due to the CNS lesion, upfront 
local therapies such as stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT) or surgical 
resection is recommended as an initial treatment. However, if the patient has minimal neurology 
symptoms, treatment can be different based on molecular profiles. In patients with driver oncogenes 
which have the potential option with blood-brain barrier (BBB) penetrable small molecules, such as 
EGFR or ALK tyrosine kinase inhibitor (TKI), upfront treatment with TKI can be considered as an 
initial treatment. On the contrary, first-line treatment for the patients without driver oncogenes remains 
controversial. 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with 
high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2).  
Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® 
(pembrolizumab) is indicated for the treatment of patients across a number of indications because of its 
mechanism of action to bind the PD-1 receptor on the T cell.  For more details on specific indications 
refer to the Investigator brochure (IB). 
 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term survival 
in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; 
malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can be expanded ex 
vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma [Dudley 
et al., 2005; Hunder et al., 2008]. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune 
reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related 
to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 


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that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2) [Greenwald et al., 2005; Okazaki et al., 2001]. 
The structure of murine PD-1 has been resolved [Zhang et al., 2004].  PD-1 and its family members 
are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif.  Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein 
kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade [Okazaki et al., 2001; 
Chemnitz et al., 2004; Sheppard et al., 2004; and Riley, 2009].  The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both molecules 
regulate an overlapping set of signaling proteins [Parry et al., 2005; Francisco, 2010].  As a 
consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in non-small 
cell lung cancer with brain metastases.  
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Population 
There has been a report from the small and retrospective studies which showed clinical efficacy of 
immune checkpoint inhibitor in CNS metastases. Clinical efficacy of pembrolizumab monotherapy 
for patients with brain metastases in 18 NSCLC is first reported in 2016 (Lancet Oncol. (2016) 17:976–
83). In this study, a cut-off of up-front local treatment was decided based on the size of the CNS lesion 
(20mm) and other concerning issues. Among the 18 patients, 33% of patients (n=6) showed either CR 
(4 patients) or PR (2 patients) with durable response ranges from 3 to 7 months. 
Efficacy Outcomes in Subjects with Melanoma or NSCLC (Interim Analysis [Data cutoff: June 30, 2015])  


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NSCLC  
(n=18) 
Melanoma  
(n=18) 
Brain metastasis response rate, % (95% CI) 
33 (14-59)a 
22 (7-48)b 
Complete response, n (%) 
4 (22) 
0 
Partial response, n (%) 
2 (11) 
4 (22) 
Stable disease, n (%) 
2 (11) 
2 (11) 
Progressive disease, n (%) 
6 (33) 
8 (44) 
Mixed response 
1 (6)c 
1 (6)d 
Systemic response rate, % (95% CI) 
33 (14-59) 
22 (7-48) 
Complete response, n (%) 
0 
2 (11) 
Partial response, n (%) 
6 (33) 
2 (11) 
Stable disease, n (%) 
1 (6) 
4 (22) 
Progressive disease, n (%) 
10 (56) 
8 (44) 
Overall survival, median (95% CI), months 
7.7 (3.5-NR) 
NR 
aFour subjects were not assessable for brain metastases response due to rapid systemic progression. bFour subjects were not assessable for brain 
metastases response due to rapid extracerebral progression and intralesional hemorrhage. No BRAF mutations were detected in those who had a response; 
however, one subject expressed a NRAS mutation. cThe subject had 30% shrinkage in target lesions but progression in non-target lesions. dThe subject had 
30% shrinkage of target lesions and development of new brain metastases.1  
NSCLC, non-small cell lung cancer; CI, confidence interval. 
   
In the updated analysis, the median follow-up duration in 42 subjects with NSCLC was 8.3 months 
(IQR, 4.5-26.2 months). Confirmed brain response was 29.7% in cohort 1 and 0% in cohort 2. The 
systemic response in cohort 1 was also 29.7%. Six of 27 subjects had discordant outcomes when 
evaluated for both CNS and systemic response.  Of these subjects, 3 subjects (11%) who had a 
response in the body developed progression in the brain and 3 subjects (11%) had the opposite results.  
 
Brain Metastasis Response Rates in Subjects with NSCLC (Updated Analysis [Data cutoff: May 21, 2018])  
 
PD-L1 expression ≥1%  
(cohort 1; n=37) 
PD-L1 expression <1% 
(cohort 2; n=5)b 
Brain metastasis response rate, % (95% CI) 
29.7 (15.9-47) 
0 
Complete response, n (%) 
4 (11) 
0 
Partial response, n (%) 
7 (19) 
0 
Stable disease, n (%) 
4 (11)a 
1 (20) 
Progressive disease, n (%) 
16 (43) 
3 (60) 
aTwo subjects were not confirmed. bOne subject was unevaluable. 
NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; CI, confidence interval.  
 
In the updated analysis, 19 of 42 subjects remained on the study for at least four months or had a brain 
metastasis response. These subjects were assessed for time to and duration of response in extracerebral 
and brain lesions. (Lancet Oncol. 2020;21(5):655-663) 


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In the updated analysis, each subject’s overall course among those who had a brain metastasis 
response or remained on trial for at least four months was evaluated. All subjects with discordant 
outcomes lived for longer than six months, with two of the three subjects who had a partial response in 
the body but progressive disease in the brain living more than two years.   
 
Time of Brain Metastasis Response, Overall Progression, and Death (Updated Analysis [Data cutoff: May 21, 2018]  
 
*Subjects in cohort 2. 
The end of the study period is indicated by the dashed line at 24 months.   
Figure reprinted from Goldberg SB, et al. Pembrolizumab for management of subjects with NSCLC and brain metastases: long-term results and 
biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncology 2020;21(5):655-663, with permission from Elsevier. 


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In the updated analysis, 37 subjects with NSCLC and PD-L1 expression ≥1% (cohort 1) were assessed 
for survival outcomes. Among the 37 subjects in cohort 1, 31 subjects progressed or died, and the 
median PFS was 1.9 months (95% CI 1.8-3.7). Twenty-six of the 37 subjects in cohort 1 had died by 
the time of data lock with a median OS of 9.9 months (95% CI 7.5-29.8). Estimated 1-year OS was 
40% (95% CI 30-64) and estimated 2-year OS was 34% (21-54). 
 
PFS and OS Outcomes in Subjects with NSCLC and Brain Metastases (Updated Analysis [Data cutoff: May 21, 
2018])  
 
 
 
Figure reprinted from Goldberg SB, et al. Pembrolizumab for management of subjects with NSCLC and brain metastases: long-term results and 
biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncology 2020;21(5):655-663, with permission from Elsevier. 
 
Another retrospective study conducted from 2011-2017 found that in 94 patients with brain metastases 
from NSCLC who underwent immunotherapy combined other treatment (such as whole-brain 
radiation therapy, surgery, stereotactic radiosurgery or systemic chemotherapy) showed the one-year 
survival rate of 48.3% (J Clin Oncol. 2018;36:214). Moreover, pembrolizumab based treatment 
demonstrated similar result in the retrospective study (n=134) by showing no difference in median 
PFS (9.0 vs. 7.9 months; HR, 0.93, P = .7) and OS (18 vs. 21 months; HR, 1.03, P = .8) between 
patients with brain metastases and no brain metastases(IASLC 2019 North America Conference on 
Lung Cancer; October 12, 2019; Chicago, Ill. Abstract OA03.02.) 
Refer to the landmark 1st line trials using pembrolizumab as monotherapy in PD-L1 > 50% (Keynote-
024), 11.7% of the patients with brain metastasis were included in pembrolizumab treated arm (N Engl 
J Med 2016; 375:1823-1833).  For this subset, the hazard ratio (HR) was 0.55 favoring the 
pembrolizumab treatment compared with chemotherapy although statistical significance was not 
reached.  
In non-squamous non-small cell lung cancer, the Keynote-189 trial included 17.8% of brain metastases 
patients in pembrolizumab and chemotherapy-treated arm. Interestingly, patients with brain metastases 
showed HR of 0.41 (95%CI 0.24-0.67) in overall survival. Although it is difficult to make the direct 
the comparison, the HR of OS in number was slightly lower in patients with brain metastases than HR 
of patients without brain metastases (HR 0.53, 95%CI 0.39-0.71). HR of PFS was 0.42 (95% CI 0.26-


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0.68) in brain metastases arm. Among patients with brain metastases, the ORR was 37.0% in the 
pembrolizumab plus chemotherapy arm and 17.1% in the chemotherapy arm.  
 
 
 
The most common adverse events of any cause for pembrolizumab plus chemotherapy arm vs 
chemotherapy alone arm was similar in both groups (N Engl J Med 2018; 378:2078-2092, Gadgeel S 
et al. J Clin Oncol 2020; Epub ahead of print. doi: 10.1200/JCO.19.03136.).  


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Pooled analyses results 
Pembrolizumab monotherapy (Mansfield AS, Herbst RS, Castro G. Jr, et al. Outcomes with 
pembrolizumab monotherapy in patients with PD-L1–positive NSCLC with brain metastases: 
pooled analysis of KEYNOTE-001, 010, 024, and 042. Oral presentation presented at European 
Society for Medical Oncology (ESMO) Congress; September 27-October 1, 2019; Barcelona, 
Spain.)  
Pooled Analysis Study Design 
 
Among subjects allocated to pembrolizumab vs chemotherapy across all the studies, 3 vs 4 with brain metastasis and 11 vs 57 without brain metastasis did 
not receive treatment.  
Q3W, every 3 weeks; Q2W, every 2 weeks; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; TPS, tumor proportion score. 
 
Baseline Characteristics of the Pooled Analysis Population 
 
With Brain Metastases 
Without Brain Metastases 
 
Pembrolizumab 
(n=199) 
Chemotherapy 
(n=94) 
Pembrolizumab 
(n=1754) 
Chemotherapy 
(n=1123) 
Age, median (range), years 
59 (31-88) 
60 (31-81) 
64 (20-93) 
64 (32-90) 
Male, % 
49.7 
56.4 
65.3 
69.3 
ECOG PS 1, % 
69.8 
69.1 
66.5 
68.7 
Nonsquamous histology, % 
86.9 
84.0 
67.3 
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Current/former smoker, % 
79.9 
81.9 
80.2 
79.1 
PD-L1 TPS ≥50%, % 
56.3 
51.1 
48.0 
53.3 
EGFR mutationa, % 
13.6 
6.4 
4.7 
1.9 
ALK alterationa, % 
1.0 
0 
0.7 
0.2 
Prior systemic therapyb, % 
 
 
 
 
1 
30.7 
30.9 
29.0 
19.1 
≥2 
41.7 
20.2 
20.5 
7.7 
aSubjects with EGFR or ALK aberrations were not excluded from enrollment in KEYNOTE-001 or KEYNOTE-010. bIncludes adjuvant and neoadjuvant 
therapies.  
ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death-ligand 1; TPS, tumor proportion score. 
 
The median duration of follow-up for the overall pooled population was 12.9 months (range, 0.1-43.7 
months).   
 
 
With Brain Metastases 
Without Brain Metastases 
PD-L1 TPS ≥50% 
Pembrolizumab 
 (n=112) 
Chemotherapy 
(n=48) 
Pembrolizumab 
 (n=842) 
Chemotherapy 
 (n=598) 
OS, median (95% CI), months 
19.7 (12.1-31.4) 
9.7 (7.2-19.4) 
19.4 (17.0-22.4) 
11.7 (10.1-13.1) 
HR (95% CI) 
0.78 (0.71-0.85) 
0.66 (0.58-0.76) 
12-month, % 
59.8 
42.5 
62.1 
49.0 
PFS,a,c median (95% CI), months 
4.1 (2.3-10.6) 
4.6 (3.5-8.4) 
6.5 (6.1-8.1) 
6.1 (5.8-6.2) 
HR (95% CI) 
0.70 (0.47-1.03) 
0.69 (0.62-0.78) 
12-month, % 
38.9 
13.5 
38.0 
23.5 
ORRa, n (%) 
38 (33.9) 
7 (14.6) 
321 (38.1) 
156 (26.1) 
DOR,a,b median (range), months 
NR (4.0+ to 41.7+) 
7.6 (2.9+ to 28.6+) 
33.9 (1.4+ to 49.3+) 
8.2 (1.6+ to 30.4+) 
DOR ≥12 monthsb, n (%) 
28 (91.7) 
1 (25.0) 
173 (74.0) 
27 (38.1) 
PD-L1 TPS ≥1% 
(n=199) 
(n=94) 
(n=1754) 
(n=1123) 
OS, median (95% CI), months 
13.4 (10.4-18.0) 
10.3 (8.1-13.3) 
14.8 (13.4-16.1) 
11.3 (10.2-12.0) 
HR (95% CI) 
0.83 (0.62-1.10) 
0.78 (0.71-0.85) 
12-month, % 
52.8 
45.7 
55.3 
46.9 
PFS,a,c median (95% CI), months 
2.3 (2.1-3.9) 
5.2 (4.2-8.3) 
4.3 (4.2-5.1) 
6.1 (6.0-6.3) 
HR (95% CI) 
0.96 (0.73-1.25) 
0.91 (0.84-0.99) 
12-month, % 
28.3 
19.1 
27.8 
23.1 
ORRa, n (%) 
52 (26.1) 
17 (18.1) 
452 (25.8) 
249 (22.2) 
DOR,a,b median (range), months 
NR (3.3 to 46.2+) 
8.3 (2.0+ to 28.6+) 
30.4 (1.4+ to 49.3+) 
8.1 (1.1+to 30.4+) 
DOR ≥12 monthsb, n (%) 
36 (83.9) 
3 (39.3) 
245 (71.2) 
39 (33.9) 
aResponse assessed per RECIST version 1.1 by blinded independent central review; bKaplan-Meier estimate; c4 subjects had missing data.3 
PD-L1, programmed death-ligand 1; TPS, tumor proportion score; OS, overall survival; CI, confidence interval; HR, hazard ratio; ORR, objective 
response rate; DOR, duration of response; NR, not reached; +, ongoing response; PFS, progression-free survival. 
 
Safety Outcomes in the Pooled Analysis Population (Data cutoff: November 5, 2018 for KEYNOTE-001; March 16, 
2018 for KEYNOTE-010; July 10, 2017 for KEYNOTE-024; and September 4, 2018 for KEYNOTE-042)  
 
Pembrolizumab 
Chemotherapy 
 
With Brain 
Metastases 
(n=196) 
Without Brain 
Metastases 
(n=1743) 
With Brain 
Metastases 
(n=90) 
Without Brain 
Metastases 
(n=1066) 
Treatment duration, median (range), months 
2.8 (0.03-39.6) 
4.7 (0.03-75.9) 
2.9 (0.03-29.5) 
3.5 (0.03-34.8)  
Treatment-related AEs, % 
66 
67 
84 
88 
Grade 3-5 
15 
18 
46 
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Leading to death 
2 
1 
3 
2 
Leading to discontinuation  
6 
8 
10 
11 
Affecting CNS 
10 
7 
27 
27 
Immune-mediated AEs and infusion reactions, %  
21 
25 
9 
8 
Safety was assessed per treatment actually received.  
AE, adverse event; CNS, central nervous system. 
 
 
Pembrolizumab and chemotherapy combination therapy (Powell SF, Rodríguez -Abreu D, Langer 
CJ, et al. Pembrolizumab plus platinum-based chemotherapy in NSCLC with brain metastases: 
pooled analysis of KEYNOTE-021, 189, and 407. Poster presented at European Society for 
Medical Oncology (ESMO) Congress; September 27-October 1, 2019; Barcelona, Spain.) 
 
Pooled Analysis Study Design 
 
Among subjects allocated to pembrolizumab + chemotherapy vs chemotherapy alone across all the studies, 3 vs 2 with brain metastasis and 3 vs 4 without 
brain metastasis did not receive treatment.4 
Q3W, every 3 weeks.; NSCLC, non-small cell lung cancer.  
 
Overall, 1298 subjects were included in the analysis across all 3 studies. The data cutoff dates were December 1, 
2017 for KEYNOTE-021; September 21, 2018 for KEYNOTE-189; and April 3, 2018, for KEYNOTE-407.  
 
Baseline Characteristics of the Pooled Analysis Population4 
 
With Brain Metastases 
Without Brain Metastases 
 
Pembrolizumab + 
Chemotherapy 
(n=105) 
Chemotherapy 
(n=66) 
Pembrolizumab + 
Chemotherapy 
 (n=643) 
Chemotherapy 
(n=484) 
Age, median (range), years 
63 (35-82) 
63.5 (47-81) 
65 (29-87) 
65 (34-88) 
Male, % 
66.7 
54.5 
66.3 
69.0 
ECOG PS 1, % 
61.0 
74.2 
61.6 
62.2 
Nonsquamous histology, % 
77.1 
62.1 
57.7 
44.0 
Current/former smoker, % 
93.3 
93.9 
87.9 
89.9 
PD-L1 TPS, % 
 
 
 
 
≥50% 
31.4 
34.8 
29.9 
28.3 
1%-49% 
23.8 
25.8 
35.0 
34.7 
Prior therapy, % 
 
 
 
 
Adjuvant/neoadjuvant 
7.6 
4.5 
5.3 
6.8 
Radiotherapy 
49.5 
51.5 
12.4 
14.0 
ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed death-ligand 1; TPS, tumor proportion score. 
 


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The median follow-up duration for subjects with vs without brain metastasis was 10.9 months (range, 
0.1-35.1 months) vs 11.0 months (range, 0.1-34.9 months).  
 
Efficacy Outcomes in the Pooled Analysis Population (Data cutoff: December 1, 2017 for KEYNOTE-021; 
September 21, 2018 for KEYNOTE-189; and April 3, 2018, for KEYNOTE-407)  
 
With Brain Metastases 
Without Brain Metastases 
 
Pembrolizumab + 
Chemotherapy 
(n=105) 
Chemotherapy 
(n=66) 
Pembrolizumab + 
Chemotherapy 
 (n=643) 
Chemotherapy 
(n=484) 
OS, median (95% CI), months 
18.8 (13.8-25.9) 
7.6 (5.4-10.9) 
22.5 (19.8-25.2) 
13.5 (11.3-15.8) 
HR (95% CI) 
0.48 (0.32-0.70) 
0.63 (0.53-0.75) 
12-month, % 
62.9 
34.9 
70.2 
53.6 
PFS,a median (95% CI), months 
6.9 (5.7-8.9) 
4.1 (2.3-4.6) 
8.8 (8.1-9.5) 
5.3 (4.8-6.1) 
HR (95% CI) 
0.44 (0.31-0.62) 
0.55 (0.48-0.63) 
12-month, % 
29.9 
6.6 
39.2 
20.1 
ORRa,b, n (%) 
41 (39.0) 
13 (19.7) 
351 (54.6) 
154 (31.8) 
DOR,a,b median (range), months 
11.3 (1.1+ to 27.9+) 
6.8 (1.3+ to 9.4+) 
12.2 (1.1+ to 29.3+) 
6.0 (1.4+ to 30.1+) 
DOR ≥12 monthsb, n (%) 
15 (45.7) 
0 
101 (50.8) 
21 (37.0) 
aResponse assessed per RECIST version 1.1 by blinded independent central review. bKaplan-Meier estimate.4 
OS, overall survival; CI, confidence interval; HR, hazard ratio; PFS, progression-free survival; ORR, objective response rate; DOR, duration of response; 
+, ongoing response.  
 
Safety Outcomes in the Pooled Analysis Population (Data cutoff: December 1, 2017 for KEYNOTE-021; September 
21, 2018 for KEYNOTE-189; and April 3, 2018, for KEYNOTE-407)  
 
Pembrolizumab + Chemotherapy 
Chemotherapy 
 
With Brain 
Metastases 
(n=102) 
Without Brain 
Metastases 
(n=640) 
With Brain 
Metastases 
(n=64) 
Without Brain 
Metastases 
(n=480) 
Treatment duration, median (range), months 
7.0 (0.03-29.1) 
6.9 (0.03-30.4) 
4.2 (0.03-18.5) 
4.3 (0.03-30.7)  
Treatment-related AEs, % 
88.2 
94.5 
82.8 
90.6 
Grade 3-5 
59.8 
50.5 
45.3 
46.9 
Led to death 
5.9 
2.0 
1.6 
1.9 
Led to discontinuation  
25.5 
21.4 
10.9 
8.1 
Affecting CNS 
32.4 
36.4 
17.2 
33.5 
Immune-mediated AEs and infusion reactions, %  
25.5 
27.8 
9.4 
10.6 
Grade 3-5 
13.7 
9.7 
1.6 
3.8 
Safety was assessed per treatment actually received.4 
AE, adverse event; CNS, central nervous system. 
 
Rationale of pembrolizumab and chemotherapy combination therapy in asymptomatic brain 
metastasis 
Most of previous studies with pembrolizumab monotherapy or pembrolizumab combined with 
chemotherapy include patients with previously treated, stable brain metastases if clinically stable ≥ 4 
weeks without corticosteroids ≥3 days before study entry, which include KEYNOTE 001, 


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KEYNOTE 024, KEYNOTE 010, KEYNOTE 042, KEYNOTE 021G, KEYNOTE 189, and 
KEYNOTE 407.  
In contrast, only KEYNOTE 189 and KEYNOTE 407 studies allow patients with asymptomatic 
brain metastasis, where no neurologic symptoms, no need for corticosteroid, and no lesion > 1.5 cm. 
Although the clinical outcome such as overall survival was improved with pembrolizumab 
monotherapy or pembrolizumab with combination chemotherapy compared with control group 
irrespective of brain metastasis, the data on efficacy of these regimens in untreated brain metastasis 
is very limited and it has not been fully established. Given that, in our study, we will investigate 
pembrolizumab and combination chemotherapy in patients with untreated brain metastases to 
evaluate the intracranial response, intracranial response duration and intracranial progression free 
survival.  
4.2.2 Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined 
below, this dose is justified by: 
 Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
 Clinical data showing meaningful improvement in benefit-risk including overall survival at 200 
mg Q3W across multiple indications, and 
 Pharmacology data showing full target saturation in both systemic circulation (inferred from 
pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK [PBPK] analysis) 
at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD -L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg Q3W versus 
10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006).  All of these studies demonstrated flat dose- and exposure-response relationships across the 
doses studied representing an approximate 5- to 7.5-fold difference in exposure.  The 2 mg/kg (or 
200 mg fixed-dose) Q3W provided similar responses to the highest doses studied.  Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg 
Q3W as the appropriate dose independent of the tumor type.  These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and not via 
direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated saturation 
of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a PBPK analysis 
was conducted to predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 
expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W achieves full PD-1 
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Finally, population PK analysis of pembrolizumab, which characterized the influence of body weight 
and other participant covariates on exposure, has shown that the fixed-dosing provides similar 
control of PK variability as weight based dosing, with considerable overlap in the distribution of 
exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported by these PK 
characteristics, and given that fixed-dose has advantages of reduced dosing complexity and reduced 
potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation across all 
pembrolizumab protocols. 
Based on the previous justification for the dose of pembrolizumab monotherapy, this study is 
designed to combine the pembrolizumab with cytotoxic chemotherapy. The dosage used for this 
study is already validated for its safety through 2 major landmark trial 
The first study keynote 189 study is designed to evaluate the clinical efficacy of 200mg 
pembrolizumab with combined with pemetrexed and carboplatin which is same regimen used for 
this trial. As shown below, this trial will adopt same dosage pemetrexed 500mg/m2 with Carboplatin 
AUC 5.0 for the non-squamous patients.  
 
The second study Keynote 407 study is designed to evaluate the clinical efficacy of 200mg 
pembrolizumab with paclitaxel and carboplatin. In this study we will evaluate the clinical efficacy 
with Paclitaxel 200mg/m2 and carboplatin AUC 6.0 for squamous patients 


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4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
Primary endpoint:  
Intracranial overall response rate 
In this study, we will evaluate the intracranial overall response rate of pembrolizumab with cytotoxic 
chemotherapy agent to evaluate the effectiveness of combination regimen in intracranial lesion. The 
overall response rate will be measured by RECIST v1.1 criteria. 
Secondary endpoint: 
1. Progression-free survival 
Progression free survival defined by the date of either disease progression or the all-cause 
mortality from the date of IP administration will be calculated.  
2. Overall survival 
Overall survival defined by date of all-cause mortality from the date of IP Administration will 
be calculated. 
3. Intracranial duration of response 
In addition to overall progression-free survival, the intracranial response will be evaluated 
separately. The duration for intracranial response will be calculated separately to evaluate the 
intracranial efficacy of IP drug 


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4. Intracranial progression-free survival 
Progression free survival of intracranial disease defined by the date of disease progression of 
intracranial lesion from the date of IP administration will be calculated. 
5. Objective response rate 
Objective response rate of disease will be measured by RECIST v 1.1 criteria. 
6. Safety profile 
Adverse event will be evaluated using CTCAE v5.0  
 
4.2.3.2 Planned Exploratory Biomarker Research 
 
The exploratory analyses based on the PD-L1 expression (by DAKO PD-L1 22C3 assay) and genomic 
profile (using scRNA and TCR sequencing) from the baseline samples will be used for the exploratory 
analyses in subjects who    are available for the PD-L1 test and genomic profiling. Also organoids 
derived from obtained tissue will be used for development to validate the drug sensitivity and explore 
the tumor characteristics in-depth using organoid.


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5.0 METHODOLOGY 
5.1 Study Population 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
1. Male/female participants who are at least 19 years of age on the day of signing informed 
consent with histologically confirmed diagnosis of stage IV non-small cell lung cancer with 
asymptomatic brain metastases will be enrolled in this study. 
 
2. Must have at least one intracranial target lesion. Intracranial lesion must be equal or greater 
than the 10mm in longest diameter. 
 
3. Have confirmation that EGFR or ALK-directed therapy is not indicated (documentation of 
absence of tumor activating EGFR mutations AND absence of ALK gene rearrangements OR 
presence of a K-Ras mutation. However, patients with squamous histology are eligible without 
genomic data) 
 
4. Have measurable disease based on RECIST 1.1 as determined by the local site 
investigator/radiology assessment. Target lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions. Otherwise, 
previously treated with radiation is not considered as measurable lesion. 
 
5. Have not received prior systemic treatment for their advanced/metastatic NSCLC. Subjects 
who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy 
was completed at least 6 months prior to the development of metastatic disease. 
 
6. Have a life expectancy of at least 3 months 
 
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Status.  
 
8. Have adequate organ function 
 
9. Male participants: 
A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol 
during the treatment period and for at least 120 days after the last dose of study treatment and 
refrain from donating sperm during this period. 
 
10. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not 
breastfeeding, and at least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  


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b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period and for at least 120 days after the last dose of study treatment. 
11. The participant (or legally acceptable representative if applicable) provides written informed 
consent for the trial.   
 
Table 2.  Adequate Organ Function Laboratory Values 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 


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5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to IP administration 
(see Appendix 3).  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137).  
 
3. Has received prior systemic anti-cancer therapy including investigational agents prior to IP 
administration as a metastatic disease treatment, including tyrosine kinase inhibitor. 
 
4. Had major surgery < 3 weeks prior to first dose 
 
5. No measurable CNS lesion other than CNS lesion treated with stereotactic radiotherapy or 
surgery 
 
6. Had received whole brain radiotherapy or stereotactic radiotherapy to CNS disease. 
 
7. Has received prior radiotherapy within 1 weeks of start of study intervention.  Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis.  A 1-week washout is permitted for palliative radiation to non-
CNS disease. 
 
8. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples of 
live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (eg, FluMist® ) are live attenuated 
vaccines and are not allowed. 
 
9. Is currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study intervention. 
 
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive 
therapy within 7 days prior to the first dose of study drug.  


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11. Has a known additional malignancy that is progressing or has required active treatment within 
the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, thyroid cancer or early gastric cancer or carcinoma in situ (eg, breast carcinoma, 
cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 
 
12. Has known active carcinomatous meningitis.  
 
13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.  
15. Has a history of (non-infectious) pneumonitis that currently required steroids or has current 
pneumonitis. 
16. Has an active infection requiring systemic therapy. 
17. Has a known history of Human Immunodeficiency Virus (HIV) infection.   
18. Has a active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive with HBV 
DNA positive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. 
These patients can be participated with appropriate treatment and prophylactic treatment based 
on the investigator’s decision.  
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the participant’s participation for the full 
duration of the study, or is not in the best interest of the participant to participate, in the opinion 
of the treating investigator.   
20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
21. Is pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose of trial 
treatment. 
22. Has had an allogenic tissue/solid organ transplant. 
 


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5.1.3 Lifestyle Considerations  
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention(s).  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to principal investigator 
within 2 working days if the outcome is a serious adverse experience (e.g. death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or newborn).  
The study Investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to principal investigator.  If a male 
participant impregnates his female partner, the study personnel at the site must be informed 
immediately and the pregnancy must be reported to principal investigator and followed as described 
in Section 6.2. 
 
 


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5.2 Trial Intervention(s) 
The intervention(s) to be used in this trial is outlined below in below Table3 
Table 3. Trial Intervention(s) 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle 
Experimental 
Pemetrexed 
500mg/m2 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle 
Experimental 
Paclitaxel 
200mg/m2 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle 
Experimental 
Carboplatin 
AUC 5.0 or 
6.0 
Q3W 
IV infusion 
Day 1 of each 3-week 
cycle 
Experimental 
Carboplatin dosage will use Calvert formula and dose not to exceed 750mg 
Total Dose (mg) = target AUC x (CrCl + 25) 
 
 
5.2.1 Timing of Dose Administration 
Trial interventions should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Schedule of Activities, Section 2.3.  Trial interventions may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial interventions will be administered on an outpatient basis. 
 
Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given 
the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is 
permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
Pemetrexed 
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes Q3W until 
progression or unacceptable toxicity. All subjects should receive the appropriate supplementation of 
vitamin B12 and folic acid and corticosteroid prophylaxis as listed below:  
 Folic Acid 350-1000 μg oral: at least 5 doses of folic acid must be taken during the 7 days 
preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of 
therapy and for 21 days after the last dose of pemetrexed.  
 Vitamin B12 1000 μg IM injection in the week preceding the first dose of pemetrexed and once 
every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as 
pemetrexed administration.  


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 Dexamethasone prophylaxis 4 mg, orally twice per day (or equivalent). Taken the day before, day 
of, and day after pemetrexed administration. Higher or additional doses are permitted for antiemetic 
prophylaxis during cycles 1-4 but not to exceed doses in MASCC guidelines. 
 
 
Paclitaxel 
Paclitaxel 200 mg/m2 will be administered as an IV infusion over 3 hours Q3W for 4 cycles as per 
local practice and labels. All subjects should be pre-medicated with oral or intravenous steroid and 
anti-histamines according to the approved product label and/or standard practice. Additional pre-
medications should be administered as per standard practice. Paclitaxel should be completely 
administered before initiating carboplatin dose. 
 
Carboplatin 
Carboplatin AUC 5 or 6 mg/mL/min (based on histology) will be administered as an IV infusion 
over 15-60 minutes Q3W for 4 cycles immediately after pemetrexed as per local practice and labels 
 
Dose modification 
Dose modification must be based on the maximum toxicity experienced during a cycle. Toxicity 
needs to resolve to Grade ≤1 or baseline prior to resuming the subsequent cycle. For individual 
subjects requiring a dose modification, treatment for each new cycle may be delayed if the scheduled 
off-drug periods are not adequate to allow for recover to Grade ≤1 or the baseline status of the 
subject. 
 
Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be interrupted or 
discontinued due to toxicity. If a dose reduction for toxicity occurs with any agent, the dose may not 
be re-escalated. Subjects can have a maximum of 2 dose modifications (if applicable) to each of the 
components of study therapy throughout the course of the study for toxicities. If a subject 
experiences several toxicities and there are conflicting recommendations, the most conservative dose 
adjustment recommended should be followed (dose reduction appropriate to the most severe 
toxicity). Subjects who require a 3rd dose modification to any particular component will have that 
agent discontinued. Reduction of one chemotherapy agent and not the other agent is appropriate if, 
in the opinion of the Investigator, the toxicity is clearly related to one of the treatments. If, in the e 
opinion of the Investigator, the toxicity is related to the combination of both chemotherapy agents, 
both drugs should be reduced according to recommended dose modifications. If the toxicity is 
related to the combination of three agents, all three agents should be reduced (if applicable), 
interrupted or discontinued according to the recommended dose modifications.  
 
Subjects may have chemotherapy discontinued and continue on pembrolizumab alone. Similarly 
subjects may discontinue pembrolizumab and continue on chemotherapy alone if appropriate.  
 
Chemotherapy may be interrupted for a maximum of 6 weeks; pembrolizumab may be interrupted 
for a maximum of 12 weeks. The Common Terminology Criteria for Adverse Events version 5.0 
(CTCAE 5.0) must be used to grade the severity of adverse events. All dose modifications should be 
based on the AE requiring the greatest dose modification. Dose modifications are detailed in Table 4 
and please refer to approved product labels for dose modification regarding the cytotoxic agent. 


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Table 4. Dose modification for Trial medications are as follows. 
 
Dose level 0 
Dose level -1 
Dose level -2 
Dose level -3 
Carboplatin 
AUC 5.0 
AUC 3.75 
AUC 2.5 
Discontinue 
Carboplatin 
AUC 6.0 
AUC 4.5 
AUC 3.0 
Dicontinue 
Pemetrexed 
500mg/m2 
375mg/m2 
250mg/m2 
Discontinue 
Paclitaxel 
200mg/m2 
150mg/m2 
100mg/m2 
Discontinue 
Pembrolizumab 
200mg fixed 
dose 
Dose reduction 
not permitted 
Dose reduction 
not permitted 
Discontinue 
 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab 
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 study data, most irAEs were reversible and could be managed with interruptions of 
pembrolizumab, administration of corticosteroids and/or other supportive care. For suspected irAEs, 
ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or 
tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab are 
provided in Table 5. 


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Table 5. Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.  
2. Pembrolizumab must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last pembrolizumab treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If pembrolizumab has been withheld, pembrolizumab may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
Corticosteroid and/or 
other therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
 
Add prophylactic 
antibiotics for 
opportunistic 
infections 
 
 
Monitor participants for signs and symptoms of pneumonitis 
 
Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid treatment 
 
Recurrent Grade 
2, Grade 3 or 4 
 
Permanently 
discontinue 
Diarrhea / Colitis  
Grade 2 or 3 
Withhold 
 
Monitor participants for signs and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, blood or mucus in stool with or 
without fever) and of bowel perforation (ie, peritoneal signs 
and ileus) 


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Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 
 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
 
 
Participants with ≥Grade 2 diarrhea suspecting colitis should 
consider GI consultation and performing endoscopy to rule 
out colitis 
 
Participants with diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake 
is not feasible, fluid and electrolytes should be substituted via 
IV infusion 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
 
Administer 
corticosteroids 
(initial dose of 
0.5 - 1 mg/kg 
prednisone or 
equivalent) 
followed by taper 
 
Monitor with liver function tests (consider weekly or more 
frequently until liver enzyme value returned to baseline or is 
stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
 
Administer 
corticosteroids 
(initial dose of 
1 - 2 mg/kg 
prednisone or 
equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold d 
 
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM 
 
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia 
 
 
Monitor participants for hyperglycemia or other signs and 
symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
 
Monitor for signs and symptoms of hypophysitis (including 
hypopituitarism and adrenal insufficiency) 


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Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
 
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated 
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 
discontinue d 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
 
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care 
 
Monitor for signs and symptoms of thyroid disorders 
Nephritis and 
renal dysfunction: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withhold 
 
Administer 
corticosteroids 
(prednisone 
1 – 2 mg/kg or 
equivalent) 
followed by taper 
 
Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
 
Based on severity 
of AE administer 
corticosteroids 
 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Persistent Grade 2 
Withhold 
 
Based on severity 
of AE administer 
corticosteroids 
 
Ensure adequate evaluation to confirm etiology or exclude 
other causes 
Grade 3 
Withhold or 
discontinue 


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based on the 
event e.  
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
a AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 - 3.0 x ULN if baseline normal; >1.5 - 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; >3.0 - 
10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or 
≤ Grade 2, pembrolizumab may be resumed. 
e Events that require discontinuation include but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, Stevens-Johnson Syndrome and toxic 
epidermal necrolysis 
 


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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 6. 
Table 6.  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (e.g. from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and 
the participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug intervention 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
study intervention with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
No subsequent dosing 


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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 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
intervention. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 


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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / 
surgical events and/or unforeseen circumstances not related to study intervention. However, intervention 
is to be restarted within 3 weeks of the originally scheduled dose and within 42 days of the previously 
administered dose, unless otherwise discussed with the Sponsor. The reason for study intervention 
interruption is to be documented in the patient's study record. 
 
5.3 Randomization or Treatment Allocation 
No randomization is allowed. Treatment allocation is based on the histologic subtype 
 
5.4 Stratification 
No stratification is planned. 
 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant's primary physician. However, the decision to continue the participant on study 
intervention requires the mutual agreement of the investigator and the participant. 
 
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, over-
the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days prior to the first dose of trial intervention and up 
to 28 days after the last dose of trial intervention should be recorded.  If participants experience an SAE 
or ECI, concomitant medications administered 28 days after the last dose of trial intervention are to be 
recorded as defined in Section 6.2. 
5.5.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 


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 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy (Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion.)   
 Live vaccines within 30 days prior to the first dose of study treatment and while participating in 
the study.  Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (eg, FluMist® ) are live attenuated vaccines and are not allowed. 
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study. All treatments that the 
Investigator considers necessary for a participant’s welfare may be administered at the discretion of 
the Investigator in keeping with the community standards of medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study.  If there is a clinical indication for any medication or vaccination specifically 
prohibited during the study, discontinuation from study therapy or vaccination may be required.  The 
final decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician.  However, the decision to continue the participant on study treatment 
requires the mutual agreement of the investigator and the participant.  
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined along with the dose modification guidelines in Section 5.2.2, 
[Table 5].  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.  
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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5.6 Participant Discontinuation Criteria 
Discontinuation of study intervention does not represent withdrawal from the study. 
As certain data on clinical events beyond study intervention discontinuation may be important to the 
study, they must be collected through the participant’s last scheduled follow-up, even if the participant 
has discontinued study intervention.  Therefore, all participants who discontinue study intervention 
prior to completion of the protocol-specified treatment period will still continue to be monitored in this 
study and participate in the study visits and procedures as specified in Section 2.3 unless the participant 
has withdrawn from the study (Section 5.7). 
Participants may discontinue study intervention at any time for any reason or be discontinued from the 
study intervention at the discretion of the investigator should any untoward effect occur.  In addition, a 
participant may be discontinued from study intervention by the investigator or the Sponsor if study 
intervention is inappropriate, the study plan is violated, or for administrative and/or other safety 
reasons.   
A participant must be discontinued from study treatment but continue to be monitored in the study for 
any of the following reasons: 
 The participant or participant’s legally acceptable representative requests to discontinue study 
intervention 
 After prolonged study intervention interruption that prohibits restarting study intervention  
 Radiographic disease progression outlined in Section 6.1.4. 
 Any progression or recurrence of any malignancy, or any occurrence of another malignancy that 
requires active treatment 
 Any study intervention-related toxicity specified as a reason for permanent discontinuation as 
defined in the guidelines for dose modification due to AEs in Section 5.2.2. 
 The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator, placed the participant at unnecessary risk from continued administration of study 
treatment. 
 The participant has a confirmed positive serum pregnancy test 
  
5.7 Participant withdrawal From Study 
A participant must be withdrawn from the study if the participant or the participant’s legally acceptable 
representative withdraws consent from the study. 
If a participant withdraws from the study, they will no longer receive study intervention or be followed 
at scheduled protocol visits. 


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Specified details regarding procedures to be performed at the time of withdrawal from the study are 
outlined in Section 6.1.6.1. 
5.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
In the event of MSD decision to no longer supply study drug, adequate notification will be provided so 
that appropriate adjustments to participant treatment can be made. 
 


 
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6.0 TRIAL ASSESSMENTS AND PROCEDURES 
6.1 Trial Procedures 
 Study procedures and their timing are summarized in The Schedule of Activities, Section 2.3.   
 Adherence to the study design requirements, including those specified in the Schedule of 
Activities is essential and required for study conduct. 
 The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (by education, training, and experience) staff. 
 All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria 
 Additional evaluations/testing may be deemed necessary by the principal investigator for reasons 
related to participant safety. In some cases, such evaluation/testing may be potentially sensitive 
in nature (eg, HIV, Hepatitis C), and thus local regulations may require that additional informed 
consent be obtained from the participant. In these cases, such evaluations/testing will be 
performed in accordance with those regulations. 
 Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of ICF may be utilized for screening or baseline purposes provided 
the procedure met the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
 All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
 
6.1.1 Administrative and General Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant or each participant’s 
legally acceptable representative prior to participating in a clinical trial. If there are changes to a 
participant’s status during the study (e.g. health requirements) the investigator must ensure appropriate 
consent is in place. 
6.1.1.2 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of the 
person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the participant must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The participant or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 


 
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participant’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations. 
If the investigator recommends continuation of study intervention beyond disease progression, the 
participant or his/her legally acceptable representative will be asked to sign consent. 
 
6.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the participant qualifies for the trial.  
6.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are considered 
to be clinically significant by the Investigator.  Details regarding the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as medical history.   
6.1.1.5 Prior and Concomitant Medications Review 
6.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the participant within 28 days 
before starting the trial.  Treatment for the disease for which the participant has enrolled in this 
study will be recorded separately and not listed as a prior medication.  
6.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant during 
the trial.  In addition, new medication started during the Second Course should be recorded. All 
medications related to reportable SAEs and ECIs should be recorded as defined in Section 6.2. 
6.1.1.6 
Disease Details and Treatments 
6.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
6.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
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6.1.1.6.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the 
last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 28 days after 
the last dose of trial treatment, the 28-day Safety Follow-up visit must occur before the first dose of 
the new therapy.  Once new anti-cancer therapy has been initiated the participant will move into 
survival follow-up.  
6.1.2 Clinical Procedures/Assessments 
6.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE Version 5.0.  Toxicities will be characterized in terms regarding seriousness, 
causality, toxicity grading, and action taken with regard to trial treatment.  
Please refer to section 6.2 for detailed information regarding the assessment and recording of AEs.   
6.1.2.2 Physical Exam 
A complete physical examination will be conducted by an investigator or medically qualified designee 
(consistent with local requirements) as per institutional standard. Height and weight will also be 
measured and recorded. 
A brief directed physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
6.1.2.3 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  The time 
points for full physical exams are described in Section 2.3.  After the first dose of study intervention, 
new clinically significant abnormal findings should be recorded as AEs.   
A comprehensive physical examination will include evaluations of the head, eyes, ears, nose, throat, neck, 
chest (including heart and lungs), abdomen, limbs, skin, and a complete neurological examination. 
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6.1.2.4 
Directed Physical Exam 
For cycles that do not require a full physical exam per the Section 2.3, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to study intervention 
administration.  New clinically significant abnormal findings should be recorded as AEs. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
6.1.2.5 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Schedule of Activities 
(Section 2.3).  Vital signs should include pulse, , blood pressure and weight.  Height will be measured 
at screening only. 
6.1.2.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, prior 
to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Schedule of Activities (Section 2.3). 
 
6.1.2.7 
Electrocardiograms 
Single 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, and [QTc] intervals.  
 
6.1.3 Clinical Safety Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for the timing 
and frequency. 
 The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF. The laboratory reports must be filed 
with the source documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
 All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the SoA. 
 If laboratory values from non protocol-specified laboratory assessments performed at the 
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clinically significant by the investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the appropriate CRF (eg, SLAB). 
 For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 days after the last dose of study intervention, every attempt 
should be made to perform repeat assessments until the values return to normal or baseline or if 
a new baseline is established as determined by the investigator. 
Refer to the Study Flow Chart (Section 2.3) for the timing of laboratory assessments. 
6.1.3.1 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2. 
 
6.1.3.2 
Pregnancy Testing 
WOCBP should be a maximum of 24-hours before the first dose/vaccination. Other women must be 
tested for pregnancy within 72 hours before the first dose of study intervention. If a urine test is 
positive or not evaluable, a serum test will be required. Participants must be excluded/discontinued 
from the study in the event of a positive test result. Repeated pregnancy test (such as monthly 
testing) may be conducted if required by local regulation.(Appendix3) 
 
6.1.4 Tumor Imaging and Assessment of Disease 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT) for extracranial 
lesion. MRI is the strongly preferred modality for imaging the brain.  The same imaging technique 
regarding modality, ideally the same scanner, and the use of contrast should be used in a participant 
throughout the study to optimize the reproducibility of the assessment of existing and new tumor 
burden and improve the accuracy of the assessment of response or progression based on imaging. 
6.1.4.1   Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of allocation.  
The site study team must review screening images to confirm the participant has measurable disease 
per RECIST 1.1.  
 
Tumor imaging performed as part of routine clinical management is acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the date of 
allocation and can be assessed by the central imaging vendor.  
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6.1.4.2   Tumor Imaging During the Study 
Tumor imaging should be performed every 6 weeks (42 days ±7 days) or more frequently if 
clinically indicated for first 12 months and 9 weeks (63 days ±7 days) thereafter.  Imaging timing 
should follow calendar days and should not be adjusted for delays in cycle starts.  Imaging should 
continue to be performed until disease progression is identified by the Investigator.  
 
6.1.4.3   End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the time of 
treatment discontinuation (±4 week window).  If previous imaging was obtained within 4 weeks 
prior to the date of discontinuation, then imaging at treatment discontinuation is not mandatory.   
For participants who discontinue study treatment without documented disease progression, start 
follow-up visit. Every 12 weeks tumor image assessment.  
6.1.4.5   RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease 
progression, and as a basis for all protocol guidelines related to disease status (eg, discontinuation of 
study treatment 
 
6.1.5 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 Collects 30cc of blood samples at the time screening. Collects 20cc of blood C1D8, C2D1, C3D1 
and disease progression. Collects Fresh tumor tissue sample or up to 15 unstained slide at the 
screening and disease progression. Tumor tissue collection and correlative blood sampling is not 
mandatory. 
If participants agree with the purpose of secondary usage and has an identifiable residual sample 
among samples obtained through other studies before participating in this trial, the tissue sample may 
be used. 
 
6.1.6  Other Procedures 
6.1.6.1 Discontinuation and withdrawal 
Participants who discontinue study intervention prior to completion of the treatment period should be 
encouraged to continue to be followed for all remaining study visits as outlined in the SoA and Section 
6.1.7.3. 
Participants who withdraw from the study should be encouraged to complete all applicable activities 
scheduled for the final study visit at the time of withdrawal. Any AEs that are present at the time of 
withdrawal should be followed in accordance with the safety requirements outlined in Section 6.2. 


 
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6.1.7 Visit Requirements 
Visit requirements are outlined in Section 2.3 – Schedule of Activities.   Specific procedure-related 
details are provided above in Section 6.1 - Trial Procedures. 
6.1.7.1 
Screening 
6.1.7.1.1 Screening Period 
Screening should be conducted within 28 days from the expected date of allocation 
6.1.7.2 
Treatment Period 
Treatment will follow the study protocol until disease progression or unacceptable toxicity. 
Beyond treatment is allowed based on the investigator’s decision 
 
6.1.7.3 
Post-Treatment Visits 
6.1.7.3.1 EOT (Safety Follow-Up Visit) 
The mandatory Safety Follow-Up Visit should be conducted approximately 28 days after the last 
dose of study intervention or before the initiation of a new anti-cancer treatment, whichever 
comes first.   
 
6.1.7.3.2 Follow-up Visits 
Participants who complete the protocol-required cycles of study intervention of who discontinue 
study intervention for a reason other than disease progression will begin the Follow-Up Phase 
Every effort should be made to collect information regarding disease status until the start of new 
anti-cancer therapy, disease progression, death, end of the study or if the participant begins 
retreatment with pembrolizumab.  Information regarding post-study anti-cancer treatment will be 
collected if new treatment is initiated.  Participants who completed all efficacy assessments 
and/or will not have further efficacy assessments must enter the Survival Follow-up Phase. 
 
6.1.7.3.3 Survival Follow-up Contacts 
Participant survival follow-up status will be assessed approximately every 12 weeks to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
6.1.7.3.4  Post Study 
Participants will be required to return to clinic approximately 28 days after the last dose of study 
intervention for the poststudy visit.  If the poststudy visit occurs less then 28 days after the last 
dose of study intervention, a subsequent follow-up telephone call should be made at 28 days post 
the last dose of study intervention to determine of any AEs have occurred since the poststudy 
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6.2 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing 
causality of AE and SAE and the procedures for completing and transmitting AE, SAE, and other 
reportable safety event reports can be found in Appendix 4.   
Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting events 
that meet the definition of an AE or SAE as well as other reportable safety events. Investigators remain 
responsible for following up AEs, SAEs, and other reportable safety events for outcome. 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE or 
SAE as well as other reportable safety events with respect to seriousness, intensity/toxicity and 
causality. 
6.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but before 
intervention allocation must be reported by the investigator if the event cause the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but not limited 
to washout or discontinuation of usual therapy, diet, or a procedure. 
 All AEs from the time of intervention allocation through 28 days following cessation of study 
intervention must be reported by the investigator. 
 All AEs meeting serious criteria, from the time of intervention allocation through 90 days 
following cessation of study intervention or 28 days following cessation of study intervention if 
the participant initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator. 
 All pregnancies and exposure during breastfeeding, from the time of intervention allocation 
through 120 days following cessation of study intervention, or 28 days following cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by the 
investigator. 
 Additionally, any SAE brought to the attention of an investigator at any time outside of the time 
period specified above must be reported immediately to principal investigator if the event is 
considered drug-related. 
 
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in former 
study participants. However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be reasonably related 
to the study intervention or study participation, the investigator must promptly notify principal 
investigator. 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and reported to 
principal investigator within the time frames as indicated in  
 
Table  


 
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Table 7  Reporting Time Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events 
Type of Event 
Reporting Time 
Period: 
Consent to 
Allocation 
Reporting Time 
Period: 
Allocation 
through Protocol-
specified Follow-
up Period 
Reporting Time Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame to Report 
Event and Follow-up 
Information to principal 
investigator: 
 
 
 
 
 
Serious Adverse Event 
(SAE) including Cancer 
and Overdose 
Report if: 
- due to protocol-
specified 
intervention 
- causes exclusion 
- participant is 
receiving placebo 
run-in or other run-
in treatment 
Report all 
Report if: 
- drug/vaccine related. 
(Follow ongoing to 
outcome) 
Within 2 business days but 
no longer than 3 calendar 
days of learning of event 
Pregnancy/Lactation 
Exposure 
Report if: 
- due to 
intervention 
- causes exclusion 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 2 business days but 
no longer than 3 calendar 
days of learning of event 
Event of Clinical 
Interest (require 
regulatory reporting) 
Report if: 
- due to 
intervention 
- causes exclusion 
Report 
- potential drug-
induced liver 
injury (DILI) 
- require regulatory 
reporting 
Not required 
Within 2 business days but 
no longer than 3 calendar 
days of learning of event 
 
 
 
 
 
 
6.2.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable safety 
events. Open-ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrence. 
6.2.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs, SAEs, and other reportable safety events including pregnancy and 
exposure during breastfeeding, events of clinical interest (ECIs), cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost to follow-
up. In addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
allocated or randomized participants for outcome. Further information on follow-up procedures is given 
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6.2.4 Sponsor Responsibility for Reporting Adverse Events  
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable country specific regulatory requirements, global laws and regulations.  
6.2.5 Pregnancy and Exposure During Breastfeeding 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any pregnancy 
or infant exposure during breastfeeding in a participant (spontaneously reported to the investigator or 
their designee) that occurs during the study are reportable to principal 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. 
6.2.6 Events of Clinical Interest (ECIs) 
Selected nonserious and SAEs are also known as ECIs and must be reported to principal investigator.  
Events of clinical interest for this study include:  
1. 
An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results. For purposes of this study, an overdose of pembrolizumab will be defined as 
any dose of 1,000 mg or greater (≥5 times the indicated dose).  No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, the 
participant should be observed closely for signs of toxicity.  Appropriate supportive treatment 
should be provided if clinically indicated.  If an adverse event(s) is associated with (“results 
from”) the overdose of a MSD product, the adverse event(s) is reported as a serious adverse 
event, even if no other seriousness criteria are met. 
2. 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*  
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the 
criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for 
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7.0 STATISTICAL ANALYSIS PLAN 
7.1 Statistical Analysis Plan Summary 
Based on the pooled analyses from Keynote-189 and 407 study, overall response rate of 
pembrolizumab with chemotherapy was around 40%. Overall response rate of chemotherapy alone was 
around 20% in patients with CNS metastases. In this study, we expect this number can be reproduced in 
the intracranial overall response. 
 
H0: 20% of intracranial response rate by historical control treated with cytotoxic chemotherapy alone 
H1: 40% of intracranial response rate by treated with pembrolizumab and cytotoxic chemotherapy 
 
Accrual time: 18 months 
Follow-up time: 12 months 
One-sided alpha: 0.05 
Power: 0.9 
 
Using the Simon’s two stage design, a total of 45 patients is needed for the minimax statistical 
analyses. Considering the 10% of dropout rate, a total of 50 patients is needed for final analyses. 
 
7.2 Statistical Analysis Plan 
This study will not conduct interim analyses and final analyses will be conducted after last patient 
reached at least 6 cycles of the treatment.  Intracranial overall response rate will be measured by 
RECIST v1.1 and patients with best response of partial response and complete response will be 
calculated as responder. Progression-free survival will be calculated by the date of either disease 
progression or the all-cause mortality from the date of IP administration. Overall-survival will be 
calculated by date of all-cause mortality from the date of IP Administration. The duration for 
intracranial response will be calculated separately to evaluate the intracranial efficacy of IP drug.  
 
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
8.1 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. 
Pembrolizumab will be provided by MSD as summarized in Table 8. 
Table 8. Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 


 
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8.2 Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
 
8.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, designee are not blinded to 
treatment.  
 
8.4 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. 
 
8.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from MSD 
or designee, the amount dispensed to and returned by the participants and the amount remaining at the 
conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange 
for disposal of all empty containers, provided that procedures for proper disposal have been 
established according to applicable federal, state, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. 
 
9.0 REFERENCES 
[1] 
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8. 
[2] 
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et 
al. Adoptive cell transfer therapy following non-myeloablative but 
lymphodepleting chemotherapy for the treatment of patients with refractory 
metastatic melanoma. J Clin Oncol 2005;23(10):2346-57. 
[3] 
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 2008;358(25):2698-703. 
[4] 
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48. 
[5] 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 
immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src 
homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. 
Proc Natl Acad Sci U S A 2001;98(24):13866-71. 


 
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[6] 
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory receptor programmed death-1. 
Immunity 2004;20:337-47. 
[7] 
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-based switch motif of programmed 
death 1 upon primary human T cell stimulation, but only receptor ligation 
prevents T cell activation. J Immunol 2004;173:945-54. 
[8] 
Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 
inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37-
41. 
[9] 
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25. 
[10] 
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, 
Kobayashi SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by 
distinct mechanisms. Mol Cell Biol 2005;25(21):9543-53. 
[11] 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42. 
[12] 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. 
iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. Epub 2017 Mar 2. 
 
 


 
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10.0 APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 2: Clinical Laboratory Tests 
 The tests detailed in Table 9 will be performed by the local laboratory. 
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5.1 of 
the protocol. 
 Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 9. Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Chemistry 
BUN 
Potassium 
AST/SGOT 
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
ULN) 
 
Albumin 
Bicarbonate 
Chloride 
Phosphorous 
 
Creatinine 
Sodium 
ALT/SGPT 
Total Protein 
 
Glucose [Indicate if 
fasting, or 
nonfasting] 
Calcium 
Alkaline 
phosphatase 
 
Routine 
Urinalysis 
 
Specific gravity 
 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
Testing 
 
[Highly sensitive serum or urine] hCG pregnancy test (as needed for WOCBP) 
Other Screening 
Tests 
 
FSH (as needed in WONCBP only) 
 
[Serum or urine] [alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) if applicable] 
 
 [Serology [(HIV antibody, HBsAg, and hepatitis C virus antibody)] [or specify other 
tests] [if applicable] 
 
 
 
 
 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; hCG=human chorionic gonadotropin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; 
ULN=upper limit of normal; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential 
 
 


 
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The investigator (or medically qualified designee) must document their review of each laboratory safety 
report. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
hormonal highly effective contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they agree 
to one of the following during the protocol defined time frame in section 5.11:  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a 
long term and persistent basis) and agree to remain abstinent 
● Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year 
when having penile-vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration. 
 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 10 during the 
protocol-defined time frame in Section 5.11.  
 


 
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Table 10.  Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least 30 days after the last dose of study treatment. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
 


 
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Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy test and in 
accordance with local requirements.  When applicable this test should be repeated a maximum of 24-
hours before the first dose/vaccination. 
Following initiation of treatment additional pregnancy testing will be performed at 2 cycle interval 
(approximately 6 weeks) intervals during the treatment period and at 30 days after the last dose of study 
treatment and as required locally. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
 


 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting 
10.1.1 Definition of AE 
AE definition 
 An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. 
 NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a study intervention. 
 NOTE: For purposes of AE definition, study intervention (also referred to as MSD product) 
includes any pharmaceutical product, biological product, vaccine, diagnostic agent, or protocol 
specified procedure whether investigational or marketed (including placebo, active comparator 
product, or run-in intervention), manufactured by, licensed by, provided by, or distributed by MSD 
for human use in this study. 
Events meeting the AE definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator. 
 Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. 
 For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term 
should reflect the clinical symptoms or abnormal test result. An overdose without any associated 
clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect.” 
      


 
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Events NOT meeting the AE definition 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
 Surgery planned prior to informed consent to treat a pre-existing condition that has not worsened. 
 
10.1.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
 The term “life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
 Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an 
elective procedure to treat a pre-existing condition that has not worsened is not an SAE. A pre-
existing condition is a clinical condition that is diagnosed prior to the use of a MSD product and 
is documented in the participant’s medical history. 
d. Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 


 
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e. Is a congenital anomaly/birth defect 
 In offspring of participant taking the product regardless of time to diagnosis. 
f. Other important medical events 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
 Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
10.1.3 Additional Events Reported in the Same Manner as SAE 
Additional events that require reporting in the same manner as SAE 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious per ICH 
definition, are reportable to principal investigator in the same time frame as SAEs to meet certain local 
requirements. Therefore, these events are considered serious by principal investigator for collection 
purposes. 
 Is a new cancer (that is not a condition of the study) 
 Is associated with an overdose of pembrolizumab 
10.1.4 Recording AE and SAE 
AE and SAE recording 
 When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory, and diagnostics reports) related to the event. 
 The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at each 
examination. 
 There may be instances when copies of medical records for certain cases are requested by the MSD. 
In this case, all participant identifiers, with the exception of the participant number, will be blinded 
on the copies of the medical records before submission to the MSD. 
 The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be 
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Assessment of intensity/toxicity 
 An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, not when it is rated as severe. 
1. 
The investigator will make an assessment of intensity for each AE and SAE (and other reportable 
safety event) according to the NCI Common Terminology for Adverse Events (CTCAE), version 
5. Any AE that changes CTCAE grade over the course of a given episode will have each change 
of grade recorded on the AE CRFs/worksheets. 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
 Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
 Grade 4: Life threatening consequences; urgent intervention indicated. 
 Grade 5: Death related to AE. 
Assessment of causality 
1. 
Did MSD product cause the AE? 
2. 
The determination of the likelihood that MSD product caused the AE will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialed document must be retained for the 
required regulatory time frame. The criteria below are intended as reference guidelines to assist 
the investigator in assessing the likelihood of a relationship between the test product and the AE 
based upon the available information. 
3. 
The following components are to be used to assess the relationship between MSD’s product and 
the AE; the greater the correlation with the components and their respective elements (in number 
and/or intensity), the more likely MSD product caused the AE: 
 Exposure: Is there evidence that the participant was actually exposed to MSD 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 
MSD product? Is the time of onset of the AE compatible with a drug-induced effect (applies 
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 Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors. 
 Dechallenge: Was MSD 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 MSD product; (3) the study is a 
single-dose drug study; or (4) MSD product(s) is/are only used 1 time.) 
 Rechallenge: Was the participant re-exposed to MSD 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 study is a single-dose drug study; or (3) MSD product(s) is/are used only 1 time.) 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND MAY HAVE 
BEEN CAUSED BY MSD PRODUCT, OR IF RE-EXPOSURE TO MSD’S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE INIRB/IEC. 
4. 
Consistency with study intervention profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding MSD product or drug class pharmacology or 
toxicology? 
5. 
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
6. 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of MSD product relationship). 


 
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 Yes, there is a reasonable possibility of MSD product relationship: 
 There is evidence of exposure to the MSD product. The temporal sequence of the AE onset 
relative to the administration of MSD product is reasonable. The AE is more likely explained 
by MSD product than by another cause. 
 No, there is not a reasonable possibility of MSD product relationship: 
 Participant did not receive the MSD product OR temporal sequence of the AE onset relative to 
administration of the MSD product is not reasonable OR the AE is more likely explained by 
another cause than the MSD product. (Also entered for a participant with overdose without an 
associated AE.) 
7. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
8. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the MSD. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to MSD. 
9. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
10. 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
11. 
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent of 
the combination. In general, causality attribution should be assigned to the combination regimen 
(ie, to all agents in the regimen). However, causality attribution may be assigned to a single agent 
if in the investigator’s opinion, there is sufficient data to support full attribution of the AE to the 
single agent. 
Follow-up of AE and SAE 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.  
 New or updated information will be recorded in the CRF.  
 The investigator will submit any updated SAE data to principal investigator within 2 business 
days but no longer than 3 calendar days of receipt of the information. 


 
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10.1.5 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Principal 
investigator 
SAE reports and any other relevant safety information are to be forwarded to the Principal 
investigator based on the local regulation.